Briefing Document

NDA 21-399

   

Drug Name

 

Medical Reviewer

Medical Team Leader

 

Martin H. Cohen, M.D.

Isagani Chico, M.D.

Grant Williams, M.D.

Documents reviewed

EDR Submissions

 

 

Table of Contents

Executive Summary *

Clinical Review *

1. Introduction and Background *

1.1 Proposed Indication, Drug Trade Name, Class, Age Groups *

1.1.1 Proposed Indication *

1.1.2 Drug Class *

1.1.3 ZD1839 mechanism of action *

1.2 State of Armamentarium for Indication(s) *

1.3 Important Milestones in Product Development *

1.3.1 Protocol Amendments - Trial 39 *

1.3.2 Sponsor-FDA Summary of Agreements *

1.4 Other Relevant Information *

1.4.1 Scientific Rationale *

1.4.2 Overview of existing treatments for non-small lung cancer *

2. Clinically Relevant Findings From Chemistry, Animal Pharmacology And Toxicology, Biopharmaceutics, And Statistics *

2.1 ZD1839 Preclinical Antitumor Activity *

2.2 Preclinical evaluation of combinations of ZD1839 with other antitumor agents *

2.3 ZD1839 Metabolism *

2.4 Toxicology *

2.4.1 Single dose toxicity *

2.4.2 Repeat dose toxicity *

2.4.3 Genotoxicity *

2.4.4 Reproductive and Developmental toxicity *

2.4.5 Significant findings by organ system *

3. Human Pharmacokinetics *

4. Description of Clinical Data and Sources *

4.1 Overall Data *

4.2 Table Listing the Clinical Trials *

4.3 Postmarketing Experience *

4.4 Literature Review *

5. Clinical Review Methods *

5.1 How the Review was Conducted *

5.2 Overview of Materials Consulted in Review *

5.3 Overview of Methods Used to Evaluate Data Quality and Integrity *

5.4 Were Trials Conducted in Accordance with Accepted Ethical Standards *

5.5 Evaluation of Financial Disclosure *

6 Integrated Review of Efficacy *

6.1 Brief Statement of Conclusions *

6.1.1 Study 39 - Sponsor’s analysis *

6.1.2 Study 39 - FDA Analysis *

6.1.3 Study 16 - Sponsor’s analysis *

6.1.4 Study 16 - FDA Analysis *

6.2 General Approach to Review of Drug Efficacy *

6.3 Detailed Review of Trials by Indication per Sponsor *

6.3.1 Investigators *

6.3.2 Common Protocol Elements – Trials 39 and 16. *

6.3.2.1 Study Objectives *

6.3.2.2 Eligibility Criteria *

6.3.2.3 Schedule of Trial Assessments *

6.3.3 Pivotal Trial 39 - Patient Population/Demography/ Disease Status/ Prior Cancer Therapy – Sponsor Analysis *

6.3.3.1 Efficacy results - Objective responses – Sponsor Analysis *

6.3.3.2 Disease-related symptom improvement – Sponsor Analysis *

6.3.3.3 Progression-free survival *

6.3.3.4 Overall survival *

6.3.3.5 QOL [FACT-L and TOI] *

6.3.3.6 Disease Control – Sponsor Analysis *

6.3.4 Supportive Trial 16 – Sponsor Analysis *

6.3.4.1 Patient Population/Demography *

6.3.4.2 Treatment Response – Sponsor Analysis *

6.3.4.3 Disease-related symptom improvement –Sponsor Analysis *

6.3.4.4 Progression-free survival and overall survival *

6.3.4.5 Subgroup analyses-Sex, Age, and Ethnicity *

6.3.5 Detailed Review of Trial 39 – FDA Analysis *

6.3.5.1 Study patients *

6.3.5.2 Study Patient Summary *

6.3.5.3 Response rate – FDA Analysis *

6.3.5.4 Responder Characteristics *

6.3.5.5 Response and Performance Status – FDA Analysis *

6.3.5.6 Performance Status and Quality of Life Relationships *

6.3.5.7 Progression free survival *

6.3.6 Detailed Review of Trial 16 per FDA *

6.3.6.1 Patient Demographics and Disease Characteristics *

6.3.6.2 Objective Response Rate *

6.3.6.3 Responder Characteristics *

6.3.6.3 Chemotherapy Sensitivity/Resistance of Responding Patients *

6.3.7 Reviewer Efficacy Conclusions Trials 39 and 16 *

6 Integrated Review of Safety *

7.1 Brief Statement of Conclusions *

7.2 Patient Exposure *

7.3 Safety Review Methods and Findings *

7.3.1 Overview of adverse events *

7.4 Adequacy of Safety testing *

7.5 Summary of Critical Safety Findings *

7.6 Adequacy of Safety Testing *

7.7 Safety Conclusions *

7 Dosing, Regimen and Administration Issues *

9 Use in Special Populations *

9.1 Tumor response by subgroups sex, age, and ethnicity *

9.2 Symptom improvement by the subgroups sex, age, and ethnicity *

9.3 Adverse Events In Special Populations-Studies - Phase II trials 39 and 16 *

9.3.1 Gender *

9.3.2 Ethnic origin *

9.3.3 Age *

9.3.4 Effect of baseline renal function *

9.3.5 Effect of baseline hepatic function *

9.3.6 Safety of ZD1839 when given in combination with other drugs *

9.3.7 Safety Of ZD1839 In Pregnancy And Lactating Women *

10 Conclusions and Recommendations *

10.1 Efficacy *

10.2 Safety *

10.3 Recommendation *

 

Table of Tables

Table 1: Differences in study populations in pivotal Trial 39 and supportive Trial 16 *

Table 2: Schedule of trial assessments *

Table 3: Demographic characteristics, ITT population in Trial 39 *

Table 4: Disease status at entry, ITT population in Trial 39 *

Table 5: Previous cancer treatment, ITT population in Trial 39 *

Table 6: Summary of objective tumor responses in the ITT population *

Table 7: Tumor response rate by baseline characteristics in Trial 39 *

Table 8: Disease-related symptom distribution at baseline by score for all patients *

Table 9: Rate of disease-related symptom improvements in Trial 39 *

Table 10: Demographic characteristics of patients in Trial 16 *

Table 11: Disease characteristics at trial entry in Trial 16 *

Table 12: Investigator's assessment of best overall objective response: *

Table 13: Disease-related symptom distribution at baseline *

Table 14: Rate of disease-related symptom improvements *

Table 15: Patients refractory or intolerant to docetaxel and/or platinum *

Table 16: Patient characteristics *

Table 17: Responders – FDA Analysis *

Table 18: Responder characteristics - ITT Population *

Table 19: Number of measurable lesions evaluated in responding patients - FDA *

Table 20: Responders refractory/intolerant to platinum and docetaxel - FDA *

Table 21: Comparison of baseline PS and baseline LCS and TOI – FDA *

Table 22: Trial 16 Demographic characteristics *

Table 23: Disease characteristics at trial entry in Trial 16 *

Table 24: Objective response rate ITT population: *

Table 25: Responder characteristics – Trial 16 *

Table 26: Summary of Responder Characteristics *

Table 27: All Responders - Prior chemotherapy and outcome *

Table 28: Number of measurable lesions evaluated in responding patients *

Table 29: Sites of Measurable/Evaluable Disease *

Table 30: Duration on trial and duration of treatment *

Table 31: Patients with therapy interruptions or dose reductions due to toxicity *

Table 32: ZD1839 Exposure in Phase I multiple-dose trials *

Table 33: Exposure to ZD1839 in the Phase I trials, by dose category *

Table 34: Overview of adverse events in Trial 0039 *

Table 35: Adverse events with an incidence of >=10% in Trial 39 *

Table 36: Drug-related adverse events with an incidence of >=5% in trial 39 *

Table 37: Drug-related adverse events of CTC Grade 3 or 4 in trial 39 *

Table 38: Deaths during or 30 days post treatment in trial 39 *

Table 39: Patients who withdrew due to drug-related adverse events in trial 39 *

Table 40: Patients who had drug-related serious adverse events in trial 39 *

Table 41: Overview of adverse events in trial 16 *

Table 42: Adverse events with an overall incidence >=10% in trial 16 *

Table 43: Drug-related adverse events >=5% in trial 16 *

Table 44: Drug-related adverse events of CTC Grade 3 or 4 in trial 16 *

Table 45: Patients who withdrew due to drug-related adverse events in Trial 0016 *

Table 46: Patients who had drug-related serious adverse events in trial 16 *

Table 47: Overview of adverse events in the Phase I multiple-dose trials *

Table 48: Adverse events >=10% in the Phase I multiple-dose trials *

Table 49: Dose limiting toxicities in the Phase I dose-escalating trials *

Table 50: Drug-related adverse events (>= 5%) in the Phase I multiple-dose trials *

Table 51: Drug-related adverse events in the Phase II and I multiple-dose patient trials *

Table 52: Skin toxicity by CTC grade in the Phase I multiple-dose trials *

Table 53: Frequency of skin adverse events by CTC grade in the Phase 11 trials *

Table 54: Ocular adverse events by dose: patients from Phase I trials *

Table 55: Gastrointestinal events by CTC grade in Phase I multiple-dose trials *

Table 56: Gastrointestinal adverse events by CTC grade in the Phase II trials *

Table 57: Phase I abnormal ECG findings *

Table 58: ECG abnormalities *

Table 59: Common adverse events by gender (Trials 39 and 16) *

Table 60: Common adverse events presented by age (pooled data from Trials 39 and 16) *

 

Table of Figures

Figure 1: Molecular Structure of ZD1839 *

Figure 2: EGFR Signal Transduction in Tumor cells (Sponsor) *

Figure 3: Trial 39 Study Population *

Figure 4: Trial 16 patient populations *

Executive Summary

ZD 1839 (Iressa™) is a new class of drug that inhibits Epidermal Growth Factor Receptor (EGFR) tyrosine kinase activity. The present NDA is a rolling submission, the last section of which was submitted August 5, 2002. The NDA is seeking accelerated approval for Iressa as monotherapy for patients receiving third line treatment for non-small cell lung cancer.

At present, there are three cisplatin-containing doublets approved for the first-line therapy of patients with locally advanced or metastatic non-small cell lung cancer (cisplatin/vinorelbine, cisplatin/paclitaxel and cisplatin/gemcitabine), and a single drug, docetaxel approved for the second-line treatment of the same patient population. Third-line treatment regimen is an unmet need.

Of the two clinical trials submitted by the sponsor, Trial 39, titled "A Randomized, Double-blind, Parallel-group, Phase II, Multicenter Trial of Two Doses of ZD1839 (Iressa™) in Patients With Advanced NSCLC Who Have Previously Received at Least Two Chemotherapy Regimens that Contained Platinum and Docetaxel Given Concurrently or as Separate Treatment Regimens", addresses that unmet need. Trial 16, titled "A randomized, double-blind, parallel-group, Phase II, multicenter trial to assess the efficacy of ZD1839 (IRESSA) 250 and 500 mg/day in patients with advanced non-small-cell lung cancer who have failed one or two previous chemotherapy regimens; at least one having contained platinum is primarily a second-line trial.

There was agreement between the FDA and the sponsor that all patients enrolled into Trial 39 must have received prior treatment with at least two chemotherapy regimens which were platinum- and docetaxel-based (platinum and docetaxel need not be given concurrently). Failure of prior chemotherapy must have been the result of disease progression within 90 days of the last dose of chemotherapy or treatment intolerance.

The quality of life evaluation was initially considered by the FDA to be exploratory. At a later time, however, FDA stated that quality of life is acceptable from a statistical standpoint, as a "co-primary" endpoint. However, it would be necessary to demonstrate that the symptom findings are credible in a single arm study and are clinically significant. Correlation with objective response may be helpful in this regard.

Both trials randomized patients to either ZD1839 250 mg/day or to 500 mg/day. The primary objectives of Trial 39 were to evaluate objective tumor response rate and symptom improvement rate. The primary objective of Trial 16 was to evaluate objective tumor response rate. Symptom improvement rate was a secondary objective.

The first patient was recruited to Trial 39 on 7 November 2000, the last on 6 April 2001.

The total intent to treat accrual was 216 patients from 30 US centers.

Trial 39 patients had performance status 0 to 2. Patients were required to be symptomatic from NSCLC as evidenced by a score of 24 points or less (asymptomatic score 28) on the lung cancer subscale (LCS) of the functional assessment of cancer therapy-lung (FACT–L) questionnaire.

The following paragraphs include efficacy results as summarized by the sponsor and efficacy results determined from the FDA analysis.

Efficacy (per sponsor):

A total of 102 Trial 39 patients were treated with ZD1839 250 mg/day, and 114 with 500 mg/day. As of the data cutoff date (1 August 2001), 39 patients were continuing in the trial.

The median age of Trial 39 treated patients was 61 years (range 30 to 84 years); 56.9% were men, and 90.7% were Caucasian. The majority of patients (88.9%) had metastatic disease. The predominant histology was adenocarcinoma (66.2%). One hundred and seventy-two patients (79.6%) had a PS of 0 to 1. Overall, the 2 dose groups were balanced with respect to demographic, disease, and prior treatment characteristics.

A total of 177 patients (81.9%) withdrew from trial treatment; the most common reasons for withdrawal were objective disease progression (150 patients [69.4% of those treated]) and adverse events (16 patients [7.4% of those treated]).

For Trial 39 the sponsor reported that the objective tumor response rate for the 250-mg/day group was 11.8% (95%CI: 6.2%, 19.7%). The tumor response rate in the 500-mg/day group was 8.8%, (95% CI: 4.3%, 15.5%). Response rate differences were not statistically significant.

For Trial 39 the sponsor reported that symptom improvement rates (Lung Cancer Subscale [LCS]).were similar for the 2 dose groups: 43.1% (95% CI: 33.4%, 53.3%) for the 250-mg/day group, and 35.1% (95%CI: 26.4%, 44.6%) for the 500-mg/day group. Patients with objective tumor response were likely to have a best overall symptom response of "improved" (95.5%), while patients with a best overall response of stable disease also had symptom improvement (71.0%).

For Trial 39 QOL was determined by the FACT-L instrument and the Treatment Outcome Index (TOI). The FACT-L questionnaire contains a total of 34 questions, divided into 5 different domains: disease-related symptoms, physical, functional, emotional, and social. Each question is scored from 0 to 4. The Treatment Outcome Index (TOI) is the total score of disease-related symptom, physical, and functional questions. Changes of 6 points or more were found to be meaningful. The complete FACT-L questionnaire was filled out by patients every 28 days at the end of a treatment period. while disease-related symptom scores were obtained on a weekly basis. The overall compliance of filling out the questionnaire was 86%.

The sponsor reported that QOL improvement rates were marginally higher in the 250-mg/day than in the 500-mg/day group: for Treatment Outcome Index (TOI) they were 33.3% (95% CI: 24.3%, 43.4%) and 20.2% (95% CI: 13.2%, 28.7%), respectively, and for FACT-L they were 34.3% (95% CI: 25.2%, 44.4%) and 22.8% (95% CI: 15.5%, 31.6%), respectively. The improvement in total FACT-L and TOI scores was associated with improvement in disease-related symptoms, as measured by the Lung Cancer Subscale (LCS).

For Trial 39 the sponsor reported that median progression-free survival was similar for the 2 dose groups: 59 days (95% CI: 56 days, 86 days) for the 250-mg/day group, and 60 days (95% CI: 49 days, 67 days) for the 500-mg/day group. With a minimum follow-up of 4 months, median survival was similar between the 2 dose groups, 185 days for the 250-mg/day group compared to 183 days for the 500-mg/day group.

For Trial 16, 210 patients from 43 centers were entered: 108 patients at 24 non-Japanese centers, and 102 patients at 19 Japanese centers. As of the data cut-off date (22 May 2001) 53 (25.2%) patients were continuing in the trial. The mean age of patients in the trial was 59.6 years; 70.5% were men, 48.6% were Caucasian and 48.6% were Japanese. The predominant tumor type was adenocarcinoma (62.9%) and most patients were Stage IV (80.5%).

For Trial 16 the objective response rate for Caucasian patients was 10.8% (11/102) and the response rate of Japanese patients was 27.5% (28/102). Reasons to discount some of these responses will be discussed subsequently in the FDA analysis.

The sponsor analysis of disease related symptoms in Trial 16 patients indicated that symptom improvement rates were similar for the 2 dose groups: 40.3% (95% CI: 28.5%, 53.0%) for the 250-mg/day group, and 37.0% (95% CI: 26.0%, 49.1%) for the 500-mg/day group. The overall symptom improvement rate was 38.6%. Patients with objective tumor response were more likely to have a best overall symptom response of "improved" (77.8%) than patients without a tumor response (29.2%). In addition, more than half the patients (53.3%) with stable disease experienced symptom improvement, whereas patients with progressive disease usually did not show any benefits in symptoms.

Similarly, sponsor analysis of QOL (Trial 16) indicated that improvement rates were similar for the 250-mg/day and 500-mg/day groups: for TOI they were 20.9% (95% CI: 11.9%, 32.6%) and 17.8% (95% CI: 9.8%, 28.5%), respectively, and for FACT-L they were 23.9% (95% CI: 14.3%, 35.9%) and 21.9% (95% CI: 13.1%, 33.1%), respectively. The overall QOL improvement rates were 19.3% for TOI, and 22.9% for FACT-L. Patients with objective tumor response were more likely to have a best overall response of "improved" in TOI and FACT-L (both 51.9%) than patients without a tumor response (11.5% and 15.9%, respectively).

Improvements in TOI and FACT-L happened rapidly with a median time to improvement of 29 days ie, at the first measurement post-baseline.

The median number of progression-free survival days was similar for the 2 Trial 16 dose groups: 83 days (95% CI: 61 days, 86 days) for the 250-mg/day group, and 85 days (95% CI: 59 days, 116 days) for 500-mg/day group. With a minimum follow-up of 4 months, median survival was not calculable for all groups due to insufficient events; 68% of patients in the 250-mg/day group were alive at 4 months compared to 79% in the 500-mg/day group.

In Trial 39 and Trial 16 the majority of patients received ZD1839 for >1 month, with approximately one-third receiving ZD1839 for >3 months. ZD1839 was generally well tolerated at both doses. However, fewer patients on the 250-mg/day dose experienced Grade 3 or 4 drug-related adverse events or withdrew due to drug-related adverse events. There were fewer drug interruptions due to adverse events in the 250-mg/day group (thirty-one patients (15.1%) who received ZD1839 250 mg daily versus 56 patients (25.5%) in the 500-mg/day group. Dose reductions due to toxicity occurred in 0.5% of patients at the 250-mg dose versus 9.5% of patients at the 500-mg dose group.

Drug-related adverse events experienced by at least 10% of patients in the 250-mg/day group were diarrhea, rash, acne, dry skin, nausea, and vomiting SGPT/ALT increased, and SGOT/AST increased. There was no evidence of cumulative toxicity.

Efficacy (per FDA):

The FDA agrees with an overall response rate of 10.2% in Trial 39 and with an objective response rate of 10.8% (11/102) for Trial 16 Caucasian patients and an objective response rate of 27.5% (28/102) for Trial 16 Japanese patients. There are several bothersome issues raised by the efficacy review of Trials 39 and 16, however. These are considered below.

Study Design: The two submitted randomized trials compared two dose levels of Iressa. There was no comparator treatment regimen. Since both Iressa dose levels displayed comparable efficacy the evaluation of quality of life and symptom relief is problematic.

Study eligibility –In Trial 39 eligible patients must have received at least two prior chemotherapy regimens. They must also have received a platinum agent and docetaxel administered either concurrently or sequentially. Prior regimens must have failed due either to progression while on therapy or because of treatment intolerance. Only 139 of 216 Trial 39 study patients (64%) met these eligibility criteria. Eleven patients (5%) were platinum refractory/intolerant but taxotere sensitive, 58 patients (27%) were taxotere refractory/intolerant but platinum sensitive, and 8 (4%) were not refractory/intolerant to either drug. For each of the above patient groups the response rate was approximately 10%.

For Trial 16, eligibility criteria mandated that patients must have received one, or a maximum of two, prior chemotherapy regimens, one of which must have included platinum. They must also have recurrent or refractory disease. In fact, however, only 35% of study patients were chemotherapy resistant, having progressed on either first- or second-line chemotherapy. Sixty-five percent of study patients had not progressed on prior therapy. Based on the refractoriness to prior chemotherapy, patients in Trial 16 constituted a more favorable group that might be expected to have higher objective response rates than patients in trial 39.

Study patient characteristics -As might be expected from the treatment eligibility requirements of Trial 39, the enrolled study population, (locally advanced or metastatic disease patients who have failed platinum, docetaxel and other chemotherapy and who have a performance status of 0 to 2) is not typical of a population of newly diagnosed NSCLC patients of similar stage and performance status. The latter population might be expected to have a median survival of 6 to 9 months if stage IV at diagnosis and 16 to 18 months if stage III at diagnosis. Patients enrolled in this study have survived for a considerably longer time (48% of patients surviving more than 2 years from initial diagnosis to study randomization). Striking also, is the percent of study patients with adenocarcinoma alone or mixed with squamous cell carcinoma (73.6%). This is expected as adenocarcinoma has the slowest tumor doubling time of all lung cancer histologies. Thus slow growing tumors that produced few to modest systemic effects were selected.

Like patients enrolled into Trial 39, Trial 16 patients had a relatively long time from initial diagnosis to study randomization (median 12.1 months; mean 15.9 months) and also had a high percentage of adenocarcinoma alone (63%) or with other histologies (3%). Thus, this study was also enriched for less aggressive, slowly growing tumors.

Treatment response - Since the large majority of patients enrolled in both trials had stage IV disease it might be expected that patients would have multiple sites of disease and, therefore, multiple measurable lesions. That was not the case. Among the 18 responding patients in trial 39 who had measurable disease (4 responders having evaluable but non-measurable disease) 5 patients had only a single lesion measured and 6 had two lesions measured. As smaller lesions are more likely to respond to chemotherapy than larger lesions, better blood flow, better oxygenation, etc., it was of interest to look at the sum of the areas of measurable lesions in responders. In trial 39, the baseline total tumor area of the measurable lesions was less than 10 cm2 in 5 of 18 responders. In Trial 39 the site of the measurable lesion in patients with only one measurable tumor was lung in 4 patients and liver in one patient. The site of the measurable lesion in patients with two measurable tumors was lung only in 2 patients, lung and liver in 2 patients, lung and lymph node in 1 patient and liver only in 1 patient.

In Trial 16 thirty-eight of the 39 responding patients had measurable lesions. Among the measurable disease patients 16 patients had only a single lesion measured and 12 had two lesions measured. In trial 16 baseline total area of measurable lesions was less than 10 cm2 in 3 of 11 responding Caucasian patients and 11 of 21 responding Japanese patients. Baseline total area of measurable disease was <5 cm2 in 6 responding Japanese patients and no Caucasian patients. In Trial 16 nineteen responders had lung only disease (primary tumor site with or without contralateral lung involvement. The second most common sites of involvement were lung plus regional lymph node disease (6 patients).

Response rate - A widely accepted medical oncology principle is that for each chemotherapy regimen failed the probability of responding to a subsequent regimen decreases and responses are of shorter duration. If we accept this premise then we expect that the Iressa response rate in Trial 39 patients who are refractory to two or more prior chemotherapy regimens should be lower than the response rate of Trial 39 patients who have failed less than two regimens. This was not the case. Response rates of both groups were approximately 10%. Similarly, it is expected that the response rate of patients in Trial 16 should be higher than the response rate of Trial 39 patients. Caucasian patients in trial 16 also had a 10% response rate. While Japanese patients in Trial 16 had a response rate of 28% there are confounding factors (see above).

Disease Related Symptom improvement – The meaningfulness of the sponsor’s evaluation of symptom relief and quality of life is open to question. Because Iressa 250 mg/day and 500 mg/day had comparable efficacy results there was no comparator regimen for QOL/symptom relief analysis. There are also methodologic issues including early progressors being censored, and the use of concomitant medications that might have contributed to symptom relief.

Overall Conclusions-FDA: While there are hints of drug activity, i.e. an objective response rate of 10.8% in the third-line treatment setting, the absence of a non- ZD1839 treated control group makes it difficult to evaluate these results. The fact that the study population was enriched for slowly growing, less aggressive cancers further complicates evaluation of results. Other confounding factors are failure to adhere to the eligibility criteria, limited number of measurable lesions, and relatively small tumor volumes (<10 cm2) in 5 of 18 responders who had measurable disease in trial 39 and in 3 of 11 responding Caucasian patients and 11 of 28 responding Japanese patients in Trial 16.

There are fundamental study design issues with the sponsor’s quality of life improvement and symptom benefit analyses including absence of a suitable control group, absence of blinding as all patients received ZD1839, dropout of patients with early disease progression and meaningfulness of the criteria used to designate benefit.

ZD1839 was generally well tolerated. Fewer patients on the 250-mg/day dose experienced Grade 3 or 4 drug-related adverse events or withdrew due to drug-related adverse events. There were less drug interruptions due to adverse events in the 250-mg/day group. Dose reductions due to toxicity occurred in only 1.0% of patients at the 250-mg dose versus 8.8% of patients in the 500-mg dose group. Drug-related adverse events experienced by at least 10% of patients in the 250-mg/day group were diarrhea, rash, acne, dry skin, nausea, and vomiting. There was no evidence of cumulative toxicity, and the majority of drug-related adverse events were reversible.

Addendum: On August 19, 2002 the sponsor released the results of their phase III first-line NSCLC studies (INTACT 1 and 2; Iressa NSCLC Trials Assessing Combination Therapy). Two large randomized trials, accruing over 2000 patients, used an add-on design in which patients were randomized to receive either Iressa or placebo together with standard combination chemotherapy, gemcitabine/cisplatin in one study and carboplatin/paclitaxel in the other. At the time of this report study results were mature with approximately 70% of patients having died in each treatment arm. There was no survival benefit from Iressa treatment in either trial. Similarly, secondary endpoints, i.e. response rate and time to progression, also failed to show statistically significant differences. Results were unambiguous.

These results raise a question regarding accelerated approval of Iressa. Accelerated approval regulations require additional studies that demonstrate clinical benefit. Can FDA consider accelerated approval when it has already been demonstrated in the INTACT trials that there is no survival advantage?

 

Clinical Review

1. Introduction and Background

1.1 Proposed Indication, Drug Trade Name, Class, Age Groups

1.1.1 Proposed Indication

IRESSATM is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer who have previously received platinum-based chemotherapy.

1.1.2 Drug Class

ZD1839 (IRESSATM) is an anilinoquinazoline with the chemical formula N-(3-chloro-4fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoline-4-amine and the molecular structure shown in Figure 1. The compound is a white powder with a molecular formula of C22H24ClFN403 and molecular weight of 446.9.

 

Figure 1: Molecular Structure of ZD1839

1.1.3 ZD1839 mechanism of action

ZD1839 is an inhibitor of EGFR TK activity that completely blocks EGFR autophosphorylation with resultant complete blockade of signal transduction from the EGFR. The EGFR is a member of a sub-family, the HER or erbB family, which includes three other members, erbB2/erbB3/erbB4; HER2(neu)/HER3/HER4), in addition to EGFR. Binding of the cognate ligand, for example, EGF or transforming growth factor cc (TGFcc) to the extracellular domain of EGFR initiates a signal transduction cascade that can influence many aspects of tumor cell biology including growth, survival, metastasis, and angiogenesis, as well as tumor cell sensitivity to chemotherapy and radiation therapy (Figure 2).

 

 

Figure 2: EGFR Signal Transduction in Tumor cells (Sponsor)

    1. State of Armamentarium for Indication(s)

There are no approved therapies for stage IIIB/IV ambulatory (PS 0 to 2) NSCLC patients who have progressed on two or more prior regimens (third-line). This is a highly selected population, however, as the large majority of advanced/metastatic NSCLC patients have either died or are non-ambulatory at that point in time. Docetaxel is approved as second- line NSCLC treatment. There are three approved cisplatin containing regimens for first-line NSCLC chemotherapy

1.3 Important Milestones in Product Development

Selected Discussion Between The Food And Drug Administration and the sponsor;

It was agreed that a pivotal trial entitled "A randomized, double blind, parallel-group, Phase II, multicenter trial of 2 doses of ZD1839 in patients with advanced NSCLC who have previously progressed or were intolerant of at least 2 chemotherapy regimens that contained platinum and docetaxel given concurrently or as separate treatment regimens" (Trial ZD18391L/0039, was acceptable as a registration trial in this indication. Trial features include:

 

 

 

 

Summary of other development discussions, excluding protocol changes for Trial 39:

A clinical pharmacology program was agreed upon. The highlights of the agreement are as follows:

Since renal clearance is not a major route of excretion for ZD1839, a formal renal impairment study would not be conducted. However, the eligibility criteria of Trial 0039 were extended to include patients with moderate renal impairment in an attempt to assess the effect of renal impairment using a population pharmacokinetic analysis approach.

The drug interaction package consists of the following studies:

18391L/0027: A randomized, open-label, 2-way crossover, Phase I trial to assess the effect of itraconazole, a CYP3A4 inhibitor, on the pharmacokinetics of ZD1839 in healthy male volunteers.

18391L/0030: A randomized, open-label, 2-way crossover, Phase I trial to assess the effect of rifampicin on the pharmacokinetics of a single oral dose of ZD1839 in healthy male volunteers.

18391L/0038: An open Phase I study to assess the inhibitory effect of ZD1839 (IRESSA) on CYP2D6, by comparing the pharmacokinetics of metoprolol (a CYP2D6 substrate), in the presence and absence of ZD1839, in patients with solid tumors.

18391L/0051: A randomized, open-label, crossover, Phase I study to assess the effect of itraconazole, a CYP3A4 inhibitor, on the pharmacokinetics of ZD1839 at doses of 250 and 500 mg in healthy male volunteers

The plan to characterize and quantify ZD1839 metabolites was accepted

A study to assess the effect of hepatic impairment of the pharmacokinetics of ZD1839 is underway (1 8391L/0032) but will not be completed in time for the submission of this NDA.

The plan for population pharmacokinetic analysis was accepted. It was agreed that population PK document will be a stand-alone report and will not be required for the submission of this NDA.

 

1.3.1 Protocol Amendments - Trial 39

Amendment 1: submitted on 09/19/00

Amendment 2: submitted on 01/15/01

Amendment 3: submitted on 01/15/01

Amendment 4: submitted on 08/02/01

1.3.2 Sponsor-FDA Summary of Agreements

It is clear from review of FDA comments to sponsor questions (Facsimile 8/11/00, reiterated in facsimile 9/8/00) that all patients enrolled into trial 39 must have documented progression while receiving a docetaxel-containing regimen and a platinum-containing regimen. Exposure to paclitaxel but not docetaxel is not acceptable. Sponsor response to the facsimile of 8/11/00 suggested that prior regimen failure should include progression or intolerance. The FDA agreed and stated "Patients must have received prior treatment with at least two chemotherapy regimens which are docetaxel- and platinum-based (platinum and docetaxel need not be given concurrently). Prior regimens must have failed the patient because of progression or toxicity". Sponsor agreed (8/16/00).

From the standpoint of accelerated approval this was an important agreement. There is no available therapy for third-line treatment for advanced/metastatic NSCLC patients. There are approved treatment regimens for first-line (cisplatin regimens) and second-line (docetaxel) treatment.

Quality of life evaluation was initially considered to be exploratory (1/10/00). The 8/11/00 meeting minutes stated, however, that quality of life is acceptable as a "co-primary" endpoint. "However, it is your task to demonstrate that the symptom findings are credible in a single arm study and are clinically significant. Correlation with objective response may be helpful in this regard".

It was also agreed that the intent to treat population should serve as the primary analysis population, rather than evaluable patients.

    1. Other Relevant Information

1.4.1 Scientific Rationale

Non-small cell lung cancer (NSCLC) was selected as the initial therapeutic target for ZD1839 because the majority of these tumors overexpress EGFR. Further, phase I clinical studies with ZD1839 provided evidence of antitumor activity in patients with NSCLC. The later studies, together with published studies demonstrating the clinical efficacy of specific, antibody-mediated blockade of erbB2 in patients with breast cancer, provided "proof of principal" that the erbB/HER proteins are important targets for cancer therapy.

1.4.2 Overview of existing treatments for non-small lung cancer

Lung cancer is the most common adult malignancy and accounts for 30% of cancer related deaths in men and 25% of cancer related deaths in women. In the year 2001, an estimated 169,500 patients will be diagnosed with lung cancer in the United States and 157,000 will die (American Cancer Society 2001). Approximately three-quarters of these patients will have NSCLC of whom most will have locally advanced or metastatic disease at diagnosis.

Cytotoxic chemotherapy drugs used to treat good performance patients with newly diagnosed and recurrent advanced NSCLC includes both cisplatin and carboplatin, vinorelbine, paclitaxel, docetaxel and gemcitabine. Three cisplatin-containing doublets have been FDA approved for first-line treatment based on increased survival. A meta-analysis demonstrated that median survival was improved by approximately 6 weeks in patients treated with combination chemotherapy when compared with patients treated with supportive care alone (Non-small Cell Lung Cancer Collaborative Group 1995).

Following inevitable first progression or recurrence, the only therapeutic option is additional chemotherapy. In the second-line setting, 2 randomized Phase III trials report that the median survival with docetaxel was significantly better than the supportive care arm. Docetaxel 75 mg/m2 response rates were 5.5% and 6.7%, respectively.

In addition to limited effectiveness, the use of chemotherapy for palliative treatment of advanced, recurrent NSCLC has limitations due to well-known toxicities. Chemotherapy frequently causes marrow toxicity with associated potentially life-threatening infectious and bleeding complications. Many of the chemotherapy agents used to treat non-small cell lung cancer are associated with peripheral neuropathy. One of the consequences of chemotherapy-induced toxicity is that it can be self-limiting, thus potentially compromising efficacy.

 

 

 

 

 

 

 

 

 

 

2. Clinically Relevant Findings From Chemistry, Animal Pharmacology And Toxicology, Biopharmaceutics, And Statistics

2.1 ZD1839 Preclinical Antitumor Activity

The antitumor activity of ZD1839 was demonstrated in tests with a range of xenografts derived from different human tissues. ZD1839 was particularly effective against human (vulval) squamous carcinoma-derived cell line A431, which overexpresses EGFR. ZD1839 inhibited the growth of A431 xenografts in a dose-dependent manner and complete inhibition was observed in animals receiving a daily oral dose of 200 mg/kg ZDI 839. Long term treatment (3 to 4 months) completely suppressed A431 tumor growth, and

withdrawal of drug treatment allowed tumor growth to resume. When ZD1839 treatment was applied to large, well-established A431-derived tumors, rapid tumor regression was observed, which was sustained for the duration of drug treatment. Tumors re-grew when drug treatment was withdrawn. Thus ZD1839 has a cytostatic effect on tumor cell growth, stressing the importance of continuous drug treatment to maintain antitumor activity. No evidence for the development of drug resistance emerged, since no A431tumor re-grew during ZD1839 treatment.

2.2 Preclinical evaluation of combinations of ZD1839 with other antitumor agents

The antiproliferative activity of ZDI839, alone or in combination with cytotoxic drugs with different mechanisms of action, was investigated in human ovarian (OVCAR-3), breast (MCF-10A ras; ZR-75-1) and colon (GEO) cancer cell lines, which express EGFR and TGFa. ZD1839 inhibited colony forming ability in a concentration-dependent manner through cytostatic antiproliferative and pro-apoptotic mechanisms. Combining ZD1839 with platins (cisplatin, oxaliplatin, carboplatin), taxanes (paclitaxel, docetaxel), topoisomerase inhibitors (doxorubicin, etoposide, topotecan) or the antimetabolite raltitrexed, markedly enhanced the apoptotic cell death induced by single agent treatment. In studies with colon cancer (GEO) xenografts combined treatment with ZD1839 and cytotoxic agents produced tumor growth arrest and extended the survival of tumor bearing animals. In contrast, combination with gemcitabine had no effect on the latter's cytotoxic activity, and combination with vinorelbine was poorly tolerated.

2.3 ZD1839 Metabolism

Studies of the metabolism of [14C]-ZD1839 were conducted with rat, dog and human hepatocytes, which showed that the compound was metabolised quite extensively in all three species. Using human hepatic microsomes ZD1839 oxidative metabolism was catalysed almost exclusively by CYP3A4. Thus concomitant administration of inducers and inhibitors of CYP3A4 could potentially alter ZD1839 clearance in man. ZD1839 has no obvious enzyme inducing potential and is considered unlikely to produce clinically significant drug interactions due to induction or inhibition of P450 dependent metabolism of coadministered compounds.

The potential contribution of five ZD1839 metabolites identified in humans, to the pharmacological activity of ZD1839, was assessed by measurement of their in vitro kinase and cell growth inhibitory activity. Each of the five known metabolites demonstrated potent and selective EGFR kinase inhibition, similar to that of ZD1839. However, when tested for their capacity to inhibit EGF-stimulated cell growth, all of the metabolites were less potent than ZD1839. For example, the major human metabolites M523595 and M537194 were 14- and 7-fold, respectively, less potent than ZD1839. This modest level of activity in cells suggests that the metabolites are unlikely to contribute in a significant manner to the pharmacological activity of ZD1839.

2.4 Toxicology

2.4.1 Single dose toxicity

Following a single oral dose of ZD1839 at 2000 mg/kg to rats, there was a 5 day interval prior to the onset of abnormal signs. All animals showed adverse signs, leading to 4 premature deaths in females. The cause of death of 1 of these 4 decedents was a perforated duodenal ulcer. Other compound-related findings were present in tissues of these animals, including the kidneys, liver, skin and upper gastrointestinal tract. No abnormalities were seen in mice given the same oral dose nor in rats and mice at the maximum achievable dose of 20 mg/kg by the intravenous route. Single oral doses of up to 1000 mg/kg to dogs produced no deaths, but caused adverse effects that had a rapid onset, but were reversible. These effects comprised emesis, diarrhea, loss of skin tone, reduced blood pressure, reduced appetite, loss of body weight and increased plasma ALT, AST and ALP activities.

2.4.2 Repeat dose toxicity

The no effect dose level after administration of ZD1839 to rats and dogs for up to 1 month was 2 mg/kg/day. A dose of 10 mg/kg/day showed only minor changes in red blood cell parameters, plasma protein, and albumin in the 1 month dog study and no adverse effects in the 1 month rat study. A dose of 40 mg/kg/day in the rat for a month, produced reversible increases in plasma ALT and AST levels, but with no pathological correlate. There were histopathological changes in the ovaries of rats (reduced corpora lutea) and in the eyes (corneal epithelial atrophy), kidneys (papillary necrosis), and skin of both rats and dogs, all of which showed signs of partial or full reversibility, 4 weeks after drug withdrawal. These changes were attributed to the pharmacological effects of ZD1839. Reversible prolonged PR intervals, with large variations between individual measurements were recorded for 2 out of 12 dogs at 40 mg/kg/day. In addition, one of these two dogs also showed second degree heart block.

The findings in the 6-month studies were consistent with those detected in the 1 month studies and were similarly attributed to the pharmacological effects of ZD1839. These studies commenced with a high dose of 25 mg/kg/day, however this was not tolerated and the dose level was reduced to 15 mg/kg/day from day 11 in dogs and from week 9 in rats. The no adverse effect dose level, after administration of ZD1839 to rats and dogs for up to 6 months, was 1 mg/kg/day. At 5 mg/kg/day, rats and dogs showed skin lesions and the rats had reversible corneal atrophy of the eyes. These eye effects were more evident in both species at 15 mg/kg/day, but still showed signs of recovery. However, at this dose level in dogs, some areas of opacity developed that did not fully recover during the 12 week withdrawal period. Evidence of an effect on liver function was detected in the rat at 5 mg/kg/day; this was more pronounced in both species at 15 mg/kg/day. In addition, in the rat at this dose, there was hepatocellular necrosis, associated with the increases in plasma liver enzyme levels. A single female dog showed evidence of a reversible effect on P-R interval, similar to that seen in the I month study, at the 15 mg/kg/day dose level.

Multiple dose studies of up to 14 days duration have been conducted in rats and dogs, by the intravenous route. In rats a no effect dose level of 1 mg/kg/day was identified, following once daily bolus intravenous administration of ZD1 839 for 14 days. Compound related effects were seen in the skin, ovary, and uterus of rats receiving 5 or 20 mg/kg/day and were similar to those lesions observed in the oral studies. In dogs bolus intravenous dosing to dogs of ZD1839, at all dose levels, resulted in occasional transient swellings on/around the dosing sites in some animals. The swelling subsided within I to 3 days of first being observed. Swelling was not seen in control animals. The only histopathological changes at the injection sites were consistent with the mechanical trauma of intravenous injection and were essentially similar in all groups, including controls. Minimal folliculitis was found in the eyelid and skin of some dogs, at all dose levels. This effect was consistent with the findings seen in oral toxicity studies.

2.4.3 Genotoxicity

ZD1839 has shown no evidence of genotoxic potential in in vitro and in vivo assays.

2.4.4 Reproductive and Developmental toxicity

In developmental studies in the rat and rabbit, there was no evidence of teratogenicity in either species. However, at maternally toxic doses in the rabbit, there was fetotoxicity (reduced fetal weights). In the rat pre- post-natal development studies, significant pup mortality in the neonatal period was seen at 20 mg/kg/day (a maternally toxic dose). The no effect dose levels for the developmental and pre and post natal development studies were 5 mg/kg/day and 1 mg/kg/day, respectively. The rat fertility studies showed an effect on ovulation, with reduced fertility at 20 mg/kg/day, with no effects being seen at a dose of 10 mg/kg/day.

When 14C-ZD1839 was dosed orally to pregnant rats and rabbits, radioactivity was found in maternal blood and fetal tissues demonstrating trans-placental transfer of drug-related material. Similarly, in lactating rats dosed with 14C-ZD1839, concentrations of radioactivity in milk were 11 to 19 times higher than those in blood, with ZD1839 accounting for the majority of the radioactivity.

2.4.5 Significant findings by organ system

Ovary: The decreases in ovarian weights, in rats receiving ZD1839 at 40 mg/kg/day in the 1 month study and 15/25 mg/kg/day in the 6 month study, were associated with a reduction in the numbers of corpora lutea. This effect was fully reversed at the end of the withdrawal period. Furthermore, there was evidence of reduced female fertility in the rat at 20 mg/kg/day.

Eye: In the 1 month studies in both rats and dogs, there was evidence for an effect in the eye, detected as corneal epithelial atrophy. This effect had fully reversed at the end of the withdrawal period, although in the dog there was still residual corneal translucency visible ophthalmologically. In the 6 month studies, similar changes were found; in the dog, at the highest dose tested (25/15 mg/kg/day), the corneal translucencies progressed to corneal opacities, which did not reverse during the withdrawal period. When measured in the dog, there were no changes in tear production rates and the corneal changes were readily identifiable at ophthalmological examination.

Skin: Changes were seen in the skin of rats (inflammatory changes in eyelids, muzzle and inguinal regions) and dogs (inflammatory changes in eyelid region, degenerative changes in hair shafts), which were reversing or had fully reversed by the end of the withdrawal period. Increased white blood cell counts and decreased red blood cell parameters also were seen in a number of the rat and dog studies and were considered to be a sequel to chronic inflammatory skin lesions.

Kidney: In the 1 month studies, renal papillary necrosis was seen in rats and in one dog given ZD1839 at 40 mg/kg/day. This finding was also seen in the 6 month studies, but only at the top dose levels (rats, 15 mg/kg/day; dogs, 25 mg/kg/day (subsequently reduced to 15 mg/kg/day) in a single decedent female). At the end of the withdrawal period in rats, the sequelae of papillary necrosis were observed

Liver: In the rat 6 month study, hepatocellular necrosis and eosinophilic sinusoidal macrophage infiltration were observed with ZD1839 at doses of 5 and 25/15 mg/kg/day. These histopathological changes in rats were clearly associated with increases in plasma liver enzymes (ALP, ALT and AST). Elevated plasma liver enzymes (AST and ALT) were also detected, but no morphological changes were observed in the top dose group (40 mg/kg/day) of the rat 1 month study. No increases in liver enzymes or liver histopathology were observed in dogs.

Gastrointestinal tract: Villous stunting and ulceration of the gastrointestinal tract were observed after administration of single 2000 mg/kg doses of ZD1839 to rats, and villous atrophy/erosions were observed in the 50 and 125 mg/kg/day dose groups in a rat 14 day study. Loose feces were observed in females, on at least one occasion, in the 50 mg/kg/day dose group in the 14 day study. There were no salient findings in the gastrointestinal tract of rats in the 1 and 6 month studies (top doses were 40 and 25/15 mg/kg/day, respectively). Loose feces were recorded in dogs in the 14 day, 1 month, and 6 month studies, with no associated histopathological correlate.

Heart: The lengthened PR intervals, with large variations between individual measurements in 2 out of 12 dogs and the second degree heart block (week 4, ZD1839 40 mg/kg/day) in one of these two dogs also showed that ZD1839 can impair atrioventricular conduction. There was also evidence for a similar effect, in a single animal, in the 6 month study at the top dose level of 15/25 mg/kg/day.

3. Human Pharmacokinetics

A summary of pharmacokinetic conclusions regarding ZD1839 is listed below:

 

 

 

 

 

 

 

 

  1. Description of Clinical Data and Sources
  2. 4.1 Overall Data

    NDA 21-399 contains the primary data from two randomized, double-blind, parallel-group, Phase II, multicenter trial of two doses of ZD1839 (Iressa) in patients with advanced/metastatic NSCLC. One trial (Trial 39) includes patients who have previously received at least two chemotherapy regimens that contained platinum and docetaxel given concurrently or as separate treatment regimens (third-line indication). This trial addresses an unmet need. The second trial (Trial 16) includes patients who have failed one or two previous chemotherapy regimens; at least one having contained platinum (primarily second-line indication for which docetaxel is approved). Approximately 50% of patients enrolled in Trial 16 were Japanese. The primary objective of both trials was to evaluate objective tumor response rate and symptom improvement rate with ZD1839 at oral doses of 250 and 500 mg daily. For both trials accrual began in the fall of 2000 and was completed in early 2001.

     

     

     

     

     

     

     

     

     

     

     

     

     

     

     

     

     

     

     

     

     

     

     

     

     

     

     

     

    1. Table Listing the Clinical Trials
    2.  

      Table 1: Differences in study populations in pivotal Trial 39 and supportive Trial 16

      Trial 39 Trial 16

      At least 2 chemotherapy regimens One or a maximum of 2 chemotherapy regimens

      Prior platinum and docetaxel, given Prior platinum

      concurrently or sequentially

      Prior regimens must have failed due to either Considered recurrent or

      unacceptable toxicity or progression while refractory

      on therapy.

      If PD, last dose of chemotherapy within

      90 days prior to trial entry

      Symptomatic at trial entry based upon an

      LCS score of <24 a; FACT-L required for

      randomization

      If treated CNS metastases, patients allowed to: Patients allowed if CNS

      enter 1 week post-completion of definitive metastases were clinically

      treatment (if without neurological deficits), and radiologically stable

      or enter 2 weeks (if stable or improving > 2 months prior to entry

      neurological deficits)

      Patients with another malignancy within

      past 5 years able to confound diagnosis

      and/or staging of NSCLC were excluded.

      Curatively-treated cervical cancer or

      non-melanotic skin cancer eligible

      100 Japanese patients and 100 non-Japanese patients required


      a Asymptomatic score is 28.

       

    3. Postmarketing Experience

None

4.4 Literature Review

The sponsor submitted an extensive literature list. The reviewer was familiar with most of the clinical data included in those publications.

5. Clinical Review Methods

5.1 How the Review was Conducted

Efficacy and safety review is based on electronic CRT’s and hard copy data submitted by the sponsor concerning studies 39 and 16. Additional safety data concerning ZD1839 came from Trials 0005, V-15-11, 0011 and 0012.

    1. Overview of Materials Consulted in Review

The following materials were reviewed

5.3 Overview of Methods Used to Evaluate Data Quality and Integrity

Queries of electronic data performed by the FDA reviewer were compared to the sponsor report. Any discrepancies in results prompted a communication to the sponsor aimed at discovering the cause of the discrepancy. All discrepancies, resolved and unresolved, are indicated in the FDA review section of this document.

Tumor measurements and CT-scans from responding patients were independently analyzed by FDA review. Response durations were also confirmed.

Quality of life data obtained from study patients was compared to performance status ratings done by health care professionals. Because performance status is the most important prognostic factor for advanced/metastatic NSCLC patients it was hoped to expore possible correlations between the evaluations.

The FDA also performed an exploratory analysis to determine whether treatment with ZD1839 treatment resulted in improvement in shortness of breath and cough, two common lung cancer symptoms. A positive result of this analysis required a two-point improvement in the specific symptom lasting at least 4 weeks. Because concomitant medication may have contributed to, or have been totally responsible for, any improvement the medication that patients were receiving at the time improvement was noted was reviewed. Classes of drugs considered candidates to improve shortness of breath included narcotics, bronchodilators, antidepressants/anxiolytics, oxygen, prednisone, and transfusions/epoetin. Classes of drugs considered to improve cough included the above list, minus transfusions/epoetin, plus antibiotics and cough suppressant syrups.To be counted the concomitant medication had to have been started no earlier than the onset of treatment.

5.4 Were Trials Conducted in Accordance with Accepted Ethical Standards

Studies were conducted in accordance with the Declaration of Helsinki, 21 CFR 312 and 314, Directive 91/507/EEC of the European community, and ICH Harmonized Tripartite Guidelines for Good Clinical Practice. The ptrotocol, amendments and study reports were reviewed by IRB’s. Written informed consent was required of all study patients.

5.5 Evaluation of Financial Disclosure

6 Integrated Review of Efficacy

6.1 Brief Statement of Conclusions

6.1.1 Study 39 - Sponsor’s analysis

In study 39 patients with locally advanced or metastatic NSCLC who had previously received and failed at least 2 prior chemotherapy regimens containing platinum and docetaxel therapy, dosing with 250-mg/day or 500-mg/day ZD1839 demonstrated objective tumor response rates of 11.8% and 8.8%, respectively and disease-related symptom improvement rates of 43.1% and 35.1%, respectively. Median progression-free survival times were 59 days and 60 days, respectively. Median survival rates between the 2 dose groups were 185 days for the 250-mg/day group compared to 183 days for the 500-mg/day group

6.1.2 Study 39 - FDA Analysis

FDA agrees with the response rate reported by the sponsor, i.e. 22 partial responses among 216 patients (10.2%, 95% CI 6.5%, 15%). FDA analysis indicated, however, that only 139 of the 216 patients were actually refractory/intolerant to both a platinum drug and to docetaxel. A second concern was that an additional 32 patients were declared to be refractory to therapy within 30 days of starting that therapy. If these individuals are also considered ineligible this would bring the total eligible population to 107 patients. While exclusion of ineligible patients does not appreciably change the overall response rate it does decrease the lower bound of the 95% CI to about 5%.

As might be expected, in a study that is enrolling locally advanced or metastatic NSCLC patients who have failed platinum, docetaxel and other chemotherapy and who still have a performance status of 0 to 2, the patients in this study are not typical of a population of newly diagnosed NSCLC patients of similar stage and performance status. The latter population might be expected to have a median survival of 6 months (stage IV) to 18 months (stage III). Patients in trial 39 had a median time from diagnosis to randomization of 19 months (range 1 to 197 months) and had received a median of 3 prior chemotherapy regimens (range 1 to 6). The 22 ZD1839 responding patients (13 stage IV at diagnosis, 7 stage III) had median time from diagnosis to randomization of 18.5 months (range 8 months to 52 months). Also striking was the fact that 18 of the 22 responders were female and that 19 of the 22 responders had an adenocarcinoma. Adenocarcinoma has the slowest tumor doubling time of all lung cancer histologies. Demography and disease status of study patients is found in Tables 3 and 4, pages 43-44.

      1. Study 16 - Sponsor’s analysis

In patients with locally advanced or metastatic NSCLC who had previously received at least one chemotherapy regimen containing platinum, dosing with 250-mg/day or 500-mg/day ZD1839 resulted in: 1) objective tumor response rates of 18.4% and 19.0%, respectively; 2) disease-related symptom improvement rates of 40.3% and 37.0%, respectively; 3) disease control rates of 54.4% and 51.4%, respectively; 4) QOL improvement rates for TOI of 20.9% and 17.8%, and for FACT-L of 23.9% and 21.9%, respectively median progression-free survival times of 83 days and 85 days, respectively.

Significant differences were observed between Japanese and non-Japanese patients with respect to tumor response, disease control, progression-free survival, and overall survival. No correlation between demographic/pathophysiological factors (including ethnicity) and ZD1839 exposure were identified.

6.1.4 Study 16 - FDA Analysis

Trial 16 is a supporting trial primarily including second-line patients. As in trial 39 eligibility issues were identified by FDA. By FDA analysis 136 of the 209 patients (65.1%) in the ITT population had not progressed during or after prior chemotherapy treatment. The median/mean time from diagnosis to randomization was 12.1/15.9 months (range 0.1 to 125 months). There was 1 complete response and 38 partial responses. Eleven of 102 Caucasian patients were responders compared to 28 of 102 Japanese patients. Thirty-four responders had an adenocarcinoma and 1 had a mixed adenocarcinoma-squamous cell carcinoma. Seventy-four percent of responders had not progressed on prior chemotherapy. The majority of responding patients had lung tumors only or lung plus nodal involvement. Progression free survival and overall survival was comparable to the sponsor’s estimates. Demography and disease status of study patients is found in Tables 24 and 25, pages 66-67.

6.2 General Approach to Review of Drug Efficacy

The efficacy database consists of two phase II, open label trials in patients with locally advanced or metastatic NSCLC, who had previously received and failed at least 2 prior chemotherapy regimens containing platinum and docetaxel therapy or who had previously received at least one chemotherapy regimen containing platinum, who were randomized to ZD1839 250-mg/day or 500-mg/day.

    1. Detailed Review of Trials by Indication per Sponsor
      1. Investigators
      2.  

         

         

         

         

         

         

         

         

         

         

         

         

         

         

         

         

         

         

         

         

         

         

         

         

        Investigator Study:Site

         

        Kathy Albain MD 18391 L/0039:2251

        Professor A H Calvert 18391L/0012:002

        Loyola University Medical Center

        Department of Oncology

        2160 S. I st Avenue Room 109,

        Northern Centre for Cancer

        Maywood EL60153 USA

        Treatment

        Dr J-P Armand 18391L/0012:008

        Newcastle General

        Department of Medical Oncology

        Westgate Road

        Institute Gustave Roussy

        Newcastle upon Tyne NE4 6BE UK

        Rue Camille Desmoulins

        Dr S Casinu. 18391L/0016:704

        Villejuif9485 France

        Oncologia Medica Azienda

        Dr J Baselga, 18391L/0012:005

        Ospedaliera. di Panna

        Department of Oncology

        Viale Gramsci 14

        Vall d'Hebron General Hospital

        43 100 Parma Italy

        Paseo Val] dHebron 119-129

        John Cole MD 18391L/0039:2059

        08035 Barcelona Spain

        Oschner Cancer Institute

        Dr J Baselga 18391L/0016:005

        New Orleans LA 70121-2483 USA

        Vall d'Hebron General Hospital

        Jeffrey Crawford MD 18391L/0039:2072

        Paseo Vall d'Hebron 119-129

        Duke University Medical Center

        08035 Barcelona Spain

        Room 25178

        Dr R Basser 18391L/0016:109

        Morris Building Box 3198

        Western Hospital

        Durham NC 277 10 USA

        Gordon Street

        Dr L Dirix 18391L/00 16:205

        Footscray

        AZ St Augustinus

        Melbourne VIC 3011 Australia

        Oncologisch Centrum

        Chandra P Belani MD 18391L/0039

        Oosterveldlaan 24

        University of Pittsburgh Cancer

        B-26 10 Wilrijk Belgium

        Institute

        Dr J E Dixon 18391L/0003:002

        200 Lothrop Street

        Inveresk Research International Ltd,

        Pittsburgh PA 15213-2546 USA

        Tranent,

        Dr T Bjork 18391L/0012:010

        Edinburgh EH33 2NE, UK

        Department of Urology

        Professor J Y Douillard 18391L/0016:415

        Malmo University Hospital

        CRLCC Rene Gauducheau.

        105 02 Malmo Sweden

        Bd Jacques Monod

        Julie R Brahmer MD 18391L/0039:2256

        44805 Saint-Herblain France

        Hopkins Bunting-Blaustein

        Dr D Ferry 18391L/0005:004

        Cancer Research

        CRC Trials Unit

        Building G94 1650 Orleans Street

        Clinical Research Block

        Baltimore MD 21231 - 1000 USA

        Queen Elizabeth Hospital

        Dr R Callaghan 18391L/00 16:251

        Edgbaston

        I Hopelands Court

        Birmingham B 15 2TT UK

        Hopelands Road

        David R Gandara 18391L/0039:2252

        4001 Overport South Africa

        University of California

        Davis Cancer Center

        4501 X Street

         

        Sacramento CA 95817-2229 USA

           

         

         

        Dr U Gatzerneier 18391L/0016:501

        Dr F Imamura. 18391L/0016:822

        Krankenhaus Grosshandsdorf

        Osaka Medical Centre for Cancer

        Onkologischer Schwerpunkt

        and Cardiovascular Diseases

        Wohrendamm, 80

        1-3-3 Nakarmchi

        22927 Grosshansdorf Germany

        Higashinarie-ku, Osaka, Japan

        Hal Gerstein MD 18391L/0039:2274 Cancer Research of Long Island

        170 Great Neck Road Suite 100

        Mohammad Jahanzeb MD 18391L/0039:2057

        Comprehensive Cancer Center at

        Great Neck NY 11201 USA

        Boca Raton

        Professor G Giaccone 18391L/0016:601

        21020 State Road 7

        Academisch Ziekenhuis Vrije Universiteit Afdeling

        De Boelelaan 1117

        Boca Raton FL 33428 USA

        Leonard A Kalman MD 18391L/0039:2085

        1081 HV Amsterdam The Netherlands

        Oncology Hematology Group of

        South Florida

         

        8940 North Kendall Drive Suite 300E

         

        Miami Fl, 33176 USA

        Dr L Gianni 18391L/0012:007

        Joseph Kash MD 18391L/0039:2271

        Department of Oncology

        Edwards Hospital Cancer Center

        Istituto Nazionale Tumon*

        120 Spalding Drive Suite 400

        Via Venezian

        Naperville IL 60540 USA

        120 100 Milano MI Italy

        Dr N Katakami 18391L/0016:812

        John Hamm MD 18391L/0039:2273

        Kobe Municipal Central Citizens

        Norton Healthcare Inc

        Hospital

        Louisville Oncology

        4-6 Minatoshimanaka-cho

        315 E Broadway 5th Floor

        Chuo-ku, Kobe-shi

        Louisville KY 40202 USA

        Hyougo Japan

        Lisa Hammond MD 18391L/0039:2010

        Professor E Kaukel 18391L/0016:503

        Cancer Therapy Research Center

        Krankenhaus Harburg

        7979 Wurzba6h Road Room 271

        Lungenstation

        San Antonio TX 78229 USA

        Eissendorfer Pferdeweg 52

        Professor A Harris 18391L/0012:004

        21075 Hamburg GenTiany

        ICRF Clinical Oncology Unit

        Professor S Kaye 18391L/0012:001

        Churchill Hospital

        Beaston Oncology Centre

        Headington

        Western Infirmary

        Oxford OX3 7LJ UK

        Glasgow G I 16NT UK

        Dr R Herbst 1839 1 L/001 1:002

        Karen Kelly MD 18391L/0039:2253

        University of Texas MD 18391L/0039:2002

        B171 UCHSC

        4200 E 9th Avenue

        Anderson Cancer Center

        Denver CO 80262 USA

        1515 Holcombe Boulevard, Box 80

        Professor D Kerr 18391LJO035:001

        Houston TX 77030-4009 USA

        CRC Institute for Cancer Studies

        Dr T Horai 18391L/0016:818

        Queen Elizabeth University Hospital

        Japanese Foundation for Cancer

        Trust

        Research

        Birmingharn, B 15 2TH UK

        Cancer Institute Hospital

        Dr A Lockton 18391L/0027:001

        1-37-1 Kami-lkebukuro

        AstraZeneca Clinical Pharmacology

        Toshima-ku Tokyo Japan

        Unit Nottingham

        Dr D G Kieback 18391L/0012:006

        E Floor South Block

        Department of Obstetrics and

        Queen's Medical Centre

        Gynaecology I

        Derby Road

        University Hospital Freiburg

        Nottingham NG7 2LTH UK

        Hugstetter Strasses 55

         

        79106 Freiburg Germany

         

        Dr K Kiura 18391L/0016:803

         

        Okayama University Medical

        Dr P LoRusso 18391L/001 1:003

        Department

        Harper Hospital at Wayne State

        2-5-1 Shikada-cho

        University

        Okayama-shi, Okayama, Japan

        3990 John R Street, Room 530

        Dr M Kris 18391L/0005:002

        Detroit MI 48201-2097 USA

        Memorial Sloan-18391L/0039:2012

        Stuart Lutzker MD 18391L/0039:2008

        Kettering Cancer Center

        York Avenue

        Cancer Institute of New Jersey

        195 Little Albany Street

        New York, NY 10021-6007 USA

        New Brunswick NJ 08901-1914 USA

        Dr S Kudou 18391L/0016:815

        Thoma J Lynch MD 18391L/0039:2028

        Osaka Municipal University 1839N-15-11

        Massachusette General Hospital

        Medical Department

        Box 2, 100 Blossom Street

        1-5-7 Asahi-cho

        Boston MA 02114 USA

        Abenoku-Ku

        Dr A M Maddox 18391L/00 11:001

        Osaka-sh, Osaka, Japan

        University of Arkansas Cancer

        Dr A Laight 18391L/0030:001

        Research Center

        Clinical Pharmacology Unit 18391L/0031:001

        4301 West Markham, Slot 508

        Little Rock AR 72205-7101 USA

        AstraZeneca Pharmaceuticals 18391L/0033:001

        Dr A M Maddox 18391L/0039:2101

        University of Arkansas Cancer

        Mereside 18391L/0034:001

        Research Center

        Alderley Park 18391L/0051:001

        4301 West Markham, Slot 508

        Macclesfield SKI 0 4TG UK

        Little Rock AR 72205-7101 USA

        Dr J L G Larriba 183911/0016:916

         

        Hospital Clinico S Carlos de Madrid

         

        Departmento Oncologia

        Professor C Manegold 18391L/0016:504

        c) Martin Lagos S/N

        Thoraxkllnik Heidelberg-Rohrbach

        28040 Madrid Spain

        Innere Medizin Hamatologie

        Corey Langer, MD 18391L/0039:2115

        Intemistische Onkologie

        Fox Chase Cancer Center

        Amalienstrasses 5

        770 Burholme Avenue

        69126 Heidelberg Germany

        Philadelphia PA 19111-2412 USA

        Dr N Masuda 18391L/0016:813

        Rogerio Lilenbaum MD 18391L/0039:2102

        Osaka Prefecural Habikino Hospital

        3-7-1 Habikino

        Comprehensive Cancer Center

        Habikino-shi, Osaka, Japan

        Mt Sinai Medical Center

         

        4306 Alton Road

         

        Miami Beach Fl, 33140-2840 USA

         

        Dr K Matsui 18391L/0016:813

        Dr K Noda 18391L/0016:804

        Osaka Prefecural Habikino Hospital

        Kanagawa Prefectural Cancer Centre

        3-7-1 Habikino

        1- 1 -2 Nakao

        Habikino-shi

        Asahi-ku

        Osaka Japan

        Yokoharna-shi

        Dr. I Meyer 18391L/0028:001

        Kanagawa Japan

        Quintiles GmbH

        Dr OM Nwose 183911/0051:001

        Geschaftsstelle Freiburg

        Clinical Pharmacology Unit

        Obere Hardstrasse 8-16

        AstraZeneca Pharmaceuticals

        Freiburg D79114 Germany

        Mereside, Alderley Park

        Dr B Milleron 18391L/0016:414

        Macclesfield, Cheshire SKI 0 4TG UK

        Hopital Tenon

        Timothy Panella MD 18391L/0039:2044

        Service de Pneumologie

        Thompson Cancer Survival Center

        Rue de la Chine

        Clinical Trials Department

        75970 Paris Cedex 20 France

        1915 White Avenue

        Dr P Mitchell 18391L/001 6:110

        Knoxville TN 37916 USA

        Austin & Repatriation Medical

        Diane Prager MD 18391L/0039:2255

        Centre

        UCLA Medical Center

        Cancer Clinical Trials Centre

        10945 Le Conte Avenue

        Studley Road

        Suite 2333 PUVB

        Heidelberg VIC 3084 Australia

        Los Angeles CA 90024-2828 USA

        Dr D Moro-Sibilot 18391L/0016:416

        Professor J L Pujol 18391L/0016:417

        Hopital A Michallon

        Hopital A de Villeneuve

        Service de Pneumologie

        Service de Pneumologie

        BP217X

        371 Avenue du Doyen Giraud

        38000 Grenoble France

        34295 Montpellier Cedex France

        Dr K Nakagawa 18391L/0016:805

        Dr.M.Ranson 18391L/0005:003

        Kinki University Medical 1839N-15-11

        CRC, Department of Medical 18391L/0012:003

        Department Hospital

        Oncology, 18391L/0035:002

        377-2 Oonohigashi

        Christie NFIS Trust 18391L/0038:001

        Osakasayama-shi, Osaka Japan

        Wilinslow Road,

        Ronald Natale 18391L/0039:2090

        Withington, Manchester M2 9BX. UK

        Cedars Sinai Comprehensive Cancer

         

        Center

        Dr B Rapaport 18391L/0016:257

        8700 Beverley Blvd Suite C-2000

        Medical Oncology Centre of

        Los Angeles CA 90048 USA

        Rosebank

        Dr.S.Negoro 1839N-15-11

        177 Jan Smuts Avenue

        Osaka City General Hospital

        2193 Parktown North South Africa

        Respiratory Tract Internal Medicine

        Dr E Raymond 18391L/0012:008

        Dr Y Nishiwaki 18391L/0016:821

        Department of Medical Oncology

        National Cancer Centre East Hospital

        Institute Gustave Roussy

        6-5-1 Kashiwanoha

        Rue Camille Desmoulins

        Kashiwa-shi Chiba Japan

        Villejuif 9485 France

        Dr D Rischin 18391L/0012:011

        Mansoor Salch MD 18391L/0039:2270

        Division of Haematology 18391L/001 6:111

        Georgia Cancer Specialist

        and Medical Oncology

        1872 Montreal Road

        Peter MacCallum Cancer Institute

        Tucker GA 30084 USA

        St Andrews Place East Melbourne 3002

        Allen Sandier MD 183911/0039:2011

        Dr R Rosell 18391L/0016:908

        Vanderbilt University Medical Center

        Hospital Universitario Germans

        1956 The Vanderbilt Clinical

        Trais I Pujol

        Hematology and Oncology Dept

        Departmento Oncologia

        Nashville TN 37232-5536 USA

        Ctra Del Canyet

         

        SIN Badalona

        Dr A Santoro 18391L/0016:712

        08915 Barcelona Spain

        U 0 Oncologia Medica

        Dr M Rosenthal 18391L/0016:112

        ed Ematologia Istituto Clinico

        Royal Melbourne Hospital

        Humanitas

        Grattan Street

        Via Manzoni 58

        Parkville

        20089 Rozzano (MI) Italy

        Melbourne VIC 3050 Australia

        Dr T Sawa 183911/0016:820

        Dr M Rothenberg 18391L/001 1:004

        Gifu Citizens Hospital

        Division of Hernatology-Oncology

        7-1 Kashima-cho

        Department of Medicine

        Gifu-shi

        1956 The Vanderbilt Clinic

        Gifu Japan

        Nashville TN 37232-5536 USA

        Professor G Scagliotti 18391L/0016:713

        Dr E Rowinsky 18391L/0005:001

        Divisione di Pneumologia

        Cancer Therapy & Research Center

        Oncologia Azienda

        7979 Wurzbach Rd

        Ospedaliera S Luigi

        San Antonio TX 78229 USA

        Regione Gonzole

        Dr E Rubin 18391L/001 1:008

        10043 Orbassano (TO) Italy

        Cancer Institute of New Jersey

        Joan Schiller MD 18391L/0039:2064

        195 Little Albany Street

        University of Wisconsin Cancer

        New Brunswick NJ 08901-1914 USA

        Center

        Dr P Ruff 18391L/0016:258

        600 Highland Avenue Room K 4/636

        Johannesburg Hospital

        Madison WI 53792-6164 USA

        Haernatology and Oncology

        Arthur Skanin MD 18391L/0039:2201

        Department

        Dana-Farber Cancer Institute

        York Road

        Lowe Center for Thoracic Oncology

        2193 Parktown South Aftica

        44 Binney Street

        Dr H Saka 18391L/00 16:801

        Boston MA 02115 USA

        National Nagoya Hospital

        Dr C Slabber 18391L/0016:259

        4-1-1 Sannornaru

        Mary Potter Oncology Centre

        Naka-ku.

        c/o Totius Street and George Storar

        Nagoya-shi

        Street

        Aichi Japan

        Groenklook

         

        Pretoria South Africa

        Dr E Small 18391L/001 1:005

        M Roy Thomas MD 18391L/0039:2026

        University of California at San

        Mid Dakota Clinic

        Francisco Comprehensive Cancer

        401 N 9th Street

        Center

        Bismarck ND 58501 USA

        1600 Divisardaro Street 3rd Floor

        Professor J Vansteenkiste 18391UO016:207

        San Francisco CA94115 USA

        UZ Gasthuisberg Longziekten

        Charalampox Spiridonidis 18391L/0039:2107

        Respiratoire Oncologie

        Oncology Consultants Inc

        Herestraat 49

        8100 Ravine's Edge Court Suite 100

        B-3000 Leuven Belgium

        Columbus OH 43235 USA

        Dr K Watanabe 18391L/0016:808

        Philip Stella MD 18391L/0039:2236

        Yokohama Citizens Hospital

        5301 E Huron Drive

        56 Okasawa-cho

        Ann Arbor MI 48106 USA

        Hodogaya-ku

        Dr T Sugiura 18391L/0016:817

        Yokohama-shl

        Aichi Prefectural Cancer Centre

        Kanagawa Japan

        1-1 Kanokoden

        Professor D Webb 18391L/0001:002

        Chikusa-ku

        Clinical Research Centre,

        Nagoya-shi

        Department of Medicine,

        AichiJapan

        The University of Edinburgh,

        Dr M Takada 18391L/0016:811

        Western General Hospital,

        Rinku. General Medical Centre

        Edinburgh EI-14 2XU UK

        Municipal Izumisano Hospital

        Dr C H Wilder-Smith 18391L/0036:001

        2-23 Rinku Oral Kita

        Gastroenterology Group Practice

        lzurnisano-shi

        Physiology and Nociception

        Osaka Japan

        Research Group

        Dr I Takata 18391L/0016:802

        University of Berne

        National Hospital Shikoku

        Bubenbergplatz 11

        Cancer Centre

        CH-3011 Berne Switzerland

        13 Horinouchi

        Dr S Yano 18391L/0016:814

        Matsuyama-shl

        Tokushima University Medical

        Ehime Japan

        Department

        Dr K Takeda 18391L/0016:807

        2-50-1 Kuramoto-cho

        Osaka Municipal General Medical

        Tokushima-shi

        Centre

        Tokushima Japan

        2-13-22 Hon-street

        Dr R A Yates 18391L/0001:001

        Miyakojima

        Miyakojima-ku

        Osaka-shi

        Osaka Japan

        Clinical Pharmacology Unit, 18391L/0002:001 183911/0010:001

        Zeneca Pharmaceuticals 18391L/0003:001

        Mereside, Alderley Park,

        Macclesfield, Cheshire SKI 0 4TG UK

        Dr T Tamura 18391L/0016:819

        Dr A Yokoyama 183911/0016:800

        National Cancer Centre 1839N- 15-11:001

        Niigata Prefecural Cancer Centre

        Central Hospital

        Niigata Hospital

        5-1-1 Tsukiji

        2-15-3 Kawagishi-cho

        Chuo-ku

        Niigata-shl, Niigata, Japan

        Tokyo Japan

         

      3. Common Protocol Elements – Trials 39 and 16.

6.3.2.1 Study Objectives

The primary objectives in Trials 39 and 16 were objective tumor response rate of ZD1839 at both 250 mg and 500 mg daily doses, disease-related symptom improvement rate and safety profile characterization of 250 mg and 500 mg daily ZD1839. Secondary objectives were disease control rates (responses + stable disease), progression-free survival and overall survival, time to worsening of symptoms, changes in Quality of Life, and, in trial 16, to evaluate potential differences between Japanese and non-Japanese patients.

6.3.2.2 Eligibility Criteria

Both trials required histologically confirmed advanced NSCLC. Patients had to be at least 18 years old, had to have at least 1 bi-dimensionally measurable lesion with clearly defined margins or non-measurable but evaluable disease at trial entry, had to be WHO performance status of 0 to 2 and had to provide written consent to participate in the trial. Both trials permitted patients with stable brain metastases to be enrolled.

The 2 trials, however, differed on several key eligibility criteria. These criteria ensured that the patient population in Trial 39 had more advanced and refractory disease, and required presence of disease-related symptoms at baseline in order to assess symptom improvement rates. For trial 39 patients must have failed prior platinum and docetaxel, given concurrently or sequentially. Failure of prior regimens must be due to either unacceptable toxicity or progression while on therapy. If PD, last dose of chemotherapy must be within 90 days prior to trial entry. For trial 16 eligible patients must be recurrent or refractory to one or a maximum of 2 chemotherapy regimens that included prior platinum. Trial 16 required 100 Japanese patients and 100 non-Japanese patients.

6.3.2.3 Schedule of Trial Assessments

The schedule of trial assessments is listed in Table 2.

Table 2: Schedule of trial assessments

Event or assessment Screening Monthly (every 28 days) Discontinuation

Day -14 to 0 -7 to 0 1 14 28/1

Visit 1 2 3+

General events or assessments

Informed consent x

Demography x

Medical history and cancer treatments x

Concurrent illness/therapy xa x x x

Physical examination (performance, xa x x x

status, weight and vital signs)

Pregnancy test, if appropriate x

Blood sampling for pharmacokinetics

analysis x x x

Dispense tablets x x

Efficacy assessments

Tumor assessment xb x x

Quality of life (FACT-L) x x

Lung cancer subscale (LCS) symptom

checklistf Weekly

EGFR status (recut sections, paraffin x

embedded tissue block, or slides from

diagnosis or later)

Survival x x

a if a parameter or condition was assessed within 7 days before randomization and findings were consistent with the eligibility criteria, then reassessment on Day 1 was not required.

b Tumor assessment was required within 14 days before randomization, approximately 28 days and 56 days after randomization, and approximately every 8 weeks thereafter.

6.3.3 Pivotal Trial 39 - Patient Population/Demography/ Disease Status/ Prior Cancer Therapy – Sponsor Analysis

Overall, 221 patients from 30 centers in the US were randomized, of whom 216 received trial treatment. Five patients were randomized but did not receive ZD1839 treatment due to either disease progression, a serious adverse event, or screening failure.

Patient populations are summarized in Figure 3. Of the 216 patients treated (ITT population), 181 were considered evaluable for the per-protocol (PP) population (ie, had no significant protocol violations or deviations). Patient demography is summarized in Table 3 while disease status at entry is summarized in Table 4.

Figure 3: Trial 39 Study Population

Number of patients randomized a

n=221

ITT population b

n=216


250-mg/day group 500-mg/day group

n=102 n=114


WD c On-study WD c On-study

N=84 N=18 N=93 N=21



PD d AE e PD d AE e

N=78 N=5 N=72 N=11

a Patients who signed informed consent to participate in the trial.

b Patients who were randomized and received at least 1 dose of trial drug.

c Number of patients who withdrew from trial

d Number of patients who withdrew from the trial due to progressive disease.

e Number of patients who withdrew from the trial due to an adverse event.

 

 

 

 

 

 

 

 

 

Table 3: Demographic characteristics, ITT population in Trial 39

Characteristic ZD1839 dose Total

250 mg/day 500 mg/day

N=102 N= 114 N=216

Age (y)

Mean (SD) 59.3 (11.0) 60.7 (10.3) 60.0(10.7)

Median 61.0 62.0 61.0

Range 34 to 84 30 to 80 30 to 84

Age distribution (y), n

18-64 64 (62.7) 66 (57.9) 130 (60.2)

>65 38 (37.3) 48 (42.1) 86 (39.8)

Sex, n (%)

Male 60 (58.8) 63 (55.3) 123 (56.9)

Female 42 (41.2) 51 (44.7) 93 (43.1)

Origin, n (%)

White 93 (91.2) 103 (90.4) 196 (90.7)

Black 3 (2.9) 4 (3.5) 7 (3.2)

Asian a 1 (1.0) 3 (2.6) 4 (1.9)

Hispanic 2 (2.0) 3 (2.6) 5 (2.3)

Other b 3 (2.9) 1 (0.9) 4 (1.9)

a Includes categories of Asian and Oriental. b Includes Hawaiian, Israeli, Taiwanese, and origin unreported (n=1 each).

 

 

 

 

 

 

 

 

 

 

 

 

 

Table 4: Disease status at entry, ITT population in Trial 39

Characteristic, n (%) of patients ZD1839 dose Total

250 mg/day 500 mg/day

N=102 N=114 N=216

Disease type

Measurable 87 (85.3) 103 (90.4) 190 (88.0)

Nonmeasurable and evaluable 15 (14.7) 11 (9.6) 26 (12.0)

WHO performance status

0 18 (17.6) 15 (13.2) 33 (15.3)

1 64 (62.7) 75 (65.8) 139 (64.4)

2 19 (18.6) 23 (20.2) 42 (19.4)

3 0 1 (0.9) 1 (0.5)

Not recorded 1 (1.0) 0 1 (0.5)

Tumor histology type

Squamous 14 (13.7) 18 (15.8) 32 (14.8)

Adenocarcinoma 70 (68.6) 73 (64.0) 143 (66.2)

Undifferentiated 9 (8.8) 8 (7.0) 17 (7.9)

Large cell 2 (2.0) 3 (2.6) 5 (2.3)

Squamous and adeno 7 (6.9) 9 (7.9) 16 (7.4)

Not recorded 0 3 (2.6) 3 (1.4)

Current disease status

Locally advanced 15 (14.7) 9 (7.9) 24 (11. 1)

Metastatic 87 (85.3) 105 (92.1) 192 (88.9)

Sites of metastatic disease

Adrenal gland 12 (11.8) 15 (13.2) 27 (12.5)

Bone 25 (24.5) 32 (28.1) 57 (26.4)

Brain 19 (18.6) 15 (13.2) 34 (15.7)

Liver 20 (19.6) 31 (27.2) 51 (23.6)

Lung 53 (52.0) 71 (62.3) 124 (57.4)

Lymph nodes 43 (42.2) 53 (46.5) 96 (44.4)

Skin or soft tissue 6 (5.9) 5 (4.4) 11 (5.1)

Other a 11 (10.8) 16 (14.0) 27 (12.5)

a Includes sites of pleural and pericardial effusion.

ITT Intent-to-treat, WHO World Health Organization.

 

 

 

 

 

 

 

 

 

 

 

Previous cancer treatment is provided in Table 5.

 

Table 5: Previous cancer treatment, ITT population in Trial 39

Characteristic ZD1839 dose Total

250 mg/day 500 mg/day

N=102 N=114 N=216

Number of prior

chemotherapy regimens, n (%)

1 a 2(2.0) 0 2 (0.9)

2 41(40.2) 48(42.1) 89 (41.2)

3 31(30.4) 41(36.0) 72 (33.3)

4 or more 28(27.5) 25(21.9) 53 (24.5)

Reason for discontinuation of most

recent chemotherapy, n (%)

Progressive disease 82(80.4) 88(77.2) 170 (78.7)

Unacceptable toxicity 15(14.7) 23(20.2) 38 (17.6)

Completion of therapy b 1 (1.0) 1 (0.9) 2 (0.9)

Other b 4(3.9) 2(l.8) 6 (2.8)

Interval from diagnosis to

randomization (months)

Median/mean 23.8/28.5 16.6/23.7 19.6/26.0

Minimum 1 4 1

Maximum 172 197 197

Prior taxane use, n (%)

Docetaxel only 22(21.6) 32(28.1) 54 (25.0)

Docetaxel and paclitaxel 79(77.5) 81 (71.1) 160 (74.1)

Paclitaxel only c 1 (1.0) 1 (0.9) 2 (0.9)

Other prior cancer treatment, n

Radiotherapy 74(72.5) 74(64.9) 148 (68.5)

Surgery 59(57.8) 62(54.4) 121 (56.0)

a Patients who did not receive 2 prior chemotherapy regimens were excluded from the PP population; however, it was determined upon data clarification that 1 of these patients (Patient 2102/0028) did have more than 1 prior regimen. Correction of the start dates of prior chemotherapy could not be made before database lock, however, so the number of prior regimens listed in the database remains 1. The patient was not excluded from the PP population.

b Patients who did not fail prior treatment due to disease progression or unacceptable toxicity were excluded from the PP population.

c Patients who did not receive prior docetaxel treatment were excluded from the PP population.

 

 

 

 

6.3.3.1 Efficacy results - Objective responses – Sponsor Analysis

Tumor assessments were performed 14 days before the start of treatment (randomization); 28 days and 56 days after randomization, and approximately every 8 weeks thereafter.

Summary data for best tumor response are summarized in Table 6. A total of 12 (11.8%; 95% CI: 6.2%, 19.7%) patients showed partial responses in the 250-mg/day group and ten (8.8%; 95% CI: 4.3%, 15.5%) patients showed partial responses in the 500-mg/day group. Patients with stable disease were distributed proportionately between groups with 31 (30.4% of the treatment group) in the 250-mg/day group and 31 (27.2% of the treatment group) in the 500-mg/day group.

 

Table 6: Summary of objective tumor responses in the ITT population

ZD1839 dose

Parameter 250 mg/day 500 mg/day

N=102 N=114

Number of patients with tumor response [n, 12(11.8) 10(8.8)

Partial response in measurable disease 9 9

Partial response in non-measurable disease 3 1

Number of patients with SD [n, 31(30.4) 31(27.2)

Number of patients with PD [n, 54(52.9) 59(51.8)

The majority of the objective partial responders with measurable disease (72.2%, 13/18) had total tumor volumes > 10 cm2; only 3 patients had total tumor volumes < 5 cm2 Reductions in tumor size occurred in mainly lung (20 patients), liver (4 patients), lymph nodes (5 patients), but also occurred in adrenal (1 patient), kidney (1 patient), and bone (1 patient). All but 1 patient (95.5%, 21/22) also had disease-related symptoms improvement as measured by the LCS. These disease-related symptom improvements were observed by nearly all patients within 4 weeks of starting treatment.

The majority of patients (72.7%, 16/22) who achieved a response did so by the third (4 patients) or fourth week (12 patients); 3 patients achieved a response by Week 7, 1 by Week 12, and 2 by Week 16..

Baseline characteristics of patients who had a tumor response (PR or PRNM) are presented in Table 7.

 

 

 

 

Table 7: Tumor response rate by baseline characteristics in Trial 39

Tumor response a

Characteristic, n (%) of patients n b Yes No

(N=22) (N= 194)

Disease type

Measurable 190 18 (9.5) 172 (88.7)

Non-measurable only 26 4(15.4) 22 (84.6)

Disease status at trial entry

Locally advanced 24 0 24(100.0)

Metastatic 192 22 (11.5) 170 (88.5)

WHO performance status

0-1 172 16 (9.3) 156 (90.7)

2 42 6 (14.3) 36 (85.7)

3 1 0 1 (100.0)

Not recorded 1 0 1 (100.0)

Number of prior number of treatments

1 2 0 2(100.0)

2 89 7(7.9) 82 (92.1)

3 72 7 (9.7) 65 (90.3)

4 or more 53 8 (15.1) 45 (84.9)

Gender

Female 93 18 (19.4) 75 (80.6)

Male 123 4(3.3) 119(96.7)

Age

18-64 130 13 (10.0) 117(90.0)

>65 86 9(10.5) 77 (89.5)

Ethnic origin

White 196 17 (8.7) 179 (91.3)

Non-white c 20 5 (25.0) 15 (75.0)

Histology

Squamous 32 2 (6.3) 30 (93.7)

Adenocarcinoma 143 19 (13.3) 124(86.7)

Undifferentiated 17 1 (5.9) 16(94.1)

Large cell 5 0 5 (100.0)

Squamous and adenocarcinoma 16 0 16(100.0)

Not recorded 3 0 3 (100.0)

a Both doses combined.

b Number of total patients in a given category.

c Includes Black, Asian/Oriental, and Hispanic.

The majority of tumor responses (77.3%, 17/22) were ongoing at the time of data cutoff (minimum follow-up of 4 months). The median duration of tumor response could not be calculated for the 250-mg/day group (10 of the 12 patients have not progressed); the median duration of tumor response for the 500-mg/day group was estimated at 136 days. The range of duration of tumor responses was 1+ to 7+ months in the 250-mg/day group and 2+ to 4+ months in the 500-mg/day group.

6.3.3.2 Disease-related symptom improvement – Sponsor Analysis

Trial 39 used the Lung Cancer Subscale (LCS) of the Functional Assessment of Cancer Therapy for Lung Cancer (FACT-L) instrument to assess disease-related symptoms. The maximum or "best" score is 28, which indicates no symptoms; the minimum or "worst" score is 0 indicating that the patient is severely bothered by all 7 symptoms. Patients had to have a LCS score of 24 or less as a eligibility criterion.

Weekly assessments of disease-related symptoms were made. Changes from baseline in the LCS score were assessed at each visit as improved or worsened if the score had shifted at least 2 points in either direction. To be considered as having "disease-related symptom improvement", the patient had to sustain a 2-point or more improvement in their total LCS score for a minimum of 4 weeks without interim worsening to minimize potential for false positive responses.

The overall completion compliance was 84%. There was no apparent difference in compliance between the doses.

LCS baseline characteristics

The baselines distribution of each LCS item by score for all patients is presented in Table 8. The median baseline score for LCS was 16.0 and 81 % of the patients had baseline scores less than 20.

 

Table 8: Disease-related symptom distribution at baseline by score for all patients

Baseline score [n(%)]

Disease-related symptom Most No

N Symptomatic Symptomatic Sx

0 1 2 3 4

Shortness of breath 216 28 (13.0) 70 (32.4) 62 (28.7) 36 (16.7) 20(9.3)

Coughing 215 32 (14.9) 62 (28.8) 48 (22.3) 42 (19.5) 31(14.4)

Chest tightness 212 13 (6.1) 23 (10.8) 44 (20.8) 66 (31.1) 66(31.1)

Ease of breathing 213 28 (13.1) 37 (17.4) 85 (39.9) 41 (19.2) 22(10.3)

Weight loss 216 10(4.6) 17 (7.9) 42 (19.4) 50 (23.1) 97(44.9)

Clarity of thinking 215 7 (3.3) 6 (2.8) 40 (18.6) 61 (28.4) 101(47.0)

Poor appetite 214 24(11.2) 35 (16.4) 60 (28.0) 53 (24.8) 42 (19.6)

The disease-related symptom improvement rate data are summarized in Table 9.

The symptom improvement rates were similar for the 2 dose groups. Of the 84 patients who had symptom improvement, the maximum LCS scores improved by a median of 7.0 points. Symptom improvement occurred soon after the start of treatment Median time (days) to improvement was 10.0 days and 9.0 days for the two treatment groups

 

Table 9: Rate of disease-related symptom improvements in Trial 39

ZD1839 dose assignment

Parameter 250 mg 500 mg

N=102 N=114

Number of patients with symptom improvement 44 40

Rate of response (%) 43.1 35.1

Lower 95% confidence interval 33.4 26.4

Upper 95% confidence interval 53.3 44.6

The median duration of symptom improvement was not calculable for the 250-mg/day group because 80% (35/44) of patients who had an improvement were still showing an improvement at the data cutoff. The median duration of symptom improvement was estimated at 164 days for the 500-mg/day group.

6.3.3.3 Progression-free survival

Progression-free survival was defined as the time from randomization to the assessment PD, death, or censoring at last assessment visit. The median progression-free survival was similar between the 2 dose groups: 59 days (95% CI: 56, 86) for the 250-mg/day group and 60 days (95% CI: 49, 67) for the 500-mg/day group.

6.3.3.4 Overall survival

As of the data cutoff of 1 August 2001, 53 (52.0%) of the patients in the 250-mg/day group were alive compared to 57 (50.0%) of the patients in the 500-mg/day group. With a minimum follow-up of 4 months, median survival was similar between the 2 dose groups, 185 days for the 250-mg/day group compared to 183 days for the 500-mg/day group.

 

6.3.3.5 QOL [FACT-L and TOI]

The FACT-L questionnaire contains a total of 34 questions, divided into 5 different domains: disease-related symptoms, physical, functional, emotional, and social. Each question is scored from 0 to 4. The Treatment Outcome Index (TOI) is the total score of disease-related symptom, physical, and functional questions. TOI changes of 6 points or more were found to be meaningful. The complete FACT-L questionnaire was filled out by patients every 28 days at the end of a treatment period. while disease-related symptom scores were obtained on a weekly basis

The highest QOL score (ie, the best QOL score) that can be attained for:

There were no significant differences (ie, 6 points for either FACT-L or TOI) in median baseline scores between the different groups for FACT-L and TOL Baseline scores for FACT-L ranged from 29.0 to 126.0, and for TOI ranged from 14.0 to 78.0. The overall compliance of filling out the questionnaire was 86%.

Summary of QOL findings

FACT-L improvement rate was higher in the 250-mg/day group (34.3%; 95% CI: 25.2%, 44.4%) than in the 500-mg/day group (22.8%; 95% CI: 15.5%, 31.6%).

TOI improvement rate was higher in the 250-mg/day group (33.3%; 95% CI: 24.3%, 43.4%) than in the 500-mg/day group (20.2%; 95% CI: 13.2%, 28.7%) (Summary Tables T4.4.2.1 and T4.4.2.2, Trial 39 CTR).

Time to FACT-L and TOI improvement was similar for each dose group with a median of 30 days (both FACT-L and TOI) for the 250-mg/day group and 29 days (TOI, 500-mg/day group) and 31 days (FACT-L, 500-mg/day group)

Because of the short time to data cutoff, many patients were censored, and there were not enough events to produce duration of improvement medians or confidence intervals for either FACT-L or TOL

 

The sponsor stated that all but 1 patient (95.5%, 21/22) of patients who showed a tumor response also showed an improvement in disease-related symptoms as measured by the LCS. The majority (77.4%, 65/84) of patients with disease control (PR+PRNM+SD) showed improvement in their LCS score with the stable disease patients having a 71.0% (44/62) symptom improvement rate. Patients with the best response of disease progression showed the smallest proportion (16.8%, 19/113) of patients with improved LCS scores. The FDA does not agree (see Executive Summary and page 64.

6.3.3.6 Disease Control – Sponsor Analysis

Patients defined as having disease control were those who had a best response rating of CR, PR (including PRNM) or SD that was maintained for at least 28 days from the first demonstration of that rating (ie, could not occur prior to 56 days from start of treatment).

The disease control rates were similar between the 2 dose groups: 42.2% (95% CI: 32.4%, 52.3%) in the 250-mg/day group and 36.0% (95% CI: 27.2%, 45.5%) in the 500-mg/day group. The median durations of disease control were similar in both dosage groups (125 days, 250-mg/day group; 111 days, 500-mg/day group). The duration of disease control was computed from the first post-baseline visit rather than the baseline visit. Time from randomization to disease progression would be approximately 28 days longer.

 

6.3.4 Supportive Trial 16 – Sponsor Analysis

6.3.4.1 Patient Population/Demography

Overall, 210 patients from 43 centers in Europe, Japan, and other countries around the world were randomized, of whom 209 received trial treatment. One patient was randomized but did not receive ZD1839 treatment due to a screening failure.

Patient populations are summarized graphically in Figure 4. Of the 209 patients treated (ITT population), 208 were considered evaluable for response and 140 were considered evaluable for symptom improvement.

 

Figure 4: Trial 16 patient populations

Number of patients randomized

n=210

I

ITT population

n=209


250-mg/day 500-mg/day

group n=103 group n=106


Evaluable for response Evaluable-for-symptom

n=208 improvement n=140




I l

250-mg/day 500-mg/day 250-mg/day 500-mg/day

n=103 n=105 n=67 n=73

The demographic characteristics of these patients are summarized in Table 10.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Table 10: Demographic characteristics of patients in Trial 16

Demographic characteristic Randomized treatment

ZD1839 ZD1839 All

250 mg/day 500 mg/day patients

(n= 104) (n= 106) (n~2 10)

Age (years)

Mean (standard deviation) 60.3(9.5) 58.9(9.7) 59.6(9.6)

Median 61.0 60.0 60.0

Range 28 to 85 37 to 78 28 to 85

Age group (number [%] of patients)

18 to 64 69(66.3) 77(72.6) 146(69.5)

>65 35(33.7) 29(27.4) 64(30.5)

Sex (number [%] of patients)

Women 26(25.0) 36(34.0) 62(29.5)

Men 78(75.0) 70(66.0) 148(70.5)

Origin (number [%] of patients)

White 49(47.1) 53(50.0) 102(48.6)

Black 2(l.9) 0 2(l.0)

Hispanic 2(l.9) 0 2(l.0)

Oriental 0 1 (0.9) 1 (0.5)

Japanese 51(49.0) 51(48.1) 102(48.6)

Other 0 1 (0.9) 1 (0.5)

.

Disease status/previous treatment at entry

The disease characteristics of patients at trial entry are presented in Table 11.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Table 11: Disease characteristics at trial entry in Trial 16

Characteristic Randomized treatment

ZD1839 ZD1839 All

250 mg/day 500 mg/day patients

(n= 104) (n= 106) (n=210)

Previous cancer treatment, n

Failed 1 previous chemotherapy regimen 104(100.0) 106(100.0) 210(100.0)

Failed 2 previous chemotherapy regimens 46 (44.2) 46 (43.4) 92 (43.8)

Prior Radiotherapy 52 (50.0) 48 (45.3) 100(47.6)

Prior Surgery 32 (30.8) 25 (23.6) 57 (27.1)

Other 4 (3.8) 9 (8.5) 13 (6.2)

WHO performance status (score), n (%)

Normal activity (0) 18 (17.3) 20 (18.9) 38 (18.1)

Restricted activity (1) 73 (70.2) 72 (67.9) 145 (69.0)

In bed:<=50% of the time (2) 13 (12.5) 14 (13.2) 27 (12.9)

Histology type, n (%)

Adenocarcinoma 64 (61.5) 68 (64.2) 132 (62.9)

Squamous 25 (24.0) 18 (17.0) 43 (20.5)

Large cell 9 (8.7) 9 (8.5) 18 (8.6)

Undifferentiated 3 (2.9) 8 (7.5) 11 (5.2)

Squamous and adenocarcinoma 3 (2.9) 3 (2.8) 6 (2.9)

Interval from diagnosis (months)

Median/mean (months) 12.2/17.2 11.7/14.6 12.1/15.9

Minimum (months) 0.1 2.3 0.1

Maximum (months) 125 59.5 125

Current disease status, n (%)

Locally advanced 25 (24.0) 20 (18.9) 45 (21.4)

Metastatic 79 (76.0) 86 (81.1) 165 (78.6)

Other tumor sites recorded at trial entry, n

Adrenal 10 (9.6) 9 (8.5) 19 (9.0)

Liver 11 (10.6) 22 (20.8) 33 (15.7)

Bone 25 (24.0) 28 (26.4) 53 (25.2)

Lymph nodes 45 (43.3) 51 (48.1) 96 (45.7)

Lung 63 (60.6) 59 (55.7) 122 (58.1)

Skin/soft tissue 7 (6.7) 7 (6.6) 14 (6.7)

Brain 13 (12.5) 14 (13.2) 27 (12.9)

Other a 42 (40.4) 40 (37.7) 82 (39.0)

a Includes sites of pleural and pericardial effusion.

6.3.4.2 Treatment Response – Sponsor Analysis

Summary data for best overall objective response are presented in Table 12. A total of 119 (18.4%; 95% CI: 11.5%, 27.3%) patients showed partial responses in the 250-mg/day group. Twenty (19.0%; 95% CI: 12.1%, 27.9%) patients showed tumor responses in the 500-mg/day group: 1 patient had a complete tumor response, 19 patients had partial responses. Patients with stable disease were distributed proportionately between groups with 37 (35.9% of the treatment group) in the 250-mg/day group and 34 (32.4% of the treatment group) in the 500-mg/day group.

 

Table 12: Investigator's assessment of best overall objective response:

Best tumor response 250 mg ZD1839 500 mg ZD1839

N=103 N=105

Complete response [n, 0 l(l.0)

Partial response + partial response in

non-measurable disease [n, 18+1(18.4) 19+0(18.1)

Stable disease [n, (%)] 37(35.9) 34(32.4)

Progressive disease [n, 42(40.8) 44(41.9)

Overall, 17.9% of second-line patients had objective response, and 19.8% of third-line patients had objective response. There was no marked difference in response rates between patients who had failed 1 or 2 previous regimens regardless of whether they had prior docetaxel therapy. Responses occurred in patients with performance status of 2 (3.7%, 1/27) and in patients with non-measurable, evaluable disease (33.3%, 1/3). Women (34.4%, 21/61) appeared to have higher response rates than men (12.2%, 18/147). Responses occurred in almost all histologies, but occurred more often in adenocarcinomas (26.0%, 34/131) than in squamous (7.0%, 3/43) or other (6.3%, 2/32) histologies. Response rates were comparable in patients age 18-64 and those >=age 65 (19.4% and 17.2%, respectively. Responses were higher in a predominantly Japanese population than in the white population 25.9 and 11%, respectively.

The median duration of tumor response could not be calculated for either dosage group. The majority of tumor responses (87.2%, 34/39) were ongoing at the time of data cutoff.

6.3.4.3 Disease-related symptom improvement –Sponsor Analysis

For Trial 16, patients were not required to be symptomatic for trial entry based on their baseline LCS scores. In order to evaluate disease-related symptom improvement in a symptomatic patient population (similar to Trial 39), a subset of the per-protocol population with a baseline

 

LCS score of <=24 was analyzed. Sixty-seven patients in the 250-mg/day group and 73 patients in the 500-mg/day group comprised the evaluable for symptom improvement population.

The overall compliance for the disease-related symptom questionnaire (LCS) was 74% and there was no apparent difference in compliance across the doses. Higher compliance was associated with a PS of 0 or 1 (vs PS 2), second-line (vs third-line), and Japanese (vs non-Japanese) patients.

LCS baseline characteristics

The distribution of each LCS item by score for all patients is presented in Table 13. Median baseline scores for LCS were 18.0 for the 2 dose groups indicating that this was a symptomatic population.

 

Table 13: Disease-related symptom distribution at baseline

Baseline score [n(%)]

Disease-related symptom Most Less No

N Symptomatic Symptomatic Symptoms

0 1 2 3 4

Shortness of breath 140 16 (11.4) 29(20.7) 35(25.0) 43(30.7) 17(12.1)

Coughing 140 16(11.4) 29(20.7) 35(25.0) 31 (22.1) 29(20.7)

Chest tightness 136 3 (2.2) 18(13.2) 27(19.9) 37(27.2) 51(37.5)

Ease of breathing 138 19 (13.8) 23 (16.7) 42(30.4) 42(30.4) 12(8.7)

Weight loss 139 10(7.2) 16(11.5) 17(12.2) 36(25.9) 60(43.2)

Clarity of thinking 137 10(7.3) 16(11.7) 16(11.7) 43(31.4) 52(38.0)

Poor appetite 135 17(12.6) 19(14.1) 33(24.4) 41 (30.4) 25 (18.5)

 

Symptom improvement rate

The disease-related symptom improvement rate data are summarized in Table 14. The symptom improvement rates were similar for the 2 dose groups. Of the 54 patients who had disease-related symptom improvement, the maximum LCS score improved by a median of 7.0 points.

 

 

 

 

 

 

 

Table 14: Rate of disease-related symptom improvements

ZD1839 dose assignment

Parameter 250 mg/day 500 mg/day

N=67 N=73

Patients with symptom improvement (n) 27 27

Rate of response (%) 40.3 37.0

Lower 95% confidence interval 28.5 26.0

Upper 95% confidence interval 53.0 49.1

6.3.4.4 Progression-free survival and overall survival

Progression-free survival

The median number of progression-free survival days was similar for the 2 dose groups: 83 days (95% CI: 61, 86) for the 250-mg/day group, and 85 days (95% CI: 59, 116) for 500 mg/day group.

Overall survival

With a minimum follow-up of 4 months, 68% of patients in the 250-mg/day group and 79% in the 500-mg/day group were alive at data cutoff.

6.3.4.5 Subgroup analyses-Sex, Age, and Ethnicity

More women experienced tumor responses at either the 250-mg/day and 500/mg day doses (36.0%; 95% CI: 18.0%, 57.5% and 33.3%; 95% CI: 18.6%, 51.0%, respectively) than men (12.8%; 95% CI: 6.3%, 22.3% and 11.6%; 95% CI: 5.1%, 21.6%, respectively). No trend was seen for tumor response rates in either dose group between patients 18 to 64 years old and 65 years of age or older.

In Trial 16, where approximately one-half of the patients were Japanese, higher tumor response rates were seen in non-white patients in both the 250-mg/day dose group and 500-mg/day group (25.5% and 26.4%, respectively) than for white patients (10.4% and 11.5%, respectively).

Efficacy between Japanese and non-Japanese patients was more fully evaluated in Trial 16 and significant differences were observed with respect to tumor response, disease control, progression-free survival, and overall survival. Multivariate analyses showed that a portion of the differences were confounded with imbalances in baseline factors. This suggested that a portion of the remaining differences could be explained by imbalances in unknown prognostic factors as a result of patient selection rather than a true ethnic difference. The results regarding a potential ethnic difference were inconclusive due to the non-randomized comparison, and the limitations of the data.

 

Symptom improvement by the subgroups sex, age, and ethnicity

The symptom improvement rates were similar between male and female patients in both dose groups: in male patients, 40.8% (95% CI: 27.0%, 55.8%; 250-mg/day group) and 34.8% (95% CI: 21.4%, 50.3%; 500-mg/day group), and in female patients, 38.9% (95% CI: 17.3%, 64.3%; 250-mg/day group) and 40.7%% (95%CI: 22.4%, 61.2%, 500-mg/day group). Likewise, symptom improvement rates by age or ethnicity were similar between dose groups.

In contrast to the other efficacy parameters, there was no significant difference observed for the disease-related symptom improvement rate between the Japanese and non-Japanese patients.

6.3.5 Detailed Review of Trial 39 – FDA Analysis

6.3.5.1 Study patients

Pivotal trial 39 eligibility required that patients must have failed prior platinum and docetaxel, given concurrently or sequentially, due to either progression on therapy or within 90 days of completion of therapy or because of unacceptable toxicity.

This eligibility criterion was met for 139 of the 216 ITT patients (64%) in this trial. The 139 number was obtained by querying Dataset RS00075 (Previous Cancer Treatment). Variable WDREAS (Reason for withdrawal) was used to select patients with progression or unacceptable toxicity (1=progressive disease and 9=unacceptable toxicity). The results of this query are summarized in Table 15.

 

Table 15: Patients refractory or intolerant to docetaxel and/or platinum

 

Platinum Refractory/intolerant

Taxotere Refractory/ Intolerant

 

Yes

No

Yes

139

58

No

11

8

6.3.5.2 Study Patient Summary

As might be expected, in a study that is enrolling locally advanced or metastatic NSCLC patients who have failed platinum, docetaxel and other chemotherapy and who still have a performance status of 0 to 2, the patients in this study are not typical of a population of newly diagnosed NSCLC patients of similar stage and performance status. The latter population might be expected to have a median survival of 6 to 9 months if stage IV at diagnosis and 16 to 18 months if stage III at diagnosis. Patients enrolled in this study have survived for a considerably longer time (see Table 16 for data on time from lung cancer diagnosis to study randomization as well as other pertinent patient information). Striking is the percent of study patients with adenocarcinoma alone or mixed with squamous cell carcinoma (73.6%). This is expected as adenocarcinoma has the slowest tumor doubling time of all lung cancer histologies

 

Table 16: Patient characteristics

Characteristic, n (%) of patients ZD1839 dose Total

250 mg/day 500 mg/day

n=102 n=114 n=216

WHO performance status

0 18 (17.6) 15 (13.2) 33 (15.3)

1 64 (62.7) 75 (65.8) 139 (64.4)

2 19 (18.6) 23 (20.2) 42 (19.4)

3 0 1 (0.9) 1 (0.5)

Not recorded 1 (1.0) 0 1 (0.5)

Tumor histology type

Squamous 14 (13.7) 18 (15.8) 32 (14.8)

Adenocarcinoma 70 (68.6) 73 (64.0) 143 (66.2)

Squamous + adenocarcinoma 7 (6.9) 9 (7.9) 16 (7.4) Undifferentiated 9 (8.8) 8 (7.0) 17 (7.9)

Large cell 2 (2.0) 3 (2.6) 5 (2.3)

Not recorded 0 3 (2.6) 3 (1.4)

Current disease status

Locally advanced 15 (14.7) 9 (7.9) 24 (11. 1)

Metastatic 87 (85.3) 105 (92.1) 192 (88.9)

Months from diagnosis to

randomization

Median 23.8 16.6 19.6

<12 n (%) 20 (19.6) 39 (34.2) 59 (27.3)

12-24 32 (31.3) 34 (29.8) 66 (30.6)

25-36 26 (25.5) 28 (24.6) 54 (25.0)

37-48 12 (11.8) 2 (1.8) 14 (6.5)

49-60 6 (5.9) 5 (4.4) 11 (5.1)

>60 6 (5.9) 6 (5.3) 12 (5.6)

Number of prior chemotherapy

regimens, n (%)

1 2(2.0) 0 2 (0.9)

2 41(40.2) 48(42.1) 89 (41.2)

3 31(30.4) 41(36.0) 72 (33.3)

4 or more 28(27.5) 25(21.9) 53 (24.5)

6.3.5.3 Response rate – FDA Analysis

FDA agrees with the sponsor that there were 22 patients who had a partial response, 12 in the ZD1839 250 mg/day group and 10 in the 500 mg/day group. In 18 patients response was demonstrable by tumor measurements while 4 patients (3 in the 250 mg group, 1 in the 500 mg group) had a PR in non-measurable disease. The response rate for the ITT population was 10.2% (95% C.I. 6.5%, 15%) The sponsor also determined the percent of patients who maintained stable disease but this was not felt to be a meaningful parameter because study patients likely had slow growing cancers.

6.3.5.4 Responder Characteristics

Characteristics of the 22 responding patients are summarized in Tables 17 and 18. Because of small numbers and comparable efficacy results patients receiving ZD1839 250mg/day and 500 mg/day are considered as one group in Table 19. While stage at diagnosis varied all patients had metastatic disease at the time of ZD1839 treatment.

 

Table 17: Responders – FDA Analysis

Cen

ter

Dx To

Rand (m)

Rand

Age at

Entry

Stage

at Dx

# Prior

Regimens

Pt

Dose

Sex

PS

Histol

2002

0287

250

10

53

F

2

Adeno

IV

3

2011

0166

500

50

73

F

2

Adeno

II

5

2011

0167

250

20

44

M

2

Adeno

IV

4

2011

0230

500

8

65

F

2

Squam

IIIB

2

2012

0293

500

16

42

F

1

Adeno

IIIA

3

2028

0111

500

34

68

F

1

Adeno

IV

5

2064

0077

250

28

67

F

1

Adeno

IV

4

2064

0084

250

13

41

F

1

Adeno

IV

3

2072

0141

500

21

68

F

2

Adeno

I

2

2090

0037

250

9

46

F

0

Adeno

IV

4

2090

0048

250

15

34

M

0

Undiff

IV

2

2090

0049

500

14

61

F

1

Adeno

IV

4

2090

0052

250

32

66

F

1

Squam

IV

4

2090

0217

250

33

51

F

0

Adeno

IIIB

4

2090

0222

500

17

70

M

1

Adeno

IIIA

2

2118

0170

250

14

61

F

1

Adeno

IV

2

2201

0258

500

17

47

F

1

Adeno

IIIB

3

2255

0302

250

18

60

F

1

Adeno

IIIB

3

2255

0338

250

21

80

F

2

Adeno

IIIA

3

2255

0340

500

19

70

M

0

Adeno

IV

3

2256

0250

250

52

46

F

1

Adeno

IV

2

2271

0197

500

28

58

F

1

Adeno

IV

2

 

 

 

 

 

 

 

Table 18: Responder characteristics - ITT Population

Characteristic

Number of responders

Sex

Female

Male

18/93

4/123

Histology

Adenocarcinoma

Squamous

Undifferentiated

19/143

2/32

1

Months from diagnosis to ZD1839 randomization

<12

13-24

25-36

>50

 

3

12

5

2

Prior chemotherapy regimens (n)

2

3

4

5

 

7

7

6

2

Thirteen of the 22 responders were stage IV at diagnosis. The median number of months from diagnosis to study randomization for this group of patients was 19 months, range 9 to 52 months.

Table 19 summarizes the number of measurable lesions for 18 of the 22 responding metastatic disease NSCLC patients (4 patients had only evaluable disease). As indicated the majority of responding patients had only 1 or 2 lesions that were measured. The site of the measurable lesion in patients with only one measurable tumor was lung in 4 patients and liver in one patient. The site of the measurable lesion in patients with two measurable tumors was lung only in 2 patients, lung and liver in 2 patients, lung and lymph node in 1 patient and liver only in 1 patient. Baseline total tumor area of measurable lesions was less than 10 cm2 in 5 of 18 responding patients with measurable lesions

 

 

 

 

 

 

Table 19: Number of measurable lesions evaluated in responding patients - FDA

Measurable lesions (n)

Responding patients (n)

0

4

1

5

2

6

3

2

4

3

6

1

8

1

 

Among the 139 patients deemed by the FDA to be platinum/taxotere refractory/intolerant there were 14 patients with a partial response, (response rate 10.1%, (95% C.I. 5%, 17%). These patients are listed in Table 20.

 

Table 20: Responders refractory/intolerant to platinum and docetaxel - FDA

Cen ter

Dx To

Rand (m)

Rand

Age at

Entry

Stage

at Dx

# Prior

Regimens

Pt

Dose

Sex

PS

Histol

2002

0287

250

10

53

F

2

Adeno

IV

3

2011

0167

250

20

44

M

2

Adeno

IV

4

2011

0230

500

8

65

F

2

Squam

IIIB

2

2028

0111

500

34

68

F

1

Adeno

IV

5

2064

0084

250

13

41

F

1

Adeno

IV

3

2072

0141

500

21

68

F

2

Adeno

I

2

2090

0037

250

9

46

F

0

Adeno

IV

4

2090

0048

250

15

34

M

0

Undiff

IV

2

2090

0049

500

14

61

F

1

Adeno

IV

4

2090

0052

250

32

66

F

1

Squam

IV

4

2090

0217

250

33

51

F

0

Adeno

IIIB

4

2118

0170

250

14

61

F

1

Adeno

IV

2

2255

0338

250

21

80

F

2

Adeno

IIIA

3

2255

0340

500

19

70

M

0

Adeno

IV

3

It is of interest that response rates of the 139 patient doubly refractory/intolerant population and the remaining 77 patient less refractory/intolerant population (8 responses) were comparable. Higher response rates are generally expected in less refractory patients.

6.3.5.5 Response and Performance Status – FDA Analysis

Because performance status is universally recognized as an important, and possibly the most important, prognostic factror for survival it was of interest to explore whether treatment response was associated with improvement of performance status. This analysis should be considered as hypothesis generating as it had not been prespecified in the protocol and because benefit was arbitrarily determined to be an improvement of one PS grade on two consecutive observations. For the 22 responding patients;

5 patients were PS 0 at baseline and maintained that PS throughout treatment.

17 patients were PS 1 or 2 at baseline. Of those patients

9/17 improved their PS by 1 grade,

1/17 improved PS by 2 grades,

1/17 had a PS decline of 2 grades,

6/17 maintained their PS throughout treatment.

6.3.5.6 Performance Status and Quality of Life Relationships

It was also of interest to compare PS score (generated by a physician or other health care professional and quality of life score generated by the patient (Table 21). Two quality of life scales, the lung cancer subscale (LCS) and treatment outcome index (TOI) were compared. On the LCS patients would score 28 if they had no shortness of breath, no weight loss, clear thinking, no cough, good appetite, no chest tightness and easy breathing and would score zero if they were very affected by the above symptoms. The TOI is the sum of the LCS + the 7 item physical well being component (lack of energy, nausea, trouble meeting needs of family, pain, side effects of treatment, feeling ill and forced to spend time in bed) + the 7 item functional well being component (able to work [including work at home], work is fulfilling, enjoyment of life, accepting illness, sleeping well, enjoyment of things done for fun, contentment with quality of life). Total TOI score ranges from 0 = very adversely affected to 84 = not at all adversely affected. The scoring system for the LCS is that a change of > +2 will be considered improved, < -2 worsened, otherwise no change. The scoring system for the TOI is that a change of > +6 was considered improved, < -6 worsened, otherwise no change.

 

Table 21: Comparison of baseline PS and baseline LCS and TOI – FDA

   

Lung Cancer Subscale

Treatment Outcome Index

PS

Patients (n)

Median

Range

Median

Range

0

33

19

11-24

55

20-75

1

139

17

2-27

49

14-78

2

42

15

8-23

43

23-66

PS is universally recognized as the most important prognostic factor for efficacy and toxicity in advanced/metastatic disease non-small cell lung cancer. The observation that there was wide variation in LCS and TOI scores for each PS score suggests a complex interrelationship between these variables. Perhaps patients with PS 0 and a high LCS and /or TOI score will do especially well.

 

6.3.5.7 Progression free survival

FDA analysis agrees with sponsor analysis. Median time from randomization to progression or death was 59.0 days (95% CI 56.0-86.0) for the 102 patients treated with ZD1839 250 mg/day and 60.0 days (95% CI 49.0-67.0) for the 114 patients treated with ZD1839 500 mg/day.

6.3.6 Detailed Review of Trial 16 per FDA

Two-hundred ten patients from 43 centers in Europe, Japan and other countries around the world were randomized. One randomized patient was not treated leaving 209 patients in the ITT population.

6.3.6.1 Patient Demographics and Disease Characteristics

Pertinent demographic characteristics are summarized in Table 22.

Table 22: Trial 16 Demographic characteristics

Characteristic Randomized treatment

ZD1839 ZD1839 All

250 mg/day 500 mg/day patients

(n= 104) (n= 106) (n=210)

Age (years)

Median 61.0 60.0 60.0

Range 28 to 85 37 to 78 28 to 85

Sex (number [%] of patients)

Women 26 (25.0) 36 (34.0) 62 (29.5)

Men 78 (75.0) 70 (66.0) 148 (70.5)

Origin (number [%] of patients)

White 49 (47.1) 53 (50.0) 102 (48.6)

Black 2 (l.9) 0 2 (l.0)

Hispanic 2 (l.9) 0 2 (l.0)

Oriental 0 1 (0.9) 1 (0.5)

Japanese 51 (49.0) 51 (48.1) 102 (48.6)

Other 0 1 (0.9) 1 (0.5)

.

Diseasc characteristics of study 16 patients are listed in Table 23.

 

 

 

 

 

Table 23: Disease characteristics at trial entry in Trial 16

Characteristic Randomized treatment

ZD1839 ZD1839 All

250 mg/day 500 mg/day patients

(n= 103) (n= 106) (n=209)

Previous cancer chemotherapy, n (%)

Platinum as first or second line Rx 103(100.0) 106(100.0) 209(100.0)

Progression on first line therapy 26 (25.2) 29 (27.4) 55 (26.3)

Progression on second line therapy 23 (22.3) 12 (11.3) 35 (16.7)

Progression on either 1st or 2nd line chemo 36 (35.0) 37 (34.9) 73 (34.9)

No progression on chemotherapy 67 (65.0) 69 (65.1) 136 (65.1)

WHO performance status (score), n (%)

0 18 (17.3) 20 (18.9) 38 (18.1)

1 73 (70.2) 72 (67.9) 145 (69.0)

2 13 (12.5) 14 (13.2) 27 (12.9)

Histology type, n (%)

Adenocarcinoma 64 (61.5) 68 (64.2) 132 (62.9)

Squamous 25 (24.0) 18 (17.0) 43 (20.5)

Large cell 9 (8.7) 9 (8.5) 18 (8.6)

Undifferentiated 3 (2.9) 8 (7.5) 11 (5.2)

Squamous and adenocarcinoma 3 (2.9) 3 (2.8) 6 (2.9)

Interval from diagnosis (months)

Median/mean (months) 12.2/17.2 11.7/14.6 12.1/15.9

Minimum (months) 0.1 2.3 0.1

Maximum (months) 125 59.5 125

Current disease status, n (%)

Locally advanced 25 (24.0) 20 (18.9) 45 (21.4)

Metastatic 79 (76.0) 86 (81.1) 165 (78.6)

6.3.6.2 Objective Response Rate

 

Table 24: Objective response rate ITT population:

Best tumor response 250 mg ZD1839 500 mg ZD1839 Total

N=103 N=106 N= 209

Complete response [n, (%)] 0 l (l.0) 1 (0.5)

Partial response [n, (%)] 19 (18.4) 19 (18.2) 38 (18.2)

6.3.6.3 Responder Characteristics

Tables 25 and 26 summarizes disease status of the 39 responding patients.

 

 

Table 25: Responder characteristics – Trial 16

CEN

TER

STAGE

MOs

DIAG

PT

DOSE

HISTOL

T Stage

N

M

PS

SEX

ORIGIN

AGE

0712

0002

500

Adeno

3

0

1

1

F

Cauc

60

7.8

0259

0001

250

Adeno

3

2

0

1

F

Cauc

59

15.6

0415

0004

250

Squam

4

2

0

0

M

Cauc

61

21.7

0415

0006

500

Ad&Sq

4

3

1

1

M

Cauc

70

17.3

0416

0006

500

Adeno

4

0

1

1

F

Cauc

68

15.3

0601

0001

500

Adeno

4

0

1

1

M

Cauc

59

12.7

0601

0002

500

Adeno

4

0

1

1

F

Cauc

54

18.6

0601

0004

250

Adeno

4

0

1

1

F

Cauc

52

8.3

0601

0007

250

Adeno

0

3

1

0

M

Cauc

59

4.1

0916

0006

500

Undiff

4

2

1

1

M

Cauc

69

15.4

0111

0001

250

Adeno

0

3

1

0

F

Cauc

74

84.6

0804

0003

250

Adeno

2

0

1

0

F

Japan

59

10.1

0804

0001

500

Adeno

4

0

1

1

F

Japan

59

14.4

0803

0003

500

Adeno

3

2

1

0

M

Japan

71

11.3

0802

0001

250

Adeno

3

2

1

1

M

Japan

67

1.8

0801

0004

250

Squam

4

0

1

1

F

Japan

74

6.2

0801

0003

250

Adeno

4

0

1

1

F

Japan

61

15.4

0800

0001

500

Adeno

4

2

1

1

F

Japan

57

26.9

0805

0011

250

Adeno

0

0

1

1

M

Japan

59

ND

0800

0003

250

Adeno

0

0

1

1

M

Japan

56

28.1

0815

0007

250

Adeno

2

0

1

1

F

Japan

70

12.2

0822

0004

250

Adeno

4

2

0

1

M

Japan

53

13.8

0821

0003

500

Adeno

4

2

1

1

F

Japan

51

18.1

0821

0002

500

Adeno

4

3

1

1

M

Japan

37

7.6 6164383561644

0819

0009

250

Adeno

2

0

1

1

M

Japan

61

1.9

0819

0008

500

Adeno

4

0

0

0

M

Japan

52

15.9

0819

0007

500

Adeno

4

3

1

1

M

Japan

58

7.5

0819

0006

500

Adeno

4

2

0

1

M

Japan

40

3.7

0804

0005

250

Adeno

4

1

1

1

F

Japan

54

9.3

0818

0002

500

Adeno

4

2

1

1

F

Japan

55

17.4

0805

0009

250

Adeno

4

3

1

1

F

Japan

67

16.8

0815

0005

250

Adeno

0

2

1

1

M

Japan

28

ND

0815

0002

250

Adeno

0

0

1

1

M

Japan

60

54.0

0814

0012

250

Adeno

2

2

1

2

M

Japan

69

16.4

0814

0003

500

Adeno

4

3

1

1

F

Japan

61

11.0

0813

0002

500

Adeno

4

2

1

1

F

Japan

57

21.8

0807

0004

500

Squam

2

2

1

0

F

Japan

63

8.2

0807

0001

500

Adeno

4

0

0

1

F

Japan

64

ND

0818

0003

500

Adeno

4

3

1

1

F

Japan

74

23.0

ND = no data

 

Table 26: Summary of Responder Characteristics

Characteristic

n (%)

Age

Median

Range

59

28 - 74

Sex

Male

Female

18 (46.2)

21 (53.8)

Origin

Caucasian

Japanese

11 (28.2)

28 (71.8)

ZD1839 Dose

250 mg

500 mg

19 (48.7)

20 (51.3)

Histology

Adencarcinoma

Adenocarcinoma+squamous cell

Squamous cell

Undifferentiated

34 (87.2)

1 (2.5)

3 (7.7)

1 (2.5)

Performance Status

0

1

2

7 (17.9)

31 (79.5)

1 (2.6)

Stage

M0

M1

5 (12.8)

34 (87.2)

Months from diagnosis

Median

Range

14.9

1.8 - 84.6

 

6.3.6.3 Chemotherapy Sensitivity/Resistance of Responding Patients

Responder resistance/sensitivity to prior chemotherapy is summarized in Table 27. Twenty-nine of the 39 responders had not progressed on any prior chemotherapy treatment.

 

 

 

 

 

 

 

Table 27: All Responders - Prior chemotherapy and outcome

Prior chemotherapy

N (%)

Number of Prior chemotherapy regimens

1

2

21 (53.8)

18 (46.2)

Progression on first-line chemotherapy

6 (15.4)

Progression on second-line chemotherapy only

3 (7.7)

Progression on both 1st & 2nd line chemotherapy

1 (2.5)

No progression on chemotherapy

29 (74.4)

Two episodes of progression were not included in this table. One patient 804/03 was recorded as having progressed on second line treatment on the day of treatment and a second patient 819/06 was deemed to have progressive disease one day after first-line treatment. Among the responding patients that had progressed on prior chemotherapy there were 2 Caucasians and 8 Japanese, including the one patient 805/11 who progressed on both first- and second-line treatment..

Table 28 summarizes the number of measurable lesions for 38 of 39 patients with measurable lesions who had an objective tumor response. As indicated the majority of responding metastatic disease patients had only one or two lesions that were measured. Baseline total area of measurable lesions was less than 10 cm2 in 3 of 11 Caucasian patients and 11 of 21 Japanese patients who had measurable lesions and who responded to therapy. Baseline total area of measurable disease was <5 cm2 in 6 Japanese patients and no Caucasian patients

 

Table 28: Number of measurable lesions evaluated in responding patients

Measurable lesions (n)

Responding patients (n)

0

1

1

16

2

12

3

5

4

3

6

1

8

1

Table 29 demonstrates site(s) of measurable and non-measurable disease for the 39 responding patients. Nineteen responders had lung only disease (primary tumor site with or without contralateral lung involvement. The second most common sites of involvement were lung plus regional lymph node disease (6 patients).

 

 

Table 29: Sites of Measurable/Evaluable Disease

Measurable and non-measurable tumor location

Responding patients (n=39)

Lung only

19

Lung + nodes

6

Lung + nodes + adrenal

1

Lung + nodes + liver

1

Lung + nodes + bone

2

Lung + bone

4

Lung + bone + liver

1

Lung + liver

1

Lung + subcutaneous

1

Nodes only

2

Nodes + adrenal + liver

1

6.3.7 Reviewer Efficacy Conclusions Trials 39 and 16

There are several bothersome issues raised by the Iressa efficacy review. These are listed below.

  1. Study eligibility –
  2. Accelerated approval requires an improvement over available therapy. In advanced/ metastatic NSCLC the clinical setting where there is no "available therapy" is third-line chemotherapy. Therefore, Trial 39 eligible patients must have received at least two prior chemotherapy regimens including a platinum agent and docetaxel administered either concurrently or sequentially. Prior regimens must have failed due either to progression while on therapy or because of treatment intolerance. Only 139 of 216 trial 39 study patients (64%) met these eligibility criteria. Eleven patients (5%) were platinum refractory/intolerant but taxotere sensitive, 58 patients (27%) were taxotere refractory/intolerant but platinum sensitive, and 8 (4%) were not refractory/intolerant to either drug.

    Trial 16 did not address an unmet medical need and it is, therefore, only a supporting study. In Trial 16 eligible patients must have received one or a maximum of two prior chemotherapy regimens one of which must have included platinum. They must also have recurrent or refractory disease, both presumably indicating the presence of chemotherapy resistant disease. In fact, however, only 35% of study patients were chemotherapy resistant having progressed on either first- or second-line chemotherapy. Sixty-five percent of study patients had not progressed on prior therapy.

    Based on the refractoriness to prior chemotherapy patients in Trial 16 constituted a more favorable group that might be expected to have higher objective response rates than patients in trial 39 (see paragraph 4).

  3. Study patient characteristics
  4. As might be expected from the treatment eligibility requirements of trial 39, the enrolled study population, i.e. (locally advanced or metastatic disease patients who have failed platinum, docetaxel and other chemotherapy and who have a performance status of 0 to 2) is not typical of a population of newly diagnosed NSCLC patients of similar stage and performance status. The latter population might be expected to have a median survival of 6 to 9 months if stage IV at diagnosis and 16 to 18 months if stage III at diagnosis. Patients enrolled in this study have survived for a considerably longer time (48% of patients surviving more than 2 years from initial diagnosis to study randomization). Striking, also, is the percent of study patients with adenocarcinoma alone or mixed with squamous cell carcinoma (73.6%). This is expected as adenocarcinoma has the slowest tumor doubling time of all lung cancer histologies. Thus slow growing tumors that produced few to modest systemic effects were selected. It is uncertain as to whether patient symptomatology was primarily due to tumor or to comorbid illness.

    Trial 16 patients, like trial 39 patients, had a relatively long time from initial diagnosis to study randomization (median 12.1 months; mean 15.9 months) and also had a high percentage of adenocarcinoma alone (63%) or with other histologies (3%).

  5. Treatment response
  6. Based on response criteria, a patient who had measurable disease, with or without non-measurable but evaluable disease or non-measurable/non-evaluable disease, could not be declared a responder unless there was >50% decrease in the sum of the area of measurable lesions. Since the large majority of patients enrolled in both trials had stage IV disease it might be expected that patients would have multiple sites of disease and, therefore, multiple measurable lesions. That was not the case. Among the 18 responding patients in trial 39 who had measurable disease (4 responders having evaluable but non-measurable disease), 5 patients had only a single lesion measured and 6 had two lesions measured. Similarly, in Trial 16, among the 38 responding patients with measurable lesions, 16 patients had only a single lesion measured and 12 had two lesions measured. As smaller lesions are more likely to respond to chemotherapy than larger lesions, if for no other reason then measurement error, it was of interest to look at the sum of the areas of measurable lesions in responders. In trial 39, the baseline total tumor area of the measurable lesions was less than 10 cm2 in 5 of 18 responders. In trial 16 baseline total area of measurable lesions was less than 10 cm2 in 3 of 11 Caucasian patients and 11 of 21 Japanese patients who had measurable lesions and who responded to therapy. Baseline total area of measurable disease was <5 cm2 in 6 Japanese patients and no Caucasian patients. In Trial 39 the site of the measurable lesion in patients with only one measurable tumor was lung in 4 patients and liver in one patient. The site of the measurable lesion in patients with two measurable tumors was lung only in 2 patients, lung and liver in 2 patients, lung and lymph node in 1 patient and liver only in 1 patient. In Trial 16 nineteen responders had lung only disease (primary tumor site with or without contralateral lung involvement. The second most common sites of involvement were lung plus regional lymph node disease (6 patients).

  7. Response rate

A widely accepted medical oncology principle is that for each chemotherapy regimen failed the probability of responding to a subsequent regimen decreases and responses are of shorter duration. If one accepts this premise then it is to be expected that the Iressa response rate in Trial 39 patients who are refractory to two or more prior chemotherapy regimens should be lower than the response rate of patients who have failed less than two regimens. This was not the case. Response rates of both groups were approximately 10%. The constancy of response rates in patients progressing on two or more chemotherapy regimens, patients progressing on one regimen and patients not refractory to any chemotherapy is of concern.

  1. Integrated Review of Safety

7.1 Brief Statement of Conclusions

ZD1839 was generally well tolerated at both doses. However, fewer patients on the 250-mg/day dose experienced Grade 3 or 4 drug-related adverse events or withdrew due to drug-related adverse events. There were fewer drug interruptions due to adverse events in the 250-mg/day group. Dose reductions due to toxicity occurred in 1.0% of patients at the 250-mg dose versus 8.8% of patients at the 500-mg dose group.

Drug-related adverse events experienced by at least 10% of patients in the 250-mg/day group were diarrhea, rash, acne, dry skin, nausea, and vomiting. There was no evidence of cumulative toxicity, and the majority of drug-related adverse events were reversible.

In study 16, similar to study 39, ZD1839 was generally well tolerated at both doses. However, fewer patients on the 250-mg/day dose experienced Grade 3 or 4 drug-related adverse events or withdrew due to drug-related adverse events. Drug-related adverse events experienced by at least 10% of patients in the 250-mg/day group were rash, diarrhea, pruritus, dry skin, nausea, acne, SGPT/ALT increased, and SGOT/AST increased. There was no evidence of cumulative toxicity, and the majority of drug-related adverse events were reversible.

    1. Patient Exposure
    2. In the Phase II trials, 425 patients were exposed to ZD1839 (216 patients in Trial 0039, and 209 patients in Trial 0016). The majority of patients in both trials received ZD1839 for >1 month, with approximately one-third receiving ZD1839 for >3 months. Duration of exposure in Trials 0039 and 0016 is summarized in Table 30.Thirty-one patients (15.1%) who received ZD1839 250 mg daily had an interruption in therapy, and 1 patient (0.5%) had a dose reduction due to toxicity. This compares to 56 (25.5%) and 21 (9.5%) patients, respectively, who received ZD1839 500 mg daily (Table 31).

      In the Phase I multiple-dose trials, 270 patients were exposed to a range of doses of ZD1839 from 50 to 1000 mg daily. Nearly half the patients (46.7%) received ZD1839 for >1 month, with 47 patients (17.4%) receiving ZD1839 for >3 months. Nineteen (7.0%) patients had dose reductions due to toxicity; all occurred at doses >=300 mg/day, with 14 occurring in the 72 patients who received doses >=600 mg/day.

       

      Table 30: Duration on trial and duration of treatment

      Category Trial 0039 Trial 0016

      250 mg 500 mg 250 mg 500 mg

      (n=102) (n=114) (n=103) (n=106)

      Number of days on trial a

      Mean (standard deviation) 75.7(53.0) 69.5(49.9) 87.0(53.9) 86.9(57.9)

      Maximum 232 232 229 219

      Number of days on treatment b

      Mean (standard deviation) 72.6(51.9) 62.7(47.3) 85.1 (54.2) 81.5(56.5)

      Maximum 213 232 227 219

      Number of months on treatment (number [%] of patients)

      <1 month 41 (40.2) 38(33.3) 19(18.4) 27(25.5)

      1 to 3 months 24(23.5) 41 (36.0) 46(44.7) 39(36.8)

      >3 to 6 months 36(35.3) 34(29.8) 34(33.0) 33 (31.1)

      >6 to 8 months 1 (1.0) 1(0.9) 4(3.9) 7(6.6)

      a date of last dose minus date of first dose plus 1, ignoring any dose interruptions.

      b days of drug exposure: time from first dose to last dose minus the number of days off treatment. If a patient withdrew at the end of a treatment interruption his/her exposure would be underestimated by the length of the final interruption.

      FDA comment: Duration of treatment confirmed using dataset THR1639.

       

       

      Table 31: Patients with therapy interruptions or dose reductions due to toxicity

      Category Number (%) of patients

      Pivotal Trial 0039 Supportive Trial 0016

      250 mg 500 mg 250 mg 500 mg

      (n= 102) (n= 114) (n= 103) (n=106)

      Therapy interruption 15(14.7) 26(22.8) 16(15.5) 30(28.3)

      Dose reduction 1 (1.0) 10(8.8) 0(0.0) 11(10.4)

      In both trials, the proportion of patients who had interruptions in therapy was lower in the 250mg/day group than in the 500-mg/day group. These interruptions were spread throughout the treatment periods with the highest number occurring during the first 28 days. The main reasons for interrupting therapy were skin reactions and GI disturbances.

      Across the 2 trials, there was only 1 (0.5%) dose reduction in the 250-mg/day group compared to 21 (9.5%) in the 500-mg/day group. The occurrence of these dose reductions in the patient population was distributed throughout the treatment periods and was frequently associated with skin reactions and GI disturbances.

      FDA comment: Dose reductions and delays in drug treatment are confirmed using dataset THR1639.

      Phase I trials: patients with solid tumors

      The exposure of patients with solid tumors to ZD1839 in the Phase I multiple-dose trials is presented in Table 32.

      Table 32: ZD1839 Exposure in Phase I multiple-dose trials

      Exposure Trial

      0005 0011 0012 0038 V-15-11

      (n=64) (n=69) (n=88) (n=18) (n=31)

      Total days of dosing

      Total 2241 6808 6239 458 a 1048

      Mean 35.0 98.7 70.9 25.4 33.8

      Median 28b 56 43 28 14

      Minimum 1 1 5 7 2

      Maximum 205a 506 458 28 182c

      a Only includes data collected for the first 28-day treatment period.

      b Because of the dosing schedule in Trial 0005 (ie, 14 days with drug, 14 days without), 28 days is equivalent to 2 months on trial, and 205 days is equivalent to 14 months on trial.

      c Because of the dosing schedule in Trial V-15-11 (ie, 14 days with drug, 14 days without), 182 days is equivalent to 13 months on trial.

       

      The exposure of patients to ZD1839 within these dose categories is presented in Table 33.

      Table 33: Exposure to ZD1839 in the Phase I trials, by dose category

      Exposure ZD1839 dose category

      <225 mg 250 mg a 500 mg b >525 mg

      (n=51) (n=75) (n=72) (n=72)

      Total days of dosing

      Total 2356 5776 3883 4780

      Mean 46.2 77.0 53.9 66.4

      Minimum 1 1 7 5

      Maximum 458 506 404 395

      Number of months on Rx

      (number [%] of patients)

      <1 month 38(74.5) 31(41.3) 41(56.9) 34(47.2)

      1 to 3 months 10(19.6) 28(37.3) 19(26.4) 22(30.6)

      >3 to 6 months 1(2.0) 8(10.7) 9(12.5) 10(13.9)

      >6 months 2(3.9) 8(10.7) 3(4.2) 6(8.3)

      a Including doses between 225 mg and 300 mg, inclusive.

      b Including doses between 400 mg and 525 mg, inclusive.

      In Trial 0035, nineteen patients received a single 50 mg iv dose of ZDI 839, and 17 of these patients also received a single 250 mg oral dose of ZD1839.

      Dose reductions

      None of the 95 patients in Trials 0005 and V-15-11 (16 of whom received 525 mg/day ZD1839, and 15 of whom received 700 mg/day ZD1839) had a dose reduction.

      In Trial 0011, a total of seven (10.1%) patients had a dose reduction attributed to drug-related adverse events; treatment in 6 of these patients was also interrupted because of toxicity. All reductions or interruptions of trial medication occurred in patients assigned to doses of >=600 mg/day.

      In Trial 0012, nine (10.2%) patients had a dose reduction attributed to drug-related adverse events; treatment in all of these patients was also interrupted because of toxicity. All reductions or interruptions of trial medication occurred in patients assigned to doses of at least 300 mg/day; 7 out of 9 dose reductions occurred among the 40 patients who were assigned >600 mg/day.

      In Trial 0038, three (16.7%) patients stopped taking the 500 mg daily dose of ZD1839 due to adverse events. Treatment was interrupted in each case, and all 3 patients subsequently resumed ZD1839 treatment at the lower dose of 250 mg daily.

      FDA Comment: Data on drug exposure, dose reductions and dose delays was confirmed in Section 5 of the sponsor safety report of each individual study. Specific datasets containing this data were not provided.

    3. Safety Review Methods and Findings

Sponsor safety data bases for study 39 9AE, AE FLGS, LAB, LAB 1096, LAB 1097, LABS, RS01409, RS01438, RS01438a, S00103, S01363, and for study 16 ADVERSE, ECG, LAB01096, LAB01097, RS01438, S01949, S01963,S01964, S01965, S01966, SCHIRMER, SKINCHAR, TRANSAM.

FDA Comment: In the analysis of AE’s the sponsor’s convention of not counting an AE if it was present before the start of treatment (irrespective of how long it persisted after the start of treatment was followed. While this was an arbitrary decision any other method for counting AE’s would be equally arbitrary.

7.3.1 Overview of adverse events

An overview of adverse events occurring in Trial 0039, by the dose of ZD1839 received at trial entry, is summarized in Table 34.

Table 34: Overview of adverse events in Trial 0039

Category Number (%) of patients

250 mg/day 500 mg/day

(n=102) (n=114)

All adverse events 101 (99.0) 112(98.2)

drug related 74(72.5) 97(85.1)

Deaths

due to adverse event(s) 6(5.9) 5(4.4)

due to drug-related adverse event(s) 0(0.0) 1 (0.9)

Withdrawals

due to adverse event(s) 4(3.9) 11 (9.6)

due to drug-related adverse event(s) 1(1.0) 5(4.4)

due to serious adverse event(s) 4(3.9) 8(7.0)

due to drug-related serious adverse 1(1.0) 1(0.9)

event(s)

Serious adverse events 28(27.5) 27(23.7)

drug-related 4(3.9) 5(4.4)

CTC Grade 3 or 4 adverse events 41 (40.2) 53(46.5)

drug related 7(6.9) 20(17.5)

 

The most frequent adverse events experienced by >=25% of patients receiving ZD1839 250 mg/day were diarrhea (56.9%), rash (48.0%), asthenia (28.4%), dyspnea (28.4%), nausea (26.5%), and acne (25.5%). Some adverse events, most notably diarrhea, rash, asthenia, acne, and dry skin, occurred less frequently in patients receiving ZD1839 250 mg/day than patients receiving 500 mg/day. Those adverse events with an incidence of >=10% in either dose group are presented in Table 35.

Table 35: Adverse events with an incidence of >=10% in Trial 39

Adverse event Number of patients

250 mg/day 500 mg/day

(n=102) (n=114)

Diarrhea 58 (56.9) 85 (74.6)

Rash 49 (48.0) 63 (55.3)

Asthenia 29 (28.4) 41 (36.0)

Dyspnea 29 (28.4) 26 (22.8)

Nausea 27 (26.5) 31 (27.2)

Acne 26 (25.5) 38 (33.3)

Anorexia 24 (23.5) 31 (27.2)

Pain 23 (22.5) 15 (13.2)

Cough increased 22 (21.6) 23 (20.2)

Vomiting 22 (21.6) 21 (18.4)

Dry skin 17 (16.7) 30 (26.3)

Peripheral edema 15 (14.7) 11 (9.6)

Chest pain 14 (13.7) 15 (13.2)

Back pain 14 (13.7) 13 (11.4)

Constipation 13 (12.7) 8 (7.0)

Weight loss 12 (11.8) 12 (10.5)

Pharyngitis 11(10.8) 16 (14.0)

Pruritus 11 (10.8) 10 (8.8)

Sinusitis 11 (10.8) 4 (3.5)

Abdominal pain 10 (9.8) 14 (12.3)

Fever 8 (7.8) 12 (10.5)

Dehydration 5 (4.9) 13 (11.4)

Drug-related adverse events with an incidence of >=5% in either dose group are presented in Table 36.

The most frequent drug-related adverse events experienced by >=10% of patients receiving ZD1839 250 mg/day were diarrhea (48.0%), rash (43.1%), acne (24.5%), dry skin (12.7%), nausea (12.7%), and vomiting (11.8%). With the exception of vomiting, the incidence of these events was lower at the 250-mg/day dose than at the 500-mg/day dose.

The majority of patients receiving ZD1839 250 mg/day who experienced drug-related adverse events had events that were CTC Grades 1 or 2 (67 out of 74 patients; 90.5%). Drug-related adverse events generally occurred for the first time in Treatment Periods 1 or 2, and the safety profile of ZD1839 did not appear to change with chronic dosing (up to a maximum of nearly 8 months of treatment).

Table 36: Drug-related adverse events with an incidence of >=5% in trial 39

Drug-related adverse event Number of patients

(COSTART term)' 250 mg/day 500 mg/day

(n=102) (n=l 14)

Diarrhea 49 (48.0) 76 (66.7)

Rash 44 (43.1) 61 (53.5)

Acne 25 (24.5) 37 (32.5)

Dry skin 13 (12.7) 30 (26.3)

Nausea 13 (12.7) 20 (17.5)

Vomiting 12 (11.8) 10 (8.8)

Pruritus 8 (7.8) 10 (8.8)

Anorexia 7 (6.9) 11 (9.6)

Asthenia 6 (5.9) 5 (4.4)

Weight loss 3 (2.9) 6 (5.3)

' A patient may have had more than 1 adverse event.

COSTART Coding Symbols for Thesaurus of Adverse Reaction Terms.

Adverse events with CTC Grades 3 or 4

Thirteen (12.7%) patients on ZD1839 250-mg/day had CTC Grade 4 adverse events compared to 20 (17.5%) on the 500-mg/day dose. Two (2.0%) patients at the 250-mg/day dose had Grade 4 adverse events that were considered drug related (asthenia and thrombocytopenia) compared to 3 (2.6%) at the 500-mg/day dose (dehydration, lung hemorrhage, and ALT/SGPT increased).

Twenty-eight (27.5%) patients at the 250-mg/day dose had CTC Grade 3 adverse events compared to 33 (28.9%) on the 500-mg/day dose. Five (4.9%) patients at the 250-mg/day dose had Grade 3 adverse events that were considered drug related compared to 17 (14.9%) at the 500-mg/day dose.

Diarrhea and acne were the only drug-related adverse events of CTC Grade 3 or 4 severity with an incidence of ~3% in either dose group (see Table 37).

Table 37: Drug-related adverse events of CTC Grade 3 or 4 in trial 39

Adverse event Number (%) of patients

and CTC grade 250 mg/day 500 mg/day

(n=102) (n=1 14)

Asthenia

Grade 3 1(1.0) 1 (0.9)

Grade 4 1(1.0) 0(0.0)

Diarrhea, Grade 3 1(1.0) 6(5.3)

Gastrointestinal disorder,

Grade 3 0(0.0) 1(0.9)

Nausea, Grade 3 l(l.0) 1 (0.9)

Rectal disorder, Grade 3 1(1.0) 0(0.0)

Vomiting, Grade 3 1(1.0) 3(2.6)

Thrombocytopenia, Grade 4 1(1.0) 0(0.0)

Dehydration

Grade 3 0(0.0) 2(l.8)

Grade 4 0(0.0) 1(0.9)

Peripheral edema, Grade 3 1(1.0) 0(0.0)

AST/SGOT increased,

Grade 3 0(0.0) 2(l.8)

ALT/SGPT increased

Grade 3 0(0.0) 1 (0.9)

Grade 4 0(0.0) 1 (0.9)

Dyspnea, Grade 3 1(1.0) 0(0.0)

Epistaxis, Grade 3 1(1.0) 0(0.0)

Lung hemorrhage, Grade 4 0(0.0) 1 (0.9)

Acne, Grade 3 0(0.0) 4(3.5)

Pruritus, Grade 3 0(0.0) 1 (0.9)

Rash, Grade 3 0(0.0) 3(2.6)

Scrotal edema, Grade 3 1(1.0) 0(0.0)

Deaths

The number (%) of patients who died during Trial 0039, and the primary cause of death (disease related or adverse event), are summarized in Table 38.

 

 

 

 

 

 

 

Table 38: Deaths during or 30 days post treatment in trial 39

Category Number (%) of patients a

250 mg/day 500 mg/day

(n= 102) (n=1 14)

Patients who died 22(21.6) 27(23.7)

Patients whose death was

considered cancer related a 21 (20.6) 26(22.8)

Patients who had an adverse event

that resulted in death 6(5.9) 5(4.4)

a Death reported as cancer related by the investigator. Includes 9 patients who also had an adverse event with an outcome of death.

For the 11 patients who had an adverse event that resulted in death the death was considered cancer related by the investigator for 9 out of 11 of these patients. The remaining 2 patients (2107/0034 and 2107/0035) died of cardiovascular events (arrhythmia and acute myocardial infarction, respectively); both had a history of cardiovascular disease. Only 1 patient (2107/0145; 500 mg/day group) had an adverse event (lung hemorrhage) that led to death that was considered possibly related to ZD1839 by the investigator. This patient's death was also reported as cancer related.

Adverse events leading to withdrawal

The incidence of withdrawals from ZD1839 treatment due to adverse events was lower in the 250-mg/day group (3.9%) than in the 500-mg/day group (9.6%).

One patient (1.0%) in the 250-mg/day group, and 5 patients (4.4%) in the 500-mg/day group, were withdrawn due to adverse events that were considered to be possibly drug related by the investigator. The identification of these patients is presented in Table 39. The only drug-related adverse events that led to withdrawal in more than 1 patient were diarrhea, acne, and rash (2 patients each).

 

 

 

 

 

 

 

 

 

Table 39: Patients who withdrew due to drug-related adverse events in trial 39

Center/patient Tumor type Adverse Serious CTC grade Outcome Days on

number event (yes/no) treatment

250-mg/day group

2255/0302 Adenocarcinoma Asthenia Yes 4 Ongoing 140 a

500-mg/day group

2044/0182 Squamous Acne No 3 Recovered 71

Rash No 3 Ongoing

2102/0071 Adenocarcinoma Acne No 3 Ongoing 92

2107/0035 Adenocarcinoma Diarrhea No I Ongoing 63

2107/0145 Squamous and Lung Yes 4 Died 11 b

adenocarcinoma hemorrhage

2251/0063 Adenocarcinoma Abd. pain No I Recovered 14

Headache No I Recovered

Diarrhea No I Recovered

Epistaxis No I Recovered

Pruritus No 2 Recovered

Rash No 2 Recovered

a Reported term progressive neurologic deterioration. Onset of the event occurred on Day 85; the duration of treatment is based on the date of the last dose at the time of data cutoff.

b Onset of the event (patient began coughing up blood) occurred on Day 3; the patient was withdrawn and subsequently died on Day 11.

Eleven patients withdrew because of adverse events that were not considered drug related (including 2 patients who also had drug-related adverse events that led to withdrawal). Among the 11 patients, the only events that led to withdrawal in more than 1 patient were pneumonia (4 patients), dyspnea (3 patients), and apnea (2 patients).

Serious adverse events

Twenty-eight patients (27.5%) at the 250-mg/day dose had at least 1 serious adverse event compared to 27 (23.7%) at the 500-mg/day dose. Of these patients, 4 at the 250-mg/day dose, and 5 at the 500-mg/day dose, had drug-related serious adverse events. Dehydration and asthenia were the only drug-related serious adverse events reported by more than 1 patient.

Identification of patients with drug-related serious adverse events is presented in Table 40.

 

 

 

 

 

Table 40: Patients who had drug-related serious adverse events in trial 39

Center/ Tumor type Adverse event CTC Outcome Withdrawn Days on

patient description grade because of the treatment at

event (yes/no) at time of event

event

250-mg/day group

2064/0077 Adenocarcinoma Rectal disorder 3 Recovered No 115

Thrombocytopenia 4 Recovered No 114

Epistaxis 3 Recovered No 115

2118/0172 Squamous and Asthenia 3 Ongoing No 18

adenocarcinorna

2251/0066 Adenocarcinoma Peripheral edema 3 Recovered No 91

Scrotal edema 3 Ongoing No 91

2255/0302 Adenocarcinoma Asthenia 4 Ongoing Yes 85

500-mg/day group

2090/0047 Adenocarcinoma. Dehydration 4 Ongoing No 1 day post trt

2090/0220 Adenocarcinoma. Increased AST/SGOT 3 Recovered No 65

Increased ALT/SGPT 4 Recovered No 65

2107/0145 Squamous and Lung hemorrhage 4 Died Yes 3

adenocarcinoma

2251/0064 Adenocarcinoma Dehydration 3 Recovered No 23

2252/0274 Adenocarcinoma Nausea 3 Ongoing No 81

Vomiting 3 Ongoing No 81

Dehydration 3 Ongoing No 81

Phase II Supportive Trial 0016

An overview of adverse events occurring in Trial 0016 is summarized in Table 41. Adverse events are reported by the dose of ZD1839 assigned at trial entry.

Table 41: Overview of adverse events in trial 16

Category Number of patients

250 mg/day 500 mg/day

(n=103) (n=106)

All adverse events 101(98.1) 106(100)

drug related 88(85.4) 102(96.2)

Deaths

due to adverse event(s) 4(3.9) 1 (0.9)

due to drug-relatcd adverse event(s) 0(0.0) 1 (0.9)

Withdrawals

due to adverse event(s) 7(6.8) 12(11.3)

due to drug-related adverse event(s) 2(l.9) 10(9.4)

due to serious adverse event(s) 6(5.8) 6(5.7)

due to drug-related serious adverse event(s) 1(1.0) 4(3.8)

Serious adverse events 21(20.4) 27(25.5)

drug-related 3(2.9) 12 (11.3)

CTC Grade 3 or 4 adverse events 33(32.0) 54(50.9)

drug related 9(8.7) 32(30.2)

Nearly all patients (99.0%) in Trial 16 had at least 1 adverse event. Those adverse events with an incidence of >=10% in either dose group are presented in Table 42.

 

Table 42: Adverse events with an overall incidence >=10% in trial 16

Adverse event Number of patients

250 mg/day 500 mg/day

(n=103) (n=106)

Diarrhea 50(48.5) 71(67.0)

Rash 49(47.6) 74(69.8)

Pruritus 32(31.1) 39(36.8)

Dry skin 30(29.1) 31 (29.2)

Asthenia 26(25.2) 23(21.7)

Nausea 25(24.3) 37(34.9)

Pharyngitis 19(18.4) 25(23.6)

Anorexia 18(17.5) 30(28.3)

ALT/SGPT increased 17(16.5) 26(24.5)

Vomiting 16(15.5) 34(32.1)

AST/SGOT increased 16(15.5) 24(22.6)

Dyspnea 16(15.5) 15(14.2)

Pain 13(12.6) 27(25.5)

Acne 13(12.6) 17(16.0)

Constipation 12(11.7) 14(13.2)

Cough increased 11 (10.7) 13 (12.3)

Weight loss 10(9.7) 17(16.0)

Abdominal pain 10(9.7) 14(13.2)

Conjunctivitis 9(8.7) 13 (12.3)

Stomatitis 9(8.7) 12(11.3)

Fever 8(7.8) 21 (19.8)

Rhinitis 7(6.8) 13(12.3)

Hernaturia 7(6.8) 11(10.4)

Epistaxis 5(4.9) 19(I7.9)

Drug-related adverse events in Trial 0016 with an overall incidence of >=5% are presented in Table 43. The majority of patients receiving ZD1839 250 mg/day who experienced drug-related events had events that were CTC Grades 1 or 2 (79 out of 88 patients; 89.8%). Drug-related adverse events generally occurred for the first time in Treatment Period 1, and the safety profile of ZD1839 did not appear to change with chronic dosing (up to a maximum of nearly 8 months of treatment).

 

 

 

 

 

 

 

Table 43: Drug-related adverse events >=5% in trial 16

Drug-related adverse event Number of patients

250 mg/day 500 mg/day

(n= 103) (n=106)

Rash 48(46.6) 73(68.9)

Diarrhea 41 (39.8) 61 (57.5)

Pruritus 31 (30.1) 38(35.8)

Dry skin 28(27.2) 31 (29.2)

Nausea 13(12.6) 25(23.6)

ALT/SGPT increased 13(12.6) 25(23.6)

Acne 13(12.6) 15(14.2)

AST/SGOT increased 11(10.7) 24(22.6)

Pain 10(9.7) 17(16.0)

Anorexia 9(8.7) 20(18.9)

Asthenia 8(7.8) 11 (10.4)

Exfoliative dermatitis 8(7.8) 9(8.5)

Stomatitis 8(7.8) 8(7.5)

Vomiting 6(5.8) 21 (19.8)

Hernaturia 6(5.8) 5(4.7)

Seborrhea 6(5.8) 4(3.8)

Blepharitis 5(4.9) 6(5.7)

Conjunctivitis 4(3.9) 10(9.4)

Nail disorder 4(3.9) 9(8.5)

Abdominal pain 3(2.9) 8(7.5)

Epistaxis 2(l.9) 12(11.3)

Weight loss 2(l.9) 6(5.7)

' A patient may have had more than 1adverse event.

Adverse events with CTC Grades 3 or 4

Twelve (11.7%) patients at the 250-mg/day dose had CTC Grade 4 adverse events compared to 12 (11.4%) at the 500-mg/day dose. No drug-related CTC Grade 4 events were reported in the 250-mg/day group. Six patients (5.7%) had drug-related CTC Grade 4 adverse events in the 500-mg/day group.

Twenty-one (20.4%) patients at the 250-mg/day dose had CTC Grade 3 adverse events compared to 42 (39.6%) at the 500-mg/day dose. Eight (7.8%) patients at the 250-mg/day dose had drug related CTC Grade 3 events compared to 24 (22.6%) at the 500-mg/day dose.

Diarrhea, ALT/SGPT increased, and rash were the only drug-related adverse events of CTC Grade 3 or 4 severity with an incidence ~3% in either dose group (see Table 44).

 

Table 44: Drug-related adverse events of CTC Grade 3 or 4 in trial 16

Adverse event Number of patients

and CTC grade 250 mg/day 500 mg/day

(n=103) (n=106)

Asthenia, Grade 3 0(0.0) 1 (0.9)

Shock, Grade 4 0(0.0) 1 (0.9)

Atrial fibrillation, Grade 3 1(1.0) 0(0.0)

Bundle branch block, Grade 3 1(1.0) 0(0.0)

Deep thrombophlebitis, Grade 4 0(0.0) 1 (0.9)

Anorexia, Grade 3 0(0.0) 1 (0.9)

Constipation, Grade 3 1(1.0) 0(0.0)

Diarrhea, Grade 3 0(0.0) 7(6.6)

Gastrointestinal hemorrhage, Grade 3 0(0.0) 1 (0.9)

Liver function tests abnormal, Grade 3 0(0.0) 1 (0.9)

Melena, Grade 3 0(0.0) 1 (0.9)

Nausea, Grade 3 1(1.0) 1 (0.9)

Anemia

Grade 3 0(0.0) 1 (0.9)

Grade 4 0(0.0) 2 (l.9)

Alkaline phosphatase increased, Grade 3 1(1.0) 0(0.0)

Dehydration, Grade 3 1(1.0) 0(0.0)

Hypoproteinemia, Grade 3 0(0.0) 1 (0.9)

AST/SGOT increased

Grade 3 0(0.0) 2(l.9)

Grade 4 0(0.0) 1 (0.9)

ALT/SGPT increased

Grade 3 2(l.9) 5(4.7)

Grade 4 0(0.0) 1 (0.9)

Dyspnea, Grade 3 0(0.0) 1 (0.9)

Hypoxia, Grade 3 0(0.0) 1 (0.9)

Interstitial pneumonia, Grade 3 0(0.0) 1 (0.9)

Pneumonia

Grade 3 0(0.0) 1 (0.9)

Grade 4 0(0.0) 1 (0.9)

Acne, Grade 3 0(0.0) 2(l.9)

Exfoliative dermatitis, Grade 3 0(0.0) 2(l.9)

Nail disorder, Grade 3 0(0.0) 1 (0.9)

Pruritus, Grade 3 0(0.0) 1 (0.9)

Rash

Grade 3 1 (1.0) 6(5.7)

Grade 4 0(0.0) 1 (0.9)

Seborrhea, Grade 3 1 (1.0) 0(0.0)

 

 

Deaths

Twenty-three (22.3%) patients in the 250-mg/day group died during treatment or post-treatment (ie, within 30 days after the last dose of ZD1839) compared to 12 (11.3%) in the 500-mg/day group. Four (3.9%) patients in the 250-mg/day group had adverse events with an outcome of death. Three of these deaths were considered cancer related. In addition, 1 (0.9%) patient in the 500mg/day group had an adverse event with an outcome of death. None of these 5 deaths associated with adverse events were considered by the investigator to be possibly related to trial medication. However, for 1 patient (0207/0001), the investigator felt unable to assign causality. On review of this case, an AstraZeneca physician assigned a causality of "drug related". This patient was a 62year-old white woman with advanced NSCLC (adenocarcinoma; Stage IV who was assigned to the 500-mg/day dose. Fifty-nine days after starting trial therapy, she had acute respiratory insufficiency: pneumonia and died 2 days after onset. The adverse event was CTC Grade 4.

Adverse events leading to withdrawal

The incidence of withdrawals from ZD1839 treatment due to adverse events was lower in the 250-mg/day group (6.8%) than in the 500-mg/day group (11.3%).

Two patients (1.9%) in the 250-mg/day group, and 10 patients (9.4%) in the 500-mg/day group, were withdrawn due to adverse events that were considered to be possibly drug related by the investigator. The identification of these patients is presented in Table 45. The only drug-related adverse events that led to withdrawal of more than 1 patient were rash, pneumonia, increased ALT/SGPT, and increased AST/SGOT.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Table 45: Patients who withdrew due to drug-related adverse events in Trial 0016

Center/patient Tumor type Adverse event Serious CTC Outcome Days on

number (yes/no) grade treatment

250-mg/day group

0259/0007 Squamous Bundle branch block Yes 3 Ongoing 112

0815/0004 Adenocarcinoma ALT/SGPT increased No 3 Resolved 41

500-mg/day group

0207/0001 Adenocarcinoma Pneumonia Yes 4 Died 59

0259/0002 Adenocarcinoma Diarrhea No 3 Ongoing 2

Nausea No 3 Resolved 2

Vomiting No 2 Ongoing 2

0259/0005 Adenocarcinoma Rash No 1 Ongoing 10

0804/0001 Adenocarcinoma Liver function tests No 3 Ongoing 57

abnormal

0804/0002 Adenocarcinoma Pneumonia Yes 3 Ongoing 87

Hypoxia Yes 3 Resolved 88

0805/0002 Adenocarcinoma Generalized edema Yes 2 Ongoing 24

Hypoproteinernia Yes 3 Ongoing 57

0807/0002 Adenocarcinoma ALT/SGPT increased No 4 Resolved 29

AST/SGOT increased No 4 Resolved 29

0808/0002 Adenocarcinoma Deep thrombophlebitis Yes 4 Ongoing 92

0819/0008 Adenocarcinoma ALT/SGPT increased No 3 Ongoing 29

AST/SGOT increased No 3 Ongoing 43

0820/0003 Squamous Rash No 3 Resolved 7

Serious adverse events

Twenty-one patients (20.4%) at the 250-mg/day dose had at least 1 serious adverse event compared to 27 (25.5%) at the 500-mg/day dose. Of these patients, 3 at the 250-mg/day dose, and 12 at the 500-mg/day dose, had drug-related serious adverse events (Table 46).

 

 

 

 

 

 

 

 

 

 

 

Table 46: Patients who had drug-related serious adverse events in trial 16

Center/patient Tumor type Adverse event CTC Outcome Withdrawn Days on

number grade because of the treatment at

adverse event time of event

(yes/no)

250-mg/day group

0207/0003 Adenocarcinorna Diarrhea 2 Ongoing No 30

0259/0007 Squamous Bundle branch 3 Ongoing Yes 112

block

0601/0009 Adenocarcinoma Dehydration 3 Resolved No 33

500-mg/day group

0111/0003 Adenocarcinoma Asthenia 3 Ongoing No 14

0205/0002 Adenocarcinoma Anemia 4 Ongoing No 26

GI hemorrhage 3 Ongoing No 26

Melena 3 Ongoing No 26

Shock 4 Ongoing No 26

0207/0001 Adenocarcinoma Pneumonia 4 Died Yes 59

025110001 Adenocarcinoma Acne 3 Ongoing No 11

0259/0004 Squamous Nausea 2 Resolved No 1

Vomiting 2 Resolved No 1

0416/0004 Adenocarcitiorna Diarrhea 3 Resolved No 59

0601/0010 Undifferentiated Diarrhea 3 Resolved No 14

0804/0002 Adenocarcinoma Pneumonia 3 Ongoing Yes 87

Hypoxia 3 Resolved Yes 88

0805/0002 Adenocarcinoma Generalized edema 2 Ongoing Yes 24

Anemia 3 Ongoing No 57

Hypoproteinemia 3 Ongoing Yes 57

0808/0001 Large cell Dyspnea 3 Ongoing No 17

Interstitial 3 Resolved No 17

pneumonia

0808/0002 Adenocarcinoma Deep 4 Ongoing Yes 92

thrombophlebitis

0818/0003 Adenocarcinoma Rash 2 Resolved No 32

 

Phase I trials: patients with solid tumors

      1. Overall incidences of adverse events

An overview of adverse events for patients with solid tumors who received ZD 183 9 in the Phase I multiple-dose trials (0005, 0011, 0012, 0038, and V- 15-11) is summarized by dose in Table 47.

 

 

Table 47: Overview of adverse events in the Phase I multiple-dose trials

Category Number (%) of patients a

<225 mg 250 mg b 500 rng c >525 mg All doses

(n=5 1) (n=75) (n=72) (n=72) (n=270)

All adverse events 51 (100) 74(98.7) 72(100) 71 (98.6) 268(99.3)

drug related 28(54.9) 58 (77.3) 65(90.3) 68(94.4) 219(81.1)

Deaths

due to adverse event(s) 2(3.9) 8(10.7) 3(4.2) 1 (1.4) 14(5.2)

due to drug-related adverse event(s) 0(0.0) 0(0.0) 0(0.0) 0(0.0) 0(0.0)

Withdrawals

due to adverse event(s) 5(9.8) 7(9.3) 7(9.7) 19(26.4) 38(14.1)

due to drug-related adverse event(s) 1 (2.0) 2(2.7) 3(4.2) 18(25.0) 24(8.9)

due to serious adverse event(s) 3(5.9) 5(6.7) 4(5.6) 8(11.1) 20(7.4)

due to drug-related serious adverse 0(0.0) 1(1.3) 1 (1.4) 7(9.7) 9(3.3)

Serious adverse events 15(29.4) 22(29.3) 13(18.1) 29(40.3) 79(29.3)

drug-related 1 (2.0) 4(5.3) 1(1.4) 14(19.4) 20(7.4)

CTC Grade 3 or 4 adverse events 22(43.1) 34(45.3) 25(34.7) 37(51.4) 118(43.7)

drug related 1 (2.0) 5(6.7) 7(9.7) 26(36.1) 39(14.4)

a Patients may appear in more than 1 category of adverse event.

b Including doses between 225 mg and 300 mg, inclusive.

c Including doses between 400 mg and 525 mg, inclusive.

 

Adverse events

Nearly all patients (99.3%) in the Phase I multiple-dose trials experienced at least 1 adverse event. Adverse events with an overall incidence >=10% are presented by dose category in Table 48.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Table 48: Adverse events >=10% in the Phase I multiple-dose trials

Adverse event Number (%) of patients a

<225 mg 250 mg b 500mg c >525 mg All doses

(n=51) (n=75) (n=72) (n=72) (n=270)

Diarrhea 18(35.3) 34(45.3) 42(58.3) 58(80.6) 152(56.3)

Rash 14(27.5) 27(36.0) 35(48.6) 45(62.5) 121 (44.8)

Nausea 18(35.3) 19(25.3) 26(36.1) 32(44.4) 95(35.2)

Asthenia 13(25.5) 26(34.7) 23 (31.9) 26(36.1) 88(32.6)

Vomiting It (21.6) 22(29.3) 21(29.2) 23(31.9) 77(28.5)

Anorexia 10(19.6) 18(24.0) 20(27.8) 23(31.9) 71 (26.3)

Dry skin 4(7.8) 14(18.7) 19(26.4) 23(31.9) 60(22.2)

Acne 4(7.8) 16(21.3) 19(26.4) 17(23.6) 56(20.7)

Abdominal pain 15(29.4) 5(6.7) 10(13.9) 21 (29.2) 51(18.9)

Cough increased 10(19.6) 15(20.0) 12(16.7) 14(19.4) 51(18.9)

Dyspnea 8(15.7) 15(20.0) 15(20.8) 11 (15.3) 49(18.1)

Headache 12(23.5) 13(17.3) 13 (18.1) 8(11.1) 46(17.0)

Pharyngitis 8(15.7) 12(16.0) 8(11.1) 14(19.4) 42(15.6)

Constipation 12(23.5) 12(16.0) 11 (15.3) 5(6.9) 40(14.8)

Pain 10(19.6) 8(10.7) 14(19.4) 8(11.1) 40(14.8)

Conjunctivitis 9(17.6) 10(13.3) 8 (11.1) 12(16.7) 39(14.4)

Dry mouth 5(9.8) 9(12.0) 5(6.9) 19(26.4) 38(14.1)

Pruritus 4(7.8) 5(6.7) 12(16.7) 16(22.2) 37(13.7)

Somnolence 10(19.6) 9(12.0) 9(12.5) 9(12.5) 37(13.7)

AST/SGOT increased 7(13.7) 8(10.7) 12(16.7) 7(9.7) 34(12.6)

Fever 9(17.6) 10(13.3) 3(4.2) 9(12.5) 31(11.5)

ALT/SGPT increased 5(9.8) 7(9.3) 9(12.5) 8(11.1) 29(10.7)

Anemia 4(7.8) 9(12.0) 8 (11.1) 7(9.7) 28(10.4)

Back pain 3(5.9) 8(10.7) 6(8.3) 10(13.9) 27(10.0)

a patients may have had more than 1 adverse event.

b Including doses between 225 mg and 300 mg, inclusive.

c Including doses between 400 mg and 525 mg, inclusive.

Dose-limiting toxicities

In Trials 0005 and V- 15-11, dose escalation was to proceed up to 925 mg/day unless there was dose limiting toxicity. Dose escalation ceased at 700 mg/day in both of these trials; in Trial 0005, three patients experienced drug-related CTC Grade 3 or 4 diarrhea at this dose level, and in Trial V- 15 -11, two patients experienced CTC Grade 3 diarrhea and increased ALT/SGPT at this dose level (see Table 49).

In Trials 0011 and 0012, dose escalation was to proceed up to 1000 mg/day unless dose-limiting toxicities were recorded. In Trial 0011, dose-limiting toxicities were experienced in the first 28-day treatment period by 3 patients receiving ZD1839 800 mg; the events experienced were diarrhea, diarrhea and pruritus, and conjunctivitis and rash (see Table 49). In Trial 0012, dose escalation proceeded up to the maximum permitted dose level of 1000 mg/day. At this dose level, 5 patients experienced dose-limiting toxicities which, for 4 of these patients, included Grade 3 diarrhea (see Table 49).

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Table 49: Dose limiting toxicities in the Phase I dose-escalating trials

Trial ZD1839 Center/ Tumor type Adverse event CTC dose (mg) Patient grade

0005 400 0001/0061 Ovarian ALT increased 3

AST increased 4

525 0004/0071 Esophageal Acne 3

700 0001/0081 Ovarian Diarrhea 4

0002/0083 NSCLC Diarrhea 3

0004/0081 Ovarian Vomiting 3

Abdominal pain 3

Diarrhea 3

0011 150 0001/0001 NSCLC GGT increased 3

800 0002/0105 NSCLC Diarrhea 3

0004/0107 Colorectal Diarrhea 3

Pruritus 3

0008/0101 NSCLC Conjunctivitis 2

Rash 3

1000 0004/0121 NSCLC Diarrhea 3

0005/0123 Prostate Diarrhea 3

Dehydration 3

0008/0122 NSCLC Urticaria 3

Diarrhea 3

Rash 3

0012 225 0011/0027 Prostate Nausea 3

300 0010/0054 Prostate Diarrhea 3

400 0005/0065 Colorectal Rash 3

0011/0061 Ovarian Pain 3

Pruritus 3

Depression 3

600 0008/0090 Ovarian Diarrhea 3

0011/0081 Head & neck Somnolence 3

800 0001/0110 Colorectal Asthenia 4

0005/0108 Colorectal Diarrhea 3

1000 0001/0123 Ovarian Diarrhea 3

Somnolence 3

Hematemesis 3

Hypokalemia 3

Acne 3

0006/0129 Ovarian Diarrhea 3

0006/0132 Ovarian Diarrhea 3

Dehydration 3

0007/0126 Colorectal Diarrhea 3

0011/0122 NSCLC Somnolence 3

V-15-11 700 0008/0003 Lung ALT increased 3

0009/0004 Colorectal Diarrhea 3

 

Drug-related adverse events

A total of 219 patients (81.1%) had at least 1 adverse event that was attributed to trial medication. Drug-related adverse events with an overall incidence of >=5% are presented in Table 50.

The most frequent drug-related adverse events were diarrhea, rash , acne, dry skin, nausea, pruritus, and vomiting. These are similar to the most frequent drug-related adverse events reported in the Phase II trials. .

 

Table 50: Drug-related adverse events (>= 5%) in the Phase I multiple-dose trials

Drug-related adverse event Number (%) of patients a

<225 mg 250 mg b 500 mg c >525 mg d All doses

(n=51) (n=75) (n=72) (n=72) (n=270)

Diarrhea 6(11.8) 24(32.0) 31 (43.1) 56(77.8) 117(43.3)

Rash 8(15.7) 23(30.7) 34(47.2) 45(62.5) 110(40.7)

Acne 4(7.8) 15(20.0) 18(25.0) 17(23.6) 54(20.0)

Dry skin 1 (2.0) 12(16.0) 16(22.2) 22(30.6) 51 (18.9)

Nausea 1 (2.0) 7(9.3) 12(16.7) 22(30.6) 42(15.6)

Pruritus 2(3.9) 3(4.0) 9(12.5) 15(20.8) 29(10.7)

Vomiting 2(3.9) 4(5.3) 5(6.9) 17(23.6) 28(10.4)

Asthenia 1 (2.0) 5(6.7) 6(8.3) 11 (15.3) 23 (8.5)

Dry mouth 2(3.9) 4(5.3) 2(2.8) 15(20.8) 23(8.5)

Anorexia 1 (2.0) 2(2.7) 5(6.9) 11 (15.3) 19(7.0)

AST/SGOT increased 1(2.0) 4(5.3) 7(9.7) 5(6.9) 17(6.3)

ALT/SGPT increased 1(2.0) 4(5.3) 5(6.9) 5(6.9) 15(5.6)

a patients may have had more than 1 drug-related adverse event.

b Including doses between 225 mg and 300 mg, inclusive.

c including doses between 400 mg and 525 mg, inclusive.

d doses of ZD1839 of >525 mg

Adverse events with CTC grades 3 or 4

Overall, 118 patients (43.7%) had CTC Grade 3 or 4 adverse events. Thirty-nine patients (14.4%) had Grade 3 or 4 events that were considered drug related, and these occurred with increasing frequency with increasing dose. As in Trial 39, diarrhea was the only drug-related adverse event of CTC Grade >=3 severity with an incidence of >=3% in the total population. Seventeen out of 19 patients who experienced drug-related CTC Grade 3 or 4 diarrhea were receiving mg/day.

 

 

 

 

 

Deaths

A total of 14 out of 270 (5.2%) patients had adverse events in the Phase I multiple-dose trials that had an outcome of death. These patients were distributed across doses from 150 mg/day to 800 mg/day, and none of these events were considered by the investigators to be possibly related to ZD1839.

Withdrawals due to adverse events

A total of 38 out of 270 (14.1%) patients withdrew from ZD1839 therapy due to one or more adverse events. In 24 of these patients, the adverse events were considered to be possibly drug related; in 16 cases, withdrawal was due to gastrointestinal symptoms with 12 cases due to drug related diarrhea.

Serious adverse events

Seventy-nine (29.3%) patients experienced at least 1 serious adverse event. The commonest serious adverse events reported (>2%; 6 or more patients) were abdominal pain (4.4%), dyspnea (3.7%), dehydration (3.0%), asthenia (2.6%), diarrhea (2.6%), and anemia (2.2%).. Twenty (7.4%) patients experienced drug-related serious adverse events. Only 4 of these patients were receiving doses <=525 mg/day.

All drug-related adverse events with a frequency >=5% in any of the Phase II and I multiple-dose patient trials is summarized in Table 51.

 

 

 

 

 

 

 

 

 

 

 

 

 

Table 51: Drug-related adverse events in the Phase II and I multiple-dose patient trials

Number (%) of patients

Phase II Trial 0039 Phase II Trial 0016 Phase I trials

Drug-related AE

250 mg/day 500 mg/day 250 mg/day 500 mg/day 225 to 300 mg/day 400 to 525

(n=102) (n=1 14) (n=103) (n=106) (n=75) (n=72)

Diarrhea 49(48.0) 76(66.7) 41 (39.8) 61 (57.5) 24(32.0) 31 (43.1)

Rash 44(43.1) 61 (53.5) 48(46.6) 73(68.9) 23(30.7) 34(47.2)

Acne 25(24.5) 37(32.5) 13 (12.6) 15(14.2) 15(20.0) 18(25.0)

Dry skin 13(12.7) 30(26.3) 28(27.2) 31 (29.2) 12(16.0) 16(22.2)

Nausea 13(12.7) 20(17.5) 13 (12.6) 25(23.6) 7(9.3) 12(16.7)

Vomiting 12(11.8) 10(8.8) 6(5.8) 21 (19.8) 4(5.3) 5(6.9)

Pruritus 8(7.8) 10(8.8) 31 (30.1) 38(35.8) 3(4.0) 9(12.5)

Anorexia 7(6.9) 11(9.6) 9(8.7) 20(18.9) 2(2.7) 5(6.9)

Asthenia 6(5.9) 5(4.4) 8(7.8) 11(10.4) 5(6.7) 6(8.3)

Nail disorder 4(3.9) 3(2.6) 4(3.9) 9(8.5) 1 (1.3) 1 (1.4)

Exfol. Dermatitis 4(3.9) 1 (0.9) 8(7.8) 9(8.5) 3(4.0) 3(4.2)

Weight loss 3(2.9) 6(5.3) 2(1.9) 6(5.7) 0(0.0) 1(1.4)

Abdominal pain 3(2.9) 5(4.4) 3(2.9) 8(7.5) 2(2.7) 3(4.2)

Epistaxis 2(2.0) 3(2.6) 2(1.9) 12(11.3) 0(0.0) 0(0.0)

Dry mouth 2(2.0) 3 (2.6) 4(3.9) 2(1.9) 4(5.3) 2(2.8)

Pain 2(2.0) 1(0.9) 10(9.7) 17(16.0) 1 (1.3) 1(1.4)

ALT increased 1 (1.0) 3 (2.6) 13(12.6) 25(23.6) 4(5.3) 5(6.9)

AST increased 1 (1.0) 3(2.6) 11 (10.7) 24(22.6) 4(5.3) 7(9.7)

Conjunctivitis 1(1.0) 3(2.6) 4(3.9) 10(9.4) 1(1.3) 4(5.6)

Blepharitis 1(1.0) 1(0.9) 5(4.9) 6(5.7) 0(0.0) 0(0.0)

Taste perversion 0(0.0) 5(4.4) 1 (1.0) 5(4.7) 2(2.7) 5(6.9)

Stomatitis 0(0.0) 3(2.6) 8 (7.8) 8(7.5) 1 (1.3) 1(1.4)

Seborrhea 0(0.0) 0(0.0) 6(5.8) 4(3.8) 0(0.0) 2(2.8)

Hematuria 0(0.0) 0(0.0) 6(5.8) 4(4.7) 1 (1.3) 2(2.8)

LDH increased 0(0.0) 0(0.0) 1 (1.0) 1(0.9) 4(5.3) 1(1.4)

 

The incidence of withdrawals due to drug-related adverse events was low across the ZD1839 clinical program especially for patients receiving doses of 250 mg/day or similar; 3 out of 205 (1.5%) patients who received ZD1839 250 mg/day in the Phase 11 trials were withdrawn due to drug-related adverse events (asthenia, bundle branch block, and increased ALT/SGPT), and 3 out of 126 (2.4%) patients in the Phase I multiple-dose trials receiving doses of >=300 mg/day were withdrawn due to drug-related adverse events (anorexia, nausea, and diarrhea).

7.4 Adequacy of Safety testing

Safety testing was adequate.

 

 

 

 

7.5 Summary of Critical Safety Findings

Skin

Phase I patients with solid tumors

In the Phase I multiple dose trials in 270 patients with solid tumors, dose related toxicities to the skin have been consistently observed. 192 patients (71.1%) reported adverse events. The most common of these events were rash (44.8%), acne (20.7%), dry skin (22.2%), and pruritus (13.7%). The incidence and severity of skin events in these trials increased with escalating dose and was a dose limiting toxicity in some patients. Patients with rash frequently had associated reports of dry skin, acne, pruritus, and other skin symptoms.

Seven patients experienced drug-related dose-limiting skin toxicity (CTC grade 3); pruritus (n=2 at 400 mg/day and 800 mg/day respectively), acne (n=2, 525 mg/day and 1000 mg/day, respectively), rash (n=2, 400 mg/day and 800 mg/day respectively) and one patient had urticaria plus rash (1000 mg/day).

Fewer events of skin toxicity were reported at doses = 500 mg/day than at doses >500 mg/day. Skin events of rash, acne, dry skin and pruritus were mild, predominantly CTC grade 1or 2 and generally resolved during the treatment period or following cessation of therapy), Eleven patients reported 15 drug-related skin events of CTC grade 3. None were reported at <225 mg dose level, only 1 patient experienced CTC grade 3 rash at the nominal 250 mg dose level (0011/0002/0044, 300 mg), 1 event each of acne, pruritus and rash were reported at the 500 mg dose level and 11 events were reported at the >525 mg level. (2 acne, 1 dry skin, 1 hair disorder [abnormal lashes], 1 pruritus, 5 rash, and 1 urticaria). Three patients withdrew from ZD1839 due to acne (525 mg/day), rash (one patient receiving 400 mg and one, 800 mg/day) and hair disorder (800 mg/day).

Four patients (1.5%) reported urticaria in these Phase I multiple dose trials (1 at 150 mg/day [CTC grade 2], 1 at 500 mg/day [CTC grade 1] and 2 at 1000 mg/day [CTC grades 1 and 3]). With the exception of 1 patient (150 mg/day) the events were considered drug-related. The onset of the events occurred on days 29, 4, 1, and 5 for the patients receiving 150 mg/day, 500 mg/day and the 2 patients on 1000 mg/day, respectively. None of the events were considered serious and no patients were withdrawn due to urticaria.

The frequency of skin adverse events by CTC grade in the Phase I multiple-dose trials is shown in Table 52.

 

 

 

 

 

 

Table 52: Skin toxicity by CTC grade in the Phase I multiple-dose trials

Adverse event CTC grade Number (%) of patients

<225 mg 250 mg 500 mg >525 mg All doses

(n=5 1) (n~75) (n=72) (n=72) (n=270)

Rash 1 12(23.5) 19(25.3) 24(33.3) 22(30.6) 77(28.5)

2 2(3.9) 7(9.3) 10(13.9) 18(25.0) 37(13.7)

3 0(0) l(l.3) l(l.4) 5(6.9) 7(2.6)

Acne 1 2(3.9) 14(18.7) 12(16.7) 7(9.7) 35(13.0)

2 2(3.9) 2(2.7) 6(8.3) 8(11.1) 18(6.7)

3 0(0) 0(0) 1(l.4) 2(2.8) 3 (1.1)

Pruritus 1 4(7.8) 4(5.3) 8(11.1) 9(12.5) 25(9.3)

2 0(0) 1 (1.3) 3(4.2) 6(8.3) 10(3.7)

3 0(0) 0(0) l(l.4) 1(1.4) 2(0.7)

Dry Skin 1 4(7.8) 14(18.7) 18(25.0) 19(26.4) 55(20.4)

2 0(0) 0(0) l(l.4) 3(4.2) 4(l.5)

3 0(0) 0(0) 0(0) l(l.4) l(0.4)

Phase II monotherapy trials

In the Phase II pivotal Trial 39 and supportive Trial 16 where 205 patients received 250 mg/day and 220 patients had 500 mg/day ZD1839, 323 patients (75.3%) experienced skin events (66.8 % at 250 mg/day and 84.5% at 500 mg/day). Rash (55.3%), acne (22. 1%), dry skin (25.4%), pruritus (21.6%) were the most common events reported. Other reported terms relating to rash were, vesiculobullous rash (1.4%), pustular rash (0.5%), and ichthyosis (0.9%). Patients with rash frequently had associated reports of dry skin, acne, pruritus or other skin symptoms eg, exfoliative dermatitis commonly described as desquamation (5.4%). Two hundred -and- seventy-five patients had at least one episode of rash or acne. Seventy-three patients reported rash and pruritus, 51 patients had acne plus rash, and 22 patients had acne plus pruritus.

Skin adverse events by CTC grade in the Phase II trials is presented in Table 53.

 

Table 53: Frequency of skin adverse events by CTC grade in the Phase 11 trials

Adverse event CTC grade ZD1839 Treatment

250 mg (n=205) 500 mg (n=220)

Acne 1 30(14.6) 27(12.3)

2 9(4.4) 22(10.0)

3 0(0) 6(2.7)

Dry Skin 1 43(21.0) 50(22.7)

2 4(2.0) 11(5.0)

Pruritus 1 36(17.6) 41(18.6)

2 7(3.4) 6(2.7)

3 0(0) 2(0.9)

Rash 1 71 (34.6) 74(33.6)

2 26(12.7) 53(24.1)

3 1 (0.5) 9(4.1)

4 0(0) 1(0.5)

Rash

In 192 patients overall (81.7%) the rash first occurred during the first treatment period; in 32 patients (13.6%) the rash began during treatment periods 2 or 3, and 11 patients (4.7%) first had rash during treatment period 4 or beyond. Four patients in the 500 mg/dayZD1839 group were withdrawn from the trial due to skin rash. There were no withdrawals due to rash in the 250 mg/day group.

Acne

A total of 94 patients (22.1 %) had adverse events of acne (19.0% at 250 mg/day and 25.0% at 500 mg/day). In the majority of patients (74.5%, 70/94 events) the acne occurred during the first treatment period. Two patients at the 500mg/day dose were withdrawn from the study due to CTC grade 3 drug-related acne. No patients were withdrawn due to acne in the 250 mg/day group. In the majority of patients with acne (55.3%) the event was documented to have resolved (51.3% at 250 mg /day and 58.2% at 500 mg/day) either during the treatment period or following cessation of therapy. In 42 patients the acne was reported to be 'ongoing'. The majority of these ongoing events are CTC grade 1 (66.7%) and 14 patients are still ongoing in the trial hence resolution of the event is still possible.

For rashes and acne that did not resolve or improve spontaneously a variety of agents were used to manage the skin symptoms, seen during treatment. These included steroid creams, either topical or systemic antibiotics, topical or systemic anti-histamines and occasionally retinoid creams. The successfulness of these agents in treating the skin conditions has varied between patients, with each agent showing some efficacy but not across all patients.

Pruritus

A total of 92 patients (21.6%) had adverse events of pruritus (21 % at 250 mg/day and 22.3% at 500 mg/day). In the majority of patients (58.7%, 54/92 patients) the pruritus occurred during the first treatment period. One patient receiving 500 mg/dayZD1839 was withdrawn from the trial due to CTC grade 2 pruritus and rash, both events were considered drug-related. The majority (59.8%) of the events were documented to have resolved either during the treatment period or following cessation of therapy (51.2% at 250 mg/day and 67.3% at 500 mg/day). Of the 92 patients with pruritus, 80 were reported to have had rash and/or acne.

Dry Skin

A total of 108 patients (25.4%) had adverse events of dry skin. Sixty-nine of the 108 patients (63.9%) had the first occurrence of dry skin during the first treatment period. There were no patients withdrawn from the trial due to dry skin. The majority (52.8%) of the events were documented to have resolved (55.3% at 250 mg/day and 50.8% at 500 mg/day) either during the treatment period or following cessation of therapy. Of the 108 patients with dry skin, 85 patients were reported to have had rash and or acne.

Nail Disorders

A total of 26 patients across both trials (6.1 %) had 29 events reported which were termed nail disorders (9 patients at 250 mg/day and 17 patients at 500 mg/day). These disorders included paronychia (11), ingrown nails (6), nail changes (4), breaking nail (2), onycholysis (2), nail ridging (1), finger (1) or nail (1) discoloration and nail loss (1). Events for 20 of these patients (3.9% at 250 mg/day and 5.5% at 500 mg/day) were considered possibly related to ZD1839. One patient at the 500mg/day dose had a grade 3 paronychia that occurred on day 12 of treatment and resolved after 92 days. Of the remaining patients, 14 had CTC grade 1 events (2.4% at 250 mg/day and 4.1 % at 500 mg/day) and 11 had CTC grade 2 (2.0% at 250 mg/day and 3.2% at 500 mg/day). None of these events was serious and the majority of these events resolved.

Other Skin Disorders

Toxic epidermal necrolysis (CTC grade 4) and erythema mulitforme (CTC Grade unknown) occurred in 1 patient each. These are from a database of greater than 8000 patients exposed to ZD1839.

Ophthalmologic Toxicity

Phase I multiple dose ranging studies

In the Phase I multiple dose trials in patients with solid tumors, ophthalmic monitoring was performed every 2 weeks and included visual acuity, slit-lamp examination with fluorescein and Rose Bengal staining, lid eversion and Schirmer's test.

Baseline findings were seen at all dose levels in 181 patients (67%). During the trial new ophthalmology findings were reported in 122 patients. 68 patients from trials 0005, 0011 and 0012 experienced decreased tear production (measured by Schirmer's test). Data from over 837 routine slit lamp examinations revealed no identifiable trend in abnormalities. The ophthalmological data observed were thought to represent variance within a normal population, and were not believed to be related to trial treatment. Of significance the intensive ophthalmological monitoring did not reveal any findings representative of those detected in the pre-clinical studies eg, diffuse corneal translucency and corneal atrophy.

The number of patients with ocular adverse events, by dose, from Phase I trials is presented in Table 54.

 

 

 

 

 

Table 54: Ocular adverse events by dose: patients from Phase I trials

Adverse event Number (%) of patients

ZD1839 ZD1839 ZD1839 ZD1839 All

<225 mg/day 250 mg/day 500 mg/day >500 mg/day patients

(n=5 1) (n~75) (n=72) (n=72) (n=270)

Total 18(35.3) 22(29.3) 19(26.4) 26(36.1) 85(31.5)

Abnormal vision 1 (2.0) 0(0) 0(0) 0(0) 1 (0.4)

Ambylopia 5(9.8) 8(10.7) 1 (1.4) 0(0) 14(5.2)

Blepharitis 3(5.9) 0(0) 4(5.6) 1(1.4) 8(3.0)

Blindness 0(0) 1 (1.3) 0(0) 0(0) 1 (0.4)

Cataract specified 0(0) 0(0) 0(0) 1(1.4) 1(0.4)

Conjunctivitis 9(17.6) 10(13.3) 8(11.1) 12(16.7) 39(14.4)

Corneal lesion 0(0) 0(0) 2(2.8) 2 (18) 4(1.5)

Comeal opacity 1 (2.0) 1 (1.3) 0(0) 0(0) 2(0.7)

Corneal ulcer 0(0) 0(0) 2(2.8) 2(2.8) 4(1.5)

Dry eyes 3 (5.9) 4(5.3) 2(2.8) 11 (15.3) 20(7.4)

Eye disorder 3 (5.9) 3(4.0) 0(0) 3(4.2) 9(3.3)

Eye hemorrhage 0(0) 2(2.7) 0(0) 1(1.4) 3(l.1)

Eye pain 2(3.9) 0(0) 2(2.8) 0(0) 4(l.5)

Glaucoma 0(0) 0(0) 1 (1.4) 0(0) 1 (0.4)

Keratoconjunctivitis 0(0) 1(1.3) 0(0) 0(0) 1 (0.4)

Keratitis 1 (2.0) 0(0) 0(0) 2(2.8) 3 (1.1)

Lacrimation disorder 1 (2.0) 0(0) 1 (1.4) 0(0) 2(0.7)

Photophobia 1 (2.0) 1(1.3) 0(0) 0(0) 2(0.7)

Retinal disorder 0(0) 0(0) 0(0) 1 (1.4) 1(0.4)

Uveitis 1 (2.0) 0(0) 0(0) 0(0) 1 (0.4)

Visual field defect 0(0) 0(0) ](1.4) 0(0) 1(0.4)

Vitreous disorder 0(0) 1 (1.3) 0(0) 0(0) 1(0.4)

An external Ophthalmology Advisory Board, consisting of 4 international, independent ophthalmologists reviewed the ophthalmological monitoring results. This review revealed no evidence of any consistent or drug-related ophthalmologic toxicity The significant ocular adverse events reported of corneal ulcer occurred at higher doses than is currently being recommended. Even so these events were in the most part related to aberrant eyelashes and associated with symptoms of pain or discomfort. The corneal ulcers healed rapidly once lashes had been removed.

The advice from the Ophthalmology Advisory Board, in the absence of any consistent or significant ocular toxicity from the Phase I data, was that for the Phase II studies at doses of 250 mg and 500 mg/day:

Phase II monotherapy trials

In the 2 Phase II trials, complete ophthalmologic evaluations, including slit lamp examination, were performed in a minority of patients (based on phase I findings) at baseline and at trial completion or early withdrawal from the trial (at the end of treatment).

In trial 0039 only 37 (17.1%) patients had ophthalmological assessments at baseline and at either withdrawal or another post baseline visit. One patient had visual impairment noted at withdrawal but not at baseline, 3 patients had hyperemia in 1 or both eyes post baseline, and in 5 patients fluorescein staining in one or both eyes was noted post baseline. Schirmer's test was only performed at baseline in this trial.

In trial 0016, baseline ophthalmology findings were seen in 49 patients (23.4%). New findings were recorded in 38 (18.2%) patients and 78 patients (37%) experienced decreased tear production from baseline, during the trial. The decreased tear production was minimal (<5mm) in most cases and was offset by an increase in tear production in 30 (14.3%) patients.

Changes from baseline in ophthalmological evaluations in these two trials, were thought to represent variance within a normal population, to have no clinical significance and were not attributed by the investigator to be related to trial treatment.

The majority of the events were CTC grade 1 (78/102 [76.5%]) or CTC grade 2 (22/102 [21.6%]). In only 2 patients (2/102 [1.96%]) were the eye events reported as CTC grade 3; these were a serious event of cataract considered not related to trial treatment and a corneal ulcer also considered not drug-related.

Results from the ophthalmological monitoring revealed no evidence of any consistent or drug-related ophthalmologic toxicity in these trials. Although 24% of patients from these 2 monotherapy trials experienced eye symptoms/events, the events were frequently mild (CTC 1) and there was only 2 CTC grade 3 events, both of which were considered unrelated to trial therapy. The corneal erosions/ulcers were reversible and sometimes associated with aberrant eyelash growth. Only 1 of the corneal ulcers occurred at the 250 mg/day dose.

In summary, results from the comprehensive ophthalmology monitoring, including over 1500 slit lamp examinations, obtained from the Phase I/II trials did not reveal any asymptomatic findings representative of those seen in the pre-clinical studies. No evidence of any consistent or drug-related ophthalmologic toxicity was observed in these trials. There is no evidence to suggest a need for any recommendations or precautions for future use of ZD1839 beyond patients being aware that they should seek advice should they develop any eye symptoms.

Gastrointestinal Toxicity

Phase I patients with solid tumors

In the Phase I multiple dose trials in 270 patients with solid tumors, dose-related toxicities to the gastrointestinal system have been consistently observed. Gastrointestinal adverse events were reported by 221 patients (81.9%). The most common of these events were diarrhea (56.3%), nausea (35.2%), vomiting (28.5%) and anorexia (26.3%); the majority of which were CTC grade 1 or 2.

Table 55 presents the frequency of gastrointestinal events by CTC grade in the Phase I multiple dose trials. No drug-related CTC grade 3 or 4 events of stomatitis or anorexia were reported during the Phase I trials.

Table 55: Gastrointestinal events by CTC grade in Phase I multiple-dose trials

Adverse event CTC grade Number (%) of patients

(COSTART term) <225 mg 250 mg 500 mg >525 mg All doses

(n=51) (n=75) (n=72) (n=72) (n=270)

Diarrhea 1 15(29.4) 26(34.7) 30(41.7) 23 (31.9) 94(34.8)

2 3(5.9) 6(8.0) 12(16.7) 18(25.0) 39(14.4)

3 0(0) 2(2.7) 0(0) 16(22.2) 18(6.7)

4 0(0) 0(0) 0(0) 1(1.4) 1(0.4)

Nausea 1 13(25.5) 10(13.3) 17(23.6) 21 (29.2) 61 (22.6)

2 5(9.8) 7(9.3) 9(12.5) 9(12.5) 30(11.1)

3 0(0) 2(2.7) 0(0) 1(1.4) 3(l.1)

4 0(0) 0(0) 0(0) 1(1.4) 1(0.4)

Vomiting 1 10(19.6) 16(21.3) 13(18.1) 13 (18.1) 52(19.3)

2 1 (2.0) 6(8.0) 8(11.1) 8(11.1) 23(8.5)

3 0(0) 0(0) 0(0) 1 (1.4) 1 (0.4)

4 0(0) 0(0) 0(0) 1(1.4) 1(0.4)

Anorexia 1 7(13.7) 15(20.0) 13(18.1) 18(25.0) 53(19.6)

2 2(3.9) 1 (1.3) 6(8.3) 5(6.9) 14(5.2)

3 0(0) 1 (1.3) 1(1.4) 0(0) 2(0.7)

4 1 (2.0) 1 (1.3) 0(0) 0(0) 2(0.7)

Stomatitis 1 0(0) 2(2.7) 7(9.8) 5(6.9) 14(5.5)

2 1 (2.0) 0(0) 1(1.4) 3(4.2) 5(l.9)

3 0(0) 1(1.3) 0(0) 1 (1.4) 2(0.7)

Phase II monotherapy trials

Similar to the phase I trials the phase II trials observed similar gastrointestinal toxicity. In the majority of patients with GI toxicity the adverse event first was noted during treatment period 1 (Table 56).

 

 

 

 

Table 56: Gastrointestinal adverse events by CTC grade in the Phase II trials

ZD1839 Treatment

Adverse event a,c CTC grade 250 mg 500 mg

(n=205) (n=220)

Anorexia 1 28(13.7) 36(16.4)

2 10(4.9) 22(10.0)

3 4(2.0) 2(0.9)

NR 0(0) l(0.5)

Diarrhea 1 87(42.4) 102(46.4)

2 19(9.3) 39(17.7)

3 2(l.0) 15(6.8)

Nausea 1 37(18.0) 45(20.5)

2 11(5.4) 20 (9.1)

3 4(2.0) 3(l.4)

Vomiting 1 26(12.7) 36(16.4)

2 8(3.9) 15(6.8)

3 3 (1.5) 4(l.8)

4 1(0.5) 0(0)

Stomatitis b 1 11 (5.4) 21(9.5)

2 l(0.5) 3(0.7)

3 0(0) 1(0.5)

a COSTART Coding Symbols for Thesaurus of Adverse Reaction Terms.

b Stomatitis includes COSTART terms of stomatitis, mouth ulceration and aphthous stomatitis.

NR Not recorded.

c In the Phase II trials diarrhea was the most commonly reported adverse event (52.7% at 250 mg/day; 70.9% at 500 mg/day), the majority of which was CTC grade 1. There were only 2 CTC grade 3 diarrheas at the 250 mg/day dose. No patients withdrew from treatment due to a gastrointestinal event at the 250 mg/day dose.

Electrocardiograms

Phase I multiple dose ranging studies

In the Phase I trials (trials 5, 11 and 12) patients with a P-R interval of greater than 217 msec or a previous history of clinically significant cardiac dysrhythmia, any degree of atrio-ventricular block or other severe cardiac disease were excluded. All patients had a 12-lead ECG at screening, between 5 and 7 hours after the first dose, followed by weekly (trial 5) or 2-weekly (trials 11 and 12) tracings throughout the study period. A total of 1642 ECGs were recorded from the 221 patients participating in these Phase I trials. Review of data from these patients, did not suggest any significant or consistent findings. In particular, there was no indication of PR prolongation and there were no signals of QT prolongation recognized.

Of the 221 patients in Trials 5, 11 and 12, a total of 68 (30.8%) had abnormal ECG's at baseline. During these trials 17 (7.7%) patients had ECG abnormalities that were reported as adverse events. Apart from 1 patient (Trial 5 patient 0002/0081) who had a prolongation of the PR interval that was considered not clinically significant, none of these adverse events was considered by the investigator to be related to trial treatment. Electrocardiographic abnormalities are summarized in Table 57.

 

Table 57: Phase I abnormal ECG findings

Adverse event Number (%) of patients a

<225 mg 250 mg 500 mg >525 mg All doses

(n=51) (n=75) (n=72) (n=72) (n=270)

Arrhythmia 0(0.0) 0(0.0) 0(0.0) l(l.4) 1(0.4)

Atrial Fibrillation 2(3.9) 0(0.0) 3(4.2) 0(0.0) 5(l.9)

AV block 0(0.0) 0(0.0) l(l.4) 0(0.0) 1(0.4)

ECG abnormal 1(2.0) l(l.3) l(l.4) 3(4.2) 6(2.2)

Sinus bradycardia 0(0.0) 0(0) 2(2.8) 0(0.0) 2(0.7)

Tachycardia 2(3.9) 3(4.0) 0(0.0) 0(0.0) 5(l.9)

Ventricular extrasystoles 0(0.0) 3(4.0) l(l.4) 0(0.0) 4(l.5)

a patients might have more than one ECG abnormality

Phase II monotherapy studies

In the Phase II studies patients had a screening and withdrawal ECG and, additionally in trial 16, an ECG at the end of month 4.

At trial entry, 153 (36%) patients had abnormal ECG results. Of these patients, 46 were from trial 16 and 107 were from trial 39. During the trials 10 patients (4 at 250 mg/day and 6 at 500 mg/day) had ECG abnormalities reported as adverse events. Three of these patients had abnormal ECGs at baseline. Five of the events (2 arrhythmias and 3 atrial fibrillations) were CTC Grade 3 and the others were CTC Grade 1 or 2. Only 1of these adverse events was considered by the investigator to be related to trial treatment (non-serious, grade 3 atrial fibrillation) and 1 was reported as serious (unrelated, grade 3 atrial fibrillation). One of these 10 patients and an additional patient had a myocardial infarction and died within 30 days after trial treatment ended. Details of these 11 patients is as follows:

Trial 16

Patient 0804/0004 (250-mg/day group) had related, non-serious Grade 3 atrial fibrillation recorded after 87 days treatment, at the time of withdrawal due to disease progression. The adverse event resolved.

Patient 0207/0004 (250-mg/day group) had unrelated, serious Grade 3 atrial fibrillation recorded after 8 days treatment, when he withdrew due to disease progression. The adverse event resolved.

Patient 0501/0004 (500-mg/day group) had unrelated, non-serious Grade 3 arrhythmia and lung edema, Grade 2 atrial fibrillation and serious Grade 4 dyspnea recorded 13 days after entering the trial, but only having received treatment on Day I and then withdrawing with objective disease progression.

Trial 39

Patient 2008/0192 (500-mg/day group) had non-drug-related, CTC Grade 1 ectopic beats recorded after 8 days of treatment. The patient received 41 days of trial treatment. The adverse event was reported as ongoing.

Patient 2107/0035 (500-mg/day group) had non-drug-related, CTC Grade 3 irregular heart rhythm recorded 6 days after an acute myocardial infarction, which occurred on the same day the patient was withdrawn from the trial due to adverse events (drug-related diarrhea and non-drug-related myocardial infarction). The patient also had disseminated intravascular coagulation at the same time as the arrhythmia. The patient died 1 day after the onset of these events. The patient had a history of myocardial infarction and atrial fibrillation. The patient received 63 days of trial treatment.

Patient 2028/0105 (500-mg/day group) had non-drug-related, CTC Grade 3 atrial fibrillation recorded after 39 days of treatment. The adverse event resolved 3 days later. The patient received 45 days of trial treatment.

Patient 2107/0036 (500-mg/day group) had non-drug-related, CTC Grade 2 atrial fibrillation recorded after 6 days of treatment. The adverse event was reported as ongoing. The patient was withdrawn from the trial due to non-drug-related adverse events (congestive heart failure, hypoxia, and acute respiratory distress) after 7 days of treatment and died 7 days later of complications due to lung cancer.

Patient 2101/0155 (250-mg/day group) had non-drug-related, CTC Grade 1 T-wave inversion, Grade 1 axis deviation and Grade 1 left bundle branch block 2 days post treatment. Sinus tachycardia, sepsis, pneumonia, and dehydration were also reported at or near that time. The patient received 29 days of treatment and died due to metastatic NSCLC and sepsis I day after the ECG abnormalities were reported.

Patient 2101/0154 (250-mg/day group) had non-drug-related, CTC Grade 1 abnormal electrocardiogram recorded 1 day post treatment. The adverse event was reported as ongoing. The patient was withdrawn from the trial due to non-drug-related adverse events (respiratory failure and pneumonia) after 71 days of treatment.

Patient 2028/0107 (500-mg/day group) had non-drug-related, CTC Grade 1 premature ventricular contractions recorded after 163 days of treatment. The adverse event was ongoing. The patient received 195 days of treatment.

Patient 2107/0034 (250-mg/day group) had a history of myocardial infarction and had arrhythmia (CTC Grade 4) recorded as an adverse event, beginning prior to treatment. This patient died of a myocardial infarction 25 days after trial treatment ended. The patient received 111 days of trial treatment. The QTc interval at baseline was 420 msec; no follow-up ECG was performed.

These events from the 2 Phase II monotherapy studies are summarized in Table 58.

Table 58: ECG abnormalities

Adverse event Number (%) of patients

ZD1839 250 mg/day ZD1839 500 mg/day

N=205 N=220

Arrhythmia 1(0.5) 3(l.4)

Atrial Fibrillation 2(l.0) 3(l.4)

Bundle branch block 3(1.5) 0(0.0)

Electrocardiogram abnormal 2(l.0) 0(0.0)

Myocardial infarct 1(0.5) 1(0.5)

Palpitation 1(0.5) 3(l.4)

Sinus bradycardia 0(0.0) 1(0.5)

Tachycardia 5(2.4) 7(3.2)

Ventricular extrasystoles 0(0.0) 1(0.5)

There were no clear trends observed in ECGs or PR intervals for patients during trial treatment and no apparent differences between the doses. In Trial 0039, corrected QT interval was recorded at trial entry and withdrawal. Forty-two patients had their withdrawal ECG within 24 hours of the last dose of ZD1839. For these patients, there was no evidence of any prolongation of QT interval over the course of the trial,

7.6 Adequacy of Safety Testing

Safety data from Phase I and Phase II studies of relatively short follow-up suggest that ZD1839 is generally well tolerated. Long duration safety data is not yet available. It was of interest to observe that the ophthalmologic toxicity noted in pre-clinical studies was not observed in study patients.

7.7 Safety Conclusions

A total of 960 subjects (714 cancer patients, and 246 healthy volunteers) were exposed to ZD1839 in the 20 completed monotherapy trials. A total of 420 subjects (297 cancer patients, and 123 healthy volunteers) were exposed to a dose of ZDI 839 between 225 and 300 mg/day, with a maximum duration of dosing of 506 days. A total of 348 subjects (292 patients and 56 healthy volunteers) were exposed to a dose of ZDI 839 between 400 and 525 mg/day, with a maximum duration of dosing of 404 days.

Patients receiving ZD1839 250 mg/day (or similar doses) in the multiple-dose Phase I and II trials frequently experienced drug-related gastrointestinal disturbances (mainly diarrhea, sometimes associated with dehydration) and skin reactions (rash, acne, dry skin, and pruritus). The majority of drug-related adverse events were mild (CTC Grade 1) and non-cumulative, and rarely led to withdrawal of ZD1839 therapy, with only 2 CTC Grade 3 diarrheas, and 3 CTC Grade 3 skin events reported at the 250-mg/day dose in the Phase II trials.

No additional safety concerns were raised for subpopulations of men or women, the elderly, ethnic groups, patients with renal impairment, or patients with mild to moderate hepatic impairment. Evaluation of the safety data does not indicate the need for any additional safety monitoring. Few specific drug-drug interactions have been identified that could impact on the safety of ZD1839.

In patients receiving ZD1839 therapy, there have been infrequent reports of reversible corneal erosion, sometimes in association with aberrant eyelash growth. However, no evidence of any consistent or drug-related ophthalmologic toxicity was observed in the Phase II trials. Consequently, no recommendations or precautions relating to eye events are considered necessary beyond patients being aware that they should seek medical advice should they develop any eye symptoms.

Data from non-clinical, in vitro studies indicate that ZD1839 has the potential to inhibit the cardiac potential repolarization process eg, QTc interval. The clinical relevance of these findings is unknown. No clear trends were observed in ECGs or PR intervals in patients participating in the Phase II trials.

A small number of significant, asymptomatic increases in liver transaminases have been observed at the 250-mg/day dose.

There was 1 report each of toxic epidermal necrolysis and erythema multiforme.

Co-administration of ZD1839 250 mg with itraconazole, a CYP3A4 inhibitor, resulted in an 80% increase in the mean AUC of ZD1839 in healthy volunteers. This increase maybe clinically relevant to the safety of ZD1389 when used concomitantly with drugs that inhibit CYP3A4, since drug-related adverse events are related to dose and exposure.

International Normalized Ratio (INR) elevations and/or bleeding events have been reported in some patients taking warfarin while on ZD1839 therapy. Patients taking warfarin should be monitored regularly for changes in prothrombin time and INR.

In conclusion, the adverse event data reported in the Phase II and I trials conducted with ZD1839 indicate that this drug has a favorable safety profile for the intended patient population. Overall, the 250-mg/day dose was better tolerated than the 500-mg/day dose.

    1. Dosing, Regimen and Administration Issues

In the Phase I program, anti-tumor activity with tumor regression occurred in patients at ZD1839 doses from 150 mg/day to 800 mg/day. Pharmacokinetic data in patients showed up to a 8-fold interpatient exposure variability at a given dose level. Since the lowest dose at which responses were first seen was 150 mg, a minimum dose of 250 mg was chosen to minimize the chance that patients would have exposure that was below a theoretical threshold. Since median steady state plasma concentrations of the 225- and 525-mg dose levels did not overlap by more than approximately 30%, there appeared to be the potential for discrimination between doses. Upper dose levels were selected on the basis of dose-limiting toxicity and tolerability. Therefore, the higher dose of 500 mg was chosen as a dose at which ZD1839 can be taken by the patient daily with small likelihood of therapy interruption or dose reduction.

In both the pivotal Trial 39 and supportive Trial 16, there were no significant differences between the 250 mg/day and 500 mg/day dose groups in regards to tumor response rates and disease-related symptom improvement rates. FACT-L and TOI improvement rates were higher in the 250-mg/day group than the 500-mg/day group in both trials. This may in part reflect the lower toxicity seen at the 250-mg dose. Overall, the 250-mg dose is as effective as the 500-mg dose.

9 Use in Special Populations

9.1 Tumor response by subgroups sex, age, and ethnicity

More women experienced tumor responses at either the 250-mg/day and 500-mg/day doses (23.8%; 95% CI: 12.1%, 39.5%] and 15.7%; 95% CI: 7.0%, 28.6%, respectively) than men (3.3%; 95% CI: 0.4%, 11.5% and 3.2%; 95% CI: 0.4%, 11.0%, respectively). No trend was seen for tumor response rates in either dose group between patients 18 to 64 years old and 65 years of age or older. Similar tumor response rates were seen between the 2 dose groups for white patients; however, there were not enough non-white patients to draw any conclusions between patients of different ethnic origins.

9.2 Symptom improvement by the subgroups sex, age, and ethnicity

 

The symptom improvement rates, as assessed by the sponsor, were higher in female patients in both dose groups: 50.0% (95% CI: 34.2%, 65.8%; 250-mg/day group) and 49.0% (95% CI: 34.8%, 63.4%; 500-mg/day group) than male patients (3 8.3%, 95% CI: 26.1%, 51.8%; 250-mg/day group and 23.8%, 95% CI: 14.0%, 36.2%, 500-mg/day group). No discernible pattern was observed for the sponsor’s analysis of disease-related symptom improvement rates by age or ethnicity in either dose group.

9.3 Adverse Events In Special Populations-Studies - Phase II trials 39 and 16

9.3.1 Gender

Table 59 shows the incidence of 6 of the most common adverse events in the Phase II trials presented by gender. The incidence of diarrhea was higher in females than males for both doses.

 

 

 

 

 

 

 

Table 59: Common adverse events by gender (Trials 39 and 16)

Adverse event Number (%) of patients

250 mg dose 500 mg dose

Female Male Female Male

(n=67) (n=138) (n=87) (n=133)

Diarrhea 41(61.2) 67(48.6) 67(77.0) 89(66.9)

Rash 32(47.8) 66(47.8) 57(65.5) 80(60.2)

Asthenia 18(26.9) 37(26.8) 22(25.3) 42(31.6)

Dyspnea 13(19.4) 32(23.2) 14(16.1) 27(20.3)

Nausea 20(29.9) 32(23.2) 26(29.9) 42(31.6)

Acne 18(26.9) 21 (15.2) 21 (24.1) 34(25.6)

9.3.2 Ethnic origin

Data for patients other than those of White or Asian origin, is insufficient for analysis.

9.3.3 Age

Table 60 shows adverse events by age categories (<45 years; 45 to 64 years; 65 to 74 years; >=75 years. As no trials have been conducted in subjects <1 8 years of age, the safety of ZDI 839 cannot be assessed in pediatric patients. For all age groups there is more toxicity for the 500 mg/day dose than for the 250 mg/day dose. Within each dose, however, there does not seem to be significantly different toxicity by age. The small numbers of patients >75 years of age makes it difficult to draw conclusions on this group.

Table 60: Common adverse events presented by age (pooled data from Trials 39 and 16)

Adverse Number (%) of patients

event

250 mg dose 500 mg dose

<45 45 to 64 65 to 74 >=75 <45 45 to 64 65 to 74 >=75

years years years years years years years years

(n=16) (n= 116) (n=62) (n= 11) (n=21) (n=122) (n=67) (n= 10)

Diarrhea 8(50.0) 59(50.9) 34(54.8) 7(63.6) 13 (61.9) 88(72.1) 49(73.1) 6(60.0)

Rash 9(56.3) 51 (44.0) 30(48.4) 8(72.7) 13 (61.9) 80(65.6) 38(56.7) 6(60.0)

Asthenia 3 (18.8) 31 (26.7) 18(29.0) 3(27.3) 2(9.5) 38(31.1) 19(28.4) 5(50.0)

Dyspnea 4(25.0) 28(24.1) 11 (17.7) 2(18.2) 2(9.5) 24(19.7) 14(20.9) 1 (10.0)

Nausea 3 (18.8) 26(22.4) 20(32.3) 3 (27.3) 9(42.9) 38(31.1) 17(25.4) 4(40.0)

Acne 5 (31.3) 23 (19.8) 11 (17.7) 0(0.0) 1(4.8) 29(23.8) 22(32.8) 3(30.0)

 

9.3.4 Effect of baseline renal function

ZD1839 and its metabolites are not significantly excreted via the kidney (<4%).

No clinical trials have been conducted with ZD1839 in patients with severely compromised renal function.

9.3.5 Effect of baseline hepatic function

Only 5 patients in Trials 39 and 16 had hepatic impairment at trial entry (4 patients with moderate impairment, and 1 patient with severe impairment). Adverse events for these 5 patients are similar to those seen in the overall patient population. Because of small numbers no conclusions should be drawn.

9.3.6 Safety of ZD1839 when given in combination with other drugs

ZD1839 showed no enzyme induction effects in animal studies.

ZD 1839 inhibited CYP2D6 by <50% in vitro, and the magnitude of the interaction with metoprolol, a CYP2D6 substrate was tested in Trial 0038. In this trial, there was no evidence of a clinically significant change to metoprolol exposure when co-administered with ZD1839 500 mg/day.

CYP3A4 inhibitors and inducers

ZD1 839 is metabolised by CYP3A4 in vitro and may be affected by co-administration of drugs which are inhibitors or inducers of CYP3A4 in man. The magnitude of such interactions has been assessed clinically using itraconazole, a selective inhibitor of CYP3A4 (Trials 0027 and 0051), and rifampicin, a potent but relatively non-specific inducer of CYP3A4 (Trial 0030). As anticipated, co-administration of itraconazole or rifampicin with ZD1839 increased and decreased exposure to ZD1839, respectively.

A review of adverse events data according to whether patients received concomitant CYP3A4 inhibitors or inducers, respectively, shows:

Drugs which lower gastric acidity

The 250 mg tablet formulation of ZD1839 shows a significant reduction in dissolution between pH 4 and 5. Consequently, it is possible that an increase in gastric pH could reduce the bioavailability of oral Z131839. Trial 0036 was conducted to assess the effect of increased gastric pH on the relative bioavailability of a 250 mg oral dose of ZD1839 in healthy male volunteers. The increase in gastric pH achieved in these volunteers, and the duration over which elevated gastric pH was maintained, were considered to be higher and for longer than might be achieved with standard antacid treatment. However, systemic elevation of gastric pH resulted in a reduction in exposure to ZD1839, and as such, did not present any concern regarding the safety of ZD1839.

Vitamin K antagonists

A total of 37 bleeding events in 31 patients taking warfarin concomitantly with ZD1839 were identified from across the ZD1839 clinical trial program.Based on these findings it was concluded that patients taking warfarin while on ZD1839 therapy should be monitored regularly for changes in PT (prothrombin time) or INR (International Normalized Ratio).

9.3.7 Safety Of ZD1839 In Pregnancy And Lactating Women

The safety of ZD1839 in pregnant or breast-feeding women has not been established in clinical trials.

It is not known whether ZD1839 is excreted in human milk. Following oral administration of carbon-14 labeled ZD1839 to rats 14 days postpartum, concentrations of radioactivity in milk were higher than in blood. Levels of ZD1839 and its metabolites were 11 to 19-fold higher in milk than in blood, after oral exposure of lactating rats to a dose of 5 mg/kg.

10 Conclusions and Recommendations

    1. Efficacy
    2. See pages 67-69.

    3. Safety
    4. See pages 103-108

    5. Recommendation

The Medical Officer defers making a final recommendation on approval until after the ODAC discussion and recommendation. Factors that will have to be considered by ODAC include 1) the 11 percent response rate observed in Trial 39 patients and in Caucasian patients in Trial 16; 2) the difficulty in interpreting quality of life/symptom relief data in phase II trials; 3) the uncertain effect of concomitant medication on symptom and quality of life improvement; 4) the characteristics of the responding patient population, (largely comprised of individuals with slow growing, less biologically aggressive tumors) and 5) the results of the two recently completed phase III first-line NSCLC ZD1839 trials that unequivocally failed to demonstrate clinical benefit.