OVERVIEW OF CLINICAL Studies

The primary efficacy data supporting the proposed indication for the treatment of chemotherapy-refractory patients with low grade and follicular NHL, with or without transformation are derived from Study RIT-II-004. The primary efficacy data supporting the indication for the treatment of Rituxan-refractory patients with low grade and follicular NHL, with or without transformation, are derived from Study CP-97-012.Three additional studies (RIT-I-000, RIT-II-001, and RIT-II-002) provide supportive anti-tumor activity data for the proposed indications.

Safety information relevant to single agent use of Iodine I-131 tositumomab in this patient population were obtained from the five efficacy/activity studies, the interim results of an additional study (RIT-II-003) conducted as an exploratory, Phase 2 study of initial treatment in patients with low grade, follicular NHL. Additional, limited safety data are provided from the expanded access experience under Protocol CP-98-020 and supplement by data provided to the sponsor from --- sponsor-investigator INDs for the treatment of individual patients.

individual CLINICAL study results

Study RIT-II-004

Title: Multicenter, Pivotal Phase 3 Study of Iodine I 131 tositumomab (Murine) Radioimmunotherapy for Chemotherapy-Refractory Low-Grade B-Cell Lymphomas and Low-Grade Lymphomas that Have Transformed to Higher Grade Histologies.

Design: A multicenter, historically-controlled, single-arm trial in patients with chemotherapy-refractory low grade or follicular NHL, with or without transformation.

Study opened- November 22, 1996

Study closed to accrual - March 6, 1998

Data cut-off- January 28, 2002

Study Sites

Specific Aims and Objectives (original protocol)

    1. To establish the response rate, response duration, time to progression, time to treatment failure and survival after treatment with iodine I-131 tositumomab Radioimmunotherapy (RIT) in patients with chemotherapy-refractory low-grade or transformed non-Hodgkin’s lymphoma
    2. To compare these endpoints to the patient’s previous chemotherapy outcome
    3. To assess the safety of iodine I-131 tositumomab RIT
    4. To assess the quality of life of treated patients using the --------------------------- validated questionnaire.

Eligibility criteria (original protocol)

Inclusion Criteria

  1. Histologically confirmed diagnosis of CD20 positive low-grade or transformed low-grade non-Hodgkin’s lymphoma.
  2. Treatment with at least two cycles of a qualifying chemotherapy regimen (6 weeks of single agent therapy) (see below), with failure to achieve an objective response, or relapse/progression within 6 months after completion of the last qualifying chemotherapy (LQC) regimen. Patients must have objective evidence of relapse or failure to respond.
  3. Karnofsky Performance Status ³  60%; anticipated survival of 3 months.
  4. Absolute granulocyte count > 1500/mm3 and a platelet count > 100,000/mm3.
  5. Adequate renal (creatinine <2.0 mg/dL) and hepatic function (bilirubin <2.0 mg/dL).
  6. Bidimensionally measurable disease or evaluable disease.
  7. Copies of original medical notes and radiographic studies documenting the chemotherapy drugs, number of courses and dates of their LQC, response to the LQC and, for responders, the date of disease progression.

 

Exclusion Criteria

  1. An average of >25% of the intratrabecular marrow space involved with lymphoma.
  2. Prior hematopoietic stem cell transplant.
  3. Active obstructive hydronephrosis.
  4. Pregnant or nursing females.
  5. Disease progression within one year, arising in a field previously irradiated with >3500 cGy.
  6. Concurrent treatment with any other anti-cancer drugs or biologics.

Qualifying chemotherapy regimens

Original protocol

Added in amendment 1 (----------------)

Added in amendment 2 (---------------)

Monitoring Plan (Original Protocol)

  1. Baseline (Within 2 weeks of Enrollment)
  2. History and Physical with Karnofsky Status; Lab – CBC, Serum Chemistry (Creatinine, Total Bilirubin, Na K, Cl, Bun, LDH, Urinalysis Thyroid functions, HAMA);Tumor Staging consisting of Bone Marrow within 42 days of entry; CT and other radiographs as needed of the chest, abdomen, pelvis within 28 days of entry

  3. Days 0; Day 2, 3, or 4; and Day 7
  4. Whole body biodistribution, Whole body dosimetry, and calculation of therapeutic dose

  5. Treatment phase
  6. CBC weekly for weeks 3-9, 13 & 25; Serum Chemistry weeks 3, 7, 13 & 25; tumor restaging (physical examination, radiologic studies, and bone marrow biopsy [if positive at baseline]) weeks 7,13, and 25; HAMA weeks 7 & 25

  7. Follow-up (Every 13 weeks up to 2 years or until discontinuation)
  8. History and Physical with Karnofsky Status; CBC, Serum Chemistry, HAMA; Tumor restaging studies including radiologic evaluations and bone marrow biopsy

  9. Long-term follow-up: Disease status and vital status every 6 months

Treatment Plan

The treatment consisted of two intravenous infusions; an initial dosimetric infusion followed in 7 to 14 days by a therapeutic infusion.

Dose Modifications

Excessively obese patients (defined as patients weighing more than 137% of the calculated lean body mass) the calculations to determine the iodine I-131 tositumomab activity will be performed using an upper limit of mass (maximum effective mass) based upon height and gender (Table for determination of max effective mass included as Appendix 2 to the protocol).

The administered dose for patients with platelet counts between 100,001 and 150,000/cu mm will be adjusted to deliver an estimated activity of 65cGy TBD. An additional adjustment for obesity may be performed, if indicated.

Concomitant Medications

Analytic Plan (Original Protocol)

Primary and Secondary Endpoints

The primary efficacy endpoint for this study will be the Overall Response Rate and duration established on this study.

Secondary efficacy endpoint analyses for this study will be survival, time-to-progression, time-to-treatment failure established on this study. Quality of life and safety analyses will also be included as secondary endpoint analyses. In addition, the response rate, response duration, time to progression and time to treatment failure will be compared with the patient’s last qualifying chemotherapy regimen.

Statistical Considerations

The proposed sample size of 60 patients was selected to enable response rates to be estimated with a maximum standard error of 0.065.The protocol stated that any patient who is enrolled but does not complete both the trace and therapeutic dose of Anti-B1, will be replaced so that a total of 60 radioimmunotherapy treated patients will be enrolled. Projected completion of accrual was September 1997.

Establishing of Response Rate, Best Response Rate and Duration Measures

Estimates of the rates of response, complete response and overall response (complete, clinical complete and partial), will be estimated from the study response rates. All acquired data will be analyzed by intention-to-treat. Point estimates and two-sided 95% confidence intervals will be calculated. One-sided 95% confidence intervals for minimum response rates will also be calculated. Mean and median duration response, time-to-progression, time-to-treatment failure, and survival will be calculated. If the study evaluation is performed before all data have reached their respective endpoints, right censored data for duration estimates will be treated as independent censoring and Kaplan-Meier survival estimates will be employed. Time-to-progression analyses will treat patients’ withdrawals and interventions for reasons other that progression or death as independent censoring. Subgroup analyses by number of previous therapies, time from diagnosis, histology, and previous response will be performed.

Efficacy Analyses: Patients As Their Own Control

Although the eligibility criteria restrict the study to patients who completed their previous qualify chemotherapy regimen so that the appropriate comparison is based on patients who complete treatment, all acquired data will be analyzed by intention-to-treat methods. Two-sided paired-sample tests of equivalency of the response rates following RIT with the last previous qualifying chemotherapy response will be performed at the 5% level. Paired t-test and non-parametric Wilcoxon signed rank tests comparing the duration of response, time-to-progression, and tine-to-treatment failure will be performed. If right-censoring is present, pair-matched censored survival tests will be performed. No stratification is present in the study as the patients as their own control performs this function. Subgroup analyses by number of previous therapies, time from diagnosis, histology, and previous response will be performed.

Revised, Final Analytic Plan

The primary endpoint of the study was a comparison of the number of patients having a longer duration of response (i.e., >30 days longer) after iodine I 131 tositumomab therapy compared to the number of patients having a longer duration of response after their LQC regimen. For the purposes of the primary efficacy endpoint, efficacy outcomes after the LQC and iodine I 131 tositumomab therapies were assessed by the MIRROR Panel. Secondary efficacy endpoints were response rate, complete response rate, and time to progression or death.

The original sample size of 60 patients is adequate to detect a a difference of 25% in the proportion of patients experiencing a longer duration of response (greater than 30 days) when treated with iodine I 131 tositumomab therapy compared to the proportion of patients experiencing a longer duration of response (greater than 30 days) to the LQC.

There are two dichotomous treatment outcomes that are assessed in this analysis

Only the non-equivalent cases contribute to the test statistic in this approach. The null hypothesis is that the durations of response are the following the most recent chemotherapy regimen and following Iodine-131 Anti-B1 Antibody therapy.

Statistical Test Method - McNemar’s test

The assumptions used in this trial were that the expected proportion of patients responding to therapy decreases with each successive therapy. Under this assumption, it is expected that the proportion of patients responding to Iodine-131 Anti-B1 Antibody would be smaller than the proportion of patients who responded to the most recent, preceding chemotherapeutic regimen.

A test incorporating the expected decrease in response was named a modified McNemar’s test and, under the null hypothesis, the McNemar’s test statistic was expected to equal 0.375. This corresponds to 75% of the 0.5 expected under the test, which ignores the order of therapies described in the previous paragraph. A one-sided exact binomial test was used.

The McNemar’s test is a test of the equality of the probability of each of these two groups. The response rate on the comparative chemotherapy is equal to that on Iodine-131 Anti-B1 Antibody if the number of patients in Group B equals the number of patients in Group C.McNemar’s test statistic equals the proportion of patients in Group C of the patients in Group B or Group C. Under the null hypothesis, this equals 0.5.

Efficacy analyses were to be conducted on a modified intent-to-treat basis, i.e., the analyses of efficacy include all patients who received any portion of the study drug including only the dosimetric dose.

MIRROR Panel

The MIRROR Panel was composed of two radiologists and two oncologists. All were board certified in their respective disciplines. The panel reviewed both patient radiographs and patient medical notes, while masked to the investigators’ assessments of response. Efficacy endpoints include response rate, complete response rate, duration of response and time to progression based on the MIRROR Panel independent review assessment. The independent review process was coordinated by an independent CRO. The representative from the CRO facilitated the review process and ensured appropriate masking of the data and completion of the CRFs.

 

Amendments to the protocol and dates of amendment

Amendment 1- -------------------------

Amendment 2 - ------------------------

Amendment 3 --------------------------

Amendment 4 -------------------------

Amendment 5 - -----------------------

Amendment 6 - ------------------------

Amendment 7 – -------------------------

Amendment 8 – -----------------------------

Amendment to the Statistical analysis plan, not identified as a protocol amendment in the BLA -----------------------

 

STUDY RESULTS

Patient Disposition

Sixty-one patients were enrolled at 8 centers.

Study RIT-II-004: Enrollment by Protocol Amendment

Submission

Submission

Date

Cumulative Number of

Subjects Enrolled

Original Protocol

----------

4

Amendment 1

----------

21

Amendment 2

----------

22

Amendment 3

----------

26

Amendment 4

----------

53

Amendment 5

----------

58

Amendment 6

----------

61

Amendment 7

----------

61

Amendment 8

----------

61

Total Enrollment

61

Conduct of the Study

FDA’s review of the case report forms for study RIT-II-004 noted the following unreported protocol violations of eligibility criteria for Subject No: 004-014-001, 004-018-001 and 004-020-007. These violations were discovered in the course of the review of case report forms.

The subject was enrolled on December ---, 1996. The subject received fludarabine from June 3 through August 2, 1996. CT scan evaluations obtained prior to fludarabine were interpreted by the MIRROR as an SPPD of 66.66 cm². CT scans following fludarabine on Aug 21, 1996 were read with an SPPD of 43.16 cm². Baseline enrollment CT scans on study entry, December---, 1996, were read with an SPPD of 22.00 cm², documenting a decrease in the SPPD of 67%. Thus the subject had a PR to fludarabine at study entry, in violation of the eligibility criteria.

004-018-001: This 39 yo female experienced rapidly progressive disease through prior therapy. Prior treatment included cytarabine 1 gm/m2 and etoposide 100 mg/m2 IV on days 1-5, administered on October ---, (cycle 1) and November ----, 1996 (cycle 2). The second cycle was complicated by catheter-related sepsis (Staph aureus) treated with catheter removal. CBC, creatinine and liver functions were normal during that admission. The patient was re-admitted for the dosimetric dose on November ---,1996 (study day –2) with increasing pleural effusions. Following administration of the dosimetric dose on Nov. ---, 1996 (day 0), she underwent thoracentesis and chest tube placement. On study day 6, the patient was noted to have hyperbilirubinemia and increased LFTs. On Dec. --- 1996 (study day 10), she was admitted for the therapeutic dose with a history of increasing lethargy and 2-3 day history of confusion described as "trouble finding the right words". Examination reports extensive expressive and receptive dysphasia with slight impairment of memory. The patient was mildly thrombocytopenic (77,000) with worsening LFTs, notably LDH of 11, 640 IU/ml. A diagnosis of hepatic encephalopathy was made on study day 12, with progressive hepatic deterioration and death on study day 14.

004-020-007: 45 yo male with diagnosis of NHL in Dec. 1994 and multiple chemotherapeutic regimens prior to study entry, received therapeutic dose of 82 mCi (75 cGy TBD) on Jan --, 1998. Baseline CBC (12/12/97) revealed ANC 5.6, hemoglobin 12 gm/dL, and platelets 116,000. The patient responded to treatment (apparent CR) but suffered persistent thrombocytopenia through 1998 and 1999 with development of leukopenia in 1999 and a diagnosis of MDS in September 1999. The patient suffered subdural hematoma in June 2000 (secondary to thrombocytopenia) and died with progressive hemorrhage and hemoptysis on -----------------------------.

 

Subjects for whom protocol violations were identified by the sponsor, are summarized in the following table.

 

 

 

 

 

 

Patent ID

NHL

subtype

Dose

(cGy)

Study

day

Violation

type

Description

Violation of Eligibility Criteria

004-013-004 66F T75C

T

75

0

ENTRY

WBC = 2.9, current protocol required >3.5 but was being amended

004-016-002 80M T65C

T

65

-1

ENTRY

WBC = 3.5, current protocol required >3.5 but was being amended

004-016-009 68M T75L

T

75

-8

ENTRY

Bone marrow involvement based on unilateral biopsy (20-25%)

004-013-017 65M T65L

T

65

0

ENTRY

Patient received oral prednisone 13 days prior to study entry

004-020-002 50M T75C

T

75

0

ENTRY

CT scans 29 days prior to enrollment (protocol requires 28 days)

Violations of Informed Consent

004-014-006 48M L75L

L

75

-2

ENTRY

Verbal informed consent given, not signed until after enrollment (9/4/97)

004-018-001 39F T00C

T

0

-1

ENTRY

Informed consent not approved by ethics committee when signed

Violation of Eligible NHL Histology

004-021-001 51M I75C

I

75

0

ENTRY

Mantle cell, pathology re-read

Violation of Thyroid Protection Protocol

004-013-003 43M T65C

T

65

0

TREATMENT

SSKI started on same day as dosimetric dose

004-013-004 66F T75C

T

75

0

TREATMENT

Pt was started on SSKI plus potassium perchlorate rather than protocol regimen

004-013-005 63M T75L

T

75

0

TREATMENT

SSKI started on same day as dosimetric dose

004-013-006 38F L75L

L

75

0

TREATMENT

SSKI started on same day as dosimetric dose

004-013-007 55M L75L

L

75

0

TREATMENT

SSKI started on same day as dosimetric dose

004-013-009 61M L75L

L

75

0

TREATMENT

SSKI started on same day as dosimetric dose

004-013-012 66F L75L

L

75

0

TREATMENT

SSKI started on same day as dosimetric dose

004-020-008 71M L65L

L

65

0

TREATMENT

Lugols solution dosed at 5 gtts tid, protocol requires 20 gtts/day

Violation of Timing for Dose Assessment or Administration of Therapeutic Dose

004-021-002 51M L65L

L

65

15

TREATMENT

Therapeutic dose given 15 days after dosimetric dose

004-029-003 39M L75L

L

75

1

TREATMENT

Second total body count performed on day 1 and third on day 5

Violation of Therapeutic Dose Administration

004-020-005 66M L88L

L

87.8

8

TREATMENT

Calculated dose 104 mCi, actual dose 125 mCi

004-020-006 60M L75L

L

75

8

TREATMENT

Enrolled at 65 cGy, treated at 75 cGy

004-020-007 45M L75L

L

75

14

TREATMENT

Enrolled at 65 cGy, treated at 75 cGy

Financial Disclosure

Under 21 CFR 54, an applicant is required to certify all investigators and consultants have disclosed any financial arrangements that could influence the study outcome.

The following investigators disclosed one or more of the above types of financial arrangements meeting:

 

FDA Assessment of Potential Conflicts- There was no evidence that the data from these sites were significantly different from other study sites or altered the results of the study.

Bioresearch Monitoring Inspection Results

Inspections of five clinical sites were performed in support of BLA 99-0813 for Protocol RIT-II-004 entitled "Multicenter, Pivotal Phase III Study of Iodine-131 Anti-B1 Antibody (Murine) Radioimmunotherapy for Chemotherapy-Refractory Low-Grade B-Cell Lymphomas and Low-Grade Lymphomas that have Transformed to Higher Grade Histologies." In addition one of the sites (University of Nebraska) was also inspected for Protocol RIT-II-001, entitled "Multicenter, Phase II Dosimetry/Validation Study of 131Iodine-AntiB1(murine) Radioimmunotherapy for Chemotherapy-Refractory Low-Grade B-Cell Lymphomas and Low-Grade Lymphomas that have Transformed to Higher Grades" after the sponsor reported that data was missing. The inspections were conducted in accordance with CPGM 7348.811, the Inspection Program for Clinical Investigators.

Specific questions concerning the studies were included. Data audits were performed at the following five sites:

Site

Investigator

Form 483

Classification

Kaiser -

Vallejo

Dr. Fehrenbacher

No

VAI

Stanford University

Dr. Knox

Yes

VAI

University of Michigan

Dr. Kaminski

Yes

VAI

University of Washington

Dr. Press

Yes

VAI

University of Nebraska

Dr. Vose

Yes

VAI

 

Inspectional Summary Statement

The results of bioresearch monitoring inspections indicate that the deviations are not substantive, with the exceptions noted (verification of dose delivered), and that the submitted data can be considered reliable and accurate.

Study Population:

The study population consists of low grade and follicular NHL; approximately 1/3 of the patients have disease, which has transformed to a higher histologic subtype. The population has been heavily pretreated with chemotherapy (median number of prior regimens –4) but not radiotherapy. None of the patients have undergone dose-intensive chemotherapy with prior stem cell support. The majority had advance disease (stage III and IV) and 11% have bulky lesions. The characteristics of the population at study entry are summarized in the following table.

Baseline Characteristics for Patient Population in Study RIT-II-004

Baseline Characteristic

ITT population

n=61

Age (years)

Median(range)

59 (38-82)

Q1; Q3

52; 68

Gender

 

Males (%)

38 (62%)

Race

 

Caucasian (%)

59 (97%)

Histologic diagnosis at entry

 

W/o transformation

 

Low grade

37 (61%)

Intermediate grade

1 (2%)

High grade

0

With transformation

 

Low grade

0

Intermediate grade

23 (37%)

High grade

0

Stage of disease

 

I

0

II

1(2%)

III

13 (21%)

IV

47 (77%)

Missing

0

IPI category

 

0

0

1

7 (12%)

2

22 (36%)

3

22 (36%)

4

7 (12%)

5

1 (2%)

Missing

2 (3%)

Max. tumor diameter

 

< 5 cm

25 (41%)

³ 5, <10 cm

29 (48%)

> 10 cm

7 (11%)

# Prior chemo regimens

 

Median (range)

4 (2-13)

25th, 75th quartiles

3, 5

# Prior RT regimens

 

Median (range)

0 (0-7)

25th, 75th quartiles

0, 1

No Prior BMT

61 (100%)

Time from diagnosis to entry (mos)

 

Median (range)

4.4 (0.8, 27.8)

25th, 75th quartiles

2.6, 7.2

 

 

Primary Efficacy Outcome:

The response to treatment and response duration for the most recent qualifying chemotherapy regimen and for Iodine I-131 tositumomab was determined by the Expanded MIRROR panel for 60 patients; data were not reviewed for the patient who withdrew from study and received neither the dosimetric nor therapeutic dose. There were 7 patients who responded to the LQC for an ORR of 12% and a CR/CCR of 2%. There were 28 subjects who responded to Iodine I-131 tositumomab for an ORR of 47% and a CR/CCR of 20%. The response determinations by the MIRROR panel are summarized in the table below.

Treatment Response by Expanded MIRROR Panel (Effoutm dataset)

According to Treatment for Patients enrolled in RIT-II-004

Response Category

Last Qualifying Chemotherapy

IODINE I-131 TOSITUMOMAB

Complete Response

1

8

Complete Clinical Response

0

4

Partial Response

6

16

Stable Disease

5

4

Progressive disease

48

28

Total Patients

60

60

 

There were 28 patients whose disease did not respond to either therapy or for whom the duration of response to either therapy was roughly equivalent (< 30 days difference in the duration of response to either treatment). This group was classified as "Duration Equivalent".

Response to

Iodine I-131 tositumomab

No Response

to Iodine I-131 tositumomab

Responded to LQC

3

4

7

No Response to LQC

25

28

53

28

32

 

 

The remaining 32 patients achieved an objective tumor response (CR, CCR, or PR) following Iodine I-131 tositumomab, the last qualifying chemotherapy regimen, with a difference in the durations of response to Iodine I-131 tositumomab and to the last qualifying chemotherapy regimen of more than 30 days. Among these 32 patients, 27patients experienced a longer duration of response to Iodine I-131 tositumomab (difference in the durations ³ 30 days) as compared to the duration of response to last qualifying chemotherapy regimen. This group of 27 consisted of 25 patients who failed to respond to the LQC but did respond to Iodine I-131 tositumomab and 2 patients who responded to both the LQC and to Iodine I-131 tositumomab but had a longer duration of response to Iodine I-131 tositumomab than to LQC (difference in response durations ³ 30 days).

Response to

Iodine I-131 tositumomab

No Response

to Iodine I-131 tositumomab

Responded to LQC

(2 + 1)

4

7

No Response to LQC

25

28

53

(27 + 1)

32

The remaining 5 patients experienced a longer duration of response to the last qualifying chemotherapy regimen (difference in the durations ³ 30 days) as compared to the duration of response to Iodine I-131 tositumomab. This group was comprised of 4 patients who responded to the LQC but not to Iodine I-131 tositumomab and one patient who responded to both the LQC and Iodine I-131 tositumomab, in whom the duration of response to LQC was longer than to Iodine I-131 tositumomab.

 

Response to

Iodine I-131 tositumomab

No Response

to Iodine I-131 tositumomab

Responded to LQC

(2 + 1)

4

7 (2 + 5)

No Response to LQC

25

28

53

28

32

 

Based on the Expanded MIRROR Panel assessment of response and response duration as described above, the following proportions were generated for use in the primary efficacy analysis:

28/60 (47%) patients had an equivalent duration of response

32/60 (53%) patients had a non-equivalent duration of response

Primary Efficacy Analysis

The primary efficacy endpoint of the study was the comparison, as assessed by the Masked Independent Randomized Radiology and Oncology Review (MIRROR) panel, of the number of patients having a longer duration of response (i.e., more than 30 days) on their last qualifying chemotherapy regimen to the number of patients having a longer duration of response on IODINE I-131 TOSITUMOMAB™.

FDA followed the protocol defined primary endpoint and compared the duration of response on I-131 Antibody therapy to prior chemotherapy. The duration of response is linked with the response. If there is no response (SD, PD) on both (Bexaar & Prior Chemo) then these patients were classified as equivalent regardless of how long their Stable Disease (in favor of either Iodine I-131 tositumomab or prior Chemo) was or if they had a response (CR, CCR or PR), but the difference in the duration of response between Bexaar and prior Chemo was lass than 30 days. There were 28 patients in this group. The remaining 32 patients had a CR or CCR or PR on either therapy and the difference in the duration of response was more than 30 days. There were 27 patients from these 32 whose the duration of response was longer than 30 days on Iodine I-131 tositumomab as compared to Prior Chemo, and 5 from these 32 whose duration of response was longer than 30 days on prior chemo as compared to Bexaar.

Using this algorithm, the following table provides a summary of the results for the primary endpoint for confirmed responses:

Response Frequency % of 60

-------------------------------------------------------------------

Equivalent duration 28 47 %

Longer response with 27 45 %

Iodine I-131 tositumomab

Longer response with Chemo 5 8 %

The sign-rank test takes all data into account, equivalent as well as non- equivalent cases, and tests the hypothesis that overall there is a statistically change. Then two proportions can be compared.

p < 0.0001 using sign-rank test in favor of Bexaar.

Analysis of Proportions

Let p1 = proportions of equivalent responses

p2 = proportions of responses favoring Iodine I-131 tositumomab

p3 = proportions of responses favoring prior chemotherapy

Of interest is to test the null hypothesis H0 : p2 = p3 conditioned on equivalent response, i.e., ignoring equivalent response, and n becomes 32, and test is . H0 : p2 = p3 = 0.5 versus H1 : p2 ≠ p3 . The p-value for testing this H0 is < 0.0001 (Exact Binomial test) in favor of Bexaar

Note: FDA’s analysis differs slightly from the analysis of the primary efficacy endpoint as performed by the sponsor.

While, FDA and the sponsor used different approaches to assess the primary endpoint, the results of both tests were similar; both demonstrating a highly significant increase in the durations of response after Iodine I-131 tositumomab. The sponsor applied the one-sided exact McNemar's test for comparing the number of patients with longer response on Iodine I-131 tositumomab compared to the number of patients with longer response on chemotherapy. This test only accounts for patients with nonequivalent durations of response. FDA applied the Wilcoxon signed rank test using all response duration data. As the Wilcoxon signed rank test includes the magnitude of the duration of response, it is more powerful in this study (as the higher response rate after Iodine I-131 tositumomab is also associated with a longer duration of response). The sponsor approach accounts for the paired censored data. As the censored values were almost exclusively with the longest durations of response, the censoring effect is minimal. Thus, while the statistical approaches used by FDA and the sponsor differed, the conclusions were similar.

Secondary Efficacy Outcomes

  1. Comparison of other efficacy outcomes between Iodine I-131 tositumomab and LQC:

The protocol identified several secondary endpoints, including comparisons between efficacy outcomes following Iodine I-131 tositumomab as compared to the most recent qualifying chemotherapy regimen. These outcomes included comparisons of overall response rates, complete response rates, durations of overall response and of complete responses. For each of these analyses, the differences were in favor of Iodine I-131 tositumomab and were significantly different.

MIRROR Panel–Assessed Secondary Efficacy Endpoint Data:

Study RIT-II-004 (N = 60)

Secondary Efficacy Endpoints

Last Qualifying Chemotherapy
(N = 60)

Iodine I 131 tositumomab
(N = 60)

Overall Response Rate

7/60 (12%)

28/60 (47%)

Median (95% CI) duration of response for responders (months)

4.1
(3.0–5.4)

11.7
(6.9–NR)

Complete response Rate

1/60 (2%)

12/60 (20%)

Median (95% CI) duration of response for complete responders (months)

4.8

NR
(12.5–NR)

 

 

Exploratory Analyses

  1. Subset analyses of the primary efficacy analysis in patients whose disease has undergone transformation and in patients whose disease has not undergone transformation to a higher histologic subtype of NHL.

Subset analyses were done comparing Last Qualifying Chemotherapy Response – Original & Expanded MIRROR Assessed to Iodine I-131 tositumomab Confirmed Response – expanded MIRROR Assessed to evaluate if the original and expanded MIRROR assessment made any difference to the efficacy of the primary endpoint for each of the following two subset populations.

  1. Patients with low grade non-Hodgkin’s lymphoma (NHL) that has not undergone transformation (36 patients) – Not Transformed
  2. Patients with intermediate grade, follicular NHL that has not undergone transformation (1 patient)
  3. Patients with low grade non-Hodgkin’s lymphoma (NHL) that has undergone transformation (23 patients) – Transformed

Last Qualifying Chemotherapy Response Versus Iodine I-131 tositumomab Confirmed Response – expanded MIRROR Assessed

Using previously defined algorithm, the following table provides a summary of the results of the subset analysis for the primary endpoint (the patient with an intermediate grade histologic subtype of NHL was not classified as not transformed, this patient was a non-responder):

 

Low Grade/follicular Transformed

Response Frequency % of 37 Frequency % of 23

----------------------------------------------------------------------------------------------------

Equivalent response duration 11 30 % 17 74 %

Longer duration with 22 59 % 5 22 %

Iodine I-131 tositumomab

Longer duration with Chemo 4 11 % 1 4 %

p-value (sign-rank test) <0.0001 0.0625

Conclusions: There is a significant difference in favor of Iodine I-131 tositumomab for patients with low grade, untransformed NHL (p <0.0001 ), but not significantly different in patients with NHL with transformation, (p=0.0625, trend in favor of Iodine I-131 tositumomab). Iodine I-131 tositumomab activity is different in two sub-populations. The patients with NHL without transformation (all but one with low grade histologic subtype) benefit significantly more from Iodine I-131 tositumomab than transformed patients (p=0.0071, Fisher’s exact test).

  1. Assessment of response to Iodine I-131 tositumomab in patient subsets (patients with and without evidence of histologic transformation to a more aggressive (higher grade) histologic subtype.
  2. At the initiation of the study, the sponsor was urged to limit the patient population to a more homogeneous group. Specifically, the sponsor was asked to exclude subjects with evidence of histologic transformation since FDA felt this was a biologically different disease than low grade and follicular lymphoma. The sponsor declined, stating that evidence of histologic transformation was a prognostic factor but only one of many in this chemotherapy refractory population. As a result of these discussions, the protocol was to include a plan for analysis of the study results in patient subsets, i.e., those with and those without evidence of histologic transformation. As can be seen in the table below, the likelihood of achieving a response was much lower in the transformed subset.


    Response

    Category

    Response Rate in Subset without Transformation

    Response Rates in Subset with Transformation

    N =23

    CR

    14% (5/37)

    13%(3/23)

    CCR

    11% (4/37)

    0 (0/23)

    PR

    38% (14/37)

    8% (2/23)

    ORR

    62% (23/37)

    21% (5/23)

    SD

    8% (3/37)

    4% (1/23)

    PD

    30% (11/37)

    74% (17/23)

     

  3. Analyses of response according to I-131 dose administered
  4. The dose of 131-Iodine administered was derived for each subject. This exploratory analyses were conducted to assess for relationships between response to Iodine I-131 tositumomab treatment and the total dose of 131-I administered or the dose adjusted for body mass or surface area administered. The results are presented in the table below.

    Confirmed Response according to Dose of Iodine-131

    Dose Basis

    Non Response

    Response

    Total

    Dose (mCi)

    Median

    77.9

    97.7

    90.2

    Range

    (0-173.4)

    (47.2-212)

    (0-212)

    Dose (mCi/m2)

    Median

    43.9

    49.7

    46.4

    Range

    (0-83.8)

    (33-100)

    (0-100)

    Dose (mCi/kg)

    Median

    1.1

    1.2

    1.2

    Range

    (0-2)

    (0.9-2.4)

    (0-2.4)

     

     

     

     

     

     

     

     

     

     

     

     

     

     

     

     

     

     

  5. During the course of the study, the source of the tositumomab antibody was changed from ------- to Coulter. The antibodies from the different manufacturing sites were biochemically comparable and yielded a similar pharmacokinetic profile. A comparison of the response rates by antibody-source showed a slightly higher but not significantly different response rate for the -------manufactured antibody product than for the Coulter-manufactured product.

I-131-B1 Therapy Response Assessment by

Antibody Manufacturer

Antibody Manufacturer

Overall Response Rate

(No. responders/total)

Total number of patients treated

Coulter-manufactured antibody

35% (7/20)

20

---------manufactured

antibody

52% (21/40)

40

Total

46% (28/60)

60

The following figure illustrates the relative comparison of the duration of response for each patient following treatment with their LQC and following treatment with iodine I 131 tositumomab. On the left side of the figure are data from 5 patients with a longer duration of response for the LQC; in the center there are data from 29 patients with less than 30 days difference in the duration of response; and on the right side of the figure are data from 26 patients with a longer duration of response after iodine I 131 tositumomab.

 

Figure: Paired Comparison of Duration of Response


Safety Assessment

The most common and the most severe adverse events were hematologic toxicities. The following are the most common non-hematologic toxicities: asthenia (57%), fever (38%), nausea (37%), increased cough (30%), pain (25%), anorexia (25%), vomiting (22%), diarrhea (22%), abdominal pain (20%), chills (18%), infection (17%), and dyspnea (15%). The non-hematologic toxicities were predominantly mild to moderate in severity. The hematologic toxicities were predominantly severe (grade 3 or 4 according to the NCI CTC) and prolonged in nature. The profile of the hematologic toxicity is summarized in the following table.

Per-Patient Incidence of

Grade 3-4 Hematologic Toxicity

Hematologic Toxicity

Efficacy studies

n=229

Neutropenia

 

% Documented Grade 3-4 toxicity

59%

Median days to nadir (95% CI)

42 (41, 45)

25th and 75th percentiles for days to nadir

39 ; 47

Median duration of documented Grade 3-4 toxicity

30 (22, 43)

25th and 75th percentiles for duration of toxicity (days)

21; 49

   

Thrombocytopenia

 

% Documented Grade 3-4 toxicity

48%

Median days to nadir (95% CI)

34 (32, 35)

25th and 75th percentiles for days to nadir

28; 40

Median duration of documented Grade 3-4 toxicity

29 (23, 40)

25th and 75th percentiles for duration of toxicity (days)

22; 43

Anemia

 

% Documented Grade 3-4 toxicity

19%

Median days to nadir (95% CI)

48 (42, 55)

25th and 75th percentiles for days to nadir

39; 60

Median duration of documented Grade 3-4 toxicity

22 (6, 36)

25th and 75th percentiles for duration of toxicity (days)

16; 36

 

Serious Adverse Events (SAE)

There were 23 SAE reported in 17 (28%) patients. An additional 4 patients (7% of the study population) developed MDS. A summary of these events are provided below