ODAC Briefing Document for Zarnestra

NDA-021824

 

by

DODP, CDER, FDA

 

 

 

Table of Contents

 

 

I.          Basic Information                                                                                              3

 

II.         Background                                                                                                      4

 

III.       Summary of Studies Submitted                                                              7

 

IV.       CTEP-20 Study Design and Significant Milestones                                            8

 

V.        Study CTEP-20 Efficacy                                                                                  11

                        5.1       Study CTEP-20 Population and Risk Factors                                       

                        5.2       Complete Response (CR) Analyses

                        5.3       Response Duration

                 5.4       Overall Survival

 

VI.       Study CTEP-20 Safety                                                                         19

                        6.1       Drug Exposure                                                                                                                        6.2            Overall Toxicity

                        6.3       Common Adverse Events

                        6.4       Grade 3 or 4 Adverse Events

                        6.5       Significant Adverse Events that Caused Treatment

                                    Termination or Other clinically significant Outcome

                        6.6       Deaths

 

VII.      FDA’s Summary of CTEP-20 Efficacy and Safety                                            40

 

VIII.     References                                                                                                       42

List of Tables

 

Table 1: Approvals for AML and MDS. 5

Table 2: Safety Studies. 7

Table 3: Clinical Studies Submitted for Efficacy in AML. 8

Table 4: Time and Events Schedule. 10

Table 5:  Summary of Patient Population. 11

Table 6: AML Risk Factors (Study CTEP-20: Sponsor’s Elderly Poor-Risk AML Population) 11

Table 7: Response by Site (CTEP-20, Elderly Poor Risk AML Population) 12

Table 8: Cross-Tabulation of CR–Independent Central Review Versus Site Review (CTEP-20: Elderly Poor-Risk AML Population) 12

Table 9: List of Sponsor Claimed CRs with Treatment Information (CTEP-20, Elderly Poor Risk AML Population) and with FDA Footnotes. 13

Table 10: The Sponsor Summarized Investigator Claimed CR Patient’s CR duration, Time to CR, PFS and Survival. (CTEP-20, Elderly Poor Risk AML Population) with FDA Footnotes. 14

Table 11: Summary of CR Assessment by Investigator and Independent Review Grouped by Age or by Whether Patient Had Prior MDS (CTEP-20, Elderly Poor Risk AML Population) 15

Table 12: FDA Assessment of  CR Rates (CTEP-20: Reviewer Defined Elderly Poor-Risk AML Population) 16

Table 13: FDA Assessment of Duration of Confirmed Complete Response (Elderly Poor-Risk Population) 17

Table 14: FDA’s Exploratory Results of Overall Survival (Elderly Poor-Risk AML Population) 18

Table 15: Study Treatment by Cycle (Study CTEP-20: Sponsor defined Elderly Poor-Risk Subset)) 19

Table 16: Overview of Adverse Events (CTEP-20: Elderly Poor-Risk AML and All-Treated AML Data Sets) 20

Table 17: Adverse Events Reported in at Least 10% of Subjects (All Grades) – Part 1 (CTEP-20: Elderly Poor-Risk AML Subset) 21

Table 18: Adverse Events Reported in at Least 10% of Subjects (All Grades) – Part 2 (CTEP-20: Elderly Poor-Risk AML Subset) 22

Table 19: Treatment Emergent Grade 3 and 4 AEs Reported (>  5% or < 5% but may have clinical significance) - Part 1 (CTEP-20: Elderly Poor-Risk AML Subset) 23

Table 20: Treatment Emergent Grade 3 and 4 AEs Reported (>  5% or < 5% but may have clinical significance) - Part 2 (CTEP-20: Elderly Poor-Risk AML Subset) 24

Table 21: Treatment Emergent Grade 3 and 4 AEs Reported (>  5% or < 5% but may have clinical significance) - Part 3 (CTEP-20: Elderly Poor-Risk AML Subset) 25

Table 22: Treatment Emergent Grade 3 and 4 AEs Reported (>  5% or < 5% but may have clinical significance) - Part 4 (CTEP-20: Elderly Poor-Risk AML Subset) 26

Table 23: Drug-Related Serious Adverse Events (> 1 Subject, CTEP-20: Elderly Poor-Risk AML Subset) 27

Table 24: Drug-Related Adverse Events Reported in at Least 5% of Subjects – Part 1 (CTEP-20: Elderly Poor-Risk AML Subset) 28

Table 25: Drug-Related Adverse Events Reported in at Least 5% of Subjects – Part 2 (CTEP-20: Elderly Poor-Risk AML Subset) 29

Table 26: Drug-Related Adverse Events Leading to Treatment Termination (CTEP-20: Elderly Poor-Risk AML Subset) 31

Table 27: Drug-Related Adverse Events Leading to Dose Reduction (CTEP-20: Elderly Poor-Risk AML Subset) 33

Table 28: Drug-Related Adverse Events Leading to Temporary Interruption of Zanestra (CTEP-20: Elderly Poor-Risk AML Subset) 35

Table 29: Drug-Related AEs that Had Unfavorable Outcome (persistent toxicity or death) 36

Table 30: Main Cause of Death Within 30 Day of Study Termination and Within 30 Days of Receiving the Fist Dose (CTEP-20: Elderly Poor-Risk AML Population) 38

Table 31: Death during the Study Caused by Adverse Events (CTEP- 20: Elderly Poor-Risk AML Subset) 39

 

I. Basic Information:

Established Name                                        Zarnestra

Trade Name                                                  Tipifarnib

Therapeutic Class                                        Inhibitor of farnesyl transferase

Sponsor                                                         Johnson & Johnson

Designation                                                   Priority

Formulation

Zarnestra is formulated in film-coated tablets.  Each tablet contains an equivalent to 100 mg of tipifarnib base.

Proposed Dosing Regimen 

Zarnestra is administered orally with food at the dose of 600 mg twice daily for 21 days, followed by a rest period of a minimum of 7 days.  The rest period may be extended to a maximum of 42 days depending on toxicity.

Proposed Indication             

Zarnestra is indicated for the treatment of elderly patients with newly diagnosed poor-risk acute myeloid leukemia.

 

 

II. Background

 

FDA approvals for AML

 

For approval, a drug must demonstrate substantial evidence of effectiveness in a defined patient population. Generally, FDA has accepted survival and other clinically meaningful outcomes for regular approval of oncology drugs. FDA has accepted endpoints other than survival or irreversible morbidity, such as durable complete response for regular approval in hematological malignancies. This has been the case since durable remissions are associated with reduced morbidity and mortality in many hematologic malignancies.

 

In general, regular approvals for leukemia indications have been based on evaluation of complete remissions (CR) and remission duration. For second-line and refractory indications, these endpoints have been evaluated mainly in single arm trials. For first-line indications, evidence of benefit was derived from single arm and randomized trials. Randomized trials were necessary in some settings given the context of evaluating multi-drug regimens in order to provide information regarding isolation of a drug’s effect in the context of a combination regimen.

 

In the case of approvals under subpart H regulations (accelerated approval) , evidence of benefit was derived from single arm trials, with reliance on response rates. With respect to response duration, there was variability in terms of demonstration of durable remissions, and in a few cases, lack of documentation of duration of  response/remission.

Focusing on AML specifically, approvals are summarized in Table 1. First-line indications included idarubicin and daunorubicin. Both were regular approvals based on demonstration of durable remissions. In both cases, randomized trials were conducted. In the case of idarubicin, a survival advantage was also demonstrated in two randomized trials.

In the case of gemtuzumab ozogamicin, accelerated approval for patients age 60 or older with CD33+ disease who are not candidates for cytotoxic chemotherapy was based on complete remission in three single arm studies.  Although relapse-free survival was evaluated (2.3 months median RFS for age >60 and 17 months for those age < 60), duration of remission could not be reliably ascertained as 45% of patients who achieved a remission received additional anti-leukemic therapy.

 

Tretinoin and arsenic trioxide received regular approval for the second-line treatment of patients with acute promyelocytic leukemia. These approvals were based on single arm trials demonstrating significant remission rates.

In addition, 5-azacytidine (Vidaza) recently received regular approved for treatment of all subtypes of MDS, based on a 15% response rate (CR+PR) in a randomized study (n = 191) comparing Vidaza to best supportive care (CALGB 9221).  Supportive data was provided by two additional single arm trials. There were a small fraction of AML patients in CALGB 9221 and in the two single arm trials conducted. Response rates for these patient subgroups are summarized in Table 1.

Table 1: Approvals for AML and MDS

 

Drug	Indication	Trial Design	Benefit
Idarubicin	Adult AML M1-M7 in combination with other drugs (first line)	4 randomized trials in combination with cytarabine, compared to daunorubicin/cytarabine N = 823	CR rates of 67-78% versus 55-58% for dauno Survival advantage in 2 studies
Daunorubicin	Remission induction in adult ANLL	Single arm and randomized	40-50% CR rate as single agent and 53%-65% CR rate with Ara-C
Gemtuzumab ozogamicin (Mylotarg)	2nd line AML, 60 yrs or older, CD33+, not candidates for cytotoxics	3 single arm studies; total N= 142	CR = 16% CR + CRp = 30%
Tretinoin	APL, 2nd line	Single arm study (MSKCC N = 35) and two NCI cohorts (total 94 relapsed and 52 de novo patients)	MSKCC 73-80% CR rate NCI Cohorts 36-68% CR rates
Arsenic Trioxide	APL, 2nd line	Single arm study (N = 40)	CR = 70%
5-Azacytidine	MDS (clinical study included some AML patients)	Randomized trial of BSC vs BSC+ vidaza (N=191)       Two single arm trials in RAEB, RAEB-T, CMMoL or AML (N = 72 and N = 48)	Randomized study results: Overall CR+PR = 16% versus 0%  ; transfusion independence AML subgroup N = 10 in vidaza arm with 12.5% CR rate   Single arm study results: Overall CR+PR = 14% Overall CR+PR = 19% AML subgroups N=17 and N=1, combined CR rate = 18%

 

 

Standard AML 1^st line treatment and elderly poor-risk AML

Patients with newly diagnosed AML, if not treated, will progress rapidly to a fatal outcome. The treatments for AML are designed to be sufficiently aggressive to achieve complete remission because partial remission offers no substantial survival benefit.  The goal of remission induction therapy in AML is to reduce the leukemia burden to a level undetectable by standard morphologic techniques.   For almost two decades, the standard remission induction for AML has been a combination of seven days of cytarabine at 100-200 mg/m² daily with three days of daunorubicin at 60 mg/m² daily (7/3 regimen).  In patients who achieved complete remission, consolidation therapy is given. Salvage therapies are reserved for the time of relapse.  With this 7/3 combination therapy, complete remission can be expected in approximately 60% to 75% of adult patients.   Recent studies designed to improve AML induction therapy have involved changes in the higher dose of cytarabine, alternatives to the use of daunorubicin (idarubicin or mitoxantrone), the addition of other chemotherapy agents (etoposide) to the combination, and use of hematopoietic growth factors.  The results of these studies did not suggest significant clinical benefit and have changed little in standard induction therapy.

 

Elderly patients with AML present a unique clinical entity. The efficacy of therapy in elderly patients with newly diagnosed AML is limited by a higher incidence of intrinsic resistance to chemotherapy and a reduced ability to tolerate both antileukemic therapy itself and the associated supportive care (e.g., nephrotoxic anti-infective therapy). Existing data indicate that patients older than 60 years of age who have a good performance status and meet the medical criteria of adequate organ function are usually offered standard induction therapy and have an overall probability of complete remission of 50%. Other clinical studies suggest that lowering the dose of daunorubicin from 60 mg/m² to either 45 or 30 mg/m² for patients age 60 or older would diminish the incidence of severe toxicity and toxic death.  This decrease in toxicity more than overcomes any decrease in the antileukemic effects from the attenuated dose of anthracycline, as estimated by a 30-50% decrease in treatment efficacy.

 

A high rate of early treatment-related mortality is a major contributor to the lower survival rates observed in elderly patients with poor-risk AML. Reduced tolerability and increased risk factors to induction chemotherapy, both related to increasing age, represent a multifactorial risk/benefit outcome, affected by duration and severity of treatment-induced myelosuppression, gastrointestinal mucositis, baseline organ dysfunction or co-existing medical conditions leading to organ malfunction, poor performance status and pre-malignant conditions. Treatment-related mortality in elderly patients with poor-risk AML may be as high as 25%.  In a study of patients at least 80 years of age, the mortality rate at 1 month was 48%.  As a result, elderly patients with poor-risk AML often are offered palliative treatments or supportive care alone.  For such patients, the benefit-risk ratio of conventional cytotoxic chemotherapy was expected to be low; and they were not usually considered as optimal candidates to receive standard induction chemotherapy.  Retrospective analysis on 2657 AML patients whose age is 65 or older by Menzin et al., indicated that only 30% of them received chemotherapy, and there is an inverse relationship between age and likelihood of receiving induction or  palliative chemotherapy.

 

Zarnestra, a farnesyl treansferase inhibitor, has been tested in clinical studies with the aim of developing induction regimens that might result in less toxicity without a sacrifice in antileukemic effects.

 

III.  Summary of Studies Submitted:

 

There were 11 studies submitted in the Zarnestra NDA.  All 11 studies are relevant to safety and dose finding (Table 2).  The studies relevant to the Zarnestra efficacy in AML are summarized in Table 3.  The population most relevant to Zarnestra’s proposed indication, induction therapy in elderly patients with untreated poor-risk AML, is a subgroup of subjects in study CTEP-20 (79% of enrollment).  The studies INT-17 (refractory and relapsed AML) and CTEP-1 (dose escalation in hematological malignancy) are less relevant to the proposed indication.

 

Table 2: Safety Studies

Clinical Study ID	Evaluable Subjectsa	Study Design and Dosing Regimen
CTEP-20	157b/171	Single arm, open label in untreated AML.  Oral 600 mg twice daily (b. i. d.) for 21 days of each 28- day cycle
INT- 17	252	Single arm, open label in refractory and relapsed  AML, Oral 600 mg b. i. d. for 21 days of each 28- day cycle, with dose escalations to 900 mg b. i. d.
USA- 1	27	Dose escalation, single-Agent advanced solid tumor,  25 to 850 mg b. i. d. oral solution; 500 to 1,300 mg b. i. d. oral beaded capsules for 5 days followed by at least 7 days of rest
USA-3	34	Dose finding in advanced cancer, Oral 100 to 850 mg b. i. d. for the 1st 21 days of each 28- day cycle
BEL-2	28	Single arm study in advanced cancer , Oral 50 mg b. i. d. for 3 weeks (1st subject), then successive intersubject dose escalation (100 to 500 mg b. i. d.) for 3 weeks
BEL-7	9	Single arm, single agent dose finding study in solid tumors, Oral 200 to 500 mg b. i. d. for the 1st 28 days of each 35- to 42- day cycle
USA-7	9	Single arm, single agent study in bladder cancer, 300 mg b. i. d. continuous for up to 50 days
USA- 8	22	Single arm study in lung cancer, 400 mg b. i. d. for 1st 14 days of 1st 21- day cycle; intrasubject dose escalation in 100- mg b. i. d. increments from Cycle 2 on
GBR-1	76	Single agent study in breast cancer, Cohort 1: 300 or 400 mg b. i. d. continuously, Cohort 2: 300 mg b. i. d. for 1st 21 days of each 28- day cycle
INT- 10	34	Single agent study in bladder cancer, 300 mg b. i. d. for 1st 21 days of each 28- day cycle
INT-9	233 tipifarnib,   133 placebo	Randomized study in colorectal cancers, 300 mg b. i. d. for 1st 21 days of each 28- day cycle

a Number of subjects evaluated by the sponsor for safety.

b Number of all-treated AML subjects evaluated by the sponsor for safety.

Reference: Zarnestra NDA.

 

Table 3: Clinical Studies Submitted for Efficacy in AML

Clinical Study	Evaluable Subjectsa Elderly poor-risk AML / AML	Study Description	Endpoints
CTEP-20	136b/ 157 (N=171)	Single arm, open label, single agent, in previously untreated elderly poor-risk AML patients	Efficacy and safety
INT-17	99c/ 252 (N= 252)	Single arm, open label, single agent, in refractory or relapsed  AML patients	Efficacy, safety, and pharmacokinetics
CTEP-1	25/? (N = 34)	Single arm, open label, single agent, dose escalation	Phase 2 recommend dose, pharmacokinetics and initial tolerability

a Number of subjects evaluated by the sponsor for efficacy.

b Number of subjects evaluated by the sponsor for efficacy and > 75 years old or 65 to 74 years old with prior MDS.

c Number of elderly subjects (> 65 years old) evaluated for efficacy.

References:  Zarnestra NDA.

 

 

IV. CTEP-20 Study Design and Significant Milestones

 

This open-label, single-arm, multicenter study was supported and conducted by the United States National Cancer Institute (NCI) Cancer Therapy Evaluation Program (CTEP) as part of a Cooperative Research and Development Agreement with Johnson & Johnson Pharmaceutical Research and Development, L. L. C. (J&JPRD). This study opened on October 10, 2002, and originally assessed the efficacy and safety of tipifarnib in subjects with previously untreated poor-risk hematologic malignancies.  After enrolling 110 patients (amendment 6, September 16, 2003), the target population was re-defined as subjects (1) 75 years or older with newly diagnosed AML or (2) 65 to 74 years of age with secondary AML arising from prior myelodysplastic syndrome (MDS).  The study objectives were redefined as follows:

 

• The primary objective was to determine the complete response (CR) rate of tipifarnib in elderly subjects with previously untreated poor-risk acute myeloid leukemia (AML).
• Secondary objectives were to determine the progression- free survival (PFS), overall survival (OS), duration of response, and safety profile.

 

The major eligibility criteria were also redefined in amendment 6:

 

Inclusion Criteria

• Pathologic confirmation of AML (> 20% marrow or peripheral blasts).

• Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.

• Written informed consent for participation in the study, given before undergoing any study- specific procedures.

• Bilirubin within the normal range.

• Alanine transaminase (ALT) and aspartate transaminase (AST) < 2.5 × the upper limit of normal (ULN) (grade 1).

• Serum creatinine < 1.5 × ULN (grade 1).

• No active systemic infection.

• Disease- specific criteria – AML (any of the following):

o       Newly diagnosed AML in adults 75 years or older.

o       Secondary AML arising from prior MDS in adults 65 years or older.

Exclusion Criteria

• Hyperleukocytosis with > 30,000 leukemic blasts/µL.

• Acute promyelocytic (French- American- British [FAB] M3) subtype.

• Previous treatment with chemotherapy for leukemia (except for hydroxyurea).

• Disseminated intravascular coagulation (diagnosis by laboratory or clinical assessment).

• Leukemic involvement of the central nervous system (CNS).

• Concomitant radiation therapy, chemotherapy, or immunotherapy. Previous therapy for another malignancy was permitted, if at least 1 month had occurred since the subject had received any of these treatments.

• Intrinsic impaired organ function.

 

After undergoing pretreatment bone marrow aspiration and biopsy as well as other appropriate evaluations, subjects were to receive tipifarnib 600 mg by mouth (p. o.) twice daily (b. i. d.) for 21 days in 28-day cycles. Subsequent cycles were to begin 7 to 42 days following completion of tipifarnib treatment in the previous cycle (on Day 29 to 64).

 

Bone marrow aspiration and biopsy were performed at the time of peripheral blood count recovery (absolute neutrophil count [ANC] > 500/µL, platelets > 20,000/µL), but no later than Day 63, regardless of peripheral blood count recovery. Subjects underwent weekly laboratory (complete blood counts and chemistries) and clinical monitoring (Table 4).

 

Subjects who achieved a CR could receive additional tipifarnib treatment until disease progression or receive up to 3 additional cycles of tipifarnib and stop. Retreatment with tipifarnib was allowed. The decision to reinitiate tipifarnib in an individual subject was left to the discretion of the individual investigator. Subjects with progressive disease (PD) at any time during tipifarnib administration were withdrawn from the study.

 

The first follow-up visit occurred 30 days after treatment termination for subjects who did not have documented progression or had not started subsequent therapy, and every 90 days after documentation of progressive disease (PD) or start of subsequent therapy.

 

The clinical assessments are summarized in Table 4:

Table 4: Time and Events Schedule

	Baseline (within 72 hours)	Day 8	Day 15	Day 22	Day 28- 63
Signed informed consent	X
Medical historya	X			X	X
Physical examinationa	X
Bone marrow aspirate/biopsyb	Xb				Xc
CBC/differential/plateletsd	X	X	X	X	X
Chemistriesd	X	X	X	X	X
Correlative studiese	X	X			X
Microarray studiese	X				X

a Includes a detailed neurologic history and baseline neurologic examination. Documentation of any baseline neuropathy was required.

b Morphologic examination, karyotype, histochemical stains, and immunophenotype pretreatment no more than 1 week before treatment began.

c At the time of ANC and platelet recovery, or by Day 63 at the latest. Within 1 week of subsequent treatment cycle.

d Required once weekly after the first week, though recommended twice weekly or more, at the physician’s discretion.

e Correlative and microarray studies, during Cycle 1 only.

Reference: CTEP-20 study report table 1 and Appendix 1.1.

 

 

 

 

5.  Study CTEP-20 Efficacy

 

5.1 Study CTEP-20 Population and Risk Factors

FDA reviewed patient eligibility and found that patient (ID101045) should be excluded from all-treated and elderly poor-risk AML patient populations, since this patient’s baseline blast count was less than 20,000/mm³ by both the investigator and the sponsor appointed independent reviewer. However, this patient did not respond to Zarnestra treatment.  This resulted in 156 patients in the all-treated AML population and 135 patients in the elderly poor-risk AML population.  The sponsor’s and FDA’s patient population summary is as follows:

 

 

The risk factors in the elderly poor-risk AML patient subset are summarized by the sponsor in Table 5.  FDA agrees with the sponsor summary except that this summary has included one patient above, age > 75 years, that did not meet the AML eligibility criteria as discussed.  It is noteworthy that more than 80% of subjects in this study subpopulation had AML arising from prior AML.  There were 55% subject who were age 75 years or older and 49% of subjects had unfavorable karyotype in the elderly poor-risk AML subpopulation.

Table 6: AML Risk Factors (Study CTEP-20: Sponsor’s Elderly Poor-Risk AML Population)

	65-74 y prior MDS N= 61 (%)	> 75 y N= 75 (%)	Total N= 136 (%)
Risk factor
Prior MDS	61 (100)	50 (67)	111 (82)
Baseline organ dysfunctiona	31 (51)	52 (69)	83 (61)
Age > 75 years	-	75 (100)	75 (55)
Unfavorable karyotype	37 (61)	29 (39)	66 (49)
Number of risk factors per subject
1	10 (16)	4 (5)	14 (10)
2	34 (56)	26 (35)	60 (44)
3	17 (28)	30 (40)	47 (35)
4	-	15 (20)	15 (11)

 a Organ dysfunction was defined as the presence of at least 2 dysfunctional conditions. Some subjects had more than 1 type of organ dysfunction.

Reference: Zarnestra NDA CTEP-20 study report.

 

5.2 Complete Response (CR) Analyses

Complete Responses were observed in 4 of the 6 CTEP-20 study sites, as provided by the sponsor (Table 6).

Table 7: Response by Site (CTEP-20, Elderly Poor Risk AML Population)

 

Site ID	Site Name	Poor Risk Enrollment (N=136, %)	All Resp CR/PR/HR	Poor Risk CR (%)	Sponsor’s Site Audit
100	The Sidney Kimmel Cancer Center at Johns Hopkins	28 (21)	4/2/1	3 (11)	Yes
200	University of Rochester Cancer Center	16 (12)	4/0/0	4 (25)	No
300	University of Maryland Greenebaum Cancer Center	32 (24)	10/1/6	8 (25)	Yes
500	Stanford University Medical Center	35 (26)	5/1/1	5 (14)	Yes
600	Blood & Marrow Transplant Group of Georgia	2 (1)	0/0/0	0	No
700	Cornell Medical Center New York Presbyterian Hospital	22 (16)	0/1/1	0	Yes

 

Reference: Zarnestra NDA, Study CTEP-20 Table 4 and Attachment 2.1.2.1.

 

The sponsor summarized the comparative assessment of CR by the study investigator and the sponsor appointed independent reviewer as shown in Table 7.    FDA has added subtotals and footnotes to this table.  The information of all CRs claimed by the investigator is shown in Tables 8 and 9, which were summarized by the sponsor and footnoted by FDA.  FDA also explored the investigators and independent reviewer claimed CRs by age or by whether patients had prior MDS (Table 10).

Table 8: Cross-Tabulation of CR–Independent Central Review Versus Site Review (CTEP-20: Elderly Poor-Risk AML Population)

Tipifarnib 600 mg oral twice daily (N= 20)
	Local Institute Reading Compatible With:
Central Review Reading Compatible With:	Confirmed CR	Unconfirmed CR	Subtotal
Confirmed CR	15a	-	15
Unconfirmed CR	1b	2c	3
Slides not availablea	1d	1e	2
Subtotal	17	3	20

a.  Includes Subject 101021, whose bone marrow slides showing < 5% blasts after Cycle 1 were lost and could not be confirmed by central review, but the slides obtained following Cycle 2 were available and read as compatible with CR.

b.  For subject 101057, the site and the central review were not in complete agreement.  Although both the local site and independent review agreed that the blast count was < 5% after C1, the subsequent cycle blast count confirmation reading by independent review was >5% whereas that of  the site review was <5%.

c. Confirmation slides were not available for Subjects 100336 (early death) and 100318 (early progressive disease).

d.  Subject 100508 only a single on study slide was available.

e.  Subject 101049 only baseline slides were available.

Reference: Zarnestra NDA, CTEP-20 study report, Independent review report and Appendices 3 and 5.

 

Table 9: List of Sponsor Claimed CRs with Treatment Information (CTEP-20, Elderly Poor Risk AML Population) and with FDA Footnotes.

a Calculated from imputed starting date, i. e., XX June 2002 was imputed as 1 June 2002.

b Age > 74 with prior MDS. 

c. Unconfirmed CR by the site investigator.

d. Unconfirmed CR by the independent reviewer.

e. Not able to determine by the independent investigator

Reference: Zasrnestra NDA, Study CTEP-20 Report table 24.

Table 10: The Sponsor Summarized Investigator Claimed CR Patient’s CR duration, Time to CR, PFS and Survival. (CTEP-20, Elderly Poor Risk AML Population) with FDA Footnotes

 

a Two subjects received subsequent combination chemotherapy as third- line treatment, after first being retreated with tipifarnib.

b Age > 74 with prior MDS. 

c. Unconfirmed CR by the site investigator.

d. Unconfirmed CR by the independent reviewer.

e. Not able to determine by the independent investigator

Reference: Zarnestra NDA, Study CTEP-20 Report Appendix Table 25.
Table 11: Summary of CR Assessment by Investigator and Independent Review Grouped by Age or by Whether Patient Had Prior MDS (CTEP-20, Elderly Poor Risk AML Population)

 

Results		CR (%)		CRu		Unable Accessed
Reviewer		Site	Independent	Site	Independent	Site	Independent
Total (N = 135)		17 (13)	15 (11)	3	3	0	2
Age	65-74 (N=61)	10 (16)	10 (16)	2	2	0	1
	> 75 (N = 74)	7 (9)	5 (7)	1	1	0	1
Prior MDS	Yes (N = 110)	16 (14)	14 (13)	2	2	0	2
	No (N = 25)	1 (4)	1 (4)	1	1	0	0

 

After reviewing the CTEP-20 study report and data sets provided in the sponsor’s NDA, FDA agrees with the sponsor appointed independent reviewer’s assessment of CRs, i.e., 15 subjects with confirmed complete responses based on the FDA identified elderly poor-risk AML patient subgroup (one patient excluded, see section 5.1). The FDA assessment of complete response rate is summarized in Table 11.

 

Table 12: FDA Assessment of  CR Rates (CTEP-20: Reviewer Defined Elderly Poor-Risk AML Population)

 

 

 

 

5.3 Response Duration:

The FDA has explored the duration of confirmed CRs, a secondary endpoint of study CTEP-20.  Per CTEP-20 protocol, no anti-leukemia therapy other than Zarnestra was given to patients who achieved a response until after disease progression and removal from the study.  As shown in Table 12, there is a trend toward longer duration of CR in the younger age group, 65-74 year old.  In comparison to AML patients with prior MDS, there was only one patient with de novo AML who had a confirmed CR. 

 

Table 13: FDA Assessment of Duration of Confirmed Complete Response (Elderly Poor-Risk Population)

            * Number failed = number of patients who had disease progression or died.

            # Number assessed = number of patients who had a CR.

 

 

5.4 Overall Survival:

 

FDA has conducted an exploratory analysis of overall survival in the FDA defined CTEP-20 elderly poor-risk population. This analysis is considered exploratory given the single arm nature of the study design.

Table 14: FDA’s Exploratory Results of Overall Survival (Elderly Poor-Risk AML Population)

 

 

6. Study CTEP-20 Safety

 

6.1 Drug Exposure:

 

In CTEP-20, the majority of patients had 1-2 cycles of treatment (Table 14).  In addition to the exposure by cycles, the sponsor has also summarized drug exposure by cycle and by day.  FDA does not consider that there is a difference between  the two, since there were no patient self drug administration dairies implemented in study CTEP-20 and the days were based on pharmacy record, most of which are outpatient weekly dispensation records.  Of the total 171 subjects enrolled in the study CTEP-20, 158 of them had AML.  At the time of clinical cut off, 157 AML subjects were treated with at least one cycle of Zarnestra.  Of them, 136 were elderly subjects with poor-risk AML and are most relevant to the safety evaluation for the proposed indication.  Please note that one of the elderly subjects with poor-risk AML was excluded from FDA’s efficacy analysis as discussed before.

Table 15: Study Treatment by Cycle (Study CTEP-20: Sponsor defined Elderly Poor-Risk Subset))

Category, n (%)	Cycle 1 (N= 136)	Cycle 2 (N= 64)	Cycle 3 (N= 27)
Cycle duration
1-28 days	39 (29)	13 (20)	7 (26)
29-35 days	21 (15)	12 (19)	5 (19)
36-42 days	29 (21)	19 (30)	8 (30)
43-49 days	26 (19)	10 (16)	5 (19)
50-56 days	7 (5)	4 (6)	-
57- 63 days	6 (4)	3 (5)	1 (4)
> 64 days	8 (6)	3 (5)	1 (4)
Mean (SD)	36.8 (16.88)	37.6 (15.06)	36.4 (14.39)
Median	38	38	36
Range	(3; 92)	(5; 75)	(10; 85)
Starting dose, mg/day
Mean (SD)	1191 (72.5)	1000 (236.4)	993 (257.1)
Median	1200	1200	1200
Range	(600; 1200)	(400; 1200)	(400; 1200)
Cumulative dose, mg
Mean (SD)	23338 (4599.3)	19663 (6129.7)	20000 (5448.5)
Median	25200	16800	18000
Range	(3600; 25200)	(2000; 25200)	(8400; 25200)
Dose intensity, mg/day
Mean (SD)	749.4 (277.40)	597.3 (251.93)	631.2 (282.9)
Median	663.2	566.4	586.1
Range	(273.9; 1200.0)	(168.0; 1200.0)	(197.6; 1200.0)
Relative dose intensity
Mean (SD)	0.76 (0.204)	0.62 (0.216)	0.65 (0.247)
Median	0.74	0.63	0.65
Range	(0.30; 1.04)	(0.19; 1.00)	(0.22; 1.00)

Reference: Zarnestra NDA, Study CTEP-20 report Table 21 and Attachment 1.11.2.1.

 

6.2 Overall Toxicity:

The safety results for the elderly subjects with poor-risk AML and all AML subjects (21/157 patients younger than age 65) enrolled on CTEP-20 study were reviewed, with the focus on the elderly poor-risk AML population.  Overall adverse events are summarized in Table 15.  There were 98% all treatment emergent adverse events (AEs), of which 87% were thought related to the study drug by the investigator.  There were 83% treatment emergent and 61% drug related grade 3 or 4 AEs, with 15% (n=136) treatment emergent which includes 10% (n = 136) drug related severe AEs that lead to termination of the treatment.  There were 9 (7%, n = 136) deaths in the elderly poor-risk population due to treatment emergent AEs. One of them was due to AEs that related to the study drug by investigators assessment.

Table 16: Overview of Adverse Events (CTEP-20: Elderly Poor-Risk AML and All-Treated AML Data Sets)

Number (%) of Subjects With:	Elderly Poor- Risk AML			All- Treated AML
	65-74 y prior MDS N = 61 (%)	> 75 y N = 75 (%)	Total N= 136 (%)	Total (N= 157) (%)
AEs	60 (98)	74 (99)	134 (99)	155 (99)
Drug-related AEs	53 (87)	65 (87)	118 (87)	134 (85)
Grade 3 or 4 AEs	51 (84)	62 (83)	113 (83)	131 (83)
Drug- related grade 3 or 4 AEs	37 (61)	46 (61)	83 (61)	92 (59)
SAEs	38 (62)	50 (67)	88 (65)	103 (66)
Drug- related SAEs	23 (38)	35 (47)	58 (43)	64 (41)
AEs leading to treatment termination	11 (18)	10 (13)	21 (15)	26 (17)
Drug- related AEs leading to treatment terminationa	7 (11)	7 (9)	14 (10)	18 (11)
Deaths due to an AEa	2 (3)	7 (9)	9 (7)	11 (7)
Drug- related AEs resulting in deatha	0	1 (1)	1 (1)	1 (1)
Early deaths due to an AEb	2 (3)	3 (4)	5 (4)	6 (4)

 a AEs resulting in death within 30 days after treatment termination or until start of subsequent therapy, whichever was ealier.

b AEs resulting in death within 30 days after the first dose of study medication regardless of the cause of death.

Reference: Zarnestra NDA, CTEP study report Table 42 and attachments 3.1.1, 3.1.2,  3.2.1.1., 3.6.2.1, and 3.6.2.2.

 

6.3 Common Adverse Events

 

For all treatment emergent AEs, those reported most frequently (79%) were in the body-as-a-whole and gastrointestinal body systems. The most frequently reported AEs (all grades) were diarrhea (47%), fatigue (44%), nausea (38%), and rash (35%). 

AEs reported in at least 10% of all subjects are summarized below in Tables 16 and 17:

Table 17: Adverse Events Reported in at Least 10% of Subjects (All Grades) – Part 1 (CTEP-20: Elderly Poor-Risk AML Subset)

WHO Preferred Term	65-74 y prior MDS (N = 61) n (%)	> 75 y (N = 75) n (%)	Total N= 136 n (%)
Total no. subjects with at least 1 AE	60 (98)	74 (99)	134 (99)
Body as a whole –general disorders	47 (77)	60 (80)	107 (79)
Fatigue	30 (49)	30 (40)	60 (44)
Fever	21 (34)	21 (28)	42 (31)
Edema peripheral	9 (15)	13 (17)	22 (16)
Rigors	8 (13)	9 (12)	17 (13)
Chest pain	7 (11)	6 (8)	13 (10)
Gastrointestinal system disorders	45 (74)	62 (83)	107 (79)
Diarrhea	29 (48)	35 (47)	64 (47)
Nausea	25 (41)	26 (35)	51 (38)
Anorexia	15 (25)	22 (29)	37 (27)
Constipation	13 (21)	20 (27)	33 (24)
Vomiting	12 (20)	20 (27)	32 (24)
Stomatitis	11 (18)	15 (20)	26 (19)
Abdominal pain	11 (18)	11 (15)	22 (16)
Respiratory system disorders	38 (63)	46 (61)	84 (62)
Dyspnea	15 (25)	17 (23)	32 (24)
Coughing	15 (25)	12 (16)	27 (20)
Pneumonia	8 (13)	13 (17)	21 (15)
Pharyngitis	10 (16)	8 (11)	18 (13)
Central and peripheral nervous system disorders	32 (52)	45 (60)	77 (57)
Dizziness	16 (26)	20 (27)	36 (26)
Headache	17 (28)	7 (9)	24 (18)
Ataxia	5 (8)	11 (15)	16 (12)
Tremor	6 (10)	9 (12)	15 (11)
Skin and appendages disorders	38 (62)	34 (45)	72 (53)
Rash	25 (41)	23 (31)	48 (35)
Skin reaction localized	11 (18)	16 (21)	27 (20)

 (Continue)

 

Table 18: Adverse Events Reported in at Least 10% of Subjects (All Grades) – Part 2 (CTEP-20: Elderly Poor-Risk AML Subset)

WHO Preferred Term	65-74 y prior MDS (N = 61) n (%)	> 75 y (N = 75) n (%)	Total N= 136 n (%)
Platelet, bleeding, & clotting disorders	28 (46)	37 (49)	65 (48)
Purpura	10 (16)	19 (25)	29 (21)
Thrombocytopenia	12 (20)	14 (19)	26 (19)
Epistaxis	11 (18)	11 (15)	22 (16)
Metabolic and nutritional disorders	29 (48)	34 (45)a	63 (46)a
Creatinine blood increased	12 (20)	18 (24)a	30 (22)a
Dehydration	4 (7)	13 (17)	17 (13)
Hypokalemia	10 (16)	6 (8)	16 (12)
Psychiatric system disorders	27 (44)	34 (45)	61 (45)
Confusion	12 (20)	17 (23)	29 (21)
Insomnia	10 (16)	10 (13)	20 (15)
White cell disorders	26 (43)	31 (41)	57 (42)
Neutropenia febrile	18 (30)	22 (29)	40 (29)
Neutropenia	9 (15)	8 (11)	17 (13)
Resistance mechanism disorders	22 (36)	27 (36)	49 (36)
Infection bacterial	13 (21)	14 (19)	27 (20)
Moniliasis	8 (13)	6 (8)	14 ( 10)
Musculoskeletal system disorders	14 (23)	15 (20)	29 (21)
Arthralgia	8 (13)	5 (7)	13 (10)
RBC disorders	7 (11)	20 (27)	27 (20)
Anemia	7 (11)	17 (23)	24 (18)
Special senses other, disorders	8 (13)	5 (7)	13 (10)
Taste perversion	8 (13)	5 (7)	13 (10)

a For 2 subjects (101005 and 101039), hypercreatinemia was coded to urinary system disorders rather than metabolic and nutritional disorders. For consistency, these 2 subjects are included in the latter body system in this report.

Reference: Zarnestra NDA, CTEP-20 study report Table 43 and attachment 3.2.1.1.

 

6.4 Grade 3 or 4 Adverse Events

FDA agrees with the sponsor that 83% of subjects experienced Grade 3 or 4 AEs. 

The most frequent treatment emergent grade 3 or 4 hematological and nonhematologic AEs were secondary to myelosuppression, including neutropenia with or without neutropenic fever (41%), infections (27%), thrombocytopenia (17%), fatigue (13%), pneumonia (10%), rash (9%) anemia (8%), dyspnea (8%), and confusion (7%).  Besides grade 3 and 4 AEs that were reported with an incidence of 5% or greater, the reviewer has also included some less than 5% AEs that occurred in the elderly poor-risk AML subset in the reviewer’s summary (see Tables 18 and 19 and footnotes).  These AEs (marked with * in Tables 18 to 21), although less than 5%, may represent certain clinically relevant events in the view of the reviewer.  For example, the sponsor has categorized Candida infection (4%) and other fungal infection (4%) separately and therefore excluded both from the sponsor’s 5% or higher AEs summary (Table 19).  However, the true total fugal infection frequency (Candida + other) should be 8%. 

 

Table 19: Treatment Emergent Grade 3 and 4 AEs Reported (>  5% or < 5% but may have clinical significance) - Part 1 (CTEP-20: Elderly Poor-Risk AML Subset)

 

Body System WHO Preferred Term	65-74 y prior MDS (N = 61) n (%)			> 75 y (N = 75)  n (%)			Total N= 136 n (%)
	All	Grade		All	Grade		All	Grade
		3	4		3	4		3	4
Total no. subjects with grade 3 or 4 AE	51 (84)			62 (83)			113 (83)
White cell disorders	26 (43)	12 (20)	14 (23)	29 (39)	23 (31)	6 (8)	55 (40)	35 (26)	20 (15)
Neutropenia febrile	18 (30)	13 (21)	5 (8)	22 (29)	20 (27)	2 (3)	40 (29)	33 (24)	7 (5)
Neutropenia	9 (15)	1 (2)	8 (13)	7 (9)	2 (3)	5 (7)	16 (12)	3 (2)	13 (10)
Pancytopenia	4 (7)	2 (3)	2 (3)	3 (4)	3 (4)	0	7 (5)	5 (4)	2 (1)
Body as a whole	15 (25)	15 (25)	0	22 (29)	17 (23)	5 (7)	37 (27)	32 (24)	5 (4)
Allergic Reaction*	1 (2)	1 (2)	0	1 (1)	1 (1)	0	2 (1)	2 (1)	0
Fatigue	5 (8)	5 (8)	0	12 (16)	11 (15)	1 (1)	17 (13)	16 (12)	1 (1)
Fever	4 (7)	4 (7)	0	4 (5)	4 (5)	0	8 (6)	8 (6)	0
Multiple Organ Failure*	0	0	0	2 (3)	0	2 (3)	2 (1)	0	2 (1)
Pain*	0	0	0	2 (3)	1 (1)	1 (1)	2 (1)	1 (1)	1 (1)
Pain, Back*	1 (2)	1 (2)	0	2 (3)	1 (1)	1 (1)	3 (2)	2 (1)	1 (1)
Pain, Chest*	1 (2)	1 (2)	0	0	0	0	1 (1)	1 (1)	0
Pain, Leg*	0	0	0	2 (3)	2 (3)	0	2 (1)	2 (1)	0
Rigors*	2 (3)	2 (3)	0	0	0	0	2 (1)	2 (1)	0
Syncope*	1 (2)	1 (2)	0	2 (3)	2 (3)	0	3 (2)	3 (2)	0

* Grade 3/4 AEs, which frequency was less than 5% and did not include in the sponsor’s CTEP-20 study report Table 40, are included by the reviewer based on potential clinical significance.

Note: The denominator used for percentages of toxicity grade calculation were the number of subjects in each age group (65-74, or 75 and older). The denominator used for percentages in ‘ Total’ column was the number of subjects in elderly poor-risk AML subsets.

Note: Table includes adverse events reported any time during treatment until treatment termination plus 30 days or subsequent therapy, whichever is earlier. Incidence is based on the number of subjects, not the number of events.

Toxicity grade: NCI common toxicity criteria, version 2.0 (CTC, v2.0).

Reference: Zarnestra NDA, CTEP-20 study report, Attachment 3.3.1.

Continued next page

Table 20: Treatment Emergent Grade 3 and 4 AEs Reported (>  5% or < 5% but may have clinical significance) - Part 2 (CTEP-20: Elderly Poor-Risk AML Subset)

Body System WHO Preferred Term	65-74 y prior MDS N = 61 (%)			> 75 y N = 75 (%)			Total N= 136 n (%)
	All	Grade		All	Grade		All	Grade
		3	4		3	4		3	4
Resistance mechanism disorders	19 (31)	17 (28)	2 (3)	18 (24)	12 (16)	6 (8)	37 (27)	29 (21)	8 (6)
Infection bacterial	12 (20)	12 (20)	0	13 (17)	9 (12)	4 (5)	25 (18)	21 (15)	4 (3)
Sepsis	5 (8)	3 (5)	2 (3)	4 (5)	0	4 (5)	9 (7)	3 (2)	6 (4)
Infection Fungal*	4 (7)	4 (7)	0	2 (3)	2 (3)	0	6 (4)	6 (4)	0
Moniliasis*	5 (8)	5 (8)	0	0	0	0	5 (4)	5 (4)	0
Infection, other*	1 (2)	1 (2)	0	2 (3)	2 (3)	0	3 (2)	3 (2)	0
Infection Viral*	2 (3)	2 (3)	0	1 (1)	1 (1)	0	3 (2)	3 (2)	0
Gastrointestinal system disorders	13 (21)	12 (20)	1 (2)	15 (20)	14 (19)	1 (1)	28 (21)	26 (19)	2 (1)
Diarrhea	5 (8)	4 (7)	1 (2)	3 (4)	3 (4)	0	8 (6)	7 (5)	1 (1)
Nausea*	3 (5)	3 (5)	0	3 (4)	3 (4)	0	6 (4)	6 (4)	0
Vomiting*	3 (5)	3 (5)	0	3 (4)	3 (4)	0	6 (4)	6 (4)	0
Constipation*	2 (3)	2 (3)	0	2 (3)	2 (3)	0	4 (3)	4 (3)	0
Stomatitis*	2 (3)	2 (3)	0	2 (3)	2 (3)	0	4 (3)	4 (3)	0
Abdominal Pain*	2 (3)	2 (3)	0	1 (1)	1 (1)	0	3 (2)	3 (2)	0
GI Haemorrhage*	1 (2)	1 (2)	0	1 (1)	0	1 (1)	2 (1)	1 (1)	1 (1)
Melaena*	0	0	0	1 (1)	1 (1)	0	1 (1)	1 (1)	0
Respiratory system disorders	12 (20)	10 (16)	2 (3)	16 (21)	10 (13)	6 (8)	28 (21)	20 (15)	8 (6)
Pneumonia	5 (8)	5 (8)	0	9 (12)	5 (7)	4 (5)	14 (10)	10 (7)	4 (3)
Dyspnea	5 (8)	5 (8)	0	6 (8)	5 (7)	1 (1)	11 (8)	10 (7)	1 (1)
Pneumonia Lobar*	2 (3)	2 (3)	0	1 (1)	1 (1)	0	3 (2)	3 (2)	0
Hypoxia*	1 (2)	0	1 (2)	1 (1)	1 (1)	0	2 (1)	1 (1)	1 (1)
Adult Respiratory Stress Syndrome*	1 (2)	0	1 (2)	0	0	0	1 (1)	0	1 (1)
Haemoptysis*	1 (2)	1 (2)	0	0	0	0	1 (1)	1 (1)	0

See Table 19 footnotes.

Continued next page

Table 21: Treatment Emergent Grade 3 and 4 AEs Reported (>  5% or < 5% but may have clinical significance) - Part 3 (CTEP-20: Elderly Poor-Risk AML Subset)

Body System WHO Preferred Term	65-74 y prior MDS (N = 61) n (%)			> 75 y (N = 75) n (%)			Total N= 136 n (%)
	All	Grade		All	Grade		All	Grade
		3	4		3	4		3	4
Platelet, bleeding, & clotting disorders	12 (20)	7 (11)	5 (8)	15 (20)	12 (16)	3 (4)	27 (20)	19 (14)	8 (6)
Thrombocytopenia	10 (16)	5 (8)	5 (8)	13 (17)	10 (13)	3 (4)	23 (17)	15 (11)	8 (6)
Epistaxis*	1 (2)	1 (2)	0	3 (4)	3 (4)	0	4 (3)	4 (3)	0
Purpura*	1 (2)	1 (2)	0	0	0	0	1 (1)	1 (1)	0
Skin and appendages disorders	9 (15)	9 (15)	0	13 (17)	13 (17)	0	22 (16)	22 (16)	0
Rash	4 (7)	4 (7)	0	8 (11)	8 (11)	0	12 (9)	12 (9)	0
Skin reaction localized	4 (7)	4 (7)	0	6 (8)	6 (8)	0	10 (7)	10 (7)	0
Angioedema*	1 (2)	1 (2)	0	0	0	0	1 (1)	1 (1)	0
Metabolic and nutritional disorders	10 (16)	6 (10)	4 (7)	10 (13)	10 (13)	0	20 (15)	16 (12)	4 (3)
Hypokalemia	5 (8)	5 (8)	0	3 (4)	3 (4)	0	8 (6)	8 (6)	0
Dehydration*	3 (5)	2 (3)	1 (2)	3 (4)	3 (4)	0	6 (4)	5 (4)	1 (1)
Creatinine Blood Increased*	2 (3)	2 (3)	0	2 (3)	2 (3)	0	4 (3)	4 (3)	0
Psychiatric system disorders	5 (8)	5 (8)	0	12 (16)	11 (15)	1 (1)	17 (13)	16 (12)	1 (1)
Confusion	2 (3)	2 (3)	0	7 (9)	6 (8)	1 (1)	9 (7)	8 (6)	1 (1)
Hallucination*	1 (2)	1 (2)	0	2 (3)	2 (3)	0	3 (2)	3 (2)	0
Delirium*	0	0	0	2 (3)	2 (3)	0	2 (1)	2 (1)	0
Nervous System Disorders*	5 (8)	5 (8)	0	10 (13)	9 (12)	1 (1)	15 (11)	14 (10)	1 (1)
Ataxia*	0	0	0	3 (4)	3 (4)	0	3 (2)	3 (2)	0
Coma*	1 (2)	1 (2)	0	1 (1)	0	1 (1)	2 (1)	1 (1)	1 (1)
Dizziness*	0	0	0	2 (3)	2 (3)	0	2 (1)	2 (1)	0
Encephalopathy*	1 (2)	1 (2)	0	1 (1)	1 (1)	0	2 (1)	2 (1)	0
Neuropathy Peripheral*	2 (3)	2 (3)	0	0	0	0	2 (1)	2 (1)	0

See Table 19 footnotes.

Continued next page

 

 

 

Table 22: Treatment Emergent Grade 3 and 4 AEs Reported (>  5% or < 5% but may have clinical significance) - Part 4 (CTEP-20: Elderly Poor-Risk AML Subset)

Body System WHO Preferred Term	65-74 y prior MDS (N = 61)  n (%)			> 75 y (N = 75)  n (%)			Total N= 136  n (%)
	All	Grade		All	Grade		All	Grade
		3	4		3	4		3	4
Cardiovascular disorders, general	7 (11)	6 (10)	1 (2)	7 (9)	3 (4)	4 (5)	14 (10)	9 (7)	5 (4)
Hypotension	4 (7)	4 (7)	0	4 (5)	1 (1)	3 (4)	8 (6)	7 (5)	1 (1)
Cardiac failure	3 (5)	2 (3)	1 (2)	4 (5)	3 (4)	1 (1)	7 (5)	3 (2)	4 (3)
Circulatory Failure*	0	0	0	1 (1)	0	1 (1)	1 (1)	0	1 (1)
Hypotension Postural*	1 (2)	1 (2)	0	0	0	0	1 (1)	1 (1)	0
Heart Rate And Rhythm Disorders*	6 (10)	5 (8)	1 (2)	3 (4)	2 (3)	1 (1)	9 (7)	7 (5)	2 (1)
Fibrillation Atrial*	4 (7)	3 (5)	1 (2)	2 (3)	2 (3)	0	6 (4)	5 (4)	1 (1)
Arrhythmia Atrial*	2 (3)	2 (3)	0	1 (1)	0	1 (1)	3 (2)	2 (1)	1 (1)
AV Block*	1 (2)	1 (2)	0	0	0	0	1 (1)	1 (1)	0
Palpitation*	0	0	0	1 (1)	1 (1)	0	1 (1)	1 (1)	0
Tachycardia*	1 (2)	1 (2)	0	0	0	0	1 (1)	1 (1)	0
RBC disorders	1 (2)	1 (2)	0	11 (15)	11 (15)	0	12 (9)	12 (9)	0
Anemia	1 (2)	1 (2)	0	10 (13)	10 (13)	0	11 (8)	11 (8)	0
Urinary System Disorders*	0	0	0	7 (9)	6 (8)	1 (1)	7 (5)	6 (4)	1 (1)
Urinary Tract Infection*	0	0	0	3 (4)	3 (4)	0	3 (2)	3 (2)	0
Haematuria*	0	0	0	2 (3)	2 (3)	0	2 (1)	2 (1)	0
Micturition Frequency*	0	0	0	1 (1)	1 (1)	0	1 (1)	1 (1)	0
Renal Failure Acute*	0	0	0	1 (1)	0	1 (1)	1 (1)	0	1 (1)
Liver and Biliary System Disorders*	3 (5)	3 (5)	0	3 (4)	3 (4)	0	6 (4)	6 (4)	0
Bilirubinaemia*	2 (3)	2 (3)	0	3 (4)	3 (4)	0	5 (4)	5 (4)	0
Cholelithiasis*	0	0	0	1 (1)	1 (1)	0	1 (1)	1 (1)	0
Hepatic Function Abnormal*	1 (2)	1 (2)	0	0	0	0	1 (1)	1 (1)	0

See Table 19 footnotes.

 

Most frequent drug related AEs were neutropenic fever (17%), creatininemia (5%), bacterial infection (5%) and diarrhea (4%).  Drug-related grade 3 or 4 AEs that occurred in more than one subject are summarized as below:

Table 23: Drug-Related Serious Adverse Events (> 1 Subject, CTEP-20: Elderly Poor-Risk AML Subset)

WHO Preferred Term	65-74 y prior MDS  (N = 61) n (%)		> 75 y (N = 75) n (%)		Total  N= 136 n (%)
	All	Drug Related	All	Drug Related	All	Drug Related
Total no. subjects with SAEa	38 (62)	23 (38)	50 (67)	35 (47)	88 (65)	58 (43)
Neutropenia febrile	17 (28)	14 (23)	16 (21)	9 (12)	33 (24)	23 (17)
Creatinine blood increased	5 (8)	2 (3)	6 (8)b	5 (7)	11 (8)b	7 (5)
Infection bacterial	8 (13)	3 (5)	8 (11)	4 (5)	16 (12)	7 (5)
Diarrhea	2 (3)	2 (3)	4 (5)	3 (4)	6 (4)	5 (4)
Anemia	2 (3)	2 (3)	3 (4)	2 (3)	5 (4)	4 (3)
Dehydration	3 (5)	1 (2)	5 (7)	3 (4)	8 (6)	4 (3)
Fever	8 (13)	2 (3)	6 (8)	2 (3)	14 (10)	4 (3)
Neutropenia	1 (2)	1 (2)	4 (5)	3 (4)	5 (4)	4 (3)
Pancreas enzymes increased	2 (3)	2 (3)	2 (3)	2 (3)	4 (3)	4 (3)
Infection fungal	4 (7)	2 (3)	1 (1)	1 (1)	5 (4)	3 (2)
Nausea	1 (2)	1 (2)	3 (4)	2 (3)	4 (3)	3 (2)
Pancytopenia	3 (5)	3 (5)	0	0	3 (2)	3 (2)
Pneumonia	3 (5)	1 (2)	6 (8)	2 (3)	9 (7)	3 (2)
Rash	3 (5)	2 (3)	3 (4)	1 (1)	6 (4)	3 (2)
Vomiting	2 (3)	2 (3)	2 (3)	1 (1)	4 (3)	3 (2)
Ataxia	0	0	2 (3)	2 (3)	2 (1)	2 (1)
Bilirubinemia	1 (2)	1 (2)	2 (3)	1 (1)	3 (2)	2 (1)
Confusion	2 (3)	1 (2)	2 (3)	1 (1)	4 (3)	2 (1)
Fatigue	2 (3)	1 (2)	6 (8)	1 (1)	8 (6)	2 (1)
Hypotension postural	1 (2)	1 (2)	1 (1)	1 (1)	2 (1)	2 (1)
Pneumonia lobar	1 (2)	1 (2)	2 (3)	1 (1)	3 (2)	2 (1)
Skin reaction localized	2 (3)	1 (2)	6 (8)	1 (1)	8 (6)	2 (1)
Thrombocytopenia	2 (3)	1 (2)	2 (3)	1 (1)	4 (3)	2 (1)

a Some subjects had more than 1 SAE or drug-related SAE.

b For 1 subject (101005), an SAE of hypercreatinemia was coded to urinary system disorders rather than metabolic and nutritional disorders.

Reference: Zarnestra NDA, CTEP-20 study report Table 48, attachments 3.7.1.1 and 3.7.2.1.