# Presentation: 429229

## Zarnestra NDA 21824

- Qin Ryan MD, PhD
- DODP/CDER/FDA

## Outline

- Regulatory Background
- Clinical Overview and Proposed Indication
- CTEP-20 Design
- CTEP-20 Efficacy
- CTEP-20 Safety
- Summary

## Regulatory Background

## Regulatory Background

- In oncology, clinical benefit (CB) has been defined as a longer life, a better life or an effect on an established surrogate for either
- In acute leukemias, durable complete remission (CR) has been considered evidence of benefit
- In some cases where leukemia CR’s were of uncertain duration, CR was considered a surrogate reasonably likely to predict CB

## Drug Approvals for AML

## Clinical Overview

## Induction Therapy for AML 

- Untreated AML progresses rapidly to death
- Standard Rx in Adults < 60:
- 60-75% CR
- < 20% treatment related death
- DFS 20-50%
- 30-40% survive _>_ 3 years
- Factors affecting outcome: PS, organ function, co-morbidity, age, karyotype

## Induction Chemotherapy for Elderly Patients with AML

| Age | 65-74 years 
(N=1,132) | 75-84 years (N=1,082) | >85 years
(N=433) | Total
(N=2,657) |
| --- | --- | --- | --- | --- |
| Received 
chemotherapy   | 44% | 24% | 6% | 30% |

- Menzin et al., Arch Intern Med 2002, 162: 1597.

## Survival in Elderly Patients with AML

- Menzin et al., Arch Intern Med 2002, 162: 1597.

## Elderly Patients with Poor-Risk AML

- Higher mortality and morbidity seen in elderly patients with poor-risk AML  receiving standard chemotherapy

| Outcome | Age < 65 | Age >65 + Other factors |
| --- | --- | --- |
| Treatment related death | 10-20% | > 25% |
| Complete remission rate | 60-75% | 30% - 50% |
| Survival rate | 30-40% > 3 years | < 6% at 2 years |

## Clinical Program

## Zarnestra

- Farnesyl transferase inhibitor
- 100 mg Tablets
- 600 mg twice daily PO for 21 days, followed by a rest period of 7 - 42 days

## Proposed Indication

- Treatment of elderly patients with newly diagnosed poor-risk acute myeloid leukemia.

## Zarnestra NDA: AML Trials 

| Clinical Study | Elderly poor-risk AML / AML
(Total Enrolled) | Study Description | Endpoints |
| --- | --- | --- | --- |
| CTEP-20*  | 136 / 157
(N=171) | Single arm, open label, previously untreated elderly poor-risk AML patients  | Efficacy and safety  |
|  INT-17  | 99 / 252
(N= 252) | Single arm, open label, refractory or relapsed  AML patients | Efficacy, safety, and PK  |
| CTEP-1*   | 14 / 25
(N = 34) | Single arm, open label, dose escalation in hematologic malignancies | Phase 2 recommended dose, PK and tolerability  |

- * Conducted by NCI, CTEP as part of a Cooperative Research and Development Agreement
-  with J&J

## CTEP-20 Design

## CTEP-20 Design

- Open-label, single-arm, multicenter
- Population
- Original: untreated poor-risk hematological malignancies
- 6th amendment (after 110 enrollments): untreated elderly poor-risk AML
**Age > 75**
**Age 65-74 AML with prior MDS**

## CTEP-20 Design

- Primary objective
- Original: RR (CR+PR)
- 6th amendment: complete response (CR) rate in untreated elderly poor-risk AML
- Secondary objectives:
- Progression-free survival (PFS)
- Overall survival (OS)
- Duration of response
- Safety

## CTEP-20 Major Eligibility

- After amendment #6
- Inclusion:
- Untreated newly diagnosed AML
- _>_ 75
- 65-74 with prior MDS
- Confirmation with _>_ 20% BM or PB blasts
- PS 0 or 1, adequate renal and liver function.
- Exclusion: circulating blasts _>_ 30,000/uL, APL (M3), CNS leukemia, DIC

## CTEP-20 Efficacy Assessment

- Medical history and physical examination, BM aspirate and biopsy, hematological and chemistry labs at baseline and the end of each cycle
- CR determined by NCI sponsored AML criteria
- 	(Cheson et al., J Clin Oncol 8: 813-819, 1990)
- Subsequent treatment and follow up

## CTEP-20 Efficacy

## CTEP-20 Study Population

- *One elderly patient with AML did not receive treatment by the time of clinical cut off.

| Patient Population | Number of Patients |  |
| --- | --- | --- |
|  | Sponsor | FDA |
| All Enrolled | 171 | 171 |
| All Treated AML | 157 | 156  |
| Elderly poor-risk AML
	Age  75 years
	Age 65-74 years with prior MDS | 136
	75
	61 | 135
	74
	61 |
| Non AML  | 13 (8) | 14 (8) |
|             MDSb  |             8 (5) |               9  (5) |
|             CMML  |             5 (3) |               5  (3) |

## CTEP-20 Elderly Poor-Risk AML Population: Demographics 

| Number of subjects  (%)  | 65-74 y prior | > 75 y | Total |
| --- | --- | --- | --- |
| Baseline ECOG performance status | 60 | 73 | 133 |
| 0  | 19 (32) | 13 (18) | 32 (24) |
| 1  | 35 (58) | 51 (70) | 86 (65) |
| 2  | 6 (10) | 9 (12) | 15 (11) |
| Ineligible for chemotherapya  | 61 | 75 | 136 |
| Age  | 34 (56) | 72 (96) | 106 (78) |
| Risk factors  | 31 (51) | 29 (39) | 60 (44) |
| Other  | 15 (25) | 10 (13) | 25 (18) |

**a Some subjects had more than 1 reason for ineligibility for chemotherapy.**

## CTEP-20 Elderly Poor-Risk AML Population: Risk Factors 

| Risk factor | 65-74 y prior MDS
(N= 61) n (%) | > 75 y 
(N= 75) n (%) | Total 
(N= 136) n (%) |
| --- | --- | --- | --- |
| Prior MDS | 61 (100) | 50 (67) | 111 (82) |
| Baseline organ dysfunction | 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) |

## CTEP-20 Primary Endpoint: CR Rate

| Total 
(N= 135) | CR (%) | CRu | Unavailable for Assessment |
| --- | --- | --- | --- |
| Investigators | 17 (13) | 2 | 1 |
| Independent Review  | 15 (11) | 3 | 2 |
| FDA | 15 (11) | 3 | 2 |

## CTEP-20 CR Rate Analysis by FDA

| Confirmed CR / No. of Patients | CR Rate (n/N)
[95% CI] |
| --- | --- |
| 15 / 135 | 11.1%
6.6 – 18.0% |

## CTEP-20 CR Rate Subgroup Analysis by FDA

| Category | Group | Confirmed CR
 / No. of Patients | CR Rate (n/N)
[95% CI] |
| --- | --- | --- | --- |
| Age | 65 – 74 years | 10 /61 | 16.4% 
8.6 – 28.5% |
|  | ≥ 75 years | 5 / 74 | 6.8% 
3.1 – 18.8% |
| Prior MDS | Yes | 14 / 110 | 12.7% 
7.4 – 20.8% |
|  | No | 1 / 25 | 4% 
0.2 – 22.3% |
| Karyotype | Unfavorable | 5 / 65 | 7.7% 
0.1 – 9.4 |
|  | Favorable | 9 / 62 | 14.5%
0.1 – 19.8 |
|  | Unkown | 1 / 8 | 12.5%
0.7 – 53.3% |

## CTEP-20 CR Duration

| Analysis | FDA Results |
| --- | --- |
| Number failed/Number assessed | 7/15 (47%) |
| Median duration in days [95% CI] | 275
[127 – 376] |

## CTEP-20 Safety

## CTEP-20 Safety – Exposure

| Category, n (%) | Cycle 1 
136 (100) | Cycle 2 
64 (47) | Cycle 3
 27 (20) |
| --- | --- | --- | --- |
| 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) |

## CTEP-20 Safety – Dose Intensity

| Category | Cycle 1 
(N= 136) | Cycle 2 
(N= 64) | Cycle 3 
(N= 27) |
| --- | --- | --- | --- |
| Dose intensity, mg/day |  |  |  |
| Mean (SD) | 749.4 (277.40) | 597.3 (251.93) | 631.2 (282.9) |
| % of planned | 63 | 50 | 53 |
| Median | 663.2 | 566.4 | 586.1 |
| Range | (273.9; 1200.0) | (168.0; 1200.0) | (197.6; 1200.0) |

## CTEP-20 Safety – Common AEs

| Non-Hematologic  | diarrhea, fatigue, nausea, skin rash, fever, anorexia, constipation, vomiting, dyspnea, dizziness, ataxia or abnormal gait, confusion,  
bacterial infection, fungal infection |
| --- | --- |
| Hematologic | neutropenia with or without fever, purpura, thrombocytopenia, anemia |
| Metabolic | increased creatinine, hypokalemia, hyponatremia |

## CTEP-20 Safety Frequent AEs Leading to Treatment Change

| Treatment Change | Incidence
 (n=136, %) | Most Frequent AEs |
| --- | --- | --- |
| Termination | 21 (15) | increased creatinine, rash, increased pancreatic enzymes |
| Dose Reduction | 47 (35) | neutropenia, ataxia, increased creatinine or abnormal renal function, confusion, diarrhea, increased pancreatic enzymes, rash |
| Interruption | 56 (41) | neutropenia, increased creatinine, nausea/vomiting, rash, confusion, pancytopenia |

## CTEP-20 Safety – Grade 3/4 AEs

| WHO Preferred Term  | Total  N= 136   (%) |
| --- | --- |
| Total no. subjects | 113 (83) |
| Neutropenia febrile  | 40 (29) |
| Infection bacterial  | 25 (18) |
| Thrombocytopenia | 23  (17) |
| Neutropenia without fever | 16 (12) |
| Pneumonia  | 14 (10) |
| Creatinine increased  | 12 (9) |
| Rash  | 12 (9) |
| Anemia  | 11 (8) |
| Diarrhea  | 8 (6) |
| Hypokalemia | 8 (6) |

## CTEP-20 Safety - Death

| Cause of Death | Total
N= 136 (%) |
| --- | --- |
| Deaths during the study  | 31 (23) |
| Progressive disease  | 19 (14) |
| Adverse event | 9 (7) |
| Drug related | 1 (1) |
| Other | 3 (2) |
| Early deaths | 16 (12) |

## CTEP-20  – Hospitalization on Study 

| No. of patient treated  | 136 |
| --- | --- |
| Total no. of hospitalizations  | 141 |
| No. of subjects hospitalized during study, n (%) | 81 (60) |
|  1-2 hospitalizations | 71 (52) |
|  3-4 hospitalizations | 8 (6) |
| > 5 hospitalizations | 2 (1) |
| Total duration of hospitalization, days |  |
| N | 81 |
| Mean (SD) | 17.9 (14.38) |
| Median | 15.0 |
| Range | (2; 73) |

## SummaryZarnestra in Elderly Poor-Risk AML

- Durable CR : an endpoint supportive of clinical benefit in AML
-  Consider in the context of :
- 11.1% CRR with 275 days median duration
- Poor risk patient population
- 12% one-month death rate
- 60% hospitalization

## Question

- 	Does the risk benefit analysis support regular approval of Zarnestra for the first-line treatment of AML patients age 65 or older with prior MDS or age 75 and older?

## Additional Slides

## Summary

- Standard Treatment Risk & Benefit in general and in elderly poor-risk AML patients:

| Outcome versus Age | < 65 | >65 + Poor-risk |
| --- | --- | --- |
| Treatment related death | 10-20% | > 25% |
| Complete remission rate | 60-75% | 30% - 50% |
|  2 year survival rate | 30-40% > 3 years | < 6% at 2 year |

## Summary

- Zarnestra Risk & Benefit in elderly poor-risk AML patients compare to and Standard Treatment in elderly AML patients:

| Outcome versus Tx | Zarnestra | Standard  |
| --- | --- | --- |
| Complete remission rate | 11.1% | 30% - 50% |
| Treatment related death | 7% | > 25% |
| One month mortality | 12% | 30- 48% |

## Approvals for APL, MDS

## Unfavorable Karyotype

- Per the sponsor, the karyotypes described as unfavorable included:
- del 5, del 5q,
- del 7, del 7q,
- trisomy 8,
- 11q23,
- complex (> 3 abnormalities).

## Summary of Patients with or without Prior MDS 

| Population
				 | < 65 years
n (%) | 65-74 years
n (%) | 75 years
n (%) | Total
n (%) |
| --- | --- | --- | --- | --- |
| All Treated AML | 7/9 (78%) | 61/73 (84%) | 49/74 (66%) | 117/156 (75%) |
| Elderly Poor-Risk AML | 0/0 | 61/61 (100%) | 49/74 (66%) | 110/135 (81%) |
| Per Protocol | 0/0 | 48/48 (100%) | 41/55 (75%) | 89/103 (86%) |

## Sponsor’s RR by Risk Factors

|  | Total | CR | PR |
| --- | --- | --- | --- |
| Age | 136 | 20 (15) | 3 (2) |
| 65-74 y | 61 | 11 (18) | 3 (5) |
| > 75 y | 75 | 9 (12) | - |
| Karyotype unfavorable | 136 | 20 (15) | 3 (2) |
| Yes | 66 | 9 (14) | 3 (5) |
| No | 62 | 10 (16) | - |
| Not done / not available | 8 | 1 (13) | - |
| Organ dysfunction | 136 | 20 (15) | 3 (2) |
| Yes | 83 | 13 (16) | 2 (2) |
| No | 53 | 7 (13) | 1 (2) |
| Prior MDS | 136 | 20 (15) | 3 (2) |
| Yes | 111 | 18 (16) | 3 (3) |
| No | 25 | 2 (8) | - |

## CTEP-20: Complete Remission Criteria

- Bone marrow < 5% myeloblasts with normal maturation of all cell lines, an ANC _>_ 1000/uL, a platelet _>_ 100, 000/uL, absence of blasts in peripheral blood, absence of identifiable leukemic cells in the bone marrow, clearance of disease-associated cytogenetic abnormalities, and clearance of any previously existing extramedullary disease.
- CR must be confirmed 4-6 weeks after initial documentation. At least one bone marrow biopsy should be performed to confirm CR.

- NCI-Sponsored Workshop on Definitions of Diagnosis and Response in Acute Myeloid Leukemia, 1990.

## CTEP-20 Safety – Overall AEs

| 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 AE | 2 (3) | 7 (9) | 9 (7) | 11 (7) |
| Drug- related AEs resulting in death | 0 | 1 (1) | 1 (1) | 1 (1) |
| Early deaths due to an AE | 2 (3) | 3 (4) | 5 (4) | 6 (4) |

## CTEP-20 Safety – Common Non Hem. AEs

| WHO Preferred Term  | Total  N= 136  (%) |
| --- | --- |
| Diarrhea | 64 (47) |
| Fatigue | 60 (44) |
| Nausea | 51 (38) |
| Rash  | 48 (35) |
| Fever | 42 (31) |
| Anorexia | 37 (27) |
| Constipation | 33 (24) |
| Vomiting | 32 (24) |
| Dyspnea | 32 (24) |
| Dizziness | 36 (26) |
| Ataxia + abnormal gait | 27 (20) |
| Confusion | 29 (21) |

## CTEP-20 Safety – Common Hem & Met AEs

| WHO Preferred Term  | Total  N= 136  (%) |
| --- | --- |
| Neutropenia febrile | 40 (29) |
| Purpura | 29 (21) |
| Thrombocytopenia | 26 (19) |
| Anemia | 24 (18) |
| Neutropenia | 17 (13) |
| Infection bacterial | 27 (20) |
| Moniliasis and other fungal infection | 22 (16) |
| Creatinine  | 62 (46) |
| Hypokalemia | 59 (43)  |
| Hyponatremia | 57 (42) |

## CTEP-20 Safety AEs Leading to Treatment Termination

| WHO Preferred Term  | Total   N= 136   (%) |  |
| --- | --- | --- |
|  | All | Drug Related |
| Total no. subjects with AE  | 21 (15) | 14 (10) |
| Creatinine blood increased  | 4 (3) | 3 (2) |
| Rash  | 4 (3) | 3 (2) |
| Pancreas enzymes increased  | 2 (1) | 2 (1) |
| Dehydration  | 1 (1) | 1 (1) |
| Diarrhea  | 1 (1) | 1 (1) |
| Dizziness  | 1 (1) | 1 (1) |
| Fatigue  | 1 (1) | 1 (1) |
| Insomnia  | 1 (1) | 1 (1) |
| Nausea  | 1 (1) | 1 (1) |
| Neuropathy peripheral  | 1 (1) | 1 (1) |
| Sweating increased  | 1 (1) | 1 (1) |

## CTEP-20 Safety – AEs Leading to Dose Reduction (> 2%)

| WHO Preferred Term  | Total (N= 136)   (%) |  |
| --- | --- | --- |
|  | All | Drug Related |
| Total no. subjects with AE | 47 (35) | 35 (26) |
| Neutropenia febrile  | 9 (7) | 6 (4) |
| Ataxia  | 5 (4) | 5 (4) |
| Creatinine blood increased  | 6 (4) | 4 (3) |
| Confusion  | 6 (4) | 3 (2) |
| Diarrhea  | 4 (3) | 3 (2) |
| Neutropenia  | 4 (3) | 3 (2) |
| Pancreas enzymes increased  | 3 (2) | 3 (2) |
| Rash  | 5 (4) | 3 (2) |
| Renal function abnormal  | 3 (2) | 3 (2) |
| Amnesia  | 2 (1) | 2 (1) |
| Bilirubinemia  | 3 (2) | 2 (1) |
| Fatigue  | 2 (1) | 2 (1) |
| Hypotension postural  | 2 (1) | 2 (1) |
| Infection bacterial  | 3 (2) | 2 (1) |

## CTEP-20 Safety – AEs Causing Treatment Interuption (> 2%)

| WHO Preferred Term  | Total  N= 136  (%) |  |
| --- | --- | --- |
|  | All | Drug Related |
| Total no. subjects with AE | 56 (41) | 45 (33) |
| Neutropenia  | 10 (7) | 8 (6) |
| Creatinine blood increased  | 10 (7) | 7 (5) |
| Nausea  | 6 (4) | 6 (4) |
| Neutropenia febrile  | 8 (6) | 6 (4) |
| Rash  | 5 (4) | 5 (4) |
| Confusion  | 3 (2) | 3 (2) |
| Pancytopenia  | 4 (3) | 3 (2) |
| Vomiting  | 3 (2) | 3 (2) |
| Ataxia  | 2 (1) | 2 (1) |
| Bilirubinemia  | 3 (2) | 2 (1) |
| Diarrhea  | 3 (2) | 2 (1) |
| Gait abnormal  | 2 (1) | 2 (1) |
| Infection bacterial  | 3 (2) | 2 (1) |
| Infection fungal  | 2 (1) | 2 (1) |
| Neuropathy peripheral  | 2 (1) | 2 (1) |
| Pneumonia  | 4 (3) | 2 (1) |

## CTEP-20 Safety – AEs Associated with  Death

| WHO Preferred Term  | Total  N= 136 (%) |
| --- | --- |
| Total no. subjects who died | 9 (7) |
| Cardiac failure | 3 (2) |
| Sepsis | 3 (2) |
| Infection fungal | 2 (1) |
| Pneumonia | 2 (1) |
| Arrhythmia atrial | 1 (1) |
| Circulatory failure | 1 (1) |
| Fibrillation atrial | 1 (1) |
| Gastrointestinal hemorrhage | 1 (1) |
| Hypoxia | 1 (1) |
| Multiple organ failure | 1 (1) |
| Neutropenia febrile | 1 (1) |
| Pulmonary hemorrhage | 1 (1) |
| Renal failure acute | 1 (1) |

## CTEP-20: Concomitant Therapy During Treatment

|  | Total N= 136 (%) |
| --- | --- |
| Blood product transfusions | 119 (88) |
| Human RBCsa | 114 (84) |
| Platelets, human blood | 89 (65) |
| White blood cells | 3 (2) |
| Anti-infectives | 116 (85) |
| Antibiotics | 111 (82) |
| Antivirals | 71 (52) |
| Antifungals | 51 (38) |
| Hydroxyurea | 3 (2) |
| Growth factors | 12 (9) |

## CTEP-20  – Reason for Hospitalization 

| Reason for hospitalization, N = 136 (%)  |  |
| --- | --- |
| No. of subjects with recorded reason  | 81 (59) |
| AE related to study medication  | 51 (38) |
| AE related to disease | 33 (24) |
| Other reason | 18 (13) |
| Chemotherapy | 2 (1) |
| Transfusion | 2 (1) |
| AE related to medication (not tipifarnib) | 2 (1) |

## Sponsor’s Response Rate in Relapsed AML INT-17 and CTEP-1 

| Response | INT-17  
(N= 99) | CTEP -1  
(N= 22) |
| --- | --- | --- |
| CR | 2 (2%) | 2 (9%) |
| PR | 6 (6%) | 6 (27%) |