# Presentation: 754672

## Division of Oncology Drug Products Presentation NDA 21-649 Genasense (Oblimersen) for metastatic melanomaODAC  May 3, 2004

## FDA Review Team for Genasense  (G3139)

- Project Management
- Nicholette Hemingway, MPH
- Medical Review
- Robert Kane, MD
- Ann Farrell, MD
- Statistical Review
- Peiling Yang, Ph.D.
- Rajeshwari Sridhara, Ph.D.

- Pharmacology
- Lilliam Rosario, Ph.D.
- David E. Morse, Ph.D
- Chemistry
- Haripada Sarker, Ph.D.
- Hasmukh Patel, Ph.D.
- Clin. Pharm/Biopharm
- Gene Williams, Ph.D.
- Brian Booth, Ph.D.

## Presentation Outline 

- Requirements for FDA approval
- ODAC Review of Temozolomide
- Genasense (Oblimersen)  NDA 21-649
- Trial Design (GM 301)
- Primary Endpoint – Survival
- Secondary Endpoints
- Summary

## Requirements - New Drug Approval

- FD&C Act 1962 - Substantial evidence of effectiveness required by Congress
- Adequate & well-controlled investigations
- Generally understood to mean evidence from at least 2 adequate and well-controlled studies

## Requirements - New Drug Approval

- FDAMA - 1997   One trial may suffice with other confirmatory evidence
- Effectiveness Guidance Document - 1998  A single trial should be of excellent design, internally consistent, and demonstrate a compelling result – statistically strong evidence of an important clinical benefit such as survival.

## New Drug Approval Efficacy Requirement

- Regular approval
-  clinical benefit or established surrogate
- Accelerated Approval
-  uses a surrogate endpoint reasonably likely to predict clinical benefit
- confirmation of clinical benefit required

## Approved drugs - Metastatic Melanoma

- Hydroxyurea (1967) - 10% response rate
- Dacarbazine (1975) – DTIC  single arm studies
-        Response Rate (RR) = 23%  (6%CR)
-      Survival times range 5 – 9 months
-  To date, no evidence for Survival or
-      Progression-free Survival (PFS) benefit for DTIC
-  RR:  5% - 24% in other studies
- No evidence for survival advantage for any combination  over DTIC alone
- Aldesleukin (1998) – IL-2
- RR:  16%  (6% CR with duration 2-5 yrs)

## Selected Non-approved drugs for Metastatic Melanoma

- Interferon
- 1997 Interferon alfa-2b approval for adjuvant
- 	therapy of melanoma
- Temozolomide
- ODAC 1999

## Temozolomide (TMZ)

- One main study: open label, 305 patients with metastatic melanoma randomized to
-                  DTIC IV each 3 weeks
-    versus    TMZ p.o. each 4 weeks
- Primary Endpoint – Survival (superiority) from median 6 mo-DTIC to 9 mo-TMZ
- Secondary endpoints: PFS and RR

## TMZ  Results  ITT population

|  | TMZ
N=156 | DTIC
N=149 | Hazard Ratio |   
 p value |
| --- | --- | --- | --- | --- |
| Median Survival | 7.7 mo | 6.4 mo | 0.85 | 0.20 * |
| Median PFS   | 53
days | 42
days | 
0.67 | 
0.002 * |
| Overall Response Rate  | 
12.2 % | 
9.4 % |  | 
0.43 ** |
|                 * log rank                   ** Chi square |  |  |  |  |

## TMZ was not approved

- Failed Primary Endpoint: No Survival benefit
- PFS, a secondary endpoint, small magnitude
- ODAC questioned the PFS difference
- No symptomatic benefit demonstrated
- A post-hoc survival analysis using a 6 month endpoint was not convincing

## Genasense GM301 TrialRegulatory History

- July 2000  -  Phase 3 protocol began
- August 1, 2003 – Data Cutoff Date
- December 8, 2003 - NDA submission

## Genasense GM301 Trial Design

- Large, multicenter, unblinded study
- Prolonged central venous access required for Genasense (G)
- Protocol specified IRC for responders
- Intellectual, emotional, and physical ability to maintain an ambulatory infusion pump
-    (for patients assigned to G + DTIC)

## Genasense GM301 Trial Design 

- Primary Endpoint – Survival Improvement
-     Secondary endpoints:
- Progression-free survival (PFS)
- Response rate (RR)
- Duration of response
- Durable response rate (RR at 6 months)
- Performance status (PS)
- Tumor-related symptoms
- Safety

## Genasense Trial Design - GM301 

- Trial design - to show a 2 month median improvement in survival from 6 months with DTIC alone to 8 months with Genasense plus DTIC; 90% power
- Trial Primary endpoint  – survival
- Trial Primary analysis – unadjusted log rank analysis of the intention-to-treat population

## Patient Disposition – GM301

|            ITT  | G + D | D | Total |
| --- | --- | --- | --- |
| Number of Patients  Randomized | 386 | 385 | 771 |
| Less number not treated | 15 | 25 | 40 |
| Still on study after day 42 (1st assessment) | 186
(48%) | 151
(39%) | 337
 (44%) |
| Discontinued early - 
  ( < 8 cycles) | 326
(84%) | 328 (85%) | 654    (85%) |

## Genasense study GM301

- Data cutoff date August 1, 2003
- Analysis occurred at 535 deaths (70%)
- Primary Endpoint Analysis:
-    Using the protocol specified analysis with the ITT population, _no survival benefit_ was demonstrated by adding Genasense to DTIC treatment versus DTIC alone.

## GM 301:  Primary Analysis Survival Time  ITT population

|  | Number     ( %)   died | Median Survival Time | 
HR * | Log rank      p |
| --- | --- | --- | --- | --- |
| G + DTIC
  n = 386 | 266 (69%) | 274 days 9.0 mo | 
0.89 | 
0.18 |
| DTIC
  n = 385 | 269 (70%) | 238 days 7.8 mo |  |  |
|      * 95% C.I. (0.75, 1.06) |  |  |  |  |

## Statistical Review of Efficacy: 

- Progression-Free Survival (PFS)
- (Secondary Endpoint)

## Results

- Failed to demonstrate efficacy in the primary endpoint, overall survival
- at two-sided alpha level of 0.05
- Strength of efficacy findings in the secondary endpoint, progression-free survival, is uncertain

## Outline

- Review of Applicant’s Analyses and Results
- Major FDA Concern: Lesion Assessment Times
- Additional FDA Concerns

## Review of Applicant’s PFS Analyses and Results

- PFS
- Time from date of randomization to date of disease progression/death
- Recorded Date of Disease Progression
- The assessment date
- Assessment date in each cycle:
- The latest date among different lesion assessments in that cycle

## Review of Applicant’s PFS Analyses and Results

- Protocol-Specified Analysis:
- Logrank:  p-value = 0.0003
- Median:  **74** (G3139 + DTIC) vs. **49** days (DTIC)
- Cox Model (supportive): Hazard Ratio = 0.73
- Alternative Approach:
- Logrank:  p-value = 0.0006
- Median:  **61** (G3139 + DTIC) vs. **48** days (DTIC)
- Cox model (supportive): Hazard Ratio = 0.75

## Review of Applicant’s PFS Analyses and Results

- Question:
- 	Is this a true finding?

## Major FDA Concern: Lesion Assessment Times

- Imbalance in Observed Lesion Assessment Times between Treatment Arms

## Lesion Assessment Times

- Planned Timing for Lesion Assessments
- In Practice:
- Not always as planned.
- Even when assessed in planned cycles, there were differences in timing between arms.

## Determining Event Dates

- Visit 1

- Visit 2

- Randomization

- = Date of Death or actual tumor progression

**Survival Event Date**

- Visit 1

- Visit 2

- Randomization

**PFS Event Date**

- Survival Analysis

- PFS Analysis

## Summary of Time to First 3 Observed Lesion Assessments (Actual Trial Data)

|  |  |  |  |
| --- | --- | --- | --- |
| Assessment
Number | Median in days |  | Logrank 
p-value |
|  | G3139 + DTIC | DTIC |  |
| 1 | 48 | 43 | <0.001 |
| 2  | 94 | 87 | <0.001 |
| 3 | 137 | 129 | <0.001 |

## Time to 1st Assessment (Trial Data)

## Time to 2nd Assessment (Trial Data)

## Time to 3rd Assessment (Trial Data)

## Lesion Assessment Times

- Impact of Imbalance in Assessment Times on PFS Analysis:
- Bias may be introduced in estimating PFS
- Even a small imbalance may lead to incorrect conclusion

## Lesion Assessment Times

| How Bias May Be Introduced: 
A Hypothetical Example |  |  |
| --- | --- | --- |
|  | Patient 001
Control | Patient 002
Experimental |
| Actual day of DP | Day 35 |  |
| 1st time of assessment  | Day 42 | Day 48 |
| Recorded day of DP | Day 42 | Day 48 |

## Lesion Assessment Times

**Impact of systematic bias:**
- _Simulation study_
- Distribution identical in both arms (Median PFS = 50 days, 300 subjects in each arm)
- Systematic increase by 2 days in assessment time in one arm
- In 98% of the 5000 simulations p-values were < 0.05 (average p-value = 0.004)

## Additional FDA Concern 

- Missing data was observed
- Missing assessments visits
- Missing individual lesion measurements
- In presence of missing data
- Bias could be introduced, especially in an open-label study

## Summary of PFS Finding

- The claimed PFS benefit may not be a true finding because of:
- Difference in assessment intervals may explain observed PFS effect
- Questions regarding reliability of data collected in an open-label study

## Summary of Statistical Review

- Study failed to achieve the primary objective of the study – No Overall Survival Benefit
- Secondary endpoints –  PFS analysis:
- Existence of effect ?
- Magnitude of effect ?
- Multiplicity Issues

## PFS analysis - continued

- Assessments done only at 6 week intervals, however PFS difference only 2-3 weeks
- PFS difference is highly statistically significant, but may be fully accounted for by asymmetry in timing of assessments between arms
- Magnitude of the effect size is uncertain
- PFS:  Real problem: what is the clinical relevance

## Primary Endpoint – Survival No Advantage for Genasense

- Secondary endpoints:
- Progression-free survival (PFS)
- Response rate (RR)
- Response duration
- Durable response rate
- Performance status (PS)
- Tumor-related symptoms
- Safety

## Comparison of RR  data as of original NDA submission (12/8/03)

|  | G + DTIC
(N=386) | DTIC
(N=385) | difference | 
P value |
| --- | --- | --- | --- | --- |
| Genta / Investigator            |   45 
  (11.7%) |  26 
 (6.8%) | 
4.9% | 0.018 |
| Blinded  Independent  |    26  
 (6.7%) |  14     (3.6%) | 
3.1% | 0.056 |

- Comparison of RR  data as of original NDA submission (12/8/03)

## Response Concordance	

- 5 CRs identified by Genta/site investigators
- 3 in G + DTIC arm and 2 in DTIC arm
- None were adjudicated as CRs by Independent Review
- 44% of responders (CR or PR) by Genta/site investigators were determined not assessable or unconfirmed by Independent Review.
- 49% full concordance rate for response category between Genta and Independent Review.

##      Genta New Response Data             provided April 9, 2004

- New data is being examined
- Problems with data developed outside of the study protocol:
- Ascertainment bias between arms can occur when analysis is not prospectively planned
- Subsequent therapies, e.g. surgery, not part of the protocol treatment may not be applied symmetrically

## Duration of Response – Genta analysis

|  | Intent-to-Treat Population |  |
| --- | --- | --- |
|  | G + DTIC | DTIC Alone |
| Number of patients | N = 45 | N = 26 |
| Mean (SD)  Days | 175.7 (136.0) | 153.5 ( 99.2) |
| Median  Days | 126.0 | 127.5 |
| Range   (Days) | (41 , 565) | (42 , 390) |

## Durable response rateGenta Analysis

- Genta has pre-specified a response of
-     ≥ 6 months as a durable response.
- Durable response rate for G + D = 3.4%
- Durable response rate for  D = 1.3%
- Difference - not significant

## ECOG Performance Status

- There were no differences in performance status observed between study arms
-    during treatment

## Tumor-related symptoms

- There were no differences in symptoms observed between study arms
-    during treatment

## Adverse Events – Toxicity 

| Category | G + DTIC
N (%) | DTIC
N (%) |
| --- | --- | --- |
| Number of patients receiving any therapy | 371 | 360 |
| At least 1 Grade 3 or 4  
   adverse event   (AE) | 249 
(67%) | 154
 (43%) |
| At least 1 serious 
      adverse event  (SAE) | 149 
(40%) | 97 
(27%) |
| At least 1 adverse event and discontinued permanently | 69 
(19%) | 39 
(11%) |

- Adverse Events – Toxicity

## Adverse Events   Hematologic Toxicity 

| 
 | G + DTIC
 (N = 371) n (%) | DTIC 
(N = 360)
n (%) |
| --- | --- | --- |
| Grade 3 - 4  Neutropenia | 79 (21%) | 45 (12%) |
| Grade 3 - 4 Thrombocytopenia | 58 (16%) | 23 (6%) |

- Adverse Events   Hematologic Toxicity

## Adverse Events ≥ 5%Non-hematologic Toxicity 

|       AE | G + DTIC | DTIC |
| --- | --- | --- |
| Nausea | 231 (62%) | 169 (47%) |
| Pyrexia | 197 (53%) |   63 (18%) |
| Fatigue | 170 (46%) | 142 (39%) |
| Vomiting | 139 (38%) |  75 (21%) |
| Infections  |    123 (33%) |    65 (18%) |
| Anorexia |    114 (31%) |    56 (16%) |
| Headache  |      97 (26%) |    47 (13%) |

## Adverse Events ≥ 5%Non-hematologic Toxicity 

|         AE | G + DTIC | DTIC |
| --- | --- | --- |
| Rigors |     76 (21%) |    16 (4%) |
| Pruritus and Rash |      57 (15% ) |    18 (5%) |
| Injection site infection |   24 (7%) |    4 (1%) |
| Injection-site Reactions |   21 (6%) |   5 (1%) |
| Influenza-like Illness |   19 (5%) |      3 (0.8%) |
| Upper extremity  
thrombosis |   18 (5%) |      3 (0.8%) |
| *Axillary vein, Subclavian vein, Jugular vein, injection site thrombosis and superior vena caval syndrome  |  |  |

- Adverse Events **≥ 5%**Non-hematologic Toxicity

## Genasense Summary 

- GM301Trial failed its primary protocol-specified endpoint
- No Survival Benefit demonstrated with the addition of Genasense  to DTIC
- The efficacy of the control arm, DTIC alone, is consistent with other studies.

## Secondary Endpoints - PFS

- PFS: No precedent for PFS as evidence of
-           clinical benefit for metastatic melanoma
- May not be a true finding
- PFS difference may be 13 or 25 days depending on censoring technique chosen for missing data
- Clinical relevance ?

## Secondary Endpoints - Response

- 2. Response rate:
- Difference from DTIC alone:  3 - 5%
- No CRs Confirmed by IRC
- Clinical relevance ?
- 3. Durable response rate:  No sig. difference (3.4% (G+DTIC) vs. 1.3% (DTIC alone))
- 4. Response duration:  126 days (G+DTIC) versus 127.5 days (DTIC alone)

## Secondary endpoints- Genasense

-  5. Performance status:
- 	- No benefit observed from Genasense
-  6. Symptomatic benefit:  Not observed
-  7. Safety:  Greater toxicity for the   	combination of G + DTIC