FOOD AND DRUG ADMINISTRATION

Center for Drug Evaluation and Research

Oncologic Drugs Advisory Committee Meeting

May 3, 2004

**[Questions to the Committee]{.underline}**

**NDA 21-649** **Genasense (Oblimersen sodium), Genta, Inc.**

**Indication** Genasense in combination with dacarbazine is indicated
for the treatment of patients with advanced melanoma who have not
received prior chemotherapy.

Genta has submitted a single, international, multi-center, unblinded,
active control, randomized, phase 3 study (GM301) of Genasense plus
dacarbazine (DTIC) versus DTIC alone every three weeks as first-line
chemotherapy for metastatic melanoma, along with a small, supportive,
single arm, phase 1/2 study with various doses and schedules of
Genasense plus DTIC. In the phase 3 study, Genasense was given as a
continuous intravenous (IV) infusion over 5 days, requiring central
venous access and an ambulatory pump. DTIC 1000 mg/m2 IV was given over
60 minutes once every three week cycle in each study arm.

The primary endpoint of the trial was survival. Secondary endpoints were
progression-

free survival (PFS), response rate (RR), response duration, performance
status, tumor-related symptoms, and safety.

The results from the phase 3 study submitted for efficacy are presented
in the table below.

GM301 results

+----------------+------------+-----------+-------------+-----------+
| Endpoint       | G          | DTIC      | Hazard      | p-value   |
|                | enasense + | alone     | Ratio       |           |
|                | DTIC       |           |             |           |
|                |            | (N=385)   |             |           |
|                | (N=386)    |           |             |           |
+----------------+------------+-----------+-------------+-----------+
| Survival       | 274 days   | 238 days  | 0.89        | 0.18      |
+----------------+------------+-----------+-------------+-----------+
| PFS\*          | 61 days    | 48 days   | 0.75        | 0.006     |
+----------------+------------+-----------+-------------+-----------+
| Response Rate  | 11.7%      | 6.8%      |             | 0.019     |
| by             |            |           |             |           |
| Investigators  |            |           |             |           |
+----------------+------------+-----------+-------------+-----------+
| Response Rated | 6.7%       | 3.6%      |             | 0.056     |
| Confirmed by   |            |           |             |           |
| Independent    |            |           |             |           |
| Review         |            |           |             |           |
| Committee      |            |           |             |           |
+----------------+------------+-----------+-------------+-----------+

\* PFS by censoring on the date of the last complete evaluation.

Reviewer's Table

Genta proposes that these study results be considered evidence of
effectiveness. FDA has a number of important concerns. First, the study
clearly did not show the improvement in survival that was the stated
endpoint. Second, the PFS endpoint although nominally improved by
Genasense + DTIC has two important problems. First the effect is very
small, well under one month. Second in an open study, there is concern
that critical decisions such as when to obtain radiological films, could
be biased. In this study lesion assessments were done earlier in the
DTIC alone group (p \< 0.001). This could lead to earlier documentation
of progression. Thus, it is a concern whether the observed difference is
real. Except possibly for response rate, no other secondary endpoints
demonstrated an advantage of Genasense + DTIC over DTIC alone.
Furthermore, it is not clear that the small difference in PFS observed
is clinically meaningful, especially in view of the observed Genasense
toxicity.

A recent ODAC consideration of temozolomide (TMZ) for the treatment of
metastatic melanoma (NDA 21-051) appears pertinent. As in the present
application only one phase 3 trial was submitted in support of the
indication. The median survival on the DTIC arm was 6.4 months versus
7.7 months for TMZ, a difference in median survival of 1.3 months.
Although 80% of the events had occurred by the time of the analysis, the
difference was not statistically significant (p=0.2). A post-hoc
analysis suggested an improvement in survival at 6 months (61% for
temozolomide versus 51% for DTIC, p=0.063), but the Committee did not
consider this post-hoc finding to be convincing. Additional secondary
endpoints reviewed were response rate and PFS. The Agency's analysis
showed that median PFS was 1.74 months for TMZ versus 1.38 months for
DTIC, a difference of less than a month, but statistically significant
(p=0.002). Additional post-hoc exploratory analyses included possible
prolongation in PFS for some patients in the third quartile of the
survival curve before the curves came together again at 14 months. No
symptomatic benefit was identified in association with this difference.
The Agency compared response rates for the 2 arms; the ORR for TMZ was
12.2% (2.6% CR), versus 9.4% for DTIC (2.7% CR).

During the Advisory Committee meeting, members considered two questions
with regard to the Temozolomide application. The questions were:

1)  Do the results of this study, particularly the objective tumor
    response rates and response durations for the temozolomide versus
    dacarbazine, and the effect on progression-free survival, even in
    the absence of any effect on survival provide substantial evidence
    of effectiveness?

2)  Does the Committee recommend approval of temozolomide for the
    treatment of advanced metastatic melanoma?

The vote on the first question was 10 No and one abstention. On the
second question the vote was 10 No and 1 Yes.

TMZ, thus, was not recommended for approval because the trial did not
show superiority in survival to DTIC alone. The small but statistically
significant difference in PFS

(p = 0.002) and slightly higher response rate, in the absence of any
evidence of survival or symptomatic benefit, were not thought to
represent a meaningful benefit.

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In the recent case for Genasense, the GM301 study failed to demonstrate
an effect on survival, the primary trial endpoint. No effects were seen
on performance status or tumor-related symptoms, and there was greater
toxicity on the Genasense arm. The PFS improvement was significant but
the difference was very small and there may have been a difference in
progression ascertainment that favored Genasense. Similarly, a small
increase in response rate increment attributed to Genasense is somewhat
uncertain because a central reading (potentially, particularly important
in an open study) showed no significant difference. We would like the
panel to comment on whether improvement in PFS and RR of this magnitude,
apart from not being clearly identified planned study endpoints and any
reservations about the validity of the findings, would represent a
benefit both on the persuasiveness of the PFS and RR findings and one
that would outweigh the increase in toxicity seen with the combination.
No evidence from this study suggests that changes of this size represent
or are likely to predict clinical benefit, but that is an issue that
bears discussion.

Questions:

1.  Given the concerns noted above, does the committee believe that the
    small observed differences in the response rates (\< 5%) and in PFS
    (difference in median days between arms -13 days, p = 0.006)
    represent real effects of Genasense, when added to DTIC?

2.  Do the results of this study, in particular the small difference in
    RR (\<5%) and / or PFS for the combination of Genasense + DTIC
    versus DTIC alone, in the absence of a survival improvement, provide
    substantial evidence of effectiveness that outweighs the increased
    toxicity of administering the Genasense for the treatment of
    patients with metastatic melanoma who have not received prior
    chemotherapy?

3.  For regular approval of a drug for metastatic melanoma, the FDA has
    considered an improvement in survival and/or disease symptoms to
    constitute clinical benefit. However, in the December ODAC
    discussion, considerable interest was expressed in PFS as an
    endpoint in some settings, particularly where crossover to other
    treatment could obscure a potential survival benefit. In the
    metastatic melanoma setting, do you believe that a PFS benefit of
    some magnitude represents clinical benefit that could support
    regular drug approval, even in the absence of an effect on survival?

4.  If yes, please discuss what magnitude of improvement in this
    endpoint would be required to demonstrate clinical benefit and
    whether this would depend on the toxicity of the treatment?

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