Oncology Division Advisory Committee (ODAC)

Briefing Document

Fulfillment of the Accelerated Approval Requirements for the

Non-Small Cell Lung Cancer Indication:

"Ethyol (Amifostine) Reduces the Cumulative Renal Toxicity

Associated with Repeated Administration of Cisplatin in Patients with

Advanced Non-Small Cell Lung Cancer"

**TABLE OF CONTENTS**

[1 introduction 3](#introduction)

[2 WR-0053: A Phase III Trial of Intensive Cisplatin and Vinblastine ±
Amifostine (Ethyol) in Patients with Stage IIIB or IV Non-Small Cell
Lung Cancer
4](#wr-0053-a-phase-iii-trial-of-intensive-cisplatin-and-vinblastine-amifostine-ethyol-in-patients-with-stage-iiib-or-iv-non-small-cell-lung-cancer)

[2.1 Nephrotoxicity Endpoint 5](#nephrotoxicity-endpoint)

[2.2 No Reduction in Antitumor Efficacy Endpoint
6](#no-reduction-in-antitumor-efficacy-endpoint)

[2.2.1 Tumor Response Rate 6](#tumor-response-rate)

[2.2.2 Progression-Free Survival 6](#progression-free-survival)

[2.2.3 Overall Survival 7](#overall-survival)

[3 AntiTumor Efficacy Data from the phase iii experience with amifostine
8](#antitumor-efficacy-data-from-the-phase-iii-experience-with-amifostine)

[3.1 Tumor Response, Progression-Free Survival, and Overall Survival
8](#tumor-response-progression-free-survival-and-overall-survival)

[3.2 Meta-Analysis of Phase III Survival Data
9](#meta-analysis-of-phase-iii-survival-data)

[4 FDA Assessment of the Results for WR-0053
10](#fda-assessment-of-the-results-for-wr-0053)

[5 elements of a trial design required by the fda for fulfillment of the
Post-approval commitment for the nsclc indication
10](#elements-of-a-trial-design-required-by-the-fda-for-fulfillment-of-the-post-approval-commitment-for-the-nsclc-indication)

[6 implementation and challenges of a new clinical trial to fulfill the
accelerated approval requirements of the nsclc indication
14](#implementation-and-challenges-of-a-new-clinical-trial-to-fulfill-the-accelerated-approval-requirements-of-the-nsclc-indication)

[7 CONCLUSION 15](#conclusion)

[8 REFERENCES 16](#references)

# introduction

ETHYOL^^ (amifostine) is an organic thiophosphate known chemically as
ethanethiol, 2-\[(3-aminopropyl)amino\] dihydrogen phosphate (ester). It
is a phosphorylated aminothiol prodrug exerting its effect as a
selective cytoprotective agent for normal tissues against the toxicities
of chemotherapy and/or radiation. The selective cytotoxic effect of
amifostine has been demonstrated in preclinical and clinical trials of
chemotherapy and/or radiotherapy with or without amifostine
pretreatment.

The currently approved indications for intravenous administration of
ETHYOL are:

> *ETHYOL (amifostine) is indicated to reduce the cumulative renal
> toxicity associated with repeated administration of cisplatin in
> patients with advanced ovarian cancer or non-small cell lung cancer.*
>
> *ETHYOL (amifostine) is indicated to reduce the incidence of moderate
> to severe xerostomia in patients undergoing post-operative radiation
> treatment for head and neck cancer, where the radiation port includes
> a substantial portion of the parotid glands.*

The indication in non-small cell lung cancer (NSCLC) was approved under
the Accelerated Approval Regulations on 15 March 1996. This approval was
based on the results of a Phase II study of amifostine (740 and 910
mg/m^2^), cisplatin (120 mg/m^2^), and vinblastine (5 mg/m^2^) in 25
patients with Stage IV NSCLC[^1] (WR-0032) and on a commitment to the
FDA by U.S. Bioscience, Inc. (West Conshohocken, PA) to conduct a
controlled, clinical trial in patients with advanced NSCLC. WR-0053, a
Phase III Trial of Intensive Cisplatin and Vinblastine ± Amifostine
(Ethyol) in Patients with Stage IIIB or IV NSCLC, was ongoing at this
time and was offered by U.S. Bioscience, Inc. and accepted by the
Agency, if positive, to fulfill the Accelerated Approval commitment.

WR-0053 was conducted from 16 December 1994 to 30 June 1999, with final
results submitted to the Agency on 24 June 2002 as part of a
pre-supplemental new drug application (sNDA) Briefing Package (Serial
#493). Included in this submission was a meta-analysis of survival data
from the Phase III experience of amifostine in controlled, clinical
trials supporting the contention that amifostine did not affect the
antitumor efficacy of anticancer therapy. On 26 July 2002, in a response
to the sNDA Briefing Document submitted by MedImmune Oncology, Inc., the
FDA concluded that, although study WR-0053 demonstrated
nephroprotection, it did not appear to demonstrate that amifostine had
no affect on antitumor efficacy. In light of this, the Agency stated
that the completion of an appropriately sized, adequate and
well-controlled study of cisplatin-based chemotherapy in NSCLC
demonstrating that amifostine does not affect antitumor efficacy in
addition to showing protection from cisplatin-induced nephrotoxicity
should be performed. The elements of this trial design were discussed
with the Agency on 23 January 2003 in a face-to-face meeting requested
by the company. The purpose of this meeting was to seek the FDA's
guidance for the design of a trial necessary to fulfill the Phase IV
commitment.

This ODAC Briefing Document summarizes the results of the primary
endpoints of WR-0053 (i.e., nephroprotection and no reduction in
antitumor efficacy) as well as the results of the meta-analysis of
survival data from the Phase III experience of amifostine in randomized,
controlled clinical trials. In addition, this document presents the
trial design elements discussed at the 23 January 2003 meeting with the
agency of a new, adequate and well-controlled trial of cisplatin-based
chemotherapy ± amifostine in patients with advanced NSCLC. Also, some of
the issues involved in the implementation of such a trial will be
described.

# WR-0053: A Phase III Trial of Intensive Cisplatin and Vinblastine ± Amifostine (Ethyol) in Patients with Stage IIIB or IV Non-Small Cell Lung Cancer

WR-0053 was a Phase III, open-label, randomized, two-arm,
parallel-group, multicenter, multinational study designed to determine
if pretreatment with amifostine increases the therapeutic index of
comparable cisplatin doses when combined with vinblastine in the
treatment of patients with advanced NSCLC. Eligible patients included
men or women, 18 years of age or older, with histologically or
cytologically verified Stage IIIB or IV NSCLC. Other eligibility
criteria included measurable or evaluable disease, no prior chemotherapy
or biological therapy, Eastern Cooperative Oncology Group (ECOG)
performance status of 0 or 1, and adequate bone marrow, renal, and
hepatic function. In this study, patients were randomized to receive
cisplatin (120 mg/m^2^) and vinblastine (3.75 mg/m^2^) ± amifostine (740
mg/m^2^) every 4 weeks until disease progression, unacceptable toxicity,
or other reasons for patient withdrawal. Stratification factors at
randomization included treatment center, histology (adenocarcinoma vs.
squamous vs. other), disease stage (IIIB vs. IV), ECOG performance
status (0 vs. 1), and prior radiation therapy (yes vs. no).

WR-0053 was conducted between 16 December 1994 and 30 June 1999. A total
of 366 patients from 28 study centers in the United States of America
(15 centers), Europe (10 centers), and Africa (3 centers) were
randomized to receive cisplatin and vinblastine ± amifostine in this
study. Of these patients, 185 patients were randomized to receive
amifostine, cisplatin, and vinblastine (amifostine arm) and 181 patients
(180 of which were included in the intent-to-treat data set) and were
randomized to receive cisplatin and vinblastine (control arm). Both
treatment arms were well balanced in terms of baseline demographic and
tumor characteristics, and both treatment arms received comparable doses
of cisplatin and vinblastine. The median dose intensity of amifostine
was 100%.

The primary endpoint of this study was an improved therapeutic index
defined as follows:

1\. No reduction in antitumor efficacy with a reduction in
cisplatin-related nephrotoxicity; or

2\. Increase in antitumor efficacy.

-   No reduction in antitumor efficacy was based on the following
    conditions:

> a\. No more than 7% reduction in tumor response rate;
>
> b\. \>0.7 two-sided 95% lower confidence limit of hazard ratio for
> time to progression; and
>
> c\. \>0.7 two-sided 95% lower confidence limit of hazard ratio for
> survival time.

-   Cisplatin-related nephrotoxicity was defined as 25% or more decrease
    from baseline in creatinine clearance at the completion of therapy.

## Nephrotoxicity Endpoint

WR-0053 demonstrated that the addition of amifostine to the cisplatin
and vinblastine regimen resulted in a statistically significant
reduction of cisplatin-related nephrotoxicity defined as ≥25% decrease
in creatinine clearance from baseline to completion of therapy.

As shown in Exhibit 1, the incidence of protocol-defined
cisplatin-related nephrotoxicity was statistically significantly lower
in patients treated with amifostine as compared with control patients
(p\<0.001). Nephrotoxicity occurred in 49 (28%) patients in the
amifostine arm and 87 (49%) patients in the control arm. When stratified
by cisplatin dose, the incidence of cisplatin-related nephrotoxicity was
statistically significantly lower in the amifostine arm versus the
control arm (p\<0.001). Moreover, the cumulative dose to onset of
cisplatin-related nephrotoxicity was statistically significantly higher
in the amifostine arm (240 mg/m^2^) versus the control arm (120 mg/m^2^)
(p\<0.001). When nephrotoxicity was analyzed by cycle (a secondary
endpoint), the incidence was statistically significantly lower in the
amifostine arm versus the control arm at the end of each cycle for
cycles 1 through 5 (p\<0.02) and over all cycles (p\<0.001).

Exhibit 1 Summary of Cisplatin-Related Nephrotoxicity (ITT Data Set)

## No Reduction in Antitumor Efficacy Endpoint

### Tumor Response Rate

Exhibit 2 summarizes the tumor response of patients treated with
cisplatin and vinblastine ± amifostine for advanced NSCLC. As shown in
this exhibit, 56 (30%) patients in the amifostine arm and 58 (32%)
patients in the control arm achieved an objective response (CR or PR) to
therapy; this difference was not statistically significant (p=0.735).
The difference in tumor response was -2.0%, with a 95% confidence
interval of -11.5% to 7.6%. Thus, the protocol-defined criterion of no
more than 7% reduction in tumor response rate was met.

Additional analyses of tumor response (i.e., time to objective response
and duration of response) were also comparable between the two treatment
arms. The median time to objective response was 57 days in the
amifostine arm and 58 days in the control arm (p=0.134), and the median
duration of response was 118 days in the amifostine and 159 days in the
control arm (p=0.268).

Exhibit 2 Tumor Response (ITT Data Set)

+--------------------------+-------+-------+-------+--------+--------+
|                          | **    |       | **Cis |        | **P-v  |
|                          | Amifo |       | plati |        | alue** |
|                          | stine |       | n/Vin |        |        |
|                          | +**   |       | blast |        |        |
|                          |       |       | ine** |        |        |
|                          | **Cis |       |       |        |        |
|                          | plati |       | *     |        |        |
|                          | n/Vin |       | *(N=1 |        |        |
|                          | blast |       | 80)** |        |        |
|                          | ine** |       |       |        |        |
|                          |       |       |       |        |        |
|                          | *     |       |       |        |        |
|                          | *(N=1 |       |       |        |        |
|                          | 85)** |       |       |        |        |
+--------------------------+-------+-------+-------+--------+--------+
| Objective Response       |       |       |       |        |        |
+--------------------------+-------+-------+-------+--------+--------+
| CR + PR                  | 56    | (30%) | 58    | (32%)  | 0.     |
|                          |       |       |       |        | 735^a^ |
+--------------------------+-------+-------+-------+--------+--------+
| Difference of Tumor      | -2.0% |       |       |        |        |
| Response                 |       |       |       |        |        |
+--------------------------+-------+-------+-------+--------+--------+
| 95% CI (2-Sided)         | (-1   |       |       |        |        |
|                          | 1.5%- |       |       |        |        |
|                          | 7.6%) |       |       |        |        |
+--------------------------+-------+-------+-------+--------+--------+
| Best Response            |       |       |       |        |        |
+--------------------------+-------+-------+-------+--------+--------+
| CR                       | 1     | (1%)  | 4     | (2%)   |        |
+--------------------------+-------+-------+-------+--------+--------+
| PR                       | 55    | (30%) | 54    | (30%)  |        |
+--------------------------+-------+-------+-------+--------+--------+
| Stable Disease           | 69    | (37%) | 48    | (27%)  |        |
+--------------------------+-------+-------+-------+--------+--------+
| Progressive Disease      | 31    | (17%) | 40    | (22%)  |        |
+--------------------------+-------+-------+-------+--------+--------+
| Not Assessable           | 29    | (16%) | 34    | (19%)  |        |
+--------------------------+-------+-------+-------+--------+--------+
| Time to Objective        |       |       |       |        |        |
| Response (Days)          |       |       |       |        |        |
+--------------------------+-------+-------+-------+--------+--------+
| N                        | 56    |       | 58    |        |        |
+--------------------------+-------+-------+-------+--------+--------+
| Median                   | 56.5  |       | 57.5  |        | 0.     |
|                          |       |       |       |        | 134^b^ |
+--------------------------+-------+-------+-------+--------+--------+
| Range                    | (3    |       | (4    |        |        |
|                          | 2.0-1 |       | 9.0-1 |        |        |
|                          | 63.0) |       | 68.0) |        |        |
+--------------------------+-------+-------+-------+--------+--------+
| Duration of Objective    |       |       |       |        |        |
| Response (Days)          |       |       |       |        |        |
+--------------------------+-------+-------+-------+--------+--------+
| Median                   | 118   |       | 159   |        | 0.     |
|                          |       |       |       |        | 268^c^ |
+--------------------------+-------+-------+-------+--------+--------+
| Range                    | (     |       | (     |        |        |
|                          | 0.0-5 |       | 4.0-6 |        |        |
|                          | 89.0) |       | 25.0) |        |        |
+--------------------------+-------+-------+-------+--------+--------+
| ^a^ P-value based on     |       |       |       |        |        |
| Fisher's exact test      |       |       |       |        |        |
|                          |       |       |       |        |        |
| ^b^ P-value based on     |       |       |       |        |        |
| Wilcoxon rank sum test   |       |       |       |        |        |
|                          |       |       |       |        |        |
| ^c^ P-value based on     |       |       |       |        |        |
| log-rank test            |       |       |       |        |        |
|                          |       |       |       |        |        |
| CR: Complete Response;   |       |       |       |        |        |
| PR: Partial Response;    |       |       |       |        |        |
| CI: Confidence Interval  |       |       |       |        |        |
+--------------------------+-------+-------+-------+--------+--------+

### Progression-Free Survival

Exhibit 3 summarizes the progression-free survival results of this
study. The median progression-free survival was 4.14 months in the
amifostine arm and 4.73 months in the control arm, with a hazard ratio
of 0.91 and a 95.2% confidence interval of 0.72-1.15. This difference
was not statistically significant (p=0.852, based on Wilcoxon test or
p=0.417, based on the log-rank test). Given the lower bound of the
two-sided 95.2% confidence interval of 0.72, the protocol-defined
criterion of \>0.7 two-sided 95% LCL of hazard ratio for time to
progression was met.

Exhibit 3 Progression-Free Survival (ITT Data Set)

+----------------------+-----------------+-----------------+-----------+
|                      | **Amifostine    | **Cisplati      | **        |
|                      | +**             | n/Vinblastine** | P-value** |
|                      |                 |                 |           |
|                      | **Cisplati      | **(N=180)**     |           |
|                      | n/Vinblastine** |                 |           |
|                      |                 |                 |           |
|                      | **(N=185)**     |                 |           |
+----------------------+-----------------+-----------------+-----------+
| Progression-Free     |                 |                 |           |
| Survival             |                 |                 |           |
+----------------------+-----------------+-----------------+-----------+
| Median (months)      | 4.14            | 4.73            | 0.852^a^  |
+----------------------+-----------------+-----------------+-----------+
| Range                | (0.0-27.2)      | (0.0-22.4)      | (         |
|                      |                 |                 | 0.417)^b^ |
+----------------------+-----------------+-----------------+-----------+
| Hazard Ratio         | 0.91            |                 |           |
+----------------------+-----------------+-----------------+-----------+
| 95.2% CI of Hazard   | (0.72-1.15)     |                 |           |
| Ratio                |                 |                 |           |
+----------------------+-----------------+-----------------+-----------+
| ^a^ P-value based on |                 |                 |           |
| Wilcoxon test.       |                 |                 |           |
|                      |                 |                 |           |
| ^b^ P-value based on |                 |                 |           |
| log-rank test.       |                 |                 |           |
+----------------------+-----------------+-----------------+-----------+

### Overall Survival

As shown in Exhibit 4, the median survival was 8.75 months in the
amifostine arm and 9.93 months in the control arm, with a hazard ratio
of 0.83 and a 95.2% confidence interval of 0.67-1.04. This difference
was not statistically significant (p=0.288, based on Wilcoxon test or
p=0.097, based on the log-rank test). Given the lower bound of the
two-sided 95% confidence interval of 0.67, the protocol-criterion of
\>0.7 two-sided 95% LCL of hazard ratio for survival time was not met.

Exhibit 4 Overall Survival (ITT Data Set)

+----------------------+-----------------+-----------------+----------+
|                      | **Amifostine    | **Cisplati      | **P      |
|                      | +**             | n/Vinblastine** | -value** |
|                      |                 |                 |          |
|                      | **Cisplati      | **(N=180)**     |          |
|                      | n/Vinblastine** |                 |          |
|                      |                 |                 |          |
|                      | **(N=185)**     |                 |          |
+----------------------+-----------------+-----------------+----------+
| Overall Survival     |                 |                 |          |
+----------------------+-----------------+-----------------+----------+
| Median (months)      | 8.75            | 9.93            | 0.288^a^ |
+----------------------+-----------------+-----------------+----------+
| Range                | (0.1-50.5)      | (0.1-61.5)      | (0       |
|                      |                 |                 | .097)^b^ |
+----------------------+-----------------+-----------------+----------+
| Hazard Ratio         | 0.83            |                 |          |
+----------------------+-----------------+-----------------+----------+
| 95.2% CI of Hazard   | (0.67-1.04)     |                 |          |
| Ratio                |                 |                 |          |
+----------------------+-----------------+-----------------+----------+
| ^a^ P-value based on |                 |                 |          |
| Wilcoxon test.       |                 |                 |          |
|                      |                 |                 |          |
| ^b^ P-value based on |                 |                 |          |
| log-rank test.       |                 |                 |          |
+----------------------+-----------------+-----------------+----------+

Stratified analyses of overall survival including age, gender, and the
stratification factors used at randomization showed the survival of the
subset of ECOG Performance Status of 0 (ECOG PS=0) patients as having
the most impact on overall survival. Analysis of survival among patients
with ECOG PS=0 (75 patients in the amifostine arm and 72 patients in the
control arm) showed a median survival of 9.8 months in the amifostine
arm versus 17.2 months in the control arm (p=0.026). Since the
stratification factors at randomization were well balanced between the
two treatment arms, no explanation for this observation has been
identified.

The finding of 17.2 months survival among ECOG PS=0 patients in the
control arm is not consistent with other randomized trials. In a large
randomized trial comparing four platinum-based chemotherapy regimens in
1,207 patients with advanced NSCLC, the median survival for all 1,207
patients was 8 months and among PS=0 patients, the median survival was
10.8 months.[^2] In an earlier randomized trial (EST 1581) of the most
active regimens between 1981 and 1985, in which three treatment arms
were platinum-based and one arm was a combination of mitomycin C,
vinblastine, and cisplatin, the median survival of PS=0 patients was 9
months.[^3]

The risk of potential tumor protection in WR-0053 is inconclusive.
Objective response rates, progression-free and overall survival did not
show any statistically significant differences between the two treatment
arms. Objective response rates were 30% in the amifostine arm versus 32%
in the control arm (p=0.735), and median progression-free survival was
4.14 months in the amifostine arm and 4.73 months in the control arm
(p=0.417, log-rank test), with a hazard ratio of 0.91 and a 95%
confidence interval of 0.72-1.15. The tumor response and
progression-free survival results met the protocol-defined criteria for
no reduction in tumor efficacy. Median survival was 8.75 months in the
amifostine arm versus 9.93 months in the control arm. However, analysis
of overall survival in the amifostine arm did not meet the
protocol-defined criterion for non-inferiority, namely \>0.7 two-sided
95% lower confidence limit of hazard ratio.

# AntiTumor Efficacy Data from the phase iii experience with amifostine

Including WR-0053, five Phase III randomized, controlled studies of
amifostine have been completed to date. These trials consist of 1,326
patients with various cancers, including head and neck (WR-0038), rectal
(WR-9001), ovarian (WR-0001), and NSCLC (WR-0053 and WR-0056). Final
study reports for each of these trials have been submitted to the FDA.
In each of these trials, preservation of antitumor efficacy was assessed
using the parameters of tumor response, progression-free survival, and
overall survival.

## Tumor Response, Progression-Free Survival, and Overall Survival

Exhibit 5 summarizes the tumor response data from the Phase III
randomized, controlled trials of amifostine.

Exhibit 5 Summary of Tumor Response Data

+------------------------+---------+---------+--------+-------+-------+
|                        | **[R    |         |        |       |       |
|                        | esponse |         |        |       |       |
|                        | Rate    |         |        |       |       |
|                        | (%)]    |         |        |       |       |
|                        | {.under |         |        |       |       |
|                        | line}** |         |        |       |       |
+------------------------+---------+---------+--------+-------+-------+
|                        | **Amifo | **Co    | **     | **95% |       |
|                        | stine** | ntrol** | Differ | CI**  |       |
|                        |         |         | ence** |       |       |
|                        | **Arm** | **Arm** |        | **(   |       |
|                        |         |         | **in   | 2-sid |       |
|                        |         |         | R      | ed)** |       |
|                        |         |         | ates** |       |       |
+------------------------+---------+---------+--------+-------+-------+
| WR-0053: NSCLC         | 30%     | 32%     | −2%    | −1    | 7.6%  |
| (N=365)^a^             |         |         |        | 1.5%, |       |
+------------------------+---------+---------+--------+-------+-------+
| WR-0056: NSCLC         | 37%     | 34%     | 3%     | −     | 14.4% |
| (N=300)^a^             |         |         |        | 7.2%, |       |
+------------------------+---------+---------+--------+-------+-------+
| WR-0001: Ovarian       | 37%     | 28%     | 9%     | −     | 20.5% |
| (N=242)^b^             |         |         |        | 2.9%, |       |
+------------------------+---------+---------+--------+-------+-------+
| WR-0038: Head & Neck   | 54%     | 58%     | −4%    | −1    | 7.9%  |
| (N=315)^c^             |         |         |        | 6.1%, |       |
+------------------------+---------+---------+--------+-------+-------+
| WR-9001: Rectal        | 16%     | 8%      | 8%     | −     | 21.2% |
| (N=104)^d^             |         |         |        | 4.2%, |       |
+------------------------+---------+---------+--------+-------+-------+
| ^a^ Tumor response     |         |         |        |       |       |
| based on objective     |         |         |        |       |       |
| response rate (CR +    |         |         |        |       |       |
| PR)                    |         |         |        |       |       |
|                        |         |         |        |       |       |
| ^b^ Tumor response     |         |         |        |       |       |
| based on pathologic    |         |         |        |       |       |
| tumor response rate    |         |         |        |       |       |
| (CR + PR)              |         |         |        |       |       |
|                        |         |         |        |       |       |
| ^c^ Tumor response     |         |         |        |       |       |
| based on locoregional  |         |         |        |       |       |
| tumor control.         |         |         |        |       |       |
|                        |         |         |        |       |       |
| ^d^ Tumor response     |         |         |        |       |       |
| based on complete      |         |         |        |       |       |
| response rate.         |         |         |        |       |       |
+------------------------+---------+---------+--------+-------+-------+

Exhibit 6 summarizes the progression-free survival data from the Phase
III randomized, controlled trials of amifostine. As seen in this
exhibit, the progression-free survival hazard ratios appear close to
1.0.

Exhibit 6 Summary of Progression-Free Survival Data

+--------------------------+---------+---------+--------+-------------+
|                          | **      |         |        |             |
|                          | [Median |         |        |             |
|                          | (m      |         |        |             |
|                          | onths)] |         |        |             |
|                          | {.under |         |        |             |
|                          | line}** |         |        |             |
+--------------------------+---------+---------+--------+-------------+
|                          | **Co    | **Amifo | **Ha   | **95% CI**  |
|                          | ntrol** | stine** | zard** |             |
|                          |         |         |        | **          |
|                          | **Arm** | **Arm** | **R    | (2-sided)** |
|                          |         |         | atio** |             |
+--------------------------+---------+---------+--------+-------------+
| WR-0053: NSCLC (N=365)   | 4.73    | 4.14    | 0.91   | 0.72 - 1.15 |
+--------------------------+---------+---------+--------+-------------+
| WR-0056: NSCLC (N=300)   | 3.95    | 4.27    | 1.12   | 0.85 - 1.48 |
+--------------------------+---------+---------+--------+-------------+
| WR-0001: Ovarian (N=242) | 18.1    | 15.8    | 0.98   | 0.64 - 1.4  |
+--------------------------+---------+---------+--------+-------------+
| WR-0038: Head & Neck     | 8.7     | 10.8    | 1.00   | 0.70 - 1.42 |
| (N=315)                  |         |         |        |             |
+--------------------------+---------+---------+--------+-------------+
| WR-9001: Rectal (N=104)  | 5.8     | 6.8     | 1.12   | 0.73 - 1.71 |
+--------------------------+---------+---------+--------+-------------+
|                          |         |         |        |             |
+--------------------------+---------+---------+--------+-------------+

Exhibit 7 summarizes the overall survival data for the five Phase III
randomized, controlled trials of amifostine. As seen in this exhibit,
the overall survival hazard ratios for four of the five studies appear
close to 1.0. In WR-0053, the protocol-defined criterion for the
survival endpoint, namely \>0.7 lower bound of the two-sided 95% CI for
the survival hazard ratio, was not met.

Exhibit 7 Summary of Overall Survival Data

+--------------------------+---------+---------+--------+-------------+
|                          | **      |         |        |             |
|                          | [Median |         |        |             |
|                          | (m      |         |        |             |
|                          | onths)] |         |        |             |
|                          | {.under |         |        |             |
|                          | line}** |         |        |             |
+--------------------------+---------+---------+--------+-------------+
|                          | **Co    | **Amifo | **Ha   | **95%       |
|                          | ntrol** | stine** | zard** | C           |
|                          |         |         |        | onfidence** |
|                          | **Arm** | **Arm** | **R    |             |
|                          |         |         | atio** | *           |
|                          |         |         |        | *Interval** |
+--------------------------+---------+---------+--------+-------------+
| WR-0053: NSCLC (N=365)   | 9.9     | 8.8     | 0.831  | 0.666 -     |
|                          |         |         |        | 1.037       |
+--------------------------+---------+---------+--------+-------------+
| WR-0056: NSCLC (N=300)   | 9.2     | 9.7     | 1.014  | 0.795 -     |
|                          |         |         |        | 1.292       |
+--------------------------+---------+---------+--------+-------------+
| WR-0001: Ovarian (N=242) | 31.8    | 31.3    | 0.971  | 0.688 -     |
|                          |         |         |        | 1.372       |
+--------------------------+---------+---------+--------+-------------+
| WR-0038: Head & Neck     | 15.1^a^ | 21.7^a^ | 1.327  | 0.873 -     |
| (N=315)                  |         |         |        | 2.107       |
+--------------------------+---------+---------+--------+-------------+
| WR-9001: Rectal (N=104)  | 12.6    | 15.0    | 1.000  | 0.647 -     |
|                          |         |         |        | 1.546       |
+--------------------------+---------+---------+--------+-------------+
| ^a^ Time to 75% survival |         |         |        |             |
| (median survival has not |         |         |        |             |
| been reached).           |         |         |        |             |
+--------------------------+---------+---------+--------+-------------+

##  {#section .unnumbered}

## Meta-Analysis of Phase III Survival Data

A meta-analysis was performed on the survival data from the five Phase
III randomized, controlled trials. This analysis contained a total of
1,326 patients. The different weighting schemes used in the
meta-analysis for summarizing the trials and estimating mean hazard
ratios and corresponding confidence intervals as well as the results of
this meta-analysis are summarized in Exhibit 8. Overall, regardless of
how the analysis was weighted, the hazard ratio estimates were in
proximity of 1.0 with lower limits of the two-sided 95% confidence
interval of \>0.84. These findings do not suggest that antitumor
efficacy of cytotoxic therapy is altered in cancer patients receiving
amifostine.

Exhibit 8 Meta-Analysis of Survival Data From Phase III Experience of
Amifostine (N=1,327 Patients)

  ----------------- ----------------- ----------------- -----------------
                                      **95% Confidence  
                                      Intervals**       

  **Weight of       **Hazard Ratio**  **Lower Limit**   **Upper Limit**
  Studies**                                             

  Equal Weight      1.017             0.872             1.185

  Weight of Sample  1.014             0.875             1.175
  Size                                                  

  Weight of 1/SE    0.988             0.861             1.133

  Weight of 1/SE^2^ 0.962             0.843             1.098

  SE: standard                                          
  error                                                 
  ----------------- ----------------- ----------------- -----------------

The Phase III experience and the meta-analysis described above were
previously submitted to the FDA as part of the pre-sNDA Briefing
Document on July 26, 2002.

# FDA Assessment of the Results for WR-0053

The final results for WR-0053 were submitted to the Agency on 24 June
2002 as part of a pre-sNDA Briefing Package (Serial #493). On 26 July
2002, in a response to this submission, the FDA concluded that, although
study WR-0053 demonstrated nephroprotection, it did not appear to
demonstrate that amifostine had no affect on antitumor efficacy. In
light of this, the Agency stated that the completion of an appropriately
sized, adequate and well-controlled study of cisplatin-based
chemotherapy in NSCLC demonstrating that amifostine does not affect
antitumor efficacy in addition to showing protection from
cisplatin-induced nephrotoxicity should be performed.

#  {#section-1 .unnumbered}

# elements of a trial design required by the fda for fulfillment of the Post-approval commitment for the nsclc indication

Based on the finding that WR-0053 did not meet the criteria for no
affect on antitumor efficacy (although it did demonstrate protection
from cisplatin-induced nephrotoxicity), the FDA is asking that MedImmune
Oncology conduct an appropriately sized, adequate and well-controlled
study of cisplatin-based chemotherapy in NSCLC demonstrating that
amifostine does not affect antitumor efficacy in addition to showing
protection from cisplatin-induced nephrotoxicity to fulfill the
Accelerated Approval requirements of the NSCLC indication.

In light of the request for this new trial, MedImmune Oncology met with
the FDA on 23 January 2003 to seek the guidance of the Agency regarding
the appropriate trial design elements for such a trial. The main focus
of this discussion was the non-inferiority endpoint of the trial and its
effect on the sample size determination. Other issues discussed included
overall study design, patient population, primary endpoints, and
treatment regimens. One important outcome of the meeting was that the
FDA encouraged the use of a surrogate for survival such as response rate
or time to progression (TTP) as the primary endpoint of the trial, and
that overall survival could be a secondary endpoint, although both
endpoints need to be met for the trial to be positive. Thus, rather than
sizing the trial to meet a non-inferiority of survival endpoint, the
trial could be sized primarily to meet a non-inferiority of response
rate or TTP. Moreover, the FDA stated that using a fixed cutoff for the
hazard ratio confidence interval (e.g., fixed cut-off of 0.8) for the
non-inferiority endpoint was no longer acceptable to the agency, and
that a 50% retention of treatment effect defined in the literature
should be used to calculate the lower bound of the confidence interval
and therefore the sample size.

A summary of the trial design elements discussed with the Agency is
presented below along with supportive literature.

**Study Design:** Randomized, double-blind, placebo-controlled,
multicenter, multinational study

**Objectives:**

**Primary:** Compare the effect of amifostine versus placebo on the
incidence of nephrotoxicity in patients with NSCLC receiving
cisplatin-based chemotherapy. Nephrotoxicity is defined as a 25% or more
decrease from baseline in creatinine clearance at the completion of
therapy.

> Compare the effect of amifostine versus placebo on tumor response rate
> to demonstrate non-inferiority in this patient population.
> Non-inferiority in tumor response rate will be determined if the lower
> limit of the 97.5% confidence interval of the difference in response
> rate between the two treatment arms is equal to or above -8%,based on
> a treatment effect determined from the literature. Tumor response will
> be assessed using RECIST criteria.[^4]

**Secondary:** Non-inferiority in survival will be defined as the point
estimate of the hazard ratio of survival is not lower than 0.95.

**Patient** Histologically or cytologically verified Stage IIIB or IV
NSCLC;

**Population:** Measurable or evaluable disease (based on RECIST
criteria);

ECOG performance status of 0 or 1;

> No prior therapy for NSCLC

**Study Drugs:**

Amifostine: 740 mg/m^2^ as a 15-minute IV infusion given 15-30 minutes
prior to cisplatin

Placebo: Identical in appearance to amifostine and given at same
schedule

**Cisplatin-Based** Patients will be stratified by cisplatin-based
chemotherapy regimen at

**Chemotherapy:** randomization

Cisplatin/Paclitaxel: Paclitaxel: 135 mg/m^2^ over a 24-hour period on
day 1,

> Cisplatin: 75 mg/m^2^ over 30 minutes on day 2,
>
> Cycle repeats every 3 weeks

Cisplatin/Gemcitabine: Gemcitabine: 1000 mg/m^2^ over 30 to 60 minutes
on days 1, 8, 15

> Cisplatin: 100 mg/m^2^ over 30 to 120 minutes on day 1
>
> Cycle repeats every 4 weeks

Cisplatin/Docetaxel: Docetaxel: 75 mg/m^2^ over 60 minutes on day 1

> Cisplatin: 75 mg/m^2^ over 60 minutes on day 1
>
> Cycle repeats every 3 weeks

Cisplatin/Vinorelbine: Vinorelbine 25 mg/m^2^ on days 1, 8, and 15

> Cisplatin: 100 mg/m^2^ over 60 minutes on day 1
>
> Cycle repeats every 4 weeks

Patients will be treated until disease progression, unacceptable
toxicity, or other reasons for patient withdrawal.

**Primary Endpoints:**

Nephroprotection: Compare the incidence of nephrotoxicity in patients
with NSCLC receiving cisplatin-based chemotherapy. Nephrotoxicity is
defined as a 25% or more decrease from baseline in creatinine clearance
at the completion of therapy. A 40% reduction is assumed in the
incidence of nephrotoxicity between the placebo (35%) and amifostine
(21%) arms. Based on the sample size of this trial (1,150 patients, see
below), the statistical power is \>99%.

Non-Inferiority: Compare the effect of amifostine versus placebo on
tumor response rate to demonstrate non-inferiority in this patient
population. Non-inferiority in tumor response rate will be determined if
the lower limit of the 97.5% confidence interval of the difference in
response rate between the two treatment arms is equal to or above -8%
based on a treatment effect determined from the literature. Based on the
sample size of this trial (1,150 patients, see below), the statistical
power is 85%.

**Secondary Endpoint:**

Survival: Compare the effect of amifostine versus placebo on survival to
demonstrate non-inferiority in this patient population. Non-inferiority
in survival will be defined as the point estimate of the hazard ratio of
survival is not lower than 0.95. Based on the sample size of this trial
(1,150 patients, see below), the statistical power is 85%.

**Endpoint Assumption:** The primary endpoints of nephroprotection and
non-inferiority in response rate and the secondary endpoint of survival
must all be positive for this study to fulfill the requirements of the
Accelerated Approval obligation.

The sample size of this study is estimated at 1,150 patients, and is
based on the treatment effect of cisplatin derived from randomized
studies of singlet non-platinum chemotherapy and doublet cisplatin-based
chemotherapy in the first-line treatment of patients with advanced
NSCLC. This approach to the determination of the treatment effect was
recommend by the FDA. A review of the literature resulted in only one
randomized study (with complete data) comparing singlet non-platinum
therapy (vinorelbine) with doublet cisplatin-based chemotherapy
(cisplatin/vinorelbine) in the first-line treatment of advanced
NSCLC.[^5] In this study, the tumor response rate of
cisplatin/vinorelbine was 30% versus 14% for vinorelbine alone (p\<0.01)
for a treatment size of 16% and a 50% retention rate (mandated by the
FDA) of 8%. With a justified lower bound of -8%, a statistical power of
85%, and a lower limit of one-sided confidence interval of 97.5%, the
sample size was estimated at 1,150 patients. In comparison, the
calculation of sample size based on non-inferiority of survival as the
primary endpoint, using survival data from this same study (40 weeks for
cisplatin/vinorelbine vs. 31 weeks for vinorelbine) yielded an estimated
sample size of 2,600 patients. There was no sample size estimate based
on time to progression data since these data were not analyzed in the
cisplatin study.

Exhibit 9 summarizes the published randomized trial experience of
singlet non-platinum therapy and doublet cisplatin-based chemotherapy
reviewed for determining the sample size of the study. Note, all of
these studies were for first-line treatment of advanced NSCLC.

**Exhibit 9** Summary of Published Randomized Trials of Single and
Doublet Therapy in Patients with Advanced NSCLC

+------------------+------------------------+-------+----------------+
| **Study**        | **Treatment**          | **N** | **Response     |
|                  |                        |       | Rate**         |
+------------------+------------------------+-------+----------------+
| Le Chevalier, et | Cisplatin (100         | 206   | 30%            |
| al.Error:        | mg/m^2^)/              |       |                |
| Reference source |                        | 206   | 14%            |
| not found        | Vinorelbine            |       |                |
|                  |                        |       |                |
|                  | Vinorelbine            |       |                |
+------------------+------------------------+-------+----------------+
| \*Georgoulias,   | Cisplatin (80          | 140   | 35%            |
| et al.[^6]       | mg/m^2^)/              |       |                |
|                  |                        | 139   | 18%            |
|                  | Docetaxel              |       |                |
|                  |                        |       |                |
|                  | Docetaxel              |       |                |
+------------------+------------------------+-------+----------------+
| Schiller, et     | Cisplatin (75          | 288   | 21%            |
| al.Error:        | mg/m^2^)/              |       |                |
| Reference source |                        | 288   | 22%            |
| not found        | Paclitaxel             |       |                |
|                  |                        | 289   | 17%            |
|                  | Cisplatin (100         |       |                |
|                  | mg/m^2^)/              |       |                |
|                  |                        |       |                |
|                  | Gemcitabine            |       |                |
|                  |                        |       |                |
|                  | Cisplatin (75          |       |                |
|                  | mg/m^2^)/              |       |                |
|                  |                        |       |                |
|                  | Docetaxel              |       |                |
+------------------+------------------------+-------+----------------+
| Gatzemeier, et   | Cisplatin (80          | 207   | 26%            |
| al.[^7]          | mg/m^2^)/              |       |                |
|                  |                        |       |                |
|                  | Paclitaxel             |       |                |
+------------------+------------------------+-------+----------------+
| Sandler, et      | Cisplatin (100         | 260   | 30.4%          |
| al.[^8]          | mg/m^2^)/              |       |                |
|                  |                        |       |                |
|                  | Gemcitabine            |       |                |
+------------------+------------------------+-------+----------------+
| Wozniak, et      | Cisplatin (100         | 216   | 26%            |
| al.[^9]          | mg/m^2^)/              |       |                |
|                  |                        |       |                |
|                  | Vinorelbine            |       |                |
+------------------+------------------------+-------+----------------+
| Sederholm        | Gemcitabine            | 137   | 12%            |
| C.[^10]          |                        |       |                |
+------------------+------------------------+-------+----------------+
| Anderson, et     | Gemcitabine            | 150   | 19%            |
| al.[^11]         |                        |       |                |
+------------------+------------------------+-------+----------------+
| \* Results based |                        |       |                |
| on preliminary   |                        |       |                |
| data.            |                        |       |                |
+------------------+------------------------+-------+----------------+

# implementation and challenges of a new clinical trial to fulfill the accelerated approval requirements of the nsclc indication

There are several challenges in performing this new trial, the most
important of which is accrual of the required sample size to adequately
conduct the trial. The estimated sample size of the study is 1,150
patients. Assuming an accrual rate of 20 patients per month, the
enrollment period is estimated at 57.5 months or approximately 5 years,
with an added 8 months for the follow-up period. To speed accrual,
multiple cisplatin-based regimens will be investigated in this trial,
all of which have shown comparable effects on overall survival in this
patient population. However, many researchers are shying away from
high-dose cisplatin-based regimens and focusing on non-cisplatin-based
regimens such as carboplatin/paclitaxel for the treatment of advanced
NSCLC. In addition, with the advent of newer chemotherapy agents, there
will be several higher priority protocols in this patient population
competing against this trial. Therefore, accrual to this study may be
slowed, prolonging the overall duration of the trial and preventing its
completion within a reasonable period of time.

# CONCLUSION

Cumulative renal toxicity associated with cisplatin administration is
severe and a major dose-limiting toxicity of cisplatin-based therapy.
This toxicity becomes more prolonged and severe with repeated doses of
cisplatin, and can limit the ability to deliver full doses and cycles of
cisplatin. In light of the known effects of dose response on the
activity of cisplatin, this may have a significant and negative effect
on the efficacy of cisplatin administration to patients. Dose
reductions, treatment delays, and treatment discontinuation after 4 to 6
cycles of therapy are typical ways to manage cisplatin-induced
nephrotoxicity in addition to vigorous hydration and osmotic diuresis.
Despite these measures, life-threatening and sometimes fatal renal
toxicity still occurs. Cumulative irreversible nephrotoxicity can also
limit the ability to treat recurrent disease with other therapeutic
agents that require renal elimination such as carboplatin as well as
hampering the ability to administer supportive therapies such as
antibiotics.

Ethyol (amifostine) represents an important advance in the care of
oncology patients. It is the only cytoprotective agent that has been
shown to reduce the cumulative renal toxicity associated with repeated
administration of cisplatin, having done so in patients with both
advanced ovarian cancer and NSCLC. Although there is a decrease in the
use of high-dose cisplatin regimens for the treatment of NSCLC with a
shift toward non-cisplatin containing regimens, there is still a cohort
of patients in whom these regimens are used effectively, as evidenced by
the recent approval of docetaxel and cisplatin for the primary treatment
of patients with advanced NSCLC. In addition, cisplatin-based regimens
are still being used in patients who are unable to tolerate alternative
treatment or meet the expense of the more sophisticated new regimens. In
these patients, there still exists a need to ameliorate the
nephrotoxicity associated with the administration of cisplatin.

The completion of a second Phase III study in 1,150 patients for
fulfillment of the Accelerated Approval faces challenges, including slow
patient accrual and timeliness of results. In view of these challenges,
it will be helpful if the ODAC can suggest any alternative solutions for
approaches to the completion of the Accelerated Approval requirement for
Ethyol in NSCLC.

# REFERENCES

[^1]: Schiller JH, Storer B, Berlin J et al. Amifostine, cisplatin, and
    vinblastine in metastatic nonsmall cell lung cancer: A report of
    high response rates and prolonged survival. *J Clin Oncol*. 1996;
    14:1913-1921.

[^2]: Shiller JH, Harrington D, Belani CP, Langer C, et al. Comparison
    of four chemotherapy regimens for advanced non-small-cell lung
    cancer. *N Engl J Med* 2002; 346:92-96.

[^3]: Ruckdeschel JC, Finkelstein DM, Ettinger DS et al. A randomized
    trial of the four most active regimens for metastatic non-small-cell
    lung cancer. *J Clin Oncol*. 1986; 4:14-22.

[^4]: Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS,
    Rubinstein L, et al. New Guidelines to Evaluate the Response to
    Treatment in Solid Tumors. Special Article, *J Nat Canc Inst* 2000;
    92(3):205-216.

[^5]: Le Chevalier T, Brisgand D, Soria JC, et al. Long term analysis of
    survival in the European randomized trial comparing
    vinorelbine/cisplatin to vindesine/cisplatin and vinorelbine alone
    in advanced non-small cell lung cancer. *The Oncologist* 2001; 6
    (suppl 1):8-11.

[^6]: Georgoulias V, Ardavanes A, Agelidon M, et al. Preliminary
    analysis of a multicenter phase III trial comparing docetaxel (D)
    versus docetaxel/cisplatin (DC) in patients with inoperable advanced
    and metastatic non-small cell lung cancer (NSCLC) (abstract 1163).
    *Proc Am Soc Clin Oncol*, 2002; 20: 291a.

[^7]: Gatzemeier U, von Pawel J, Gottfried M, et al. Phase III
    comparative study of high-dose cisplatin versus a combination of
    paclitaxel and cisplatin in patients with advanced non-small cell
    lung cancer. *J Clin Oncol* 2000; 18(19):3390-9.

[^8]: Sandler AB, Nemunaitis J, Denham C, et al. Phase III trial of
    gemcitabine plus cisplatin versus cisplatin alone in patients with
    locally advanced or metastatic non-small cell lung cancer. *J Clin
    Oncol* 2000; 18(1):122-30.

[^9]: Wozniak AJ, Crowley JJ, Balcerzak SP, et al. Randomized trial
    comparing cisplatin with cisplatin plus vinorelbine in the treatment
    of advanced non-small cell lung cancer: a Southwest Oncology Group
    study. *J Clin Oncol* 1998; 16(7):2459-65.

[^10]: Sederholm C. Gemcitabine versus gemcitabine/carboplatin in
    advanced non-small cell lung cancer: preliminary findings in a phast
    III trial of the Swedish Lung Cancer Study Group. *Semin Oncol*
    2002; 29(3 Suppl 9):50-4.

[^11]: Anderson H, Hopwood P, Stephens RJ, et al. Gemcitabine plus best
    supportive care (BSC) vs. BSC in inoperable non-small cell lung
    cancer \-- a randomized trial with quality of life as the primary
    outcome. UK NSCLC Gemcitabine Group. Non-Small Cell Lung Cancer. *Br
    J Cancer* 2000; 83(4):447-53.