![](media/image1.wmf)**U.S. Department of Health and Human Services**

**Food and Drug Administration**

**Center for Drug Evaluation Research**

**Office of Pharmacoepidemiology and Statistical Science**

**Office of Biostatistics**

**statistical review and evaluation**

[clinical studies]{.smallcaps}

**NDA /Serial Number**: 21-661/N000

**Drug Name**: RSR13 (efaproxiral) Injection (75 or 100 mg/kg)

**Applicant**: Allos Therapeutics Inc.

**Indication(s):** Brain metastases

**Date(s):** Submission Date: December 4, 2003

PDUFA Date: June 4, 2004

ODAC Meeting Date: May 3, 2004

Review Completion Date:

**Review Priority:** Priority

**Biometrics Division**: Division of Biometrics I (HFD-710)

**Statistical Reviewer**: Rajeshwari Sridhara, Ph.D.

**Concurring Reviewer**: Kooros Mahjoob, Ph.D., Acting Director

**Medical Division**: Oncology Drug Products (HFD-150)

**Clinical Team**: Kevin Ridenhour, M.D. & Ramzi Dagher, M.D.

**Project Manager**: Ms. Christy Cottrell

**Keywords**: Active control/superiority, log-rank test, post-hoc
analysis, subgroup analyses, multiple endpoints, multiple comparisons,
Cox regression

**Table of Contents**

1 Executive Summary [1](#executive-summary)

1.1 Conclusions and Recommendations
[1](#conclusions-and-recommendations)

1.2 Brief Overview of Clinical Studies
[1](#brief-overview-of-clinical-studies)

1.3 Statistical Issues and Findings
[1](#statistical-issues-and-findings)

2 Introduction [4](#introduction)

2.1 Overview [4](#overview)

2.1.1 Background [4](#background)

2.1.2 Major Statistical Issues [5](#major-statistical-issues)

2.2 Data Sources [5](#data-sources)

3 Statistical Evaluation [6](#statistical-evaluation)

3.1 Evaluation of Efficacy [6](#evaluation-of-efficacy)

3.1.1 Study RT009 [6](#study-rt009)

3.1.1.1 Study Design [6](#study-design)

3.1.1.2 Treatment Administration [8](#treatment-administration)

3.1.1.3 Study Objectives [9](#study-objectives)

3.1.1.4 Efficacy Endpoints [9](#efficacy-endpoints)

3.1.1.5 Sample Size Considerations [10](#sample-size-considerations)

3.1.1.6 Interim Analysis [11](#interim-analysis)

3.1.1.7 Efficacy Analysis Methods [12](#efficacy-analysis-methods)

3.1.1.8 Sponsor's Results and Statistical Reviewer's Findings/ Comments
[14](#sponsors-results-and-statistical-reviewers-findings-comments)

3.1.1.8.1 Baseline Characteristics [15](#baseline-characteristics)

3.1.1.8.2 Primary Efficacy Analyses [18](#primary-efficacy-analyses)

3.1.1.8.3 Exploratory Covariate Adjusted and Subgroup Survival Analyses
[21](#exploratory-covariate-adjusted-and-subgroup-survival-analyses)

3.1.1.8.4 Secondary Efficacy Analyses [31](#secondary-efficacy-analyses)

3.2 Evaluation of Safety [33](#evaluation-of-safety)

4 Findings in Special/Subgroup Populations
[33](#findings-in-specialsubgroup-populations)

4.1 Gender, Race and Age [33](#gender-race-and-age)

4.2 Other Special/Subgroup Populations
[35](#other-specialsubgroup-populations)

5 Summary and Conclusions [36](#summary-and-conclusions)

5.1 Statistical Issues and Collective Evidence
[36](#statistical-issues-and-collective-evidence)

5.2 Conclusions and Recommendations
[37](#conclusions-and-recommendations-1)

APPENDICES [38](#appendices)

Appendix 1: List of Ineligible Patients
[38](#appendix-1-list-of-ineligible-patients)

Appendix 2: List of Patients Who Were Misclassified at Randomization
[39](#appendix-2-list-of-patients-who-were-misclassified-at-randomization)

Appendix 3: List of Patients Who Were In-evaluable (Withdrew from Study
Prior to Treatment)
[40](#appendix-3-list-of-patients-who-were-in-evaluable-withdrew-from-study-prior-to-treatment)

Appendix 4: Survival Analysis Before Addition of Co-primary Hypothesis
[41](#appendix-4-survival-analysis-before-addition-of-co-primary-hypothesis)

Appendix 5: Interim Analysis Results
[42](#appendix-5-interim-analysis-results)

Appendix 6: Exploratory Covariate Adjusted Survival Analyses in
NSCLC/Breast Primary
[43](#appendix-6-exploratory-covariate-adjusted-survival-analyses-in-nsclcbreast-primary)

Appendix 7: Exploratory Covariate Adjusted Survival Analysis in Breast
Primary
[44](#appendix-7-exploratory-covariate-adjusted-survival-analysis-in-breast-primary)

# Executive Summary

## Conclusions and Recommendations

In this reviewer\'s opinion the registration study failed to demonstrate
improved survival of RSR13 + whole brain radiation therapy (WBRT) over
WBRT alone for patients with brain metastases. It is not evident that
the apparent survival advantage observed in a single small subgroup of
patients with primary breast cancer based on post-hoc analysis is
attributable solely to the treatment effect and not due to imbalances in
known and unknown prognostic factors. Therefore, the evidence submitted
in this application based on results from a single trial, is not
convincing and does not support the sponsor's claim of efficacy in a
subgroup of patients with breast cancer primary.

## Brief Overview of Clinical Studies

The sponsor has submitted results from one phase III, comparative
clinical trial (registration trial Study RT009) comparing WBRT alone to
RSR13 + WBRT, to demonstrate efficacy of RSR13. The sponsor has also
provided supportive efficacy data from a phase II, single arm study
(Study RT008). The main focus of this review is on results from Study
RT009.

Study RT009 was a multicenter international study conducted in patients
with brain metastases. This study was initiated on February 16, 2000 and
the study was completed on September 24, 2002. The data cut-off date for
final efficacy analysis was January 31, 2003.

Study RT009 was a phase III randomized, open-label, comparative study
conducted in 538 patients from 82 international centers, who would be
receiving a standard 2-week (10-day) course of WBRT for brain
metastases. Patients were randomized (1:1) to receive RSR13 no longer
than 30 minutes prior to daily WBRT or WBRT alone. Patients were
stratified at randomization to 4 strata: (1) Radiation Therapy Oncology
Group (RTOG) recursive partitioning analysis (RPA) Class I (including
non-small cell lung, breast, and other primary cancers), (2) RPA Class
II non-small cell lung cancer (NSCLC) primary, (3) RPA Class II breast
cancer primary, and (4) RPA Class II primary tumors of various origins
(hereafter referred as other primary).

## Statistical Issues and Findings

This NDA submission is to support administration of RSR13 as an adjunct
to whole brain radiation therapy (WBRT) for patients with brain
metastases from primary breast cancer. In this NDA submission, study
RT009 is the only randomized pivotal study conducted for the efficacy
and safety of RSR13. This open-label study was designed to evaluate the
efficacy and safety of combined therapy with RSR13 + WBRT versus WBRT
alone in patients with brain metastases. This study enrolled a total of
538 patients with 267 patients who received WBRT alone and 271 patients
who received RSR13 + WBRT. The primary efficacy endpoint of this study
was survival.

Statistical Issues:

1.  Only one randomized open-label study conducted in patients with
    brain metastases, which failed to demonstrate efficacy as per the
    design of the study, in the intent-to-treat population (log-rank
    test, P-value = 0.1688) and in the co-primary subgroup of patients
    with NSCLC/Breast cancer primary (log-rank test, P-value = 0.1217).

2.  When the overall result fails to show efficacy, usually subgroup
    findings are not acceptable and subgroup analyses at best can be
    exploratory or hypothesis generating analyses (ICH E-3 guidelines,
    section 11.4.2.8: *These analyses are not intended to \"salvage\" an
    otherwise non-supportive study but may suggest hypotheses worth
    examining in other studies or be helpful in refining labelling
    information, patient selection, dose selection etc.*). When one
    starts to do multiple subgroups testing, one can easily make a false
    positive claim based on such subgroup analysis. We do not know how
    to interpret the P-values based on such post-hoc analysis.
    Furthermore, without replication of the results in a second
    well-controlled study, the subgroup analysis can not be ruled out
    for a false positive result.

3.  The sponsor wishes to claim approval based on a subgroup of patients
    with primary breast cancer. This subgroup hypothesis corresponding
    to breast cancer primary patients was not stated as a hypothesis of
    interest to be tested in the original protocol. Any subgroup
    hypothesis needs to be stated in the protocol and accordingly proper
    allocation of has to be specified. Otherwise, such post-hoc subgroup
    claim will inflate Type I error and it is difficult to interpret
    such P-values.

4.  Some of the important issues not addressed by the sponsor are:
    imbalance in patients who were ineligible (per protocol) between the
    two treatment groups; misclassification of patients in the
    randomized strata; imbalance in the number of baseline brain lesions
    in the subgroup of patients with primary breast cancer.

Findings:

The protocol specified primary analysis was unadjusted log-rank test in
the intent-to-treat (ITT) population to compare overall survival between
the two treatment arms. This study failed to demonstrate survival
benefit as presented in the following Table A.

**Table A: Primary Efficacy Survival Analysis in ITT Population**

+----------------+----------+------------------+-------------+--------+
| **Treatment**  | **Number | **Median         | **Hazard    | **     |
|                | of       | Survival in      | Ratio^2^**  | P-valu |
|                | Deaths** | Months^1^**      |             | e^3^** |
|                |          |                  | **(95%      |        |
|                |          | **(95% C.I.)**   | C.I.)**     |        |
+----------------+----------+------------------+-------------+--------+
| WBRT           | 221/267  | **4.5** (3.7,    | 0.877       | **0.   |
|                |          | 5.4)             |             | 1688** |
|                |          |                  | (0.727,     |        |
|                |          |                  | 1.057)      |        |
+----------------+----------+------------------+-------------+--------+
| RSR13 + WBRT   | 220/271  | **5.3** (4.5,    |             |        |
|                |          | 6.2)             |             |        |
+----------------+----------+------------------+-------------+--------+

^1^: Kaplan-Meier Estimates; ^2^: Hazard Ratio of RSR13 + WBRT/ WBRT;
^3^: unadjusted log-rank test.

The sponsor amended the protocol during the course of study to include a
co-primary hypothesis, to test survival difference between the two
treatment arms in a subgroup of patients with NSCLC or Breast primary
cancer. The results of these comparisons also failed to demonstrate
survival benefit as presented in Table B below.

**Table B: Co-Primary Efficacy Survival Analysis in NSCLC/Breast Primary
Cancer Subgroup\***

+----------------+----------+------------------+-------------+--------+
| **Treatment**  | **Number | **Median         | **Hazard    | **     |
|                | of       | Survival in      | Ratio^2^**  | P-valu |
|                | Deaths** | Months^1^**      |             | e^3^** |
|                |          |                  | **(95%      |        |
|                |          | **(95% C.I.)**   | C.I.)**     |        |
+----------------+----------+------------------+-------------+--------+
| WBRT           | 167/206  | **4.5** (3.8,    | 0.844       | **0.   |
|                |          | 5.4)             |             | 1217** |
|                |          |                  | (0.680,     |        |
|                |          |                  | 1.048)      |        |
+----------------+----------+------------------+-------------+--------+
| RSR13 + WBRT   | 164/208  | **5.9** (4.7,    |             |        |
|                |          | 7.0)             |             |        |
+----------------+----------+------------------+-------------+--------+

\*: Corrected for miss-classification (i.e., non-randomized subgroup);
^1^: Kaplan-Meier Estimates;

^2^: Hazard Ratio of RSR13 + WBRT/ WBRT; ^3^: unadjusted log-rank test.

The sponsor is seeking approval based on post-hoc analysis in a small
subgroup of 115 patients with Breast cancer primary. The results of
these comparisons are presented in the following Table C.

**Table C: Exploratory Survival Analysis in the Subgroup of Patients
with Primary Breast Cancer\***

+----------------+----------+------------------+-------------+--------+
| **Treatment**  | **Number | **Median         | **Hazard    | **     |
|                | of       | Survival in      | Ratio^2^**  | P-valu |
|                | Deaths** | Months^1^**      |             | e^3^** |
|                |          |                  | **(95%      |        |
|                |          | **(95% C.I.)**   | C.I.)**     |        |
+----------------+----------+------------------+-------------+--------+
| WBRT           | 47/55    | **4.6** (3.8,    | 0.552       | **0.   |
|                |          | 6.2)             |             | 0061** |
|                |          |                  | (0.359,     |        |
|                |          |                  | 0.850)      |        |
+----------------+----------+------------------+-------------+--------+
| RSR13 + WBRT   | 39/60    | **8.7** (6.0,    |             |        |
|                |          | 11.3)            |             |        |
+----------------+----------+------------------+-------------+--------+

\*: Corrected for miss-classification (i.e., non-randomized subgroup);

^1^: Kaplan-Meier Estimates; ^2^: Hazard Ratio of RSR13 + WBRT/ WBRT;

^3^: unadjusted log-rank test and not adjusted for multiple analyses.

# Introduction

## Overview 

It has been estimated that in the United States 80,000 to 170,000
patients develop brain metastases each year. Standard palliative
treatment for symptomatic lesions consists of corticosteroids and whole
brain radiation therapy (WBRT). Analysis of a large database compiled by
the Radiation Therapy Oncology Group (RTOG) indicates that the overall
prognosis of patients with brain metastasis is poor with median survival
time of 4-7 months.

### Background

RSR13 is a synthetic allosteric modifier of hemoglobin. RSR13 emulates
the function of natural allosteric modifiers such as
2,3-diphosphoglycerate (2,3-DPG). RSR13 is a small molecule that reduces
hemoglobin-oxygen binding affinity, described by an increase in p50 (the
partial pressure of oxygen \[pO~2~\] that results in 50% hemoglobin
saturation), and enhances the diffusion of oxygen from the blood to the
tissues.

Radiation therapy is currently the principal non-surgical therapy to
achieve local control of brain metastases from solid tumors. However,
the efficacy of radiation therapy (RT) is modified by the extent of
tumor oxygenation. Hypoxic tumors are more resistant to cell damage by
radiation and tumor hypoxia adversely affects the clinical prognosis of
RT. It has been reported in literature that tumors with a low median
pO~2~ have a higher in-field failure rate after RT.

Animal pharmacology studies have shown that RSR13 increases blood p50,
increases pO~2~ in non-tumor and tumor tissue, and increases oxygen
diffusive transport in non-tumor tissue. The effect of RSR13 on
hemoglobin in the red blood cell to enhance oxygen unloading from
hemoglobin, and the diffusion of that oxygen from the vascular
compartment into the hypoxic tumor cells is the basis for the
radioenhancement effect of RSR13. RSR13 does not need to diffuse into
the brain tissue, because oxygen readily diffuses across the blood brain
barrier and the cancer cell membrane to increase tumor oxygenation,
thereby increasing the effectiveness of RT. The goal of adjunctive RSR13
therapy in cancer patients is to increase tumor O~2~ concentration
thereby maximizing the cytotoxicity of the treatment modality (RT and/or
chemotherapy).

The sponsor has submitted results from one phase III, randomized,
controlled, open-label clinical trial (registration trial Study RT009)
comparing WBRT alone to RSR13 + WBRT, to demonstrate efficacy of RSR13.
The sponsor has also provided supportive efficacy data from a phase II,
single arm study (Study RT008). The main focus of this review will be on
results from Study RT009.

### Major Statistical Issues

1.  Only one randomized open-label study conducted in patients with
    brain metastases, which failed to demonstrate efficacy as per the
    design of the study, in the intent-to-treat population (log-rank
    test, P-value = 0.1688) and in the co-primary subgroup of patients
    with NSCLC/Breast cancer primary (log-rank test, P-value = 0.1217).

2.  When the overall result fails to show efficacy, usually subgroup
    findings are not acceptable and subgroup analyses at best can be
    exploratory or hypothesis generating analyses (ICH E-3 guidelines,
    section 11.4.2.8: *These analyses are not intended to \"salvage\" an
    otherwise non-supportive study but may suggest hypotheses worth
    examining in other studies or be helpful in refining labelling
    information, patient selection, dose selection etc.*). When one
    starts to do multiple subgroups testing, one can easily make a false
    positive claim based on such subgroup analysis. We do not know how
    to interpret the P-values based on such post-hoc analysis.
    Furthermore, without replication of the results in a second
    well-controlled study, the subgroup analysis can not be ruled out
    for a false positive result.

3.  The sponsor wishes to claim approval based on a subgroup of patients
    with primary breast cancer. This subgroup hypothesis corresponding
    to breast cancer primary patients was not stated as a hypothesis of
    interest to be tested in the original protocol. Any subgroup
    hypothesis needs to be stated in the protocol and accordingly proper
    allocation of has to be specified. Otherwise, such post-hoc subgroup
    claim will inflate Type I error and it is difficult to interpret
    such P-values.

4.  Some of the important issues not addressed by the sponsor are:
    imbalance in patients who were ineligible (per protocol) between the
    two treatment groups; misclassification of patients in the
    randomized strata; imbalance in the number of baseline brain
    lesions.

## Data Sources

Data used for review is from the electronic submission received on
12/3/03. The network path is
[\\\\Cdsesub1\\n21661\\N_000\\2003-12-03\\crt\\datasets.](../../../../../../../../n21661/N_000/2003-12-03/crt/datasets.)
Specifically, datasets from Study 009 were reviewed
(\\\\Cdsesub1\\n21661\\N_000\\2003-12-03\\crt\\datasets\\rt009).

# Statistical Evaluation

## Evaluation of Efficacy

The sponsor has submitted efficacy results from the following two
studies:

a)  Study RT008: A phase II non-randomized, open-label single arm study
    conducted in 69 patients from 17 centers (16 US, 1 Canada), to
    evaluate the safety and efficacy of RSR13 with WBRT in patients with
    brain metastases.

b)  Study RT009: A phase III randomized, open-label, comparative study
    conducted in 538 patients from 82 centers (40 US, 15 Canada, 4
    Australia, 4 Hungary, 3 Belgium, 3 France, 3 Germany, 3 Israel, 2
    Italy, 2 Scotland, 2 Spain and 1 UK), to evaluate safety and
    efficacy of RSR13 with WBRT compared to WBRT alone in patients with
    brain metastases.

*[Reviewer's Comment]{.underline}:*

Study RT008 is a non-randomized, single arm, open-label study and as
such can not evaluate efficacy based on overall survival. Therefore,
this review will focus only on the randomized Study RT009 and
particularly on the efficacy aspect of this study. Please refer to the
clinical review of this application for the evaluation of Study RT008.

### Study RT009

Study RT009 was a multicenter international study conducted in patients
with brain metastases. This study was initiated on February 16, 2000 and
the study was completed on September 24, 2002. The data cut-off date for
final efficacy analysis was January 31, 2003.

#### Study Design

Study RT009 was a phase III, randomized, open-label, comparative study
in patients who would be receiving a standard 2-week (10-day) course of
WBRT for brain metastases. Patients were randomized (1:1) to receive
RSR13 no longer than 30 minutes prior to daily WBRT or WBRT alone.
Patients were stratified at randomization to 4 strata: (1) Radiation
Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA)
Class I (including non-small cell lung, breast, and other primary
cancers), (2) RPA Class II non-small cell lung cancer (NSCLC) primary,
(3) RPA Class II breast cancer primary, and (4) RPA Class II primary
tumors of various origins (hereafter referred as other primary). The
decision tree utilized in the RPA classification is illustrated in
Figure 1.

Eligibility criteria included that all patients should have Karnofsky
Performance Status (KPS) ≥ 70, radiographic studies consistent with
brain metastases and a histologically or cytologically confirmed primary
malignancy. Patients with small cell lung cancer, extrapulmonary small
cell carcinomas, germ cell tumors or lymphomas were excluded from
entering the study. Patients included in the study were not to have
received prior treatment for brain metastases with WBRT, sterotactic
radiosurgery, chemotherapy, hormonal therapy, immunotherapy, or
biological agents.

All patients were to be assessed for safety from randomization until the
initial follow-up visit at 1 month after completion of the radiation
therapy (RT) course. Standard follow-up visits were required 3 months
after the completion of RT course and every 3 months thereafter until
progression, and then followed for subsequent therapies and survival.

**Figure 1: RPA Classification Decision Tree**

![](media/image2.png){width="6.429861111111111in"
height="3.6909722222222223in"}

*[Reviewer's Comments]{.underline}*:

1.  It was clearly stated in the protocol that the randomized
    stratification was purely for balance between treatment groups and
    therefore the number of patients in each of the four strata would
    not be predetermined.

2.  There were a total of 23 ineligible patients (17 patients in the
    WBRT alone arm and 6 patients in the RSR13 + WBRT arm) based on
    eligibility criteria at entry, who were entered into the study and
    treated (Please refer to Appendix 1 for the list of ineligible
    patients by treatment arm). There were greater than 2 times more
    patients who were ineligible in the control arm compared to the
    RSR13 arm. Given the open-label nature of the study there is concern
    for bias due to the apparent imbalance in ineligible patients
    between the two arms.

3.  There were a total of 25 patients who were miss-classified in the
    strata assignment at randomization (please refer to Appendix 2 for a
    complete list of miss-classified patients). This miss-classification
    is not an issue when analyzing the overall intent-to-treat (ITT)
    population (all patients as randomized to the two treatment groups)
    using unadjusted analysis. However, this miss-classification can
    lead to biased results when considering adjusted analysis because
    the true patient strata will no longer be as randomized. In
    particular, there were 6 patients where there were major
    miss-classifications: 2 patients who were randomized as RPA II,
    breast cancer were later re-classified as RPA II, NSCLC; 1 patient
    who was randomized as NSCLC was later re-classified as RPA II,
    other; and 3 patients who were randomized as RPA II, other were
    later re-classified as RPA II, NSCLC.

#### Treatment Administration

Daily administration of RSR13 required placement of a central venous
access device (CVAD). RSR13 treatment arm patients received supplemental
oxygen (4L/min via nasal cannula) beginning 5 minutes prior to
initiation of infusion, during infusion and WBRT, and for at least 15
minutes after completion of daily WBRT. Patients in the control arm of
the study did not receive a placebo. Starting dose and dosing adjustment
thereafter of RSR13 was based on gender, weight and oxygen saturation
measured by standard pulse oximetry (SpO~2~). Starting dose of RSR13 in
this study was 75 or 100 mg/kg. The dosing instructions were amended 2
times during the course of the study. Patients with SpO~2~ while
breathing room air on any WBRT day \< 90% were not treated with RSR13.
Before the second amendment, if SpO2 while breathing room air at
screening (at rest and during exercise) and on WBRT day 1 was ≥ 93% then
RSR13 100mg/kg was administered. If SpO2 while breathing room air at
screening (at rest and during exercise) and on WBRT day 1 was 90-92%
then RSR13 75mg/kg was administered. After the second protocol
amendment, if SpO2 while breathing room air at screening (at rest and
during exercise) and on WBRT day 1 was ≥ 93% then RSR13 was administered
based on gender and weight as follows: (a) Males (i) if weight ≤ 95kg
then 100 mg/kg; (ii) if weight \> 95kg then 75 mg/kg, and (b) Females
(i) if weight ≤ 70kg then 100 mg/kg; (ii) if weight \> 70kg then 75
mg/kg.

*[Reviewer's comment]{.underline}*:

The dosing regimen was changed during the course of study based on
weight and gender. Therefore it will be difficult to determine the
optimum dose that is efficacious based on the results of this study.

####  {#section .unnumbered}

#### Study Objectives

The study objectives were: (1) to determine the effect of RSR13 on
primary and secondary efficacy endpoints in patients with brain
metastases receiving daily IV doses of RSR13 administered immediately
prior to standard whole brain radiation therapy compared to patients
receiving standard whole brain radiation therapy alone, and (2) to
determine the safety of RSR13 in this patient population.

#### Efficacy Endpoints

[Primary Efficacy Endpoint]{.underline} of this study was survival.
[Secondary Efficacy Endpoints]{.underline} included time to radiographic
and time to clinical tumor progression in the brain, response rate in
the brain, cause of death, and quality of life.

*[Reviewer's Comment]{.underline}*:

In the original protocol (Jan 10, 2000), efficacy was to be established
based on the primary endpoint of survival in the intent-to-treat total
population. Subsequently in amendment 2 (June 5, 2001) *per sponsor*
after enrollment of a total of *222* patients (*172* patients in the
NSCLC/breast primary subgroup), the protocol was amended to include a
co-primary analysis in the subgroup of patients with NSCLC and breast
primary cancer. This reviewer's analysis suggested that by June 5, 2001
there were a total of *173* patients (*134* patients in NSCLC/Breast
primary subgroup) enrolled into the study (Appendix 4). The only
reasoning given by the sponsor to include this subgroup as a co-primary
was that the group of patients with NSCLC/breast primary tumors
comprised a large and homogenous subpopulation of patients. Given the
open-label nature of this study such additions of primary hypotheses are
of concern.

#### Sample Size Considerations

In the original protocol (Jan 10, 2000), a sample size requirement of a
total of **408** eligible patients was estimated based on the following
assumptions: a mix of 20% RPA class I and 80% RPA class II patients,
median survival in WBRT to be 4.57 months, an expected 35% increase in
median survival in WBRT with RSR13 (median survival of 6.17 months), 18
months of accrual, a shape parameter of 0.20, and 80% power to detect
the difference in survival at two-sided overall significance level of
0.05. It was estimated that a total of **308 deaths** from both arms
would be required to detect the survival difference in the overall ITT
population. It was expected that there might be 5% ineligible patients
and therefore a total of 408 patients were required to be entered on the
study.

This sample size calculation was amended in amendment 2 (June 5, 2001)
as follows: The sample size was increased to a total of **501** patients
in order to observe **402 deaths** by increasing the power of the study
to detect the survival difference (median survival 4.57 months versus
6.17 months in the overall ITT population) to 85%, increasing accrual
time to 27 months, and changing the shape parameter to zero (O'Brien and
Fleming). In this amendment the sponsor also **added a** **co-primary
analysis** **in the subgroup of patients with NSCLC/breast primary
tumors.** It was stated that in this subgroup a total of **308** deaths
will be required to provide a power of 75% with a two-sided significance
level of 0.05. Furthermore, in this amendment it was stated that the
expected number of patients to be enrolled into the study would be
between 501-538 patients, depending on the percentage of patients with
'other' as a primary cancer. If 25% of enrolled patients had 'other'
primary, then a total of 501 patients would be enrolled; if 30% of
enrolled patients had 'other' primary, then a total of 538 patients
would be enrolled.

*[Reviewer's Comments]{.underline}*:

1.  Reason for changing the space parameter was not specified in the
    amendment.

2.  There was no specific scientific reason given to include a
    co-primary in the subgroup of patients with NSCLC/breast primary
    other than that this was a large, homogenous subgroup.

3.  A total of 538 patients were enrolled in this study. Only 23% of the
    patients had 'other' primary tumors.

#### Interim Analysis

In the original protocol (Jan 10, 2000) it was stated that, one interim
analysis of the primary study endpoint (overall survival), would be
conducted. The interim analysis was planned to be performed when 50% of
expected events *(154 deaths)* occurred.

In the first amendment of the protocol (Mar 2, 2000) the section on
interim analysis was revised to state that a stochastic analysis would
be performed at the time of interim analysis and reported to Data Safety
Monitoring Committee (DSMC). It was also stated in this amendment that
if the significance level of the log-rank test between treatment arms
was less than *0.0077* then the null hypothesis would be rejected.
Additionally, if the stochastic analysis indicated less than 15% power
to observe the alternative hypothesis, then enrollment to the study may
be recommended to be stopped.

In the second amendment of the protocol (June 5, 2001), this section was
again revised. It stated that interim status and safely reports will be
prepared for the independent DSMC every 6 months until planned study
enrollment was achieved. Furthermore, with the revised increase in
sample size, the interim analysis for efficacy was to be conducted when
50% events (*201 deaths*) had occurred in the total patient population.
The results of interim analysis would be reported to the DSMC. If the
significance level of the log-rank test between treatment arms was less
than *0.0052* then the null hypothesis would be rejected and the DSMC
might recommend stopping enrollment to the study. On the other hand if
the analysis indicated less than 15% power to observe the alternative
hypothesis, then also it may be recommended to stop further accrual.

*[Reviewer's Comment]{.underline}*:

It appears that one interim efficacy analysis was conducted (March 22,
2002). Specific results of this interim analysis or DSMC meeting minutes
deliberating on interim efficacy results have not been submitted (Refer
to Appendix 5 for FDA analysis). Because of this interim analysis, the
significance level for testing at the time of final analysis needs to be
adjusted to maintain an overall family-wise level of significance of
0.05.

#### Efficacy Analysis Methods

**Primary Efficacy Analysis**:

In the original protocol (dated Jan 10, 2000), it was specified that the
primary endpoint, overall survival, measured from the time of
randomization into the study, would be *[compared between treatment arms
by unadjusted log-rank test]{.underline}*. The median survival time
would be estimated in both treatment arms. Other specific point
estimates of clinical interest for each treatment were 6-month and
1-year survival. It was stated that additional subgroup analyses would
be performed if there were sufficient numbers of patients across
subgroups. RPA class, site of primary cancer, and other important
covariates such as primary tumor control, age, presence of extracranial
metastases, baseline KPS, and number of metastatic lesions, would be
included in a multivariate Cox model along with treatment arm to test
the relative importance of these factors for survival.

In the first amendment of the protocol (dated March 2, 2000), it was
specified that the primary final analysis of the study would be
undertaken when all patients have been potentially followed for a
minimum of 6 months and the planned number of deaths (308) had been
observed. The primary analysis would be conducted on an
*[intent-to-treat]{.underline}* patient population using log-rank
statistic *[(unadjusted for covariates]{.underline}*) and *[evaluable
subgroup analyses might be performed to provide supportive evidence of
efficacy]{.underline}*.

In the second (dated June 5, 2001, sample size increased, co-primary
added) and third (dated October 9, 2001) amendments of the protocol, it
was specified that the primary final analysis would be undertaken when
the planned number of deaths in both the total study population (402)
and the NSCLC/breast subpopulation (308) had been observed. The primary
analysis would be conducted *[on an intent-to-treat basis]{.underline}*
and *[evaluable subgroup analyses might be performed to provide
supportive evidence of efficacy]{.underline}*. Furthermore, it was
stated that a modified Bonferroni adjustment for multiple comparisons
(co-primary analyses) would be made. The *[adjusted significance
level]{.underline}* for the final analysis after accounting for one
interim analysis was set *[at 0.048.]{.underline}*

The statistical analysis plan (SAP) which was finalized on July 29,
2002, revised the analysis data set and specified that the analysis data
set will consist of *[eligible patients only]{.underline}*. The SAP
specified that: (1) patients without brain metastases, patients with
leptomenigeal metastases, patients with confirmed primaries of small
cell lung cancer, extrapulmonary small cell carcinomas, germ cell tumors
and lymphomas and (2) patients having prior treatment for brain
metastases with WBRT or stereotactic radiosurgery, and patients with
prior surgical resection of brain metastases with no remaining lesions
would be ineligible and would be excluded from analysis. The SAP also
stated that the primary analysis of the overall patient population as
well as the NSCLC/breast subpopulation would be performed *[using the
unadjusted log-rank test]{.underline}*.

In the SAP the list of covariates that would be included in the
Cox-model was also revised. It stated that the following covariates
would be included: age (continuous as well as above and below 65 years
old), baseline weight (divided by gender as per the dosing guidelines of
amendment 2), number of cranial metastases (1, 2-3, 4 or more), baseline
cranial tumor total area, gender, RPA class, site of primary cancer,
primary tumor control, number of extracranial metastases (0, 1-2, 3 or
more), presence of liver metastases, usage of subsequent treatment
(systemic vs. non-systemic, any vs. none), baseline KPS, diagnosis
timing (definition to follow), prior treatment for cranial metastases
(yes/no; prior treatment may delay time from diagnosis to radiation
therapy), worldwide location (USA vs. Canada vs. others, North America
vs. Others), altitude, baseline hemoglobin, and size of center. Center
size was the binary variable designating a center as large or small.
Under the section on covariates, the SAP also stated that '*While
designated prospectively, supporting analyses should be [considered
exploratory in nature]{.underline}, and inferences made based on
p-values should be done so with caution. Primary reasons for exploratory
analyses are for estimation rather than hypothesis testing'*.

**Secondary Efficacy Analyses:**

The protocol has specified that the secondary endpoints, time to
radiographic tumor progression in brain and time to clinical tumor
progression in the brain, would be analyzed using cumulative incidence
model and that the treatment arms would be compared using the method of
Pepe. It is also stated that analyses within strata, within other
prognostic groups and Cox model analysis would also be performed.

Secondary endpoint response rate (best maximal response) in the brain
would be determined from MRI or CT scans and the frequency distribution
of CR:PR:SD:PD would be compared for each treatment arm. Between
treatment arms comparison would be made using Cochran-Mantel Haenzel
test.

Regarding secondary endpoint cause of death, frequency of neurologic/
non-neurologic/ undistinguishable deaths would be computed for each
treatment arm and compared between treatment arms using Cochran-Mantel
Haenzel test.

Secondary endpoint of quality of life would be determined by the Spitzer
Questionnaire and KPS assessment. The frequency distribution would be
computed for each treatment arm by time of follow-up.

*[Reviewer's Comments:]{.underline}*

1.  In the original protocol and in its amendments it was clearly stated
    that the primary analysis would be conducted in ITT population. The
    sample size and the power considerations were in fact based on ITT
    population.

2.  The co-primary hypothesis testing in the NSCLC/Breast subgroup was
    added during the course of study. The protocol did not clearly
    define this subgroup, i.e., whether patients from strata 2 and 3
    only to be included in this subgroup or include NSCLC/Breast primary
    patients in strata 1, and strata 2 and 3.

3.  In using Modified Bonferroni adjustment for co-primary analysis one
    could consider 2 methods of adjustment after accounting for one
    interim analysis: (1) compare larger of the 2 p-values with
    0.048, (a) if the larger p-value is \< 0.048, then reject both
    hypotheses, or (b) if the larger p-value is \> 0.048, then compare
    the smaller of the two p-values with 0.024 (Hochberg's SU modified
    Bonferroni procedure), or (2) the second procedure (Holm's SD
    modified Bonferroni) is (a) if the smaller of the two p-values is \>
    0.024, then both hypotheses are not significant, or (b) if the
    smaller of the p-value \< 0.024 then the corresponding hypothesis is
    significant and then test if the larger of the p-value is \< 0.048.

4.  In the original protocol and in its amendments as well as in the
    SAP, it was clearly stated that the primary analysis would be based
    on unadjusted log-rank test.

5.  The SAP was finalized after all the patients were entered into the
    study (last 3 patients were entered on July 29, 2002). Given the
    open-label nature of the study it is of concern that the analysis
    population was changed after all patients were entered into the
    study.

6.  Overall there were 23 patients who were ineligible, 17 in the
    control arm and 6 in the RSR13 arm. With greater than 2 times more
    patients who were ineligible in the control arm, given the study was
    an open-label study, there is concern for bias.

7.  There was no justification provided for the inclusion of additional
    several covariates for the exploratory Cox analysis in the SAP.

8.  The covariate 'diagnosis timing' was not defined.

9.  Because no apriori probability of type I error allocation has been
    specified, analyses of secondary efficacy endpoints can only be
    considered as exploratory and supportive to primary efficacy
    analysis.

#### Sponsor's Results and Statistical Reviewer's Findings/ Comments

In the RT009 study, a total of 538 patients were randomized to receive
WBRT alone (267 patients) or RSR13 followed by WBRT (271 patients).

##### Baseline Characteristics

Table 1 lists the number of patients entered in each of the randomized
strata. The baseline Characteristics of the overall population and
NSCLC/Breast subgroup are presented in Tables 3 & 4.

*[Reviewer's Comments]{.underline}*:

1.  There were 25 patients who were miss-classified at randomization
    according to the sponsor / CRF. Therefore the corrected numbers in
    each of the strata are presented in Table 2.

2.  It should be noted that the patients as listed in each strata in
    Table 2 are no longer as randomized.

3.  This miss-classification may not affect analysis based on ITT
    population. However analyses based on subgroups could potentially
    lead to biased results.

4.  The sponsor has reported that 9 patients (4 in the control (WBRT)
    arm and 5 in the RSR13 arm) withdrew from the study prior to WBRT
    day 1 (Appendix 3).

5.  In the overall patient population the baseline characteristics
    appear to be balanced between the two treatment arms.

6.  It should be noted that *the NSCLC/Breast subgroup* as presented in
    Table 3 *is no longer as randomized*, because: (1) NSCLC and breast
    cancer patients from the Strata 1, RPA class I, are included in this
    subgroup, and (2) patients who were miss-classified in the incorrect
    stratum at randomization are re-classified into corrected primary
    tumors based on the reported diagnosis in CRF.

**Table 1: Number of Patients as Randomized in Each Stratum by Treatment
Arm**

  ---------------------- ----------------- ----------------- -------------
  **Strata**             **WBRT**          **RSR13 + WBRT**  **Total**

  **RPA Class I**        28 (10.5%)        29 (10.7%)        57 (10.6%)

  **RPA Class II,        132 (49.4%)       132 (48.7%)       264 (49.1%)
  NSCLC**                                                    

  **RPA Class II,        51 (19.1%)        52 (19.2%)        103 (19.1%)
  Breast**                                                   

  **RPA Class II,        56 (21.0%)        58 (21.4%)        114 (21.2%)
  Other**                                                    
  ---------------------- ----------------- ----------------- -------------

**Table 2: Number of Patients as Observed in Each Stratum by Treatment
Arm**

  ---------------------- ----------------- ----------------- -------------
  **Strata**             **WBRT**          **RSR13 + WBRT**  **Total**

  **RPA Class I**        24 (9.0%)         22 (8.1%)         46 (8.6%)

  **RPA Class II,        136 (50.9%)       133 (49.1%)       269 (50.0%)
  NSCLC**                                                    

  **RPA Class II,        50 (18.7%)        56 (20.7%)        106 (19.7%)
  Breast**                                                   

  **RPA Class II,        57 (21.3%)        60 (22.1%)        117 (21.7%)
  Other**                                                    
  ---------------------- ----------------- ----------------- -------------

**Table 3: Baseline Characteristics in ITT Population**

+-------------------------------+-----------------+-------------------+
| **Characteristic**            | **WBRT**        | **WBRT + RSR13**  |
+-------------------------------+-----------------+-------------------+
| Gender: Female                | 150 (56.2%)     | 153 (56.5%)       |
|                               |                 |                   |
| Male                          | 117 (43.8%)     | 118 (43.5%)       |
+-------------------------------+-----------------+-------------------+
| Race: Caucasian               | 239 (89.5%)     | 242 (89.3%)       |
|                               |                 |                   |
| Non-Caucasian                 | 28 (10.5%)      | 29 (10.7%)        |
+-------------------------------+-----------------+-------------------+
| Age Group: \< 65 years        | 197 (73.8%)     | 196 (72.3%)       |
|                               |                 |                   |
| ≥ 65 years                    | 70 (26.2%)      | 75 (27.7%)        |
+-------------------------------+-----------------+-------------------+
| Age in yrs: Mean (S.D.)       | 57.0 (11.0)     | 57.1 (11.1)       |
|                               |                 |                   |
| Median (Range)                | 57 (23 -- 81)   | 57 (30 -87)       |
+-------------------------------+-----------------+-------------------+
| Weight in Kg: Mean (S.D.)     | 72.5 (17.1)     | 71.3 (15.0)       |
|                               |                 |                   |
| Median (Range)                | 70.5 (33 --     | 71.0 (39.8 --     |
|                               | 140.9)          | 122)              |
+-------------------------------+-----------------+-------------------+
| KPS Group: \< 90              | 124 (46.4%)     | 113 (41.7%)       |
|                               |                 |                   |
| ≥ 90                          | 143 (53.6%)     | 158 (58.3%)       |
+-------------------------------+-----------------+-------------------+
| KPS: Mean (S.D.)              | 85.2 (9.7)      | 85.1 (9.7)        |
+-------------------------------+-----------------+-------------------+
| Bidirectional product (mm^2^) | 760.8 (694.8)   | 753.6 (735)       |
| for baseline lesions: Mean    |                 |                   |
| (S.D.)                        | 587.5 (4, 4200) | 518 (16, 5080)    |
|                               |                 |                   |
| Median (Range)                |                 |                   |
+-------------------------------+-----------------+-------------------+
| Resting SpO~2~: Mean (S.D.)   | 96.8 (1.7)      | 96.7 (1.8)        |
+-------------------------------+-----------------+-------------------+
| Primary Controlled : No       | 200 (74.9%)     | 199 (73.4%)       |
|                               |                 |                   |
| Yes                           | 67 (25.1%)      | 72 (26.6%)        |
+-------------------------------+-----------------+-------------------+
| Extracranial metastases: 0    | 96 (36.0%)      | 84 (31.0%)        |
|                               |                 |                   |
| 1                             | 69 (25.8%)      | 72 (26.6%)        |
|                               |                 |                   |
| 2                             | 55 (20.6%)      | 56 (20.7%)        |
|                               |                 |                   |
| ≥ 3                           | 47 (17.6%)      | 59 (21.7%)        |
+-------------------------------+-----------------+-------------------+
| Number of Brain Lesions: 1    | 53 (20.2%)      | 45 (16.9%)        |
|                               |                 |                   |
| 2                             | 81 (30.9%)      | 82 (30.7%)        |
|                               |                 |                   |
| ≥ 3                           | 128 (48.9%)     | 140 (52.4%)       |
+-------------------------------+-----------------+-------------------+
| Liver Metastases: No          | 225 (84.3%)     | 217 (80.1%)       |
|                               |                 |                   |
| Yes                           | 42 (15.7%)      | 54 (19.9%)        |
+-------------------------------+-----------------+-------------------+
| Lung Metastases: No           | 183 (68.5%)     | 179 (66.1%)       |
|                               |                 |                   |
| Yes                           | 84 (31.5%)      | 92 (33.9%)        |
+-------------------------------+-----------------+-------------------+
| Synchronous Disease: No       | 184 (68.9%)     | 183 (67.5%)       |
|                               |                 |                   |
| Yes                           | 83 (31.1%)      | 88 (32.5%)        |
+-------------------------------+-----------------+-------------------+
| Prior Brain Mets Treatment:   | 238 (89.1%)     | 250 (92.3%)       |
| No                            |                 |                   |
|                               | 29 (10.9%)      | 21 (7.7%)         |
| Yes                           |                 |                   |
+-------------------------------+-----------------+-------------------+
| Hemoglobin (g/dL): Mean       | 13.5 (1.5)      | 13.3 (1.5)        |
| (S.D.)                        |                 |                   |
+-------------------------------+-----------------+-------------------+
| Creatinine (mg/dL): Mean      | 0.79 (0.23)     | 0.76 (0.21)       |
| (S.D.)                        |                 |                   |
+-------------------------------+-----------------+-------------------+
| Albumin (g/dL): Mean (S.D.)   | 3.70 (0.45)     | 3.65 (0.47        |
+-------------------------------+-----------------+-------------------+
| ALT (IU/L): Mean (S.D.)       | 40.9 (34.2)     | 40.5 (49.4)       |
+-------------------------------+-----------------+-------------------+
| Primary Site: NSCLC           | 151 (56.5%)     | 148 (54.6%)       |
|                               |                 |                   |
| Breast                        | 55 (20.6%)      | 60 (22.1%)        |
|                               |                 |                   |
| Other                         | 61 (22.9%)      | 63 (23.3%)        |
+-------------------------------+-----------------+-------------------+

**Table 4: Baseline Characteristics in NSCLC/Breast\* Subgroup**

+-------------------------------+-----------------+-------------------+
| **Characteristic**            | **WBRT**        | **WBRT + RSR13**  |
+-------------------------------+-----------------+-------------------+
| Gender: Female                | 130 (63.1%)     | 128 (61.5%)       |
|                               |                 |                   |
| Male                          | 76 (36.9%)      | 80 (38.5%)        |
+-------------------------------+-----------------+-------------------+
| Race: Caucasian               | 184 (89.3%)     | 184 (88.5%)       |
|                               |                 |                   |
| Non-Caucasian                 | 22 (10.7%)      | 24 (11.5%)        |
+-------------------------------+-----------------+-------------------+
| Age Group: \< 65 years        | 150 (72.8%)     | 150 (72.1%)       |
|                               |                 |                   |
| ≥ 65 years                    | 56 (27.2%)      | 58 (27.9%)        |
+-------------------------------+-----------------+-------------------+
| Age in yrs: Mean (S.D.)       | 57.1 (11.2)     | 56.9 (11.0)       |
|                               |                 |                   |
| Median (Range)                | 57 (26 -- 81)   | 57 (31 -- 80)     |
+-------------------------------+-----------------+-------------------+
| Weight in Kg: Mean (S.D.)     | 70.7 (15.9)     | 71.1 (15.0)       |
|                               |                 |                   |
| Median (Range)                | 68.8 (33 --     | 69.6 (41.1 --     |
|                               | 124.1)          | 122)              |
+-------------------------------+-----------------+-------------------+
| KPS Group: \< 90              | 89 (43.2%)      | 87 (41.8%)        |
|                               |                 |                   |
| ≥ 90                          | 117 (56.8%)     | 121 (58.2%)       |
+-------------------------------+-----------------+-------------------+
| KPS: Mean (S.D.)              | 85.7 (9.5)      | 85.1 (9.6)        |
+-------------------------------+-----------------+-------------------+
| Bidirectional product (mm^2^) | 755.6 (668.2)   | 767.8 (767.8)     |
| for baseline lesions: Mean    |                 |                   |
| (S.D.)                        | 573.5 (17 --    | 459 (16 -- 5080)  |
|                               | 3806)           |                   |
| Median (Range)                |                 |                   |
+-------------------------------+-----------------+-------------------+
| Resting SpO~2~: Mean (S.D.)   | 96.9 (1.7)      | 96.8 (1.8)        |
+-------------------------------+-----------------+-------------------+
| Primary Controlled : No       | 156 (75.7%)     | 159 (76.4%)       |
|                               |                 |                   |
| Yes                           | 50 (24.3%)      | 49 (23.6%)        |
+-------------------------------+-----------------+-------------------+
| Extracranial metastases: 0    | 76 (36.9%)      | 75 (36.0%)        |
|                               |                 |                   |
| 1                             | 51 (24.8%)      | 54 (26.0%))       |
|                               |                 |                   |
| 2                             | 42 (20.4%)      | 42 (20.2%)        |
|                               |                 |                   |
| ≥ 3                           | 37 (18.0%)      | 37 (17.8%)        |
+-------------------------------+-----------------+-------------------+
| Number of Brain Lesions: 1    | 43 (21.1%)      | 37 (18.0%)        |
|                               |                 |                   |
| 2                             | 60 (29.4%)      | 66 (32.2%)        |
|                               |                 |                   |
| ≥ 3                           | 101 (49.5%)     | 102 (49.8%)       |
+-------------------------------+-----------------+-------------------+
| Liver Metastases: No          | 176 (85.4%)     | 176 (84.6%)       |
|                               |                 |                   |
| Yes                           | 30 (14.6%)      | 32 (15.4%)        |
+-------------------------------+-----------------+-------------------+
| Lung Metastases: No           | 148 (71.8%)     | 155 (74.5%)       |
|                               |                 |                   |
| Yes                           | 58 (28.2%)      | 53 (25.5%)        |
+-------------------------------+-----------------+-------------------+
| Synchronous Disease: No       | 140 (68.0%)     | 133 (63.9%)       |
|                               |                 |                   |
| Yes                           | 66 (32.0%)      | 75 (36.1%)        |
+-------------------------------+-----------------+-------------------+
| Prior Brain Mets Treatment:   | 189 (91.8%)     | 197 (94.7%)       |
| No                            |                 |                   |
|                               | 17 (8.2%)       | 11 (5.3%)         |
| Yes                           |                 |                   |
+-------------------------------+-----------------+-------------------+
| Hemoglobin (g/dL): Mean       | 13.4 (1.5)      | 13.4 (1.4)        |
| (S.D.)                        |                 |                   |
+-------------------------------+-----------------+-------------------+
| Creatinine (mg/dL): Mean      | 0.77 (0.22)     | 0.75 (0.20)       |
| (S.D.)                        |                 |                   |
+-------------------------------+-----------------+-------------------+
| Albumin (g/dL): Mean (S.D.)   | 3.7 (0.4)       | 3.6 (0.5)         |
+-------------------------------+-----------------+-------------------+
| ALT (IU/L): Mean (S.D.)       | 39.2 (33.0)     | 41.9 (54.4)       |
+-------------------------------+-----------------+-------------------+

\*: Revised group per reclassification (corrected) and including RPA
Class I patients.

##### Primary Efficacy Analyses

Primary efficacy analysis per original protocol, comparing overall
survival between WBRT and RSR13 + WBRT, in the ITT population using
unadjusted log-rank test is presented in Table 5 (same as reported by
the sponsor). There were a total of 441/538 patients who had events
(deaths) at the time of the final analysis. The Kaplan-Meier curves for
the ITT population are illustrated in Figure 2. The efficacy analysis in
the subgroup of NSCLC/Breast primary patients is presented in Table 6
(same as reported by the sponsor). The Kaplan-Meier curves for the
NSCLC/Breast subgroup is presented in Figure 3. There were 331/414
deaths in this subgroup at the time of the final analysis.

**Table 5: Primary Efficacy Survival Analysis in ITT Population**

+----------------+----------+------------------+-------------+--------+
| **Treatment**  | **Number | **Median         | **Hazard    | **     |
|                | of       | Survival in      | Ratio^2^**  | P-valu |
|                | Deaths** | Months^1^**      |             | e^3^** |
|                |          |                  | **(95%      |        |
|                |          | **(95% C.I.)**   | C.I.)**     |        |
+----------------+----------+------------------+-------------+--------+
| WBRT           | 221/267  | **4.5** (3.7,    | 0.877       | **0.   |
|                |          | 5.4)             |             | 1688** |
|                |          |                  | (0.727,     |        |
|                |          |                  | 1.057)      |        |
+----------------+----------+------------------+-------------+--------+
| RSR13 + WBRT   | 220/271  | **5.3** (4.5,    |             |        |
|                |          | 6.2)             |             |        |
+----------------+----------+------------------+-------------+--------+

^1^: Kaplan-Meier Estimates; ^2^: Hazard Ratio of RSR13 + WBRT/ WBRT;

^3^: unadjusted log-rank test.

**Figure 2: Kaplan-Meier Survival Curves in the ITT Population**

![](media/image3.png){width="5.491666666666666in"
height="4.031944444444444in"}

**Table 6: Co-Primary Efficacy Survival Analysis in NSCLC/Breast Primary
Cancer Subgroup\***

+----------------+----------+------------------+-------------+--------+
| **Treatment**  | **Number | **Median         | **Hazard    | **     |
|                | of       | Survival in      | Ratio^2^**  | P-valu |
|                | Deaths** | Months^1^**      |             | e^3^** |
|                |          |                  | **(95%      |        |
|                |          | **(95% C.I.)**   | C.I.)**     |        |
+----------------+----------+------------------+-------------+--------+
| WBRT           | 167/206  | **4.5** (3.8,    | 0.844       | **0.   |
|                |          | 5.4)             |             | 1217** |
|                |          |                  | (0.680,     |        |
|                |          |                  | 1.048)      |        |
+----------------+----------+------------------+-------------+--------+
| RSR13 + WBRT   | 164/208  | **5.9** (4.7,    |             |        |
|                |          | 7.0)             |             |        |
+----------------+----------+------------------+-------------+--------+

\*: Corrected for miss-classification (i.e., non-randomized subgroup);

^1^: Kaplan-Meier Estimates; ^2^: Hazard Ratio of RSR13 + WBRT/ WBRT;

^3^: unadjusted log-rank test.

**Figure 3: Kaplan-Meier Survival Curves in the Subgroup of Patients
with NSCLC/Breast Primary**

![](media/image4.png){width="5.491666666666666in"
height="4.031944444444444in"}

*[Reviewer's Comments:]{.underline}*

1.  **RSR13 + WBRT treatment failed to demonstrate superior survival
    over WBRT alone in the randomized ITT population** (Table 5 and
    Figure 2 above). The final analysis was conducted after observing
    the required number of deaths (required 402 deaths, observed 441
    deaths) specified in the protocol. The median survival in the WBRT
    arm was slightly less than what was expected in the protocol design.

2.  **RSR13 + WBRT treatment failed to demonstrate superior survival
    over WBRT alone in the subgroup of patients with NSCLC/Breast
    primary** (*Co-primary analysis*, Table 6 and Figure 3 above). The
    final analysis was conducted after observing the required number of
    deaths (required 308 deaths, observed 331 deaths) specified in the
    protocol.

3.  There appears to be an imbalance between the treatment arms in the
    number of patients who were not eligible (17 in the WBRT alone arm
    and 6 in the RSR13 + WBRT arm). The results of exploratory analyses
    in eligible patients only or per-protocol patients in the overall
    population and in the NSCLC/Breast primary subgroup of patients are
    presented respectively, in the following Tables 7 and 8. These
    results also fail to demonstrate superior survival of RSR13 + WBRT
    treatment over WBRT alone.

4.  There were 30/441 early deaths within 1 month from the start of the
    study. Of the 30 deaths 16 were in the WBRT alone arm (2 Breast, 11
    NSCLC and 3 Other primaries), and 14 were in the RSR13 + WBRT arm (4
    Breast, 3 NSCLC and 7 Other primaries). It appears that there were
    more early deaths in the control arm compared to RSR13 arm in the
    NSCLC and breast primary subgroups. Given these numerical
    differences and open-label nature of the study it is uncertain if
    bias was introduced in patient selection and allocation.

**Table 7: Exploratory Survival Analysis in the Per-Protocol Overall
Population**

+----------------+----------+------------------+-------------+--------+
| **Treatment**  | **Number | **Median         | **Hazard    | **     |
|                | of       | Survival in      | Ratio^2^**  | P-valu |
|                | Deaths** | Months^1^**      |             | e^3^** |
|                |          |                  | **(95%      |        |
|                |          | **(95% C.I.)**   | C.I.)**     |        |
+----------------+----------+------------------+-------------+--------+
| WBRT           | 206/250  | **4.4** (3.7,    | 0.871       | **0.   |
|                |          | 5.3)             |             | 1549** |
|                |          |                  | (0.719,     |        |
|                |          |                  | 1.054)      |        |
+----------------+----------+------------------+-------------+--------+
| RSR13 + WBRT   | 215/265  | **5.4** (4.6,    |             |        |
|                |          | 6.3)             |             |        |
+----------------+----------+------------------+-------------+--------+

^1^: Kaplan-Meier Estimates; ^2^: Hazard Ratio of RSR13 + WBRT/ WBRT;

^3^: unadjusted log-rank test and not adjusted for multiple analyses.

**Table 8: Exploratory Survival Analysis in the Per-Protocol
NSCLC/Breast Primary Cancer Subgroup\***

+----------------+----------+------------------+-------------+--------+
| **Treatment**  | **Number | **Median         | **Hazard    | **     |
|                | of       | Survival in      | Ratio^2^**  | P-valu |
|                | Deaths** | Months^1^**      |             | e^3^** |
|                |          |                  | **(95%      |        |
|                |          | **(95% C.I.)**   | C.I.)**     |        |
+----------------+----------+------------------+-------------+--------+
| WBRT           | 157/194  | **4.4** (3.7,    | 0.815       | **0.   |
|                |          | 5.2)             |             | 0693** |
|                |          |                  | (0.654,     |        |
|                |          |                  | 1.017)      |        |
+----------------+----------+------------------+-------------+--------+
| RSR13 + WBRT   | 159/203  | **6.0** (4.7,    |             |        |
|                |          | 7.1)             |             |        |
+----------------+----------+------------------+-------------+--------+

\*: Corrected for miss-classification (i.e., non-randomized subgroup);

^1^: Kaplan-Meier Estimates; ^2^: Hazard Ratio of RSR13 + WBRT/ WBRT;

^3^: unadjusted log-rank test and not adjusted for multiple analyses.

##### Exploratory Covariate Adjusted and Subgroup Survival Analyses

The sponsor had specified exploratory covariate adjusted survival
analyses using Cox model. The sponsor had also specified exploratory
survival analyses in each of the randomized strata. In this section the
results of these exploratory analyses are presented.

In the original protocol and its amendments, 7 covariates were mentioned
as likely to be included in the Cox model (Refer to section 3.1.1.7, and
Table 9 below). After completion of accrual this analysis was revised in
the SAP to include 18 covariates (Refer to section 3.1.1.7, and Table 9
below) in various combinations of continuous and categorical variables
resulting in 48 Cox models (submitted by sponsor including 17/18
covariates, all models included the same 17 covariates, not presented
here). Results of Cox regression analysis including the 7 covariates
specified in the protocol are presented in Table 11 (FDA analysis). One
of the models including the 18 covariates in the per-protocol population
as specified in the SAP is presented in Table 12 (FDA analysis).

**Table 9: Covariates Intended to be Included in the Cox Model**

  ------------------------------------ ----------------------------------
  **Protocol Covariates**              **SAP Covariates**

  RPA Class                            RPA Class

  Site of Primary Cancer               Site of Primary Cancer

  Primary Tumor Control                Primary Tumor Control

  Age                                  Age

  Presence of Extracranial Metastases  

  Baseline KPS                         Baseline KPS

  Number of Metastatic Lesions         Number of Cranial Metastases

                                       Number of Extracranial Metastases

                                       Baseline Cranial Tumor Total Area

                                       Baseline Weight (divided by gender
                                       as per the dosing guidelines)

                                       Gender

                                       Presence of Liver Metastases

                                       Usage of Subsequent Treatment\*

                                       Diagnosis Timing

                                       Prior Treatment to Cranial
                                       Metastases

                                       Worldwide Location

                                       Altitude

                                       Baseline Hemoglobin

                                       Size of Center
  ------------------------------------ ----------------------------------

\* Not included in sponsor's adjusted Cox models

Table 10: Cox's Proportional Hazard Model Adjusting for Covariates in
the ITT Population (Protocol Planned Model)

+------------------------------------+-----------+------------+-------+
| **Covariates**                     | **Hazard  | **95%      | **P-  |
|                                    | Ratio**   | C.I.**     | value |
|                                    |           |            | ^1^** |
+------------------------------------+-----------+------------+-------+
| Treatment (RSR13 + WBRT/WBRT)      | 0.814     | 0.674,     | 0     |
|                                    |           | 0.984      | .0335 |
+------------------------------------+-----------+------------+-------+
| RPA Class (1 vs. 2)                | 0.742     | 0.471,     | 0     |
|                                    |           | 1.168      | .1973 |
+------------------------------------+-----------+------------+-------+
| Site of Primary Cancer: Breast     | 0.568     | 0.423,     | 0     |
| (Yes vs. No)                       |           | 0.764      | .0002 |
|                                    | 0.861     |            |       |
| NSCLC (Yes vs. No)                 |           | 0.682,     | 0     |
|                                    |           | 1.085      | .2050 |
+------------------------------------+-----------+------------+-------+
| Primary Tumor Control (Yes vs. No) | 1.310     | 1.006,     | 0     |
|                                    |           | 1.707      | .0453 |
+------------------------------------+-----------+------------+-------+
| Age                                | 1.014     | 1.005,     | 0     |
|                                    |           | 1.023      | .0022 |
+------------------------------------+-----------+------------+-------+
| Presence of Extracranial           | 1.138     | 0.800,     | 0     |
| Metastases (No vs. Yes)            |           | 1.618      | .4732 |
+------------------------------------+-----------+------------+-------+
| Baseline KPS                       | 0.968     | 0.958 --   | \<    |
|                                    |           | 0.978      | 0     |
|                                    |           |            | .0001 |
+------------------------------------+-----------+------------+-------+
| Number of Metastatic Lesions^2^    | 1.287     | 1.111 --   | 0     |
|                                    |           | 1.490      | .0008 |
+------------------------------------+-----------+------------+-------+

1: P-values not adjusted for multiplicity; 2: Since all patients were
supposed to have brain metastases, for the purpose of this analysis
'number of extracranial metastases' was used as the covariate in place
of 'number of metastatic lesions'.

Table 11: Cox's Proportional Hazard Model Adjusting for Covariates in
the Overall Eligible Patient Population (SAP Planned Model)\*

+-----------------------------------+------------+------------+-------+
| **Covariates**                    | **Hazard   | **95%      | **P-  |
|                                   | Ratio**    | C.I.**     | value |
|                                   |            |            | ^1^** |
+-----------------------------------+------------+------------+-------+
| Treatment (RSR13 + WBRT/WBRT)     | 0.777      | 0.640,     | 0     |
|                                   |            | 0.942      | .0103 |
+-----------------------------------+------------+------------+-------+
| RPA Class (1 vs. 2)               | 0.763      | 0.479,     | 0     |
|                                   |            | 1.215      | .2547 |
+-----------------------------------+------------+------------+-------+
| Site of Primary Cancer: Breast    | 0.602      | 0.430,     | 0     |
| (Yes vs. No)                      |            | 0.842      | .0031 |
|                                   | 0.826      |            |       |
| NSCLC (Yes vs. No)                |            | 0.640,     | 0     |
|                                   |            | 1.065      | .1409 |
+-----------------------------------+------------+------------+-------+
| Primary Tumor Control (Yes vs.    | 1.238      | 0.927,     | 0     |
| No)                               |            | 1.652      | .1481 |
+-----------------------------------+------------+------------+-------+
| Age Group ( \< 65 vs. ≥ 65 yrs)   | 1.486      | 1.178,     | 0     |
|                                   |            | 1.875      | .0008 |
+-----------------------------------+------------+------------+-------+
| Baseline KPS Group (≥ 90 vs. \<   | 1.564      | 1.283,     | \<    |
| 90)                               |            | 1.907      | 0     |
|                                   |            |            | .0001 |
+-----------------------------------+------------+------------+-------+
| Number of Cranial Metastases      | 1.148      | 1.000,     | 0     |
|                                   |            | 1.320      | .0508 |
+-----------------------------------+------------+------------+-------+
| Number of Extracranial Metastases | 1.237      | 1.102,     | 0     |
|                                   |            | 1.389      | .0003 |
+-----------------------------------+------------+------------+-------+
| Baseline Cranial Tumor Total Area | 1.071      | 0.930,     | 0     |
| (\<250, 250-1000, \> 1000)        |            | 1.233      | .3418 |
+-----------------------------------+------------+------------+-------+
| Baseline Weight Group (Low vs.    | 0.971      | 0.765,     | 0     |
| High)                             |            | 1.232      | .8096 |
+-----------------------------------+------------+------------+-------+
| Gender (Female vs. Male)          | 1.407      | 1.120,     | 0     |
|                                   |            | 1.767      | .0033 |
+-----------------------------------+------------+------------+-------+
| Presence of Liver Metastases (No  | 1.249      | 0.941,     | 0     |
| vs. Yes)                          |            | 1.658      | .1232 |
+-----------------------------------+------------+------------+-------+
| Usage of Subsequent Treatment (No | 0.910      | 0.695,     | 0     |
| vs. Yes)                          |            | 1.192      | .4937 |
+-----------------------------------+------------+------------+-------+
| Diagnosis Timing (metachronous    | 1.122      | 0.870,     | 0     |
| vs. synchronous)                  |            | 1.448      | .3737 |
+-----------------------------------+------------+------------+-------+
| Prior Treatment to Cranial        | 0.450      | 0.302,     | \<    |
| Metastases (No vs. Yes)           |            | 0.671      | 0     |
|                                   |            |            | .0001 |
+-----------------------------------+------------+------------+-------+
| Worldwide Location: USA (No vs.   | 0.921      | 0.665,     | 0     |
| Yes)                              |            | 1.275      | .6199 |
|                                   | 0.919      |            |       |
| Canada (No vs. Yes)               |            | 0.639,     | 0     |
|                                   |            | 1.322      | .6505 |
+-----------------------------------+------------+------------+-------+
| Altitude (Low vs. High)           | 1.096      | 0.805,     | 0     |
|                                   |            | 1.491      | .5604 |
+-----------------------------------+------------+------------+-------+
| Baseline Hemoglobin Group (≥ 12   | 1.336      | 1.027,     | 0     |
| vs. \< 12 g/dL)                   |            | 1.738      | .0308 |
+-----------------------------------+------------+------------+-------+
| Size of Center (Not a big site    | 0.965      | 0.762,     | 0     |
| vs. Big site)                     |            | 1.222      | .7679 |
+-----------------------------------+------------+------------+-------+

\*: Results based on a total of 528 patients; ^1^: P-values not adjusted
for multiplicity;

*[Reviewer's Comments]{.underline}*:

1.  Some of the covariates included in the model are likely to be highly
    correlated. For example, RPA Classification takes into account
    whether primary was controlled or not, age and whether there was
    metastasis in brain only or not.

2.  The models specified by the sponsor both in the protocol and in SAP
    are ambiguous and questionable. In the protocol specified model, the
    meaning of the covariate, number of metastatic lesions, is unclear.
    One could interpret it as total number of metastases (cranial +
    extracranial metastases), or number of brain lesions. Furthermore
    both the number of cranial lesions, extracranial metastases, and
    baseline tumor area appear like continuous variables, but in fact
    are categorized as zero, 1, 2 or 3. Regarding baseline cranial tumor
    area, the variable included in the model was the variable submitted
    by the sponsor as 'GBDPTOT' and the explanation given for this
    variable is that it is bi-dimensional product for baseline lesions.
    It is assumed in the above analysis that these are measurements for
    cranial lesions only. The covariate, diagnosis timing, was not
    defined in the protocol. The sponsor had used this as a categorical
    variable: synchronous diagnosis or not. One could interpret it as
    the actual time in days to the diagnosis of brain metastasis.

3.  Scientific basis or literature citation in choosing these covariates
    (either in the protocol or SAP) for the model was not provided by
    the sponsor. Some of the important covariates, such as, response to
    steroid treatment, systemic tumor activity, LDH, interval between
    primary tumor and development of brain metastases, reported in
    literature as significant prognostic factors for survival, were not
    included in these analyses and data needed for such evaluation were
    not collected.

4.  Furthermore, when appropriately adjusted for multiplicity, treatment
    differences are unlikely to be significant. P-values from these
    exploratory covariate analyses can not be taken at face value.

5.  Results from Cox regression analyses including only the randomized
    strata are presented in Tables 12-14. The treatment effect was not
    significant in any of these models. Please refer to Appendix 6 for
    exploratory Cox regression analyses in NSCLC/Breast Primary
    subgroup.

6.  The sponsor did not include the covariate 'usage of subsequent
    therapy' (as specified in the final SAP) in their Cox models

Table 12: Cox's Proportional Hazard Model Adjusting for Strata (As
Randomized) in the ITT Population

  ----------------------------------- ------------- ------------- ---------------
  **Covariates**                      **Hazard      **95% C.I.**  **P-value\***
                                      Ratio**                     

  Treatment (RT + RSR vs. RT)         0.871         0.722 --      0.1484
                                                    1.050         

  Stratum 2\*\* = RPA Class 2,        1.638         1.175 --      0.0036
  Primary Lung                                      2.284         

  Stratum 3\*\* = RPA Class 2,        1.388         0.954 --      0.0870
  Primary Breast                                    2.022         

  Stratum 4\*\* = RPA Class 2,        2.142         1.488 --      \< 0.0001
  Primary Other                                     3.083         
  ----------------------------------- ------------- ------------- ---------------

\* P-values not adjusted for multiplicity; \*\* Strata as randomized (25
patients were miss-classified)

Table 13: Cox's Proportional Hazard Model Adjusting for Re-classified
Strata in the ITT Population

  ----------------------------------- ------------- ------------- ---------------
  **Covariates**                      **Hazard      **95% C.I.**  **P-value\***
                                      Ratio**                     

  Treatment (RT + RSR vs. RT)         0.879         0.729 --      0.1799
                                                    1.061         

  Stratum 2\*\* = RPA Class 2,        1.436         1.003 --      0.0479
  Primary Lung                                      2.056         

  Stratum 3\*\* = RPA Class 2,        1.158         0.777 --      0.4714
  Primary Breast                                    1.726         

  Stratum 4\*\* = RPA Class 2,        1.933         1.313 --      0.0008
  Primary Other                                     2.846         
  ----------------------------------- ------------- ------------- ---------------

\* P-values not adjusted for multiplicity; \*\* Strata as observed or
intended (25 patients were re-classified)

Table 14: Cox's Proportional Hazard Model Adjusting for Primary Site
(Including RPA Class I and Primary Site as Observed) in the ITT
Population

  ----------------------------------- ------------- ------------- ---------------
  **Covariates**                      **Hazard      **95% C.I.**  **P-value\***
                                      Ratio**                     

  Treatment (RT + RSR vs. RT)         0.893         0.740, 1.077  0.2362

  Primary Lung                        0.774         0.617, 0.969  0.0258

  Primary Breast                      0.618         0.466, 0.821  0.0009
  ----------------------------------- ------------- ------------- ---------------

\* P-values not adjusted for multiplicity

7.  Exploratory survival analyses results in each of the primary site
    subgroups (NSCLC, Breast, and Other) are presented in Tables 15-17
    (results same as reported by the sponsor) and Kaplan-Meier Curves
    are illustrated in Figures 4-6.

**Table 15: Exploratory Survival Analysis in the Subgroup of Patients
with Primary NSCLC**

+----------------+----------+------------------+-------------+--------+
| **Treatment**  | **Number | **Median         | **Hazard    | **     |
|                | of       | Survival in      | Ratio^2^**  | P-valu |
|                | Deaths** | Months^1^**      |             | e^3^** |
|                |          |                  | **(95%      |        |
|                |          | **(95% C.I.)**   | C.I.)**     |        |
+----------------+----------+------------------+-------------+--------+
| WBRT           | 120/151  | **4.4** (3.5,    | 0.991       | **0.   |
|                |          | 5.7)             |             | 9426** |
|                |          |                  | (0.771,     |        |
|                |          |                  | 1.273)      |        |
+----------------+----------+------------------+-------------+--------+
| RSR13 + WBRT   | 125/148  | **4.9** (4.1,    |             |        |
|                |          | 6.2)             |             |        |
+----------------+----------+------------------+-------------+--------+

^1^: Kaplan-Meier Estimates; ^2^: Hazard Ratio of RSR13 + WBRT/ WBRT;

^3^: unadjusted log-rank test and not adjusted for multiple analyses.

**Figure 4: Kaplan-Meier Curves in the Subgroup of Patients with Primary
NSCLC**

![](media/image5.png){width="5.491666666666666in"
height="4.031944444444444in"}

**Table 16: Exploratory Survival Analysis in the Subgroup of Patients
with Primary Breast Cancer**

+----------------+----------+------------------+-------------+--------+
| **Treatment**  | **Number | **Median         | **Hazard    | **     |
|                | of       | Survival in      | Ratio^2^**  | P-valu |
|                | Deaths** | Months^1^**      |             | e^3^** |
|                |          |                  | **(95%      |        |
|                |          | **(95% C.I.)**   | C.I.)**     |        |
+----------------+----------+------------------+-------------+--------+
| WBRT           | 47/55    | **4.6** (3.8,    | 0.552       | **0.   |
|                |          | 6.2)             |             | 0061** |
|                |          |                  | (0.359,     |        |
|                |          |                  | 0.850)      |        |
+----------------+----------+------------------+-------------+--------+
| RSR13 + WBRT   | 39/60    | **8.7** (6.0,    |             |        |
|                |          | 11.3)            |             |        |
+----------------+----------+------------------+-------------+--------+

^1^: Kaplan-Meier Estimates; ^2^: Hazard Ratio of RSR13 + WBRT/ WBRT;

^3^: unadjusted log-rank test and not adjusted for multiple analyses.

**Figure 5: Kaplan-Meier Curves in the Subgroup of Patients with Primary
Breast Cancer**

![](media/image6.png){width="5.491666666666666in"
height="4.031944444444444in"}

**Table 17: Exploratory Survival Analysis in the Subgroup of Patients
with Primary 'Other' Cancer**

+----------------+----------+------------------+-------------+--------+
| **Treatment**  | **Number | **Median         | **Hazard    | **     |
|                | of       | Survival in      | Ratio^2^**  | P-valu |
|                | Deaths** | Months^1^**      |             | e^3^** |
|                |          |                  | **(95%      |        |
|                |          | **(95% C.I.)**   | C.I.)**     |        |
+----------------+----------+------------------+-------------+--------+
| WBRT           | 54/61    | **3.7** (2.5,    | 1.029       | **0.   |
|                |          | 6.0)             |             | 8812** |
|                |          |                  | (0.708,     |        |
|                |          |                  | 1.496)      |        |
+----------------+----------+------------------+-------------+--------+
| RSR13 + WBRT   | 56/63    | **4.0** (2.9,    |             |        |
|                |          | 5.6)             |             |        |
+----------------+----------+------------------+-------------+--------+

^1^: Kaplan-Meier Estimates; ^2^: Hazard Ratio of RSR13 + WBRT/ WBRT;

^3^: unadjusted log-rank test and not adjusted for multiple analyses.

**Figure 5: Kaplan-Meier Curves in the Subgroup of Patients with Primary
'Other' Cancer**

![](media/image7.png){width="5.491666666666666in"
height="4.031944444444444in"}

8.  Any subgroup analysis results are relevant only if overall study
    (ITT) is positive.

9.  Hypotheses testing in these subgroups, and α allocation for testing
    these subgroup hypotheses were not prespecified. Therefore, the
    P-values obtained in these subgroup analyses are not interpretable
    without a prespecified significance level.

10. There were no significant differences in the treatment effect in the
    subgroups of patients with primary NSCLC or Other Cancer.

11. The apparent treatment difference observed in the subgroup of
    patients with primary breast cancer can only be considered as
    hypothesis generating. The efficacy claim in this non-randomized,
    non-prespecified subgroup is based on post-hoc, data driven
    hypothesis testing in a very small subgroup (115 patients in total)
    of patients from a single study.

12. Well-controlled studies are required to approve a drug (21 CFR
    314.126(a): *Reports of adequate and well-controlled investigations
    provide the primary basis for determining whether there is
    \"substantial evidence\" to support the claims of effectiveness for
    new drugs*). Large, well conducted, controlled, randomized study is
    required particularly when considering single study for
    consideration of approval.

13. The Guidance for Industry: Providing clinical evidence of
    effectiveness from human drug and biological products (May 1998)
    clearly states that: '*When considering whether to rely on a single
    multicenter trial, it is critical that the possibility of an
    incorrect outcome be considered and that all the available data be
    examined for their potential to either support or undercut reliance
    on a single multicenter trial*'.

14. Furthermore, of the 115 patients with breast primary, 8 patients (6
    in WBRT arm and 2 in the RSR13 +WBRT arm) were not eligible patients
    (did not meet the inclusion criteria), 7 patients (3 in WBRT arm and
    4 in RSR13 + WBRT arm) were misclassified, 1 patient in the control
    arm was withdrawn from the study prior to receiving any treatment, 6
    patients (2 in WBRT arm, 4 in RSR13+WBRT arm) were dead within one
    month, and 15 patients (8 in WBRT arm, 7 in RSR13 + WBRT arm) were
    dead within 2 months from the start of the study. Among the patients
    who were terminated early in the RSR13 arm, 1 patient received only
    one dose, 5 patients received 2 doses only, and 2 patients received
    5 doses only.

15. There appears to be imbalance in some of the baseline patient
    characteristics favoring the RSR13 + WBRT arm compared to WBRT alone
    arm in the subgroup of patients with breast primary. These baseline
    characteristics include, weight, performance status ≥ 90, tumor
    burden, 3 or more extracranial metastases, 3 or more brain lesions,
    presence of lung metastases and prior brain metastases treatment
    (Table 18 below, bolded characteristics). Please refer to the
    clinical review of this application for other imbalances such as,
    differences in oxygen administration between the two treatment arms
    in the subgroup of patients with breast cancer primary.

16. Furthermore, in the breast primary subgroup majority were younger
    (\< 65 years old) women with metachronous diagnosis compared to the
    other subgroups.

17. Without replication of the results in a second well-controlled
    study, the subgroup analysis can not be ruled out for a false
    positive result.

18. ICH E-- 3, Section 11.4.2.8, clearly specifies guidelines for
    conducting subgroup analyses, namely, '***These analyses are not
    intended to \"salvage\" an otherwise non-supportive study but may
    suggest hypotheses worth examining in other studies or be helpful in
    refining labelling information, patient selection, dose selection
    etc.*'** Therefore, (a) Examining a subgroup of patients with
    primary breast cancer when the overall study is not-supportive, is
    not acceptable; (b) Because the randomized strata have been
    modified, the subgroup under consideration is not a randomized
    subgroup; (c) Apparent imbalances between the treatment groups with
    respect to some of the baseline characteristics may potentially be
    driving the difference in survival.

19. Although no drug has been approved for breast cancer patients with
    brain metastasis, in general the approval of drugs in advanced
    breast cancer are based on relatively large studies.

**Table 18: Baseline Characteristics in Breast\* Subgroup**

+-------------------------------+-----------------+-------------------+
| **Characteristic**            | **WBRT**        | **WBRT + RSR13**  |
+-------------------------------+-----------------+-------------------+
| Gender: Female                | 54 (98.2%)      | 60 (100.0%)       |
|                               |                 |                   |
| Male                          | 1 (1.8%)        | 0 (0.0%)          |
+-------------------------------+-----------------+-------------------+
| Race: Caucasian               | 48 (87.3%)      | 50 (83.3%)        |
|                               |                 |                   |
| Non-Caucasian                 | 7 (12.7%)       | 10 (16.7%)        |
+-------------------------------+-----------------+-------------------+
| Age Group: \< 65 years        | 45 (81.8%)      | 48 (80.0%)        |
|                               |                 |                   |
| ≥ 65 years                    | 10 (18.2%)      | 12 (20.0%)        |
+-------------------------------+-----------------+-------------------+
| Age in yrs: Mean (S.D.)       | 53.9 (11.2)     | 52.0 (11.6)       |
|                               |                 |                   |
| Median (Range)                | 53 (30-78)      | 51 (31-80)        |
+-------------------------------+-----------------+-------------------+
| Weight in Kg: Mean (S.D.)     | **68.2 (17.5)** | **73.2 (14.7)**   |
|                               |                 |                   |
| Median (Range)                | **64            | **72.9            |
|                               | (42-124.1)**    | (46.5-122)**      |
+-------------------------------+-----------------+-------------------+
| KPS Group: \< 90              | 24 (43.6%)      | 24 (40.0%)        |
|                               |                 |                   |
| ≥ 90                          | **31 (56.4%)**  | **36 (60.0%)**    |
+-------------------------------+-----------------+-------------------+
| KPS: Mean (S.D.)              | 85.3 (9.2)      | 85.5 (9.6)        |
+-------------------------------+-----------------+-------------------+
| Bidirectional product (mm^2^) | **882.1         | **761.9 (705.8)** |
| for baseline lesions: Mean    | (695.1)**       |                   |
| (S.D.)                        |                 | **578.5           |
|                               | **699           | (16-2936)**       |
| Median (Range)                | (17-3588)**     |                   |
+-------------------------------+-----------------+-------------------+
| Resting SpO~2~: Mean (S.D.)   | 97.5 (1.8)      | 96.9 (1.7)        |
+-------------------------------+-----------------+-------------------+
| Primary Controlled : No       | 37 (67.3%)      | 41 (68.3%)        |
|                               |                 |                   |
| Yes                           | 18 (32.7%)      | 19 (31.7%)        |
+-------------------------------+-----------------+-------------------+
| Extracranial metastases: 0    | 8 (14.6%)       | 7 (11.7%)         |
|                               |                 |                   |
| 1                             | 8 (14.6%)       | 14 (23.3%)        |
|                               |                 |                   |
| 2                             | 17 (30.9%)      | 20 (33.3%)        |
|                               |                 |                   |
| ≥ 3                           | **22 (40.0%)**  | **19 (31.7%)**    |
+-------------------------------+-----------------+-------------------+
| Number of Brain Lesions: 1    | 5 (9.3%)        | 13 (21.7%)        |
|                               |                 |                   |
| 2                             | 9 (16.7%)       | 13 (21.7%)        |
|                               |                 |                   |
| ≥ 3                           | **40 (74.1%)**  | **34 (56.7%)**    |
+-------------------------------+-----------------+-------------------+
| Liver Metastases: No          | 36 (65.5%)      | 39 (65.0%)        |
|                               |                 |                   |
| Yes                           | 19 (34.5%)      | 21 (35.0%)        |
+-------------------------------+-----------------+-------------------+
| Lung Metastases: No           | 23 (41.8%)      | 31 (51.7%)        |
|                               |                 |                   |
| Yes                           | **32 (58.2%)**  | **29 (48.3%)**    |
+-------------------------------+-----------------+-------------------+
| Synchronous Disease: No       | 53 (96.4%)      | 58 (96.7%)        |
|                               |                 |                   |
| Yes                           | 2 (3.6%)        | 2 (3.3%)          |
+-------------------------------+-----------------+-------------------+
| Prior Brain Mets Treatment:   | **51 (92.7%)**  | **58 (96.7%)**    |
| No                            |                 |                   |
|                               | 4 (7.3%)        | 2 (3.3%)          |
| Yes                           |                 |                   |
+-------------------------------+-----------------+-------------------+
| Hemoglobin (g/dL): Mean       | 13.0 (1.6)      | 12.7 (1.2)        |
| (S.D.)                        |                 |                   |
+-------------------------------+-----------------+-------------------+
| Creatinine (mg/dL): Mean      | 0.78 (0.28)     | 0.67 (0.12)       |
| (S.D.)                        |                 |                   |
+-------------------------------+-----------------+-------------------+
| Albumin (g/dL): Mean (S.D.)   | 3.9 (0.5)       | 3.7 (0.42)        |
+-------------------------------+-----------------+-------------------+
| ALT (IU/L): Mean (S.D.)       | 36.4 (29.5)     | 40.4 (44.9)       |
+-------------------------------+-----------------+-------------------+

\*: Revised group per reclassification (corrected) and including RPA
Class I patients.

##### Secondary Efficacy Analyses

Results submitted by the sponsor on the evaluation of secondary efficacy
endpoints will be briefly summarized in this section. The protocol
specified secondary endpoints were time to radiographic and time to
clinical tumor progression in the brain, response rate in the brain,
cause of death, and quality of life.

**Time to Radiographic Tumor Progression in the Brain**

Time to radiographic tumor progression, as determined by Central
Radiology Review, was estimated for all patients using cumulative
incidence analysis and Kaplan-Meier methods, and tested between
treatment arms using Gray's test. Death in this analysis was recorded as
a competing risk when it occurred prior to diagnosis of radiographic
progression.

Per sponsor's report, there was no statistically significant difference
in the cumulative incidence of radiographic progression between the WBRT
alone and RSR13 + WBRT arms (χ^2^ = 0.458, **p-value = 0.4986**). The
sponsor has also reported that there was no statistically significant
difference in the cumulative incidence of radiographic progression
between the WBRT alone and RSR13 + WBRT arms in the subset of patients
with NSCLC primary (p-value = 0.8142), or Breast primary (p-value =
0.8023) or Other primary (p-value = 0.3597).

**Time to Clinical Progression in the Brain**

Time to clinical tumor progression, was estimated for all patients using
cumulative incidence analysis and Kaplan-Meier methods, and tested
between treatment arms using Gray's test. Death in this analysis was
recorded as a competing risk when it occurred prior to diagnosis of
clinical progression.

Per sponsor's report, there was no statistically significant difference
in the cumulative incidence of clinical progression between the WBRT
alone and RSR13 + WBRT arms (χ^2^ = 0.595, **p-value = 0.4407**). The
sponsor has also reported that there was no statistically significant
difference in the cumulative incidence of clinical progression between
the WBRT alone and RSR13 + WBRT arms in the subset of patients with
NSCLC primary (p-value = 0.8142), or Breast primary (p-value = 0.8023)
or Other primary (p-value = 0.3597).

**Response Rate in the Brain**

Best response was determined from MRI or CT scans performed at each
follow-up visit. The distribution of best response in the brain was
compared between the treatment arms using Cochran-Mantel-Haenzel test.

According to the sponsor, 455 patients had a scan after the baseline
scan, in whom response could be assessed. The sponsor has reported that
there was no statistically significant difference in the distribution of
response between the treatment arms in this group of patients (**p-value
= 0.1226**).

**Cause of Death**

The sponsor has stated that cause of death was an inadequate endpoint
for meaningful analysis. However they have reported that by the
Cochran-Mantel-Haenzel test there was no difference in the distribution
of cause of death between the two treatment arms (**p-value = 0.5090**).
The following table was presented by the sponsor describing the cause of
death.

**Table 19: Cause of Death by Treatment Arms**

+--------------------------+----------------------+--------------------+
| **Cause of Death**       | **WBRT**             | **RSR13 + WBRT**   |
|                          |                      |                    |
|                          | **(N = 267)**        | **(N = 271)**      |
+--------------------------+----------------------+--------------------+
| **Neurologic**           | 34                   | 37                 |
+--------------------------+----------------------+--------------------+
| **Non-neurologic**       | 128                  | 128                |
+--------------------------+----------------------+--------------------+
| **Indistinguishable**    | 58                   | 53                 |
+--------------------------+----------------------+--------------------+
| **Missing/Withdrew       | 1                    | 2                  |
| Consent**                |                      |                    |
+--------------------------+----------------------+--------------------+
| **Still Alive**          | 46                   | 51                 |
+--------------------------+----------------------+--------------------+

**Quality of life**

Quality of life (QOL) was determined with the KPS assessment and the
Spitzer Questionnaire that were performed at baseline, WBRT day 10, and
all routine follow-up visits. Comparisons of QOL measures between
treatment arms focused on the 6-month and 12-month time-points and did
not included WBRT day 10.

The sponsor has reported that in the overall population, the
distributions of KPS scores were similar at all time-points between the
two treatment arms and no statistically significant differences were
observed in the distribution of KPS scores between the treatment arms at
6 months or 1 year using the Cochran-Mantel-Haenzel test (**p-value
=0.1540, p-value=0.1831**, respectively).

Spitzer Questionnaire scores were based on 5 questions each worth 0-2
points for a total of possible 10 points. Patients with at least 3 of
the 5 questions answered were given a scaled total score equivalent to
the average score per question multiplied by 5. The scores at 6-month
and 1-year follow-up visits were compared to baseline for each patient
and categorized as stable or increasing, decreased by 1-2 points, or
decreased by more than 2 points. The distribution of these categories at
6 months and 1 year was compared between treatment arms using
Cochran-Mantel-Haenzel test.

The sponsor has reported that in the overall population, the
distributions of Spitzer Questionnaire scores were similar at all
time-points between the two treatment arms and no statistically
significant differences were observed in the distribution of Spitzer
Questionnaire scores between the treatment arms at 6 months or 1 year
using the Cochran-Mantel-Haenzel test (**p-value =0.3118,
p-value=0.196**1, respectively).

*[Reviewer's Comments:]{.underline}*

1.  **None of the secondary efficacy analyses demonstrated superior
    treatment effect of RSR13 + WBRT compared to WBRT alone.**

2.  Discrepancies in the responses between the sponsor and FDA Clinical
    reviewer was observed. For details of further response evaluation
    and analyses, please refer to Clinical Review of this application.

3.  Because significant proportion of patients had cause of death as
    indistinguishable, it is difficult to interpret these results.

4.  In analyzing and interpreting the results of the QOL measures one
    should be cautious. Given that the median survival in this study is
    between 4.5 to 5.3 months, comparing treatment differences at 6
    months or at 1 year can result in biased results with many missing
    measurements.

## Evaluation of Safety

Please refer to Clinical Review of this application for safety
evaluation.

# Findings in Special/Subgroup Populations

## Gender, Race and Age

Efficacy by gender was analyzed by conducting an exploratory survival
analysis. The results of this analysis are presented in Table 20.
Efficacy by age (\< 65 years vs. ≥ 65 years was also analyzed by
conducting exploratory survival analysis. The results of this analysis
are presented in Table 21. Because majority (approximately 90%) of the
patients entered in the study were Caucasians, efficacy by race was not
evaluated.

**Table 20: Exploratory Survival Analysis by Gender in the ITT
Population**

+--------+---------------+--------+-----------+------------+--------+
| **Ge   | **Treatment** | **     | **Median  | **Hazard   | **     |
| nder** |               | Number | Survival  | Ratio^2^** | P-valu |
|        |               | of     | in        |            | e^3^** |
|        |               | De     | Mo        | **(95%     |        |
|        |               | aths** | nths^1^** | C.I.)**    |        |
|        |               |        |           |            |        |
|        |               |        | **(95%    |            |        |
|        |               |        | C.I.)**   |            |        |
+--------+---------------+--------+-----------+------------+--------+
| **Fem  | WBRT          | 1      | **5.0**   | 0.821      | **0.   |
| ales** |               | 20/150 |           |            | 1313** |
|        |               |        | (4.3,     | (0.635,    |        |
|        |               |        | 6.3)      | 1.062)     |        |
+--------+---------------+--------+-----------+------------+--------+
|        | RSR13 + WBRT  | 1      | **6.9**   |            |        |
|        |               | 16/153 |           |            |        |
|        |               |        | (4.8,     |            |        |
|        |               |        | 8.2)      |            |        |
+--------+---------------+--------+-----------+------------+--------+
| **M    | WBRT          | 1      | **3.7**   | 0.947      | **0.   |
| ales** |               | 01/117 |           |            | 6943** |
|        |               |        | (3.0,     | (0.720,    |        |
|        |               |        | 5.1)      | 1.245)     |        |
+--------+---------------+--------+-----------+------------+--------+
|        | RSR13 + WBRT  | 1      | **4.3**   |            |        |
|        |               | 04/118 |           |            |        |
|        |               |        | (3.3,     |            |        |
|        |               |        | 5.6)      |            |        |
+--------+---------------+--------+-----------+------------+--------+

^1^: Kaplan-Meier Estimates; ^2^: Hazard Ratio of RSR13 + WBRT/ WBRT;

^3^: unadjusted log-rank test and not adjusted for multiple analyses.

**Table 21: Exploratory Survival Analysis by Age Group in the ITT
Population**

+--------+---------------+--------+-----------+------------+--------+
| **Age  | **Treatment** | **     | **Median  | **Hazard   | **     |
| G      |               | Number | Survival  | Ratio^2^** | P-valu |
| roup** |               | of     | in        |            | e^3^** |
|        |               | De     | Mo        | **(95%     |        |
|        |               | aths** | nths^1^** | C.I.)**    |        |
|        |               |        |           |            |        |
|        |               |        | **(95%    |            |        |
|        |               |        | C.I.)**   |            |        |
+--------+---------------+--------+-----------+------------+--------+
| **\<   | WBRT          | 1      | **5.4**   | 0.905      | **0.   |
| 65     |               | 57/197 |           |            | 3781** |
| yrs**  |               |        | (4.2,     | (0.726,    |        |
|        |               |        | 6.4)      | 1.130)     |        |
+--------+---------------+--------+-----------+------------+--------+
|        | RSR13 + WBRT  | 1      | **5.8**   |            |        |
|        |               | 58/196 |           |            |        |
|        |               |        | (4.8,     |            |        |
|        |               |        | 6.9)      |            |        |
+--------+---------------+--------+-----------+------------+--------+
| **≥ 65 | WBRT          | 64/70  | **3.2**   | 0.802      | **0.   |
| yrs**  |               |        |           |            | 2176** |
|        |               |        | (2.8,     | (0.564,    |        |
|        |               |        | 4.2)      | 1.141)     |        |
+--------+---------------+--------+-----------+------------+--------+
|        | RSR13 + WBRT  | 62/75  | **3.8**   |            |        |
|        |               |        |           |            |        |
|        |               |        | (3.0,     |            |        |
|        |               |        | 4.7)      |            |        |
+--------+---------------+--------+-----------+------------+--------+

^1^: Kaplan-Meier Estimates; ^2^: Hazard Ratio of RSR13 + WBRT/ WBRT;

^3^: unadjusted log-rank test and not adjusted for multiple analyses.

*[Reviewer's Comments]{.underline}*:

1.  There was no significant treatment effect in either female or male
    patients. However, females appear to have longer survival than
    males.

2.  There was no significant treatment effect in either less than 65
    years old patients or 65 or older patients. However, younger
    patients (\< 65 years) appear to have longer survival than older
    patients (≥ 65 years).

## Other Special/Subgroup Populations

Effect by weight group adjusted for gender (RSR13 dose of 100mg/kg if
male and ≤ 95 kg or if female and ≤ 70 kg (low weight group), otherwise
RSR13 dose of 75 mg/kg (larger weight)) was evaluated by conducting an
exploratory survival analysis. The results of this analysis are
presented in Table 22.

Exploratory survival analysis in patients with brain disease only
(primary disease controlled and no extracranial metastases, N = 67), did
not demonstrate RSR13 effect (Hazard Ratio = 0.959, 95% C.I.: 0.538,
1.707, p-value = 0.8859). For the evaluation of efficacy in other
specific subgroup population please refer to section 3.1.1.8.3.

**Table 22: Exploratory Survival Analysis by Weight Group in the ITT
Population**

+-------------+----------+--------+-----------+------------+--------+
| **Weight    | **Tre    | **     | **Median  | **Hazard   | **     |
| Group**     | atment** | Number | Survival  | Ratio^2^** | P-valu |
|             |          | of     | in        |            | e^3^** |
|             |          | De     | Mo        | **(95%     |        |
|             |          | aths** | nths^1^** | C.I.)**    |        |
|             |          |        |           |            |        |
|             |          |        | **(95%    |            |        |
|             |          |        | C.I.)**   |            |        |
+-------------+----------+--------+-----------+------------+--------+
| **≤ 95 kg   | WBRT     | 1      | **4.4**   | 0.933      | **0.   |
| if Male or  |          | 63/198 |           |            | 5240** |
| ≤ 70 kg if  |          |        | (3.6,     | (0.752,    |        |
| Female**    |          |        | 5.2)      | 1.156)     |        |
+-------------+----------+--------+-----------+------------+--------+
|             | RSR13 +  | 1      | **4.7**   |            |        |
|             | WBRT     | 70/204 |           |            |        |
|             |          |        | (3.9,     |            |        |
|             |          |        | 5.9)      |            |        |
+-------------+----------+--------+-----------+------------+--------+
| **\> 95 kg  | WBRT     | 57/67  | **5.0**   | 0.715      | **0.   |
| if Male or  |          |        |           |            | 0841** |
| \> 70 kg if |          |        | (3.1,     | (0.488,    |        |
| Female**    |          |        | 8.3)      | 1.049)     |        |
+-------------+----------+--------+-----------+------------+--------+
|             | RSR13 +  | 50/67  | **6.8**   |            |        |
|             | WBRT     |        |           |            |        |
|             |          |        | (5.0,     |            |        |
|             |          |        | 10.5)     |            |        |
+-------------+----------+--------+-----------+------------+--------+

^1^: Kaplan-Meier Estimates; ^2^: Hazard Ratio of RSR13 + WBRT/ WBRT;

^3^: unadjusted log-rank test and not adjusted for multiple analyses.

*[Reviewer's Comments]{.underline}*:

There was no significant treatment effect in high or low weight group of
patients. However, higher weight group appears to have longer survival
than lower weight group of patients.

# Summary and Conclusions

This NDA submission is to support administration of RSR13 as an adjunct
to whole brain radiation therapy (WBRT) for patients with brain
metastases from primary breast cancer. In this NDA submission, study
RT009 is the only randomized pivotal study conducted for the efficacy
and safety of RSR13. This open-label study was designed to evaluate the
efficacy and safety of combined therapy with RSR13 + WBRT versus WBRT
alone in patients with brain metastases. This study enrolled a total of
538 patients with 267 patients who received WBRT alone and 271 patients
who received RSR13 + WBRT. The primary efficacy endpoint of this study
was survival. There was no statistically significant difference between
the two treatment arms in the ITT population (log-rank test,
P-value=0.1688). There was apparent difference in survival between the
two treatment arms in the non-randomized subgroup of patients with
primary breast cancer (log-rank test, P-value=0.006).

## Statistical Issues and Collective Evidence

1.  Only one randomized open-label study conducted in patients with
    brain metastases, which failed to demonstrate efficacy as per the
    design of the study, in the intent-to-treat population (log-rank
    test, P-value = 0.1688). The final analysis was conducted after
    observing the planned number of total deaths.

2.  The study also failed to demonstrate efficacy in the subgroup of
    patients with NSCLC/Breast primary (log-rank test, P-value=0.1217),
    which was added as a co-primary analysis subgroup during the course
    of study.

3.  When the overall result fails to show efficacy, usually subgroup
    findings are not acceptable and subgroup analyses at best can be
    exploratory or hypothesis generating analyses (ICH E-3 guidelines,
    section 11.4.2.8: *These analyses are not intended to \"salvage\" an
    otherwise non-supportive study but may suggest hypotheses worth
    examining in other studies or be helpful in refining labelling
    information, patient selection, dose selection etc.*). When one
    starts to do multiple subgroup testing, one can easily make a false
    positive claim based on such subgroup analysis. We do not know how
    to interpret the P-values based on such post-hoc analysis.
    Furthermore, without replication of the results in a second
    well-controlled study, the subgroup analysis can not be ruled out
    for a false positive result.

4.  The sponsor wishes to claim approval based on a subgroup of
    non-randomized patients with primary breast cancer. This subgroup
    hypothesis corresponding to breast cancer primary was not stated as
    a hypothesis of interest to be tested in the original protocol. Any
    subgroup hypothesis needs to be stated in the protocol and
    accordingly proper allocation of has to be specified. Otherwise,
    such post-hoc subgroup claim will inflate Type I error and it is
    difficult to interpret such P-values.

5.  There appears to be imbalances between the treatment arms favoring
    the RSR13 arm in the subgroup of patients with primary breast
    cancer. Specifically imbalances were observed in the number of brain
    lesions, tumor burden, amount of oxygen received and subsequent
    therapy (please refer to clinical review). The imbalances may
    potentially be driving the difference in survival in the subgroup.

6.  Sponsor\'s analyses adjusted for covariates are questionable.
    Results of such adjusted analyses are sensitive to inclusion or
    exclusion of a covariate. Furthermore, when appropriately adjusted
    for multiplicity, treatment differences are unlikely to be
    significant. P-values can not be taken at face value and
    non-prespecified subgroup analyses are not interpretable.

7.  The claims of improved efficacy in the primary breast cancer
    subgroup could be a false positive result and requires future
    studies to evaluate this hypothesis. In fact, the sponsor is
    currently conducting a study of WBRT versus RSR13 + WBRT in patients
    with brain metastases from breast cancer.

## Conclusions and Recommendations

In this reviewer\'s opinion the study failed to demonstrate benefits of
RSR13 + WBRT over WBRT alone for patients with brain metastases.
According to the usual requirement of the Agency for approval for
marketing a new drug, the sponsor needs to demonstrate the efficacy of
the new drug in at least two independent well-controlled clinical
trials. In case that there is only one pivotal efficacy study, like this
NDA submission, the evidence of the drug efficacy needs to be much
stronger to be convincing. Furthermore, it is not evident that the
observed apparent survival advantage in a single small subgroup of
patients with primary breast cancer based on post-hoc analysis is
attributable solely to the treatment effect and not due to imbalances in
known and unknown prognostic factors. Therefore, the evidence submitted
in this application is not convincing and does not support the sponsor's
claim of efficacy.

# APPENDICES {#appendices .unnumbered}

## Appendix 1: List of Ineligible Patients {#appendix-1-list-of-ineligible-patients .unnumbered}

  ----------------------- ----------------------- -----------------------
  **Patient ID**          **Treatment Arm**       **Primary Cancer**

  RT-009-008-1025         WBRT                    Breast

  RT-009-013-3065         WBRT                    Breast

  RT-009-013-3092         WBRT                    Breast

  RT-009-036-3068         WBRT                    Breast

  RT-009-042-1020         WBRT                    Breast

  RT-009-042-3015         WBRT                    Breast

  RT-009-018-2069         WBRT                    NSCLC

  RT-009-036-2163         WBRT                    NSCLC

  RT-009-042-2048         WBRT                    NSCLC

  RT-009-133-2227         WBRT                    NSCLC

  RT-009-142-2190         WBRT                    NSCLC

  RT-009-144-1043         WBRT                    NSCLC

  RT-009-010-4055         WBRT                    Other

  RT-009-018-4012         WBRT                    Other

  RT-009-077-4040         WBRT                    Other

  RT-009-127-4088         WBRT                    Other

  RT-009-136-4108         WBRT                    Other

  RT-009-023-3016         RSR13 + WBRT            Breast

  RT-009-136-3072         RSR13 + WBRT            Breast

  RT-009-009-2025         RSR13 + WBRT            NSCLC

  RT-009-077-2263         RSR13 + WBRT            NSCLC

  RT-009-130-2101         RSR13 + WBRT            NSCLC

  RT-009-138-4103         RSR13 + WBRT            Other
  ----------------------- ----------------------- -----------------------

## Appendix 2: List of Patients Who Were Misclassified at Randomization {#appendix-2-list-of-patients-who-were-misclassified-at-randomization .unnumbered}

+------------+----------+--------+------------+------------+---------+
| **Patient  | **T      | **RPA  | **         | **         | **      |
| ID**       | reatment | C      | Stratum^1^ | Stratum^1^ | Primary |
|            | Arm**    | lass** | as         | as         | Cancer  |
|            |          |        | E          | O          | per     |
|            |          |        | nrolled/** | bserved/** | CRF**   |
|            |          |        |            |            |         |
|            |          |        | **Ra       | **         |         |
|            |          |        | ndomized** | Intended** |         |
+------------+----------+--------+------------+------------+---------+
| RT-00      | WBRT     | 1      | 3          | 1          | Breast  |
| 9-003-3020 |          |        |            |            |         |
+------------+----------+--------+------------+------------+---------+
| RT-00      | WBRT     | 2      | 1          | 3          | Breast  |
| 9-003-3020 |          |        |            |            |         |
+------------+----------+--------+------------+------------+---------+
| RT-00      | WBRT     | 2      | **3**      | **2**      | NSCLC   |
| 9-003-3020 |          |        |            |            |         |
+------------+----------+--------+------------+------------+---------+
| RT-00      | WBRT     | 2      | **4**      | **2**      | NSCLC   |
| 9-003-3020 |          |        |            |            |         |
+------------+----------+--------+------------+------------+---------+
| RT-00      | WBRT     | 2      | **4**      | **2**      | NSCLC   |
| 9-003-3020 |          |        |            |            |         |
+------------+----------+--------+------------+------------+---------+
| RT-00      | WBRT     | 2      | 1          | 2          | NSCLC   |
| 9-003-3020 |          |        |            |            |         |
+------------+----------+--------+------------+------------+---------+
| RT-00      | WBRT     | 2      | 1          | 4          | Other   |
| 9-003-3020 |          |        |            |            |         |
+------------+----------+--------+------------+------------+---------+
| RT-00      | WBRT     | 2      | 1          | 4          | Other   |
| 9-003-3020 |          |        |            |            |         |
+------------+----------+--------+------------+------------+---------+
| RT-00      | WBRT     | 2      | 1          | 3          | Breast  |
| 9-003-3020 |          |        |            |            |         |
+------------+----------+--------+------------+------------+---------+
| RT-00      | WBRT     | 2      | **3**      | **2**      | NSCLC   |
| 9-003-3020 |          |        |            |            |         |
+------------+----------+--------+------------+------------+---------+
| RT-00      | WBRT     | 1      | 2          | 1          | NSCLC   |
| 9-003-3020 |          |        |            |            |         |
+------------+----------+--------+------------+------------+---------+
| RT-00      | WBRT     | 2      | 1          | 2          | NSCLC   |
| 9-003-3020 |          |        |            |            |         |
+------------+----------+--------+------------+------------+---------+
| RT-00      | WBRT     | 2      | **2**      | **4**      | Other   |
| 9-003-3020 |          |        |            |            |         |
+------------+----------+--------+------------+------------+---------+
| RT-00      | RSR13 +  | 2      | 1          | 4          | Other   |
| 9-003-3020 | WBRT     |        |            |            |         |
+------------+----------+--------+------------+------------+---------+
| RT-00      | RSR13 +  | 2      | 1          | 3          | Breast  |
| 9-003-3020 | WBRT     |        |            |            |         |
+------------+----------+--------+------------+------------+---------+
| RT-00      | RSR13 +  | 2      | 1          | 3          | Breast  |
| 9-003-3020 | WBRT     |        |            |            |         |
+------------+----------+--------+------------+------------+---------+
| RT-00      | RSR13 +  | 1      | 2          | 1          | NSCLC   |
| 9-003-3020 | WBRT     |        |            |            |         |
+------------+----------+--------+------------+------------+---------+
| RT-00      | RSR13 +  | 1      | 2          | 1          | NSCLC   |
| 9-003-3020 | WBRT     |        |            |            |         |
+------------+----------+--------+------------+------------+---------+
| RT-00      | RSR13 +  | 2      | 1          | 4          | Other   |
| 9-003-3020 | WBRT     |        |            |            |         |
+------------+----------+--------+------------+------------+---------+
| RT-00      | RSR13 +  | 2      | 1          | 4          | Other   |
| 9-003-3020 | WBRT     |        |            |            |         |
+------------+----------+--------+------------+------------+---------+
| RT-00      | RSR13 +  | 2      | 1          | 3          | Breast  |
| 9-003-3020 | WBRT     |        |            |            |         |
+------------+----------+--------+------------+------------+---------+
| RT-00      | RSR13 +  | 2      | 1          | 2          | NSCLC   |
| 9-003-3020 | WBRT     |        |            |            |         |
+------------+----------+--------+------------+------------+---------+
| RT-00      | RSR13 +  | 2      | **4**      | **2**      | NSCLC   |
| 9-003-3020 | WBRT     |        |            |            |         |
+------------+----------+--------+------------+------------+---------+
| RT-00      | RSR13 +  | 2      | 1          | 3          | Breast  |
| 9-003-3020 | WBRT     |        |            |            |         |
+------------+----------+--------+------------+------------+---------+
| RT-00      | RSR13 +  | 2      | 1          | 2          | NSCLC   |
| 9-003-3020 | WBRT     |        |            |            |         |
+------------+----------+--------+------------+------------+---------+

^1^: Stratum Classification: 1 = RPA Class I; 2 = RPA Class II, NSCLC
primary; 3 = RPA Class II, Breast primary; 4 = RPA Class II, Other
primary.

## Appendix 3: List of Patients Who Were In-evaluable (Withdrew from Study Prior to Treatment) {#appendix-3-list-of-patients-who-were-in-evaluable-withdrew-from-study-prior-to-treatment .unnumbered}

  ----------------------- ----------------------- -----------------------
  **Patient ID**          **Treatment Arm**       **Primary Cancer
                                                  (CRF)**

  RT-009-008-1025         WBRT                    Breast

  RT-009-023-2127         WBRT                    NSCLC

  RT-009-004-4015         WBRT                    Other

  RT-009-018-4012         WBRT                    Other

  RT-009-019-2105         RSR13 + WBRT            NSCLC

  RT-009-035-2131         RSR13 + WBRT            NSCLC

  RT-009-036-2232         RSR13 + WBRT            NSCLC

  RT-009-041-2249         RSR13 + WBRT            NSCLC

  RT-009-007-4069         RSR13 + WBRT            Other
  ----------------------- ----------------------- -----------------------

## Appendix 4: Survival Analysis Before Addition of Co-primary Hypothesis {#appendix-4-survival-analysis-before-addition-of-co-primary-hypothesis .unnumbered}

**Survival Analysis in Patients Enrolled Before Addition of Co-primary**

+----------------+----------+------------------+-------------+--------+
| **Treatment**  | **Number | **Median         | **Hazard    | **     |
|                | of       | Survival in      | Ratio^2^**  | P-valu |
|                | Deaths** | Months^1^**      |             | e^3^** |
|                |          |                  | **(95%      |        |
|                |          | **(95% C.I.)**   | C.I.)**     |        |
+----------------+----------+------------------+-------------+--------+
| WBRT           | 43/86    | **4.3** (2.8,    | 0.903       | **0.   |
|                |          | 7.2)             |             | 6408** |
|                |          |                  | (0.587,     |        |
|                |          |                  | 1.389)      |        |
+----------------+----------+------------------+-------------+--------+
| RSR13 + WBRT   | 40/87    | **4.1** (2.9,    |             |        |
|                |          | 8.1)             |             |        |
+----------------+----------+------------------+-------------+--------+

^1^: Kaplan-Meier Estimates; ^2^: Hazard Ratio of RSR13 + WBRT/ WBRT;

^3^: unadjusted log-rank test.

**Survival Analysis in the Subgroup of Patients with NSCLC/Breast
Primary Enrolled Before Addition of Co-primary**

+----------------+----------+------------------+-------------+--------+
| **Treatment**  | **Number | **Median         | **Hazard    | **     |
|                | of       | Survival in      | Ratio^2^**  | P-valu |
|                | Deaths** | Months^1^**      |             | e^3^** |
|                |          |                  | **(95%      |        |
|                |          | **(95% C.I.)**   | C.I.)**     |        |
+----------------+----------+------------------+-------------+--------+
| WBRT           | 31/67    | **4.9** (3.0,    | 0.675       | **0.   |
|                |          | 9.4)             |             | 1460** |
|                |          |                  | (0.396,     |        |
|                |          |                  | 1.152)      |        |
+----------------+----------+------------------+-------------+--------+
| RSR13 + WBRT   | 24/67    | **7.6** (4.0,    |             |        |
|                |          | \-\-- )          |             |        |
+----------------+----------+------------------+-------------+--------+

^1^: Kaplan-Meier Estimates; ^2^: Hazard Ratio of RSR13 + WBRT/ WBRT;

^3^: unadjusted log-rank test.

## Appendix 5: Interim Analysis Results {#appendix-5-interim-analysis-results .unnumbered}

**Interim Survival Analysis in All Patients using Cut-off Date of
3/22/2002 (FDA Analysis)**

+----------------+----------+------------------+-------------+--------+
| **Treatment**  | **Number | **Median         | **Hazard    | **     |
|                | of       | Survival in      | Ratio^2^**  | P-valu |
|                | Deaths** | Months^1^**      |             | e^3^** |
|                |          |                  | **(95%      |        |
|                |          | **(95% C.I.)**   | C.I.)**     |        |
+----------------+----------+------------------+-------------+--------+
| WBRT           | 122/204  | **4.4** (3.6,    | 0.750       | **0.   |
|                |          | 5.5)             |             | 0314** |
|                |          |                  | (0.576,     |        |
|                |          |                  | 0.976)      |        |
+----------------+----------+------------------+-------------+--------+
| RSR13 + WBRT   | 102/206  | **5.7** (4.0,    |             |        |
|                |          | 7.1)             |             |        |
+----------------+----------+------------------+-------------+--------+

^1^: Kaplan-Meier Estimates; ^2^: Hazard Ratio of RSR13 + WBRT/ WBRT;

^3^: unadjusted log-rank test.

**Interim Survival Analysis in the Subgroup of Patients with
NSCLC/Breast Primary using Cut-off Date of 3/22/2002 (FDA Analysis)**

+----------------+----------+------------------+-------------+--------+
| **Treatment**  | **Number | **Median         | **Hazard    | **     |
|                | of       | Survival in      | Ratio^2^**  | P-valu |
|                | Deaths** | Months^1^**      |             | e^3^** |
|                |          |                  | **(95%      |        |
|                |          | **(95% C.I.)**   | C.I.)**     |        |
+----------------+----------+------------------+-------------+--------+
| WBRT           | 93/157   | **4.5** (3.6,    | 0.694       | **0.   |
|                |          | 5.6)             |             | 0157** |
|                |          |                  | (0.511,     |        |
|                |          |                  | 0.942)      |        |
+----------------+----------+------------------+-------------+--------+
| RSR13 + WBRT   | 75/161   | **5.9** (4.3,    |             |        |
|                |          | 8.1)             |             |        |
+----------------+----------+------------------+-------------+--------+

^1^: Kaplan-Meier Estimates; ^2^: Hazard Ratio of RSR13 + WBRT/ WBRT;

^3^: unadjusted log-rank test.

## Appendix 6: Exploratory Covariate Adjusted Survival Analyses in NSCLC/Breast Primary {#appendix-6-exploratory-covariate-adjusted-survival-analyses-in-nsclcbreast-primary .unnumbered}

Cox's Proportional Hazard Model Adjusting for Covariates: Protocol
Planned Model (N = 414)

  ------------------------------------ ------------ ------------- ----------------
  **Covariates**                       **Hazard     **95% C.I.**  **P-value^1^**
                                       Ratio**                    

  Treatment (RSR13 + WBRT/WBRT)        0.780        0.627, 0.970  0.0253

  RPA Class (1 vs. 2)                  0.596        0.353, 1.005  0.0522

  Primary Tumor Control (Yes vs. No)   1.591        1.138, 2.224  0.0066

  Age                                  1.021        1.011, 1.032  \< 0.0001

  Presence of Extracranial Metastases  1.403        0.934, 2.107  0.1033
  (No vs. Yes)                                                    

  Baseline KPS                         0.970        0.959, 0.982  \< 0.0001

  Number of Metastatic Lesions^2^      1.087        0.916, 1.289  0.3390
  ------------------------------------ ------------ ------------- ----------------

1: P-values not adjusted for multiplicity; 2: Since all patients were
supposed to have brain metastases, for the purpose of this analysis
'number of extracranial metastases' was used as the covariate in place
of 'number of metastatic lesions'.

Table 11: Cox's Proportional Hazard Model Adjusting for Covariates in
the Eligible Patient Population: SAP Planned Model\*

+-----------------------------------+------------+------------+-------+
| **Covariates**                    | **Hazard   | **95%      | **P-  |
|                                   | Ratio**    | C.I.**     | value |
|                                   |            |            | ^1^** |
+-----------------------------------+------------+------------+-------+
| Treatment (RSR13 + WBRT/WBRT)     | 0.781      | 0.626,     | 0     |
|                                   |            | 0.974      | .0280 |
+-----------------------------------+------------+------------+-------+
| RPA Class (1 vs. 2)               | 0.601      | 0.347,     | 0     |
|                                   |            | 1.042      | .0698 |
+-----------------------------------+------------+------------+-------+
| Primary Tumor Control (Yes vs.    | 1.431      | 0.989,     | 0     |
| No)                               |            | 2.076      | .0573 |
+-----------------------------------+------------+------------+-------+
| Age Group (\< 65 vs. ≥ 65)        | 1.748      | 1.342,     | \<    |
|                                   |            | 2.277      | 0     |
|                                   |            |            | .0001 |
+-----------------------------------+------------+------------+-------+
| Baseline KPS Group (≥ 90 vs. \<   | 1.543      | 1.226,     | 0     |
| 90)                               |            | 1.941      | .0002 |
+-----------------------------------+------------+------------+-------+
| Number of Cranial Metastases      | 1.130      | 0.965,     | 0     |
|                                   |            | 1.323      | .1298 |
+-----------------------------------+------------+------------+-------+
| Number of Extracranial Metastases | 1.171      | 1.030,     | 0     |
|                                   |            | 1.331      | .0156 |
+-----------------------------------+------------+------------+-------+
| Baseline Cranial Tumor Total Area | 1.031      | 0.883,     | 0     |
| (\<250, 250-1000, \>1000)         |            | 1.204      | .8019 |
+-----------------------------------+------------+------------+-------+
| Baseline Weight Group (Low vs.    | 0.966      | 0.738,     | 0     |
| High)                             |            | 1.264      | .7890 |
+-----------------------------------+------------+------------+-------+
| Gender (Female vs. Male)          | 1.504      | 1.153,     | 0     |
|                                   |            | 1.961      | .0026 |
+-----------------------------------+------------+------------+-------+
| Presence of Liver Metastases (No  | 1.237      | 0.877,     | 0     |
| vs. Yes)                          |            | 1.745      | .2257 |
+-----------------------------------+------------+------------+-------+
| Usage of Subsequent Treatment (No | 0.977      | 0.714,     | 0     |
| vs. Yes)                          |            | 1.336      | .8831 |
+-----------------------------------+------------+------------+-------+
| Diagnosis Timing (Metachronous    | 1.169      | 0.878,     | 0     |
| vs. Synchronous)                  |            | 1.555      | .2851 |
+-----------------------------------+------------+------------+-------+
| Prior Treatment to Cranial        | 0.462      | 0.275,     | 0     |
| Metastases (No vs. Yes)           |            | 0.776      | .0035 |
+-----------------------------------+------------+------------+-------+
| Worldwide Location: USA (No vs.   | 0.910      | 0.623,     | 0     |
| Yes)                              |            | 1.329      | .6265 |
|                                   | 0.995      |            |       |
| Canada (No vs. Yes)               |            | 0.653,     | 0     |
|                                   |            | 1.516      | .9816 |
+-----------------------------------+------------+------------+-------+
| Altitude (Low vs. High)           | 1.084      | 0.743,     | 0     |
|                                   |            | 1.583      | .6745 |
+-----------------------------------+------------+------------+-------+
| Baseline Hemoglobin Group (≥ 12   | 1.296      | 0.951,     | 0     |
| vs. \< 12 g/dL)                   |            | 1.765      | .1004 |
+-----------------------------------+------------+------------+-------+
| Size of Center (Not a big site    | 1.074      | 0.813,     | 0     |
| vs. Big site)                     |            | 1.419      | .6141 |
+-----------------------------------+------------+------------+-------+

\*: Results based on a total of 408 patients; ^1^: P-values not adjusted
for multiplicity;

## Appendix 7: Exploratory Covariate Adjusted Survival Analysis in Breast Primary {#appendix-7-exploratory-covariate-adjusted-survival-analysis-in-breast-primary .unnumbered}

Cox's Proportional Hazard Model Adjusting for Covariates: Protocol
Planned Model (N = 115)

  ------------------------------------ ------------ ------------- ----------------
  **Covariates**                       **Hazard     **95% C.I.**  **P-value^1^**
                                       Ratio**                    

  Treatment (RSR13 + WBRT/WBRT)        0.510        0.329, 0.791  0.0027

  RPA Class (1 vs. 2)                  0.864        0.203, 3.675  0.8433

  Primary Tumor Control (Yes vs. No)   1.415        0.802, 2.494  0.2304

  Age                                  1.022        1.001, 1.044  0.0382

  Presence of Extracranial Metastases  1.446        0.411, 5.090  0.5660
  (No vs. Yes)                                                    

  Baseline KPS                         0.966        0.941, 0.992  0.0115

  Number of Metastatic Lesions^2^      1.031        0.755, 1.408  0.8461
  ------------------------------------ ------------ ------------- ----------------

1: P-values not adjusted for multiplicity; 2: Since all patients were
supposed to have brain metastases, for the purpose of this analysis
'number of extracranial metastases' was used as the covariate in place
of 'number of metastatic lesions'.

Table 11: Cox's Proportional Hazard Model Adjusting for Covariates in
the Eligible Patient Population: SAP Planned Model\*

+-----------------------------------+------------+------------+-------+
| **Covariates**                    | **Hazard   | **95%      | **P-  |
|                                   | Ratio**    | C.I.**     | value |
|                                   |            |            | ^1^** |
+-----------------------------------+------------+------------+-------+
| Treatment (RSR13 + WBRT/WBRT)     | 0.481      | 0.289,     | 0     |
|                                   |            | 0.801      | .0049 |
+-----------------------------------+------------+------------+-------+
| RPA Class (1 vs. 2)               | 0.718      | 0.209,     | 0     |
|                                   |            | 2.461      | .5978 |
+-----------------------------------+------------+------------+-------+
| Primary Tumor Control (Yes vs.    | 1.381      | 0.687,     | 0     |
| No)                               |            | 2.778      | .3651 |
+-----------------------------------+------------+------------+-------+
| Age Group (\< 65 vs. ≥ 65 yrs)    | 2.970      | 1.592,     | 0     |
|                                   |            | 5.542      | .0006 |
+-----------------------------------+------------+------------+-------+
| Baseline KPS Group (≥ 90 vs. \<   | 1.965      | 1.177,     | 0     |
| 90)                               |            | 3.281      | .0098 |
+-----------------------------------+------------+------------+-------+
| Number of Cranial Metastases      | 0.971      | 0.681,     | 0     |
|                                   |            | 1.385      | .8706 |
+-----------------------------------+------------+------------+-------+
| Number of Extracranial Metastases | 1.010      | 0.753,     | 0     |
|                                   |            | 1.353      | .9481 |
+-----------------------------------+------------+------------+-------+
| Baseline Cranial Tumor Total Area | 0.939      | 1.000,     | 0     |
| (\<250, 250-1000, \>1000)         |            | 1.000      | .7385 |
+-----------------------------------+------------+------------+-------+
| Baseline Weight Group (Low vs.    | 0.852      | 0.651,     | 0     |
| High)                             |            | 1.356      | .5263 |
+-----------------------------------+------------+------------+-------+
| Gender (Female vs. Male)          | 0.210      | 0.021,     | 0     |
|                                   |            | 2.137      | .1874 |
+-----------------------------------+------------+------------+-------+
| Presence of Liver Metastases (No  | 1.582      | 0.928,     | 0     |
| vs. Yes)                          |            | 2.698      | .0919 |
+-----------------------------------+------------+------------+-------+
| Usage of Subsequent Treatment (No | 0.669      | 0.340,     | 0     |
| vs. Yes)                          |            | 1.316      | .2443 |
+-----------------------------------+------------+------------+-------+
| Diagnosis Timing (metachronous    | 0.933      | 0.264,     | 0     |
| vs. synchronous)                  |            | 3.293      | .9142 |
+-----------------------------------+------------+------------+-------+
| Prior Treatment to Cranial        | 2.570      | 0.785,     | 0     |
| Metastases (No vs. Yes)           |            | 8.414      | .1189 |
+-----------------------------------+------------+------------+-------+
| Worldwide Location: USA (No vs.   | 0.597      | 0.280,     | 0     |
| Yes)                              |            | 1.275      | .1827 |
|                                   | 1.075      |            |       |
| Canada (No vs. Yes)               |            | 0.404,     | 0     |
|                                   |            | 2.860      | .8841 |
+-----------------------------------+------------+------------+-------+
| Altitude (Low vs. High)           | 1.063      | 0.369,     | 0     |
|                                   |            | 3.066      | .9095 |
+-----------------------------------+------------+------------+-------+
| Baseline Hemoglobin Group (≥ 12   | 1.367      | 0.748,     | 0     |
| vs. \< 12 g/dL)                   |            | 2.499      | .3100 |
+-----------------------------------+------------+------------+-------+
| Size of Center (Not a big site    | 1.346      | 0.711,     | 0     |
| vs. Big site)                     |            | 2.546      | .3612 |
+-----------------------------------+------------+------------+-------+

\*: Results based on a total of 113 patients; ^1^: P-values not adjusted
for multiplicity;

SIGNATURES/DISTRIBUTION LIST

Primary Statistical Reviewer: Rajeshwari Sridhara, Ph.D.

Date:

Concurring Reviewer: Kooros Mahjoob, Ph.D.,

> Acting Director, Division of Biometrics

Date:

cc:

HFD-150/C. Cottrell

HFD-150/K. Ridenhour

HFD-150/R. Dagher

HFD-710/R. Sridhara

HFD-710/K. Mahjoob

HFD-700/S. Dubey

HFD-700/C. Anello

c:\\NDA\\allos\\21611_statrev_RS.doc