**BRIEFING DOCUMENT FOR NDA# 21-661**

Synopsis of Clinical Component

The efficacy database consists of two clinical studies, RT-008 and
RT-009. RT-009 was a phase 3, randomized, open-label, comparative study
in 538 patients receiving a standard 2-week course of whole brain
radiation therapy for brain metastases, 30 Gy fractions per day, with
supplemental oxygen, with or without RSR13. There was no statistically
significant difference in the primary endpoint of overall survival when
analyzed using the log-rank test, median survival time 4.47 months in
the control arm vs. 5.26 months in the RSR13 arm, p-0.169. There was
also no statistically significant differences in the secondary endpoints
of time to radiographic tumor progression in the brain, time to clinical
tumor progression in the brain, response rate in the brain, cause of
death and quality of life. The sponsor is requesting approval based on
the finding of a survival advantage with RSR13 + whole brain radiation
therapy/supplemental oxygen vs. WBRT/O~2~ alone in a non-prespecified
subgroup of breast cancer patients with brain metastases. By subset
analysis, the observed median survival time for breast cancer patients
in the control arm was 4.57 months compared to 8.67 months for the RSR13
arm (p-0.0061, log-rank). The sponsor also described a response rate in
the brain in this non-prespecified breast cancer subgroup, 49.1% in the
control arm vs. 71.7% in the RSR13 arm.

RT-008 was a single-arm, multicenter phase 2 study in patients receiving
a conventional 2-week course of cranial radiation therapy with RSR13 for
brain metastases. Sixty-nine patients participated in this study. The
stated objectives included response rate in the brain, median survival,
and time to progression. In the setting of a single arm study, it is
difficult to interpret time to event endpoints such as survival and time
to progression.

The Medical Reviewer has the following concerns regarding the pivotal
Phase 3 study:

1\. There was no statistically significant difference in survival
between the two study arms of RT-009 in the intent to treat population.

2\. The sponsor's finding of a survival difference between the two study
arms of RT-009 in the breast cancer subgroup represents a
non-prespecified subgroup analysis which should be considered
exploratory.

3\. The marginal findings regarding response rate in the brain in RT-009
cannot be considered reasonably likely to predict clinical benefit since
tumor shrinkage could be attributed to radiation therapy given in both
treatment arms. Another factor in the uncertainty of this finding is
that most deaths were attributed to non-neurological or
indistinguishable causes. Other concerns regarding the assessment of
response in RT-009 include the following:

-   Confirmatory scans were not required.

-   The designation of CR/PR was given whether or not a new brain
    parenchymal lesion was documented on a particular evaluation. See
    briefing document for other concerns.

See Section IV of this briefing document for the safety analyses, which
will be presented in more detail at the Advisory Committee meeting.

# TABLE OF CONTENTS FOR BRIEFING DOCUMENT

I. Introduction and Background p. 3

II\. Description of Clinical Data and Sources p. 8

III\. Efficacy p. 10

Protocol Review (RT-009)

Trial Results

Efficacy Results -- Sponsor's Analysis

Efficacy Results- FDA Analysis

Protocol Review (RT-008)

Trial Results

Efficacy Results -- Sponsor's Analysis

Efficacy Results- FDA Analysis

IV\. Review of Safety p. 61

A. Introduction

B. Exposure

C. Adverse Events

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# Clinical Review 

## I. Introduction and Background

### A. Drug Established and Proposed Trade Name, Drug Class, Sponsor's Proposed Indication(s), Dose, Regimens, Age Groups

Generic Name: Efaproxiral Sodium

Proposed Trade Name: Excelar

Established Trade Name: RSR-13

Chemical Name: 2 -- \[ 4-\[2-(3,5-dimethylphenyl) amino\]-2-
oxoethyl\]phenoxy\]-2-methyl-propanoic acid monosodium salt

Pharmacologic Category: Radiation-sensitizing agent

Drug Class: Synthetic allosteric modifier of hemoglobin

Route of Administration: Intravenous

Dose and Regimen: 75 or 100 mg/kg daily over 30 minutes through a
central venous catheter, Monday through Friday, for 2 weeks. Concurrent
supplemental oxygen is also administered at a rate of 4 L/min via nasal
cannula or facemask beginning 5 minutes prior to initiation of infusion,
during infusion and whole brain radiation therapy (WBRT), and for at
least 15 minutes after completion of daily WBRT. WBRT must be
administered within 30 minutes of the end of the Excelar infusion.

Population Studied: Patients with brain metastases originating from
histologically confirmed solid primary malignancies, excluding small
cell carcinoma, lymphoma, and germ cell tumors.

Proposed Indication: Adjunctive therapy to whole brain radiation therapy
for the treatment of brain metastases originating from breast cancer.

### B. State of Armamentarium for Indication 

Approximately one-third to one half of all adult brain tumors result
from hematogenous dissemination of malignant cells from an extracranial
source to the central nervous system. The most common sites of origin
are the lung, breast, or melanoma skin cancers. The median survival
following treatment is only 3 -- 6 months when multiple metastatic
lesions are present and about 12 months for those with a solitary
metastatic deposit.(1) The contrast-enhanced MRI is considered the best
imaging study to diagnose brain metastases and will guide the choice of
management. There are no FDA approved drugs for the treatment of
metastatic tumors to the brain. Accepted treatment standards consist of
surgical resection followed by post-operative radiation therapy, whole
brain radiation therapy (WBRT) alone, stereotactic radiosurgery,
interstitial brachytherapy, and anecdotal reports with hormonal therapy
in cases of breast cancers responsive to hormones. The use of
chemotherapy has been disappointing. Corticosteroids aid in alleviating
peritumoral edema. The presence of seizure activity in patients with
brain metastases leads to treatment with anticonvulsant therapy. Venous
thromboembolic disease also occurs at a higher frequency in patients
with brain metastases, often requiring inferior vena caval filters or
standard anticoagulation.(2)

Corticosteroids were first used in 1957 in patients with brain
metastases originating from the breast, followed by dexamethasone in
1961. Dexamethasone has less mineralocorticoid activity and has been
included in the standard treatment ever since. Its main mechanism of
action is to reduce the permeability of tumor capillaries.(2)

Primary radiation therapy has been the mainstay of treating metastatic
tumor deposits in the brain for 40 years. The median survival of
patients with brain metastasis treated with steroids alone or no form of
treatment is 1 to 2 months. Conventional whole brain radiation therapy
(WBRT) increases the median survival to 3 -6 months. There is no
consensus on the optimal irradiation schedule for patients with brain
metastasis. Typical irradiation treatment schedules consist of total
doses of 30 - 50 Gy in 1.5 -- 4 Gy/daily fraction, usually 30 Gy in 10
fractions over 2 weeks. Occasionally, reirradiation is employed at the
time of brain recurrence in patients with previously controlled systemic
symptoms.(2)

Three randomized prospective studies have evaluated the role of surgery
as an adjunct to WBRT for patients with a single brain metastasis.
Patchell et al. randomized 48 patients to receive biopsy followed by
WBRT (36 Gy in 12 fractions) or surgical resection followed by WBRT.(3)
Patients treated with surgery followed by WBRT had fewer local
recurrences (20% vs. 52%,

p\< 0.02), improved survival (40 weeks vs. 15 weeks), and had a better
quality of life as measured by the Karnofsky Performance Scale. Vecht et
al. also randomized patients to WBRT alone or surgical resection
followed by WBRT and showed a benefit in the treatment arm consisting of
surgery followed by WBRT.(4) However, no biopsy was performed to confirm
the presence of metastatic disease to the brain and the radiation used
was an unconventional scheme using 40 Gy over 2 weeks. Conversely, Mintz
et al. observed no difference in survival or quality of life between
patients who underwent surgery plus radiotherapy and those having
radiotherapy alone.(5) The results from the 43 patients randomized in
that study may not be truly representative given their lower baseline
median Karnofsky Performance Status (KPS) and higher proportion of
extracranial disease.

Stereotactic radiosurgery is usually reserved for small ( \< 3cm)
lesions. It is performed using high energy roentgenograms produced by
the linear accelerator, gamma rays from a gamma knife, or with charged
particles produced by a cyclotron. The use of this modality results in a
higher concentrated delivery of radiation to the targeted volume and
less radiation exposure to normal non-target tissue.(2)

Interstitial brachytherapy is usually performed at the time of surgical
resection with implantation of radioactive nuclides into the wall of the
surgical cavity to deliver an additional dose of radiation therapy to
the tumor while limiting the irradiation to the surrounding brain.
Although interstitial brachytherapy is rarely performed for small
lesions suitable for radiosurgery, it may have a limited role for
metastases too large for radiosurgery.(2)

There is now evidence that the blood-brain barrier is partially
disrupted within a brain tumor. As such, the concept of the inability of
chemotherapy to enter the central nervous system has been challenged.
Other factors may be contributing to the disappointing results of
chemotherapy such as intrinsic resistance to chemotherapy of many tumors
that metastasize to the brain.(2)

In patients with hormone-responsive tumors, such as breast cancer, there
are anecdotal reports of brain metastases responding to hormonal agents,
such as tamoxifen and megestrol acetate.(2)

RSR13 is a synthetic allosteric modifier of hemoglobin (SAM), promoting
the release of oxygen to tissue, often referred to as a "right shift" of
the hemoglobin-oxygen dissociation curve. The goal of adjunctive RSR13
therapy in cancer patients with brain metastases is to increase tumor
oxygen concentrations in an effort to maximize the cytotoxicity of
radiation therapy. A Phase 2 study (N = 69) was performed to evaluate
median survival time, response rate, and time to tumor progression in
patients with brain metastases receiving RSR13. A larger Phase 3 study
(N = 538) tested the hypothesis that RSR13 will improve survival. These
two efficacy studies are the focus of this review. The sponsor is also
conducting randomized phase III studies using RSR13 + WBRT/O~2~ vs.
WBRT/O~2~ in patients with brain metastases originating from breast
cancer and NSCLC.

### 

### C. Important Milestones in Product Development

Clinical development of RSR13 commenced in July 1995. RSR13 has been
studied in 18 different Phase 1 through Phase 3 clinical trials under
three different INDs. Twelve clinical trials of RSR13 have been
conducted under IND 48,171. During the development of RSR13, studies
have been conducted under 2 additional INDs: IND 52,999 (Division of
Cardio-Renal Drug Products) for the prevention or treatment of
myocardial hypoxia and IND 53,874 (Division of Anesthetic, Critical
Care, and Addiction Drug Products) for the prevention of hypoxia
associated with surgery.

**Regulatory History**

**June 13, 1995**: IND 48,171 was submitted to the FDA.

**November 30, 1999**: An End of Phase II Meeting was held to discuss
Fast Track designation and appropriate endpoints for future Phase II
investigations.

**October 13, 2000**: Fast Track designation was granted.

**February 23, 2001**: An End of Phase II meeting was held to discuss
increasing the number of patients enrolled in study RT-009 to allow
secondary analysis of survival in the subpopulation of patients with
brain metastases for non-small cell lung cancer and breast cancer.

**November 29, 2001**: An End of Phase II Meeting was held to agree on
survival as the primary endpoint for a study in patients with newly
diagnosed non-small cell lung cancer .

**August 30, 2002**: Special Protocol Assessment requested for study
RT-013: A Phase 3 Randomized, Open-Label, Comparative Study of Induction
Chemotherapy Followed by Thoracic Radiation Therapy with Supplemental
Oxygen, with or without RSR13 (efaproxiral), in Patients with Locally
Advanced, Unresectable (Stage IIIA/IIIB) Non-Small Cell Lung Cancer.

**November 12, 2002**: A Pre-NDA meeting was held and plans were made to
submit the NDA as a rolling submission.

**July 16, 2003**: Special Protocol Assessment requested for study
RT-016: A Phase 3 Randomized, Open-Label, Comparative Study of Standard
Whole Brain Radiation Therapy with Supplemental Oxygen, with or without
Concurrent RSR13 (efaproxiral), in females with Brain Metastases from
Breast Cancer.

**July 25, 2003**: Pharmacology/Toxicology data was submitted to the FDA
as the first component of a rolling NDA.

**October 1, 2003**: CMC data was submitted to the FDA.

**December 4, 2003**: Clinical and Statistical data were submitted as
the final component of this NDA.

### D. Other Relevant Information 

RSR13 is not approved in any country.

## II. Description of Clinical Data and Sources 

##  

## A. Overall Data

NDA 21-661 contains the primary data from two efficacy studies, RT-008
and RT-009. RT-009 was conducted in 40 centers in the United States, in
addition to 15 in Canada, 4 in Australia, 4 in Hungary, 3 in Belgium, 3
in France, 3 in Germany, 3 in Israel, 3 in the United Kingdom, 2 in
Italy, and 2 in Spain. Summary information from 538 patients enrolled
into this study from 2-16-00 through 9-24-02 was included in this
submission. Rt-008 was conducted in 16 centers in the United States and
1 center in Canada. Summary information from 69 patients enrolled from
2-24-98 through 5-28-99 was included in this submission.

**B. Description of Clinical Trials RT-008 and RT-009**

Table 1: Clinical Trials Submitted to NDA 21-661

+------+----------+--------+-------+--------+-------+-------+-------+
| **S  | **       | *      | **O   | **N**  | **    | **    | **Pr  |
| tudy | Design** | *Dose, | bject |        | Durat | Tumor | imary |
| ID** |          | Route  | ive** |        | ion** | of    | Endpo |
|      |          | and    |       |        |       | Ori   | int** |
|      |          | Reg    |       |        |       | gin** |       |
|      |          | imen** |       |        |       |       |       |
+------+----------+--------+-------+--------+-------+-------+-------+
| R    | Phase 3, | [R     | Effi  | [      | 2     | Br    | Surv  |
| SR13 | ran      | SR13]{ | cacy, | RSR13] | -week | east, | ival. |
|      | domized, | .under | Sa    | {.unde | trea  | N     |       |
| RT   | ope      | line}: | fety, | rline} | tment | SCLC, |       |
| -009 | n-label, | 100 or | and   |        | phase | other |       |
|      | com      | 75     | PK    | 271    | plus  | (mela |       |
|      | parative | mg/kg  |       | en     | a 1   | noma, |       |
|      |          | c      |       | tered. | month | GU,   |       |
|      |          | entral |       | 271an  | foll  | GI).  |       |
|      |          | IV     |       | alyzed | ow-up |       |       |
|      |          | in     |       | for    | e     |       |       |
|      |          | fusion |       | effica | valua |       |       |
|      |          | over   |       | cy/266 | tion. |       |       |
|      |          | 30     |       | an     | Pat   |       |       |
|      |          | m      |       | alyzed | ients |       |       |
|      |          | inutes |       | for    | were  |       |       |
|      |          | daily  |       | s      | fol   |       |       |
|      |          | within |       | afety. | lowed |       |       |
|      |          | 30     |       |        | for a |       |       |
|      |          | m      |       | [CON   | mi    |       |       |
|      |          | inutes |       | TROL]{ | nimum |       |       |
|      |          | of     |       | .under | of 6  |       |       |
|      |          | WBRT   |       | line}: | mo    |       |       |
|      |          | up to  |       |        | nths. |       |       |
|      |          | 10     |       | 267    |       |       |       |
|      |          | doses  |       | en     |       |       |       |
|      |          | (plus  |       | tered. |       |       |       |
|      |          | supple |       | 267    |       |       |       |
|      |          | mental |       | an     |       |       |       |
|      |          | O~2~). |       | alyzed |       |       |       |
|      |          |        |       | for    |       |       |       |
|      |          | [CON   |       | effica |       |       |       |
|      |          | TROL]{ |       | cy/263 |       |       |       |
|      |          | .under |       | an     |       |       |       |
|      |          | line}: |       | alyzed |       |       |       |
|      |          | WBRT   |       | for    |       |       |       |
|      |          | (plus  |       | safety |       |       |       |
|      |          | supple |       |        |       |       |       |
|      |          | mental |       |        |       |       |       |
|      |          | O~2~)  |       |        |       |       |       |
|      |          | w      |       |        |       |       |       |
|      |          | ithout |       |        |       |       |       |
|      |          | RSR13. |       |        |       |       |       |
+------+----------+--------+-------+--------+-------+-------+-------+
| R    | Phase 2, | RSR13: | Effi  | 69     | 2     | Br    | Surv  |
| SR13 | nonran   | 100    | cacy, | e      | -week | east, | ival. |
|      | domized, | mg/kg  | Sa    | ntered | trea  | N     |       |
| RT   | op       | with   | fety, | 69     | tment | SCLC, |       |
| -008 | en-label | dose   | and   | an     | phase | other |       |
|      |          | red    | PK/PD | alyzed | plus  | (mela |       |
|      |          | uction |       | for    | a 1   | noma, |       |
|      |          | to 75  |       | eff    | month | GU,   |       |
|      |          | and 50 |       | icacy/ | foll  | GI).  |       |
|      |          | mg/kg  |       | 69     | ow-up |       |       |
|      |          | al     |       | an     | e     |       |       |
|      |          | lowed, |       | alyzed | valua |       |       |
|      |          | c      |       | for    | tion. |       |       |
|      |          | entral |       | safety | Pat   |       |       |
|      |          | IV     |       |        | ients |       |       |
|      |          | in     |       |        | fol   |       |       |
|      |          | fusion |       |        | lowed |       |       |
|      |          | over   |       |        | until |       |       |
|      |          | 30     |       |        | d     |       |       |
|      |          | m      |       |        | eath. |       |       |
|      |          | inutes |       |        |       |       |       |
|      |          | daily  |       |        |       |       |       |
|      |          | just   |       |        |       |       |       |
|      |          | prior  |       |        |       |       |       |
|      |          | to     |       |        |       |       |       |
|      |          | WBRT   |       |        |       |       |       |
|      |          | up to  |       |        |       |       |       |
|      |          | 10     |       |        |       |       |       |
|      |          | doses  |       |        |       |       |       |
|      |          | (plus  |       |        |       |       |       |
|      |          | supple |       |        |       |       |       |
|      |          | mental |       |        |       |       |       |
|      |          | O~2~)  |       |        |       |       |       |
+------+----------+--------+-------+--------+-------+-------+-------+

> Derived from applicant table 2.7.3.2.1 (Summary of Clinical Efficacy)

### 

### C. Post-marketing Experience

There is no prior post-marketing experience with this drug.

### 

### 

### 

### D. Literature Review -- An extensive literature review, including a review of some of the sources listed below, was performed by the Sponsor.

1\. Shaw, Edward G., Bourland, J. D., Marshall, Mark. Cancers of the
Central Nervous System. In: Kahn F, Potish R, eds. *Treatment Planning
in Radiation Oncology*. Baltimore: Williams and Wilkins, 1998: 491-494.

2\. Wen PY, Black PM, Loeffler JS. Treatment of Metastatic Cancer. In:
DeVita VT, Hellman S, Rosenberg SA, eds. *Cancer: Principles and
Practices*. 6^th^ Edition. Philidelphia: Lippincott, Williams and
Wilkins, 2001: 2657-2667.

3\. Patchell RA, Tibbs PA, Walsh JW, Dempsey RJ, Maruyama Y, Kryscio RJ,
Markesbery WR, Macdonald JS, Young B. A Randomized Trial of Surgery in
the Treatment of Single Metastases to the Brain. *NEJM*, 1990; 322(8):
494-500.

4\. Vecht CJ, Haaxma-Reiche EM, et al. Treatment of Single Brain
Metastases: Radiotherapy Alone or in Combination with Neurosurgery?
*Annals of Neurology* 1993; 33(6): 583-590.

5\. Mintz AP, Kestle J, Rathbone MP, Gaspar L, Hugenholtz H, Fisher B,
Duncan G, Skingley P, Foster G, LeVine M. A Randomized Trial to Assess
the Efficacy of Surgery in Addition to Radiotherapy in Patients with a
Single Cerebral Metastasis. *Cancer* 1996; 78(7): 1470-1476.

6\. Akazawa K, Nakamura T, Palesch Y. Power of Logrank Test and Cox
Regression Model in Clinical Trials with Heterogeneous Samples.
*Statistics in Medicine* 1997;16: 583-597.

7\. Gaspar L, Scott C, Rotman M, Asbell S, Phillips T, Wasserman T,
McKenna WG, Byhardt R. Recursive Partitioning Analysis (RPA) of
Prognostic Factors in Three Radiation Therapy Oncology Group (RTOG)
Brain Metastases Trials. *Int. J. Radiation Biol. Phys.*, 1997; 37(4):
745-751.

8\. Pors H, Edler von Eyben F, Sorensen OS, Larsen M. Longterm Remission
of Multiple Brain Metastases with Tamoxifen. *Journal of
Neuro-Oncology*. 1991; 10: 173-177.

9\. Gray Robert J. A Class of K-Sample Tests for Comparing the
Cumulative Incidence of a Competing Risk. *The Annals of Statistics*.
1988; 16(3): 1141-1154.

## 

## 

## 

## 

## 

## 

## 

## III. Efficacy 

### 

The efficacy review is based primarily on two multicenter trials of
RSR13 entitled:

\(1\) [RT-009]{.underline}: A Phase 3, randomized, Open-Label,
Comparative Study of Standard Whole Brain Radiation Therapy with
Supplemental Oxygen, With or Without RSR13, in Patients With Brain
Metastases

\(2\) [RT-008]{.underline}: A Phase 2 Study To Evaluate the Efficacy and
Safety of RSR13 Administered to Patients Receiving Standard Cranial
Radiation Therapy for Brain Metastases

Below, the protocols for each of these clinical trials is reviewed
independently.

+-----------------------------------------------------------------------+
| > **RT-009**:                                                         |
| >                                                                     |
| > **A PHASE 3, RANDOMIZED, OPEN-LABEL, COMPARATIVE STUDY OF STANDARD  |
| > WHOLE BRAIN RADIATION THERAPY WITH SUPPLEMENTAL OXYGEN, WITH OR     |
| > WITHOUT RSR13, IN PATIENTS WITH BRAIN METASTASES**                  |
+-----------------------------------------------------------------------+

**PROTOCOL REVIEW**

**Table 2. Protocol Milestones (Derived from Sponsor's Table 9.15, Final
Study Report)**

+-----------------------+-----------------------+-----------------------+
| **Milestone**         | **Date**              | **Comments**          |
+-----------------------+-----------------------+-----------------------+
| First patient         | 2/16/2000             | N/A                   |
| enrolled              |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Amendment #1          | 3/2/2000              | Stated MRI preferred  |
|                       |                       | over CT.              |
|                       |                       |                       |
|                       |                       | PET added as an       |
|                       |                       | option for staging.   |
|                       |                       |                       |
|                       |                       | Dosing adjustment     |
|                       |                       | Guideline was changed |
|                       |                       | to include the        |
|                       |                       | instruction "if       |
|                       |                       | SpO~2~ while          |
|                       |                       | breathing room air on |
|                       |                       | any RT day \< 90%,    |
|                       |                       | RSR13 was to be       |
|                       |                       | omitted." Physician   |
|                       |                       | judgment could be     |
|                       |                       | used in determining   |
|                       |                       | clinical significance |
|                       |                       | of an AE with respect |
|                       |                       | to omitting or        |
|                       |                       | modifying the RSR13   |
|                       |                       | dose.                 |
+-----------------------+-----------------------+-----------------------+
| Amendment #2          | 6/05/01               | Sample size increased |
|                       |                       | to 538 patients.      |
|                       |                       | Enrollment completion |
|                       |                       | extended by 6 months. |
|                       |                       |                       |
|                       |                       | In addition to small  |
|                       |                       | cell lung cancer,     |
|                       |                       | extrapulmonary small  |
|                       |                       | cell carcinomas       |
|                       |                       | excluded from         |
|                       |                       | enrollment.           |
|                       |                       |                       |
|                       |                       | Calcium channel       |
|                       |                       | blockers were added   |
|                       |                       | to the list of        |
|                       |                       | medicines that could  |
|                       |                       | potentiate or         |
|                       |                       | possibly interact     |
|                       |                       | with RSR13.           |
|                       |                       |                       |
|                       |                       | Expanded warnings     |
|                       |                       | about use of          |
|                       |                       | concomitant CCBs and  |
|                       |                       | ACE inhibitors. A     |
|                       |                       | suggestion was added  |
|                       |                       | to start RSR13 dosing |
|                       |                       | at 75 mg/kg in        |
|                       |                       | patients taking these |
|                       |                       | classes of            |
|                       |                       | antihypertensive      |
|                       |                       | medications. An       |
|                       |                       | additional            |
|                       |                       | recommendation for    |
|                       |                       | patients who had a    |
|                       |                       | previous nephrectomy  |
|                       |                       | to start dosing a 75  |
|                       |                       | mg/kg, to advise      |
|                       |                       | patients to avoid     |
|                       |                       | smoking during the    |
|                       |                       | RSR13 resaturation    |
|                       |                       | period. The Dosing    |
|                       |                       | Adjustment Guideline  |
|                       |                       | was expanded to       |
|                       |                       | include weight and    |
|                       |                       | gender. The scale for |
|                       |                       | evaluation of         |
|                       |                       | hypoxemia AEs was     |
|                       |                       | initiated.            |
|                       |                       |                       |
|                       |                       | Analysis of the       |
|                       |                       | NSCLC/breast          |
|                       |                       | population was        |
|                       |                       | incorporated.         |
+-----------------------+-----------------------+-----------------------+
| Amendment #3          | 10/09/01              | Included option to    |
|                       |                       | treat brain           |
|                       |                       | metastases with       |
|                       |                       | Cobalt 60. Clarified  |
|                       |                       | the conditions under  |
|                       |                       | which concurrent RT   |
|                       |                       | could be given to     |
|                       |                       | extracranial sites.   |
+-----------------------+-----------------------+-----------------------+
| Date of Primary       | 1/31/03               | N/A                   |
| Analysis              |                       |                       |
|                       |                       |                       |
| (Data Cutoff Date)    |                       |                       |
+-----------------------+-----------------------+-----------------------+
| NDA submitted         | 12/4/03               | N/A                   |
| completed             |                       |                       |
+-----------------------+-----------------------+-----------------------+

*Reviewer comments: The Sponsor stated that it was necessary to enroll
501 patients and observe 402 deaths to claim statistical significance in
median survival time and rule out the null hypothesis. Total enrollment
was later increased to 538 patients based on the percentage of patients
enrolled with primary cancers other than lung and breast (sample size
calculation allowed that if 25% of patients enrolled had "other"
primary, a total of 501 patients would be enrolled. If "other" primary
patients accounted for 30% of patients, then 538 patients would be
enrolled)*.

**1.0** **Objectives**

-   To determine the effect of RSR13 on primary and secondary efficacy
    endpoints in patients with brain metastases receiving daily
    intravenous doses of RSR13 administered immediately prior to
    standard WBRT/supplemental oxygen compared to patients receiving
    standard WBRT/supplemental oxygen.

-   To determine the safety of RSR13 in this patient population.

-   To assess the pharmacokinetics of RSR13 in the patient cohort
    receiving the study drug.

-   The primary efficacy endpoint in this study was survival in the
    total population. A secondary analysis of the NSCLC/breast primary
    tumor subpopulation was also planned with the addition of amendment
    \# 2.

-   Secondary efficacy variables were time to radiographic tumor
    progression, time to clinical tumor progression in the brain,
    response rate in the brain, cause of death, and quality of life.

**1.1 Overall Survival**

The primary efficacy endpoint was overall survival using the log-rank
statistic unadjusted for covariates. The primary final analyses of this
study was undertaken when the planned number of deaths in both the total
study population and the NSCLC/breast subpopulation was observed.

*Reviewer comment: While overall survival in the intent to treat
population was the primary efficacy endpoint in this study, amendment #2
made provisions for a secondary analysis of the NSCLC/breast primary
tumor subpopulation as described above. One-hundred-seventy-three
patients had been enrolled when amendment 2 was activated (protocol
version 3) . See statistical review for further comments.*

Secondary efficacy endpoints were time to radiographic tumor progression
in the brain, time to clinical tumor progression in the brain, response
rate in the brain, cause of death, and quality of life.

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

Response was determined based upon evaluation of each contrast-enhanced
MRI or CT scan performed after completion of the study treatment
regimen. Time to radiographic tumor progression in the brain was
reported by means of Kaplan-Meier estimates. Gray's test was used to
compare cumulative incidence between treatment arms. Time to first
(cranial or extracranial) progression was estimated using Kaplan-Meier.
Site of first progression (cranial, extracranial, simultaneous, died
without documented progression, or alive without documented
progression), as well as time to first failure, were summarized by
treatment arm and primary site subpopulation.

**1.3 Time to Clinical Progression in the Brain**

Clinical progression was defined as either neurological progression, as
assessed by the Neurological Function (NF) status, or as neurocognitive
deterioration as measured by the Mini Mental State Examination (MMSE),
or as the use of subsequent therapy for brain metastases such as
radiation or surgery. An increase from baseline of 1 or more points in
the NF status score indicated neurological disease progression.
Neurocognitive deterioration was defined as a decrease from baseline in
the MMSE score of 3 or more points. Time to clinical progression was
summarized using Kaplan-Meier estimates and compared between treatment
arms using cumulative incidence Grays test.

**1.4 Response Rate in the Brain**

Best response was determined for each patient from evaluation of MRI or
CT scans.

It was projected at the outset that a differential treatment effect
shown by improved

response would result in survival benefit. Treatment arms were compared
using the

Cochran-Mantel-Haenszel test.

**1.5 Cause of Death**

The frequency of neurologic/non-neurologic/indistinguishable causes of
death

was tabulated for each treatment arm and compared using the
Cochran-Mantel-Haenszel test. Neurologic causes of death included such
events as fatal cerebral edema, neurological deterioration, and
convulsions. Non-neurologic causes of death included pneumonia, acute
renal failure, cachexia, and pulmonary embolus. Patients in the
indistinguishable category could not have their causes of death
distinguished between neurologic and non-neurologic causes (see section
1.3, FDA Analysis).

**1.6 Quality of Life**

Quality of life was determined by means of the Spitzer Questionnaire and
KPS assessment.

The frequency distributions were computed for each treatment by time of
follow-up and focused on the 6 and 12-month time-points. The KPS score
was categorized analyzed using the Cochran-Mantel-Haenszel test for each
time-point.

**2.0** **Eligibility Criteria**

-   Age ≥ 18 years of age.

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-   Radiographic studies consistent with brain metastases and a
    histologically or cytologically confirmed primary malignancy,
    excluding small cell lung cancer and extrapulmonary small cell
    carcinomas, germ cell tumors, and lymphomas; or histologically or
    cytologically confirmed brain metastases consistent with a
    non-excluded primary malignancy. Patients with leptomeningeal
    metastases were not eligible.

-   Karnofsky Performance Status (KPS) ≥ 70 .

-   No prior treatment for brain metastases with WBRT, stereotactic
    radiosurgery, chemotherapy, hormonal therapy, immunotherapy, or
    biologic agents. Prior surgical resection was allowed if at least
    one measurable lesion remained. Prior and current corticosteroid
    therapy was allowed.

-   Adequate hematologic, hepatic, and renal function as defined by:
    hemoglobin ≥ 10 g/dL, WBC count ≥ 2000 cells/mm^3^ , platelet count
    ≥ 75,000/mm^3^, creatinine ≥ 2.0 mg/dL, bilirubin ≤ 2.0 mg/dL,
    alanine aminotransferase /serum glutamic-pyruvic transaminases and
    aspartate aminotransferase/serum glutamic-oxaloacetic transaminases
    ≤ 3.0 times the upper limit of normal.

-   Resting and exercise SpO2 while breathing room air ≥ 90%.

-   No other concurrent active malignancy from a second histologic site.

-   No use of any investigational drug, biologic, or device within 28
    days prior to radiation therapy day 1.

-   Adequate pulmonary function tests by simple spirometry were required
    if the patient

had a pulmonary condition that might compromise oxygen loading in the
lungs

Adequate PFTs were defined as forced vital capacity (FVC) and forced
expiratory volume in 1 second (FEV~1~) ≥ 50% of normal for that
patient's age, height, and race.

-   No chemotherapy for primary tumor or extracranial metastases within
    7 days prior to WBRT day 1; no planned chemotherapy during WBRT; no
    planned additional therapy for brain metastases through the initial
    follow-up visit (1 month after completion of the RT course).

-   No previous exposure to RSR13

-   Able to provide written informed consent.

-   If female patients who are not post-menopausal (\> 12 months since
    last menses) or surgically sterile, must have an negative serum
    β-hcg pregnancy test, and must be practicing a medically acceptable
    contraceptive regimen from the time of consent until the initial
    follow-up visit. All male patient who are not surgically sterile
    must be practicing a medically acceptable contraceptive regimen.

*Reviewer comment: Inclusion and exclusion criteria were combined under
the heading of Eligibility Criteria in Version 4 (final version) of the
RT-009 protocol. Amendment #2 specified that in addition to small cell
lung cancer, extrapulmonary small cell carcinomas were excluded from
enrollment in the study.*

**3.0 Treatment Plan**

Patients who were randomized to treatment arm A received daily RSR13
within 30 minutes prior to daily WBRT and supplemental oxygen. Patients
in treatment arm B received WBRT and supplemental oxygen without
placebo. RSR was administered using Dosing Adjustment Guidelines.
Patients in treatment arm A received an initial 100 or 75 mg/kg dose of
RSR13 at a concentration of 20 mg/mL over 30 minutes through a central
venous catheter. All RSR13 infusions were administered using a
volumetric pump. The RSR13 was given with supplemental oxygen beginning
on Day 1 of radiation initiation and continued every radiation therapy
day throughout the 10-day course of WBRT. WBRT was given within 30
minutes of completing the RSR13 infusion. Patients in both treatment
arms received supplemental oxygen for at least 35 minutes prior to,
during, and for at least 15 minutes after completion of daily WBRT. The
flow rate of supplemental oxygen was 4 L/minute as needed to maintain a
SpO~2~ measurement ≥ 90% during and after RSR13 infusion.

*Reviewer comment: According to the treatment protocol, supplemental
oxygen was to be administered beginning at least 5 minutes prior to
starting the RSR13 infusion. The supplemental oxygen was then continued
throughout the duration of the RSR13 infusion and discontinued at least
15 minutes after completion of WBRT. Whole Brain Radiation Therapy was
administered within 30 minutes after completion of the RSR13 infusion.*

Whole brain radiation therapy was given as 30 Gy at 3 Gy fractions per
day, 5 days per week over 10 days. Patients were stratified for
enrollment by RPA (recursive partitioning analysis) Classes I and II
according to the RTOG RPA of prognostic factors criteria (**Table 3**).
RPA Class II patients were further stratified by site of the primary
cancer (**Table 4**). The number of patients in each of the 4 strata was
not predetermined.

**Table 3: Recursive Partitioning Analysis (RPA)**

  ----------------------- ----------------------- -----------------------
                          **CLASS I**             **CLASS II**

  KPS \> 70               Yes                     Yes

  Primary tumor           controlled              uncontrolled

  Age                     \< 65 years             ≥ 65 years

  Metastases              Brain only              Brain and other
  ----------------------- ----------------------- -----------------------

**Table 4: Stratification at Randomization**

  ----------------------------------- ----------------- ------------- -----------
  **Stratification (pre-defined       **Total N**       **Control**   **RSR13**
  subsets)**                                                          

  RPA Class I patients                57                28            29

  RPA Class II NSCLC primary patients 263               131           132

  RPA Class II breast primary         101               49            52
  patients                                                            

  RPA Class II other primary patients 111               54            57

  Totals                              532               262           270
  ----------------------------------- ----------------- ------------- -----------

*Reviewer comment: The protocol stated that 538 patients were analyzed
for efficacy (mod 2- vol. 2, p. 14). However, only 532 patients were
calculated from the stratification at randomization table as shown
above. The sponsor was asked to clarify the discrepancy in numbers. They
responded by explaining that 6 patients were improperly stratified based
on their site of primary disease (patient numbers 2168, 3044, 3089,
4045, 4076, 4100), and were not included in the in-text table. These
same 6 patients were included in the post-text table which provides
summary information by stratum and site of primary within stratum.*

**4.0** **Treatment Modifications**

The selection of the RSR13 doses given in this study was based on the
safety and efficacy results

obtained in the Phase 2 open-label studies in which over 270 cancer
patients (which included 69 patients with brain metastases) received
repetitive daily RSR13 infusions prior to RT. In the Phase 2 study
RT-008, patients with brain metastases received WBRT with RSR13 at a
dose of 100 mg/kg over 30 minutes. Adverse events leading to RSR13
dosing discontinuation were observed at 100 mg/kg in some patients and
resulted in the initial development of dosing adjustments for individual
patients to limit side effects that could result in early
discontinuation of the study drug. Dose reductions to 75 or 50 mg/kg (or
the withholding of doses) were allowed if clinical assessments or
laboratory criteria indicated that the patient was experiencing
exaggerated pharmacological effects or toxicities. Based upon these
background data, the starting dose for RT-009 was 75 or 100 mg/kg . See
**Table 5**.

**Table 5: Dose Adjustment Guidelines**

If the SpO~2~ while breathing room air on any WBRT day was \<90%, RSR13
was to be omitted.

**DETERMINATION OF INITIAL DOSE OF RSR13**

1\. If SpO~2~ while breathing room air at screening (at rest AND during
exercise) AND on WBRT Day 1 was ≥ 93%, RSR13 was administered as
follows:

a\. Males

i\. If weight ≤ 95 kg: 100 mg/kg

ii\. If weight \> 95 kg: 75 mg/kg

b\. Females

i\. If weight ≤ 70 kg: 100 mg/kg

ii\. If weight \> 70 kg: 75 mg/kg

2\. If SpO~2~ while breathing room air at screening (at rest OR during
exercise) OR on WBRT day 1 was 90% - 92%: 75 mg/kg.

**DOSE ADJUSTMENTS AFTER THE INITIAL DOSE**

Down Titration

• Decrease from dose of 100 mg/kg to 75 mg/kg

• Omit RSR13 from dose of 75 mg/kg

**DOWN TITRATION IF ANY OF THE FOLLOWING OCCURRED:**

a\. Duration of supplemental oxygen administration was \>3 hours after
end-infusion before SpO~2~

while breathing room air returned to 90% on the previous dosing day.

b\. The patient experienced nausea and/or vomiting (Grade 2 or higher)
or clinically significant

(investigator judgment) hypotension associated with RSR13 within 12
hours after RSR13

administration on the previous dosing day.

c\. The patient developed hypoxemia which required treatment after
discharge on the previous

dosing day.

d\. SpO~2~ while breathing room air was 90% - 92% but had been ≥ 93% on
the previous dosing day.

**UP TITRATION**

• Increase from dose of 75 mg/kg to 100 mg/kg

• Resume dosing at 75 mg/kg if RSR13 dose omitted

a\. Increase from dose of 75 mg/kg administered on previous dosing day
to 100 mg/kg if SpO~2~ while breathing room air was 93% and none of the
AE listed above a-c had occurred on the previous dosing day.

b\. Resume dosing at 75 mg/kg after omitting RSR13 on the previous day:

• If SpO~2~ while breathing room air was 90% - 92% and had been 90% -
92% on the dosing day that let to omission of RSR13 dose.

• If SpO~2~ while breathing room air was ≥ 93%.

c\. Dosing was not to be resumed after omitting RSR13 pm the previous
day if SpO~2~ while breathing room air was 90% - 92% but had been 93% on
the dosing day that led to omitting the RSR13 dose.

(Derived from table 9.6, Final Study Report)

*Reviewer comment: Amendment #1 changed the Dosing Adjustment Guideline
to omit the use of RSR13 if SpO2 was \< 90% while breathing room air on
any day of radiation therapy. This was based on concerns that RSR13
could result in further hypoxemia in patients with compromised SpO~2~
levels. The rationale for this amendment was appropriate for patient
safety. Adverse events leading to dosing termination were observed in
earlier trials of RSR13. This lead to the development of these Dosing
Adjustment Guidelines that address efficacy and safety issues. These
Guidelines were used throughout the duration of whole brain radiation
therapy to determine on a daily basis whether a patient should be dosed
at 100 mg/kg, 75 mg/kg, or have RSR13 held for that day. However, a dose
of 50 mg/kg was permitted at the discretion of the investigator.*

**5.0** **Safety Monitoring**

All patients were assessed for safety, all adverse events, and all
toxicities from randomization until the initial follow-up visit at 1
month after completion of the radiotherapy course. Standard follow-up
visits were required 3 months after completion of the radiation therapy
and every 3 months thereafter, until both radiographic and clinical
progression were demonstrated and documented.

**Table 6: Safety Monitoring**

+-----------------+--------+--------+-------+-------+--------+-------+
| **Evaluation**  | **Scr  | **Base | **D2  | **    | **1    | **3   |
|                 | eening | line** | to    | D10** | month  | month |
|                 | Day    |        | D9**  |       | FU     | FU**  |
|                 | (D)**  | **D-5  |       |       | (XRT   |       |
|                 |        | to     |       |       | comple |       |
|                 | *      | D1**   |       |       | ted)** |       |
|                 | *(D-21 |        |       |       |        |       |
|                 | to     |        |       |       |        |       |
|                 | D0)**  |        |       |       |        |       |
+-----------------+--------+--------+-------+-------+--------+-------+
| Spitzer         |        | X      |       | X     | X      | X     |
| questionnaire   |        |        |       |       |        |       |
+-----------------+--------+--------+-------+-------+--------+-------+
| Resting SpO~2~  | X      | X      | X     | X     |        |       |
+-----------------+--------+--------+-------+-------+--------+-------+
| Exercise SpO~2~ | X      |        |       |       |        |       |
+-----------------+--------+--------+-------+-------+--------+-------+
| PFTs            | X      |        |       |       |        |       |
+-----------------+--------+--------+-------+-------+--------+-------+
| Physical exam   | X      | X      |       | X     | X      | X     |
+-----------------+--------+--------+-------+-------+--------+-------+
| KPS             | X      | X      |       | X     | X      | X     |
+-----------------+--------+--------+-------+-------+--------+-------+
| Neuro exam      |        | X      |       | X     | X      | X     |
+-----------------+--------+--------+-------+-------+--------+-------+
| MRI/CT          | X      |        |       |       | X      | X     |
+-----------------+--------+--------+-------+-------+--------+-------+
| EKG             | X      |        |       |       |        |       |
+-----------------+--------+--------+-------+-------+--------+-------+
| Hemat           | X      | X      |       | X     | X      |       |
| ology/chemistry |        |        |       |       |        |       |
+-----------------+--------+--------+-------+-------+--------+-------+
| Serum pregnancy | X      |        |       |       |        |       |
| test            |        |        |       |       |        |       |
+-----------------+--------+--------+-------+-------+--------+-------+
| Supplemental    |        | X      | X     | X     |        |       |
| O~6~            |        |        |       |       |        |       |
+-----------------+--------+--------+-------+-------+--------+-------+
| Mini-MSE        |        | X      |       | X     | X      | X     |
+-----------------+--------+--------+-------+-------+--------+-------+
| AE check        |        | X      | X     | X     | X      | X     |
+-----------------+--------+--------+-------+-------+--------+-------+

(Derived from table 9.1, Final Study Report)

If any of the following occurred necessitating the early discontinuation
of RSR13 in Treatment Arm A, the patient completed WBRT under Treatment
Arm B procedures:

-   The development of a significant adverse event/toxicity due to study
    participation as determined by the Investigator or patient.

-   The development of an intercurrent illness, condition, or procedural
    complication that could interfere with the patient's continuing to
    receive study drug.

-   Voluntary patient withdrawal of consent to continue receiving study
    drug.

-   The Investigator or Sponsor feels that it its medically in the best
    interest of the patient to discontinue receiving study drug.

**6.0** **Response Evaluation**

Radiographic progression was defined by radiographic criteria which were
evaluated by blinded

central review and determined from the date of randomization into the
study. Determination of radiographic tumor progression in the brain was
based on contrast enhanced MRI or CT scans taken at screening and
compared to follow-up scans taken 1 month after the end of WBRT, 3
months after the end of WBRT, and every 3 months thereafter until death.
The date of tumor progression was defined as the date of radiographic
documentation that any treated lesion had enlarged by more than 25% in
the bi-dimensional product. Maximum bi-dimensional measurements were
used to compute the bi-dimensional product and for determination of
response and radiographic progression (**Table 7**). **The appearance of
new lesions was not considered a sign of progression for the purpose of
this study. However, the diagnosis of new lesions was collected.**

The study protocol stated that predefined indicator lesions (the 3
largest well-defined lesions

identified before WBRT) would be followed for response to evaluate
treatment effect. In

patients with 1 to 3 brain metastases, all treated lesions were followed
for response. The central

reviewer could define *a priori* additional criteria for insuring the
most appropriate assessment of

response and progression, including definitions of measurable and
evaluable lesions.

**Table 7: Response Rate and Radiographic Tumor Progression in the
Brain**

+-----------------------------------+-----------------------------------+
| **Response**                      | **Bi-dimensional Size of Residual |
|                                   | Disease Compared to baseline.**   |
| **(Defined by Central Review)**   |                                   |
+-----------------------------------+-----------------------------------+
| Complete Response (CR)            | 0% for all indicator lesions,     |
|                                   | provided no treated lesion meets  |
|                                   | criteria for progression.         |
+-----------------------------------+-----------------------------------+
| Partial Response (PR)             | \>0% to ≤ 50% for all indicator   |
|                                   | lesions, provided no treated      |
|                                   | lesion meets criteria for         |
|                                   | progression.                      |
+-----------------------------------+-----------------------------------+
| Stable disease (SD)               | \>50% to ≤ 125% for 1 or more     |
|                                   | indicator lesions, provided no    |
|                                   | treated lesion meets criteria for |
|                                   | progression.                      |
+-----------------------------------+-----------------------------------+
| Progressive disease (PD)          | \>125% for any treated lesion.    |
+-----------------------------------+-----------------------------------+

(Derived from table 9.7, Final Study Report)

*Reviewer comment: For this study, a partial response was defined as up
to a 50% reduction in the bi-dimensional size of residual tumor compared
to baseline, provided no treated lesion meets criteria for progression.
Stable disease was defined as more than 50% tumor remaining after
treatment, and not more than a 25% increase in the bi-dimensional size
of residual tumor. Progressive disease represented more than a 25%
increase in the bi-dimensional product from baseline. These parameters
appear consistent with the WHO criteria of tumor response evaluation. We
requested exactly how the response criteria for RT-009 was determined.
The Sponsor replied stating that the criteria were established and
agreed upon by the investigators, study chairs, Allos clinical and
statistical personnel, and the head of the NeuroImaging Core Lab
responsible for the central review of scans.*

*Allos did not require confirmation of response. The designation of CR
or PR was based on "Best Response," which was not defined in the
protocol. The FDA sent Allos a query on how Best Response was
determined. Allos replied stating that Best Response was determined by
selecting the maximal response for a patient, starting at the one month
follow-up visit and following over time until progressive disease or
subsequent treatment of brain metastases (or death) occurred.
Furthermore, the designation of CR or PR was made irrespective of the
appearance of a new brain lesion or systemic progression.*

**7.0** **Statistical Methods**

The primary endpoint, overall survival, was compared between the
treatment arms by unadjusted log-rank test. The primary analysis of
efficacy endpoints was based on the intent-to-treat population. Enrolled
patients could be in RPA Class I or II, which have distinct estimated

MST of 7.1 and 4.2 months, respectively. Based on an assumption that
there would be a mix in this study of 20% RPA Class I and 80% RPA Class
II patients, and based upon the RTOG brain metastases database, the
estimated MST for patients treated with WBRT alone was 4.57 months.

A total of 402 events (deaths) were required to rule out the null
hypothesis with 85% power that

the hazard ratio of the 2 treatment arms was 1 versus the alternative
hypothesis that the HR

of the 2 arms was not equal to 1. Since it was assumed that up to 5% of
patients could be ineligible for the analysis, it was necessary to
enroll at least 501 patients initially. Total patient enrollment would
be 501-538 patients depending on the percentage of patients with primary
cancer other than NSCLC or breast. Sample size calculation allowed that
if 25% of patients enrolled had other primary, a total of 501 patients
would be enrolled. If other primary patients accounted for 30% of
patients, then 538 patients would be enrolled.

In the subpopulation of patients with NSCLC and breast primary, a total
of 308 deaths from both

treatment arms was required to provide 75% statistical power with a
two-sided significance level

of 0.05 for estimation and hypothesis testing of treatment effect. If
patient accrual was longer than the assumed 27 months, fewer patients
would be required to observe 402 deaths in the total population and 308
deaths in the NSCLC/breast primary cohort. If accrual was shorter than
the assumed 27 months, then either more patients or a longer follow-up
period would be required to observe the required number of deaths. The
NSCLC/breast primary site subpopulations were determined based on
pre-randomization criteria. Allos medical monitors performed a treatment
arm blinded review of all patients' primary disease classification prior
to the final analysis to assure consistent categorization of primary
disease.

The hazard ratio (HR) was compared between treatment arms using the
log-rank statistic

unadjusted for covariates. A modified Bonferroni adjustment was made for
multiple

comparisons (co-primary analyses) . A p-value \< 0.048 was required to
reject the null

hypothesis that there was no difference in HR in the 2 treatment arms.

Analyses were performed for all randomized eligible patients, the
NSCLC/breast

subpopulation, and by site of primary. Estimates of survival were
calculated based

upon the number of RSR13 doses received. Survival was also estimated
separately

by response category for each treatment arm.

The statistical analysis plan (SAP) specified 18 covariates that were
collected prior to or at baseline. Ten of these are categorical
variables. Two covariates (number of extracranial metastatic sites, and
number of cranial lesions) are ordered and continuous. Five variables
are analyzed multiple ways: KPS, age and Hgb are considered as both
continuous and categorical, altitude is analyzed as categorical and
continuous in both untransformed and log transformed scales, and area of
cranial lesions is analyzed as ordered and continuous (3 levels), and in
log transformed scale. These 5 covariates with multiple definitions,
allow for 48 combinations. Cox multiple regression was performed on all
48 combinations using 17 of the 18 covariates that were defined at
baseline. Cox single regression, multiple regression including all
covariates, and stepwise Cox multiple regression models were performed.
In addition to the baseline covariates, the Cox models were also run
with subsequent therapy covariates per SAP.

*Reviewer comment: The sample size was increased to a maximum of 538
patients with amendment #2 to allow for a statistically powered survival
analysis of patients in the non-small cell lung cancer/breast cancer
primary subpopulation , in addition to the survival analysis of all
patients.*

**TRIAL RESULTS**

[\*Informed consent]{.underline}

The individual investigator was responsible for preparing the written
informed consent document for RT-009. A template for informed consent
was provided by the Sponsor. The investigator was allowed to rearrange
or reword the contents of the template, and add other elements or
language, provided the meaning and content were not changed or deleted.
The Sponsor reviewed the informed consent form used before any patient
was enrolled. Written informed consent was obtained from all patients
who participated in this study prior to enrollment.

[\*Randomization]{.underline}

Patients were randomized 1:1 to Treatment Arms A or B according to a
permuted block design, balancing by institution within strata. The
randomization was stratified by RPA Classes I and II and within RPA
Class II by site of primary cancer (NSCLC vs. breast vs. other), for a
total of 4 strata. Patients were assigned a 4-digit patient
identification number with the first digit corresponding to the stratum
number followed by the other 3 digits being numbered in the order of
randomization sequentially within the stratum. The number served as
patient identification for all data collected under the study.

A total of 2271 patients were screened in order to obtain the 538
patients who were randomized

into the study: 57 RPA Class I (10.6%) and 481 RPA Class II (89.4%)
patients (Figure 10.1).

The most frequent reasons for failure to enroll screened patients were
"patient unwilling to give

consent" and "KPS \<70", both accounting for 312 (17.9%) screen
failures. RPA Class I patients

represented 10.6% of the total enrollment, thereby meeting the protocol
projected mix of

10%-25% RPA Class I patients (Section 9.1). RPA Class II patients were
stratified according to

the site of the primary cancer (NSCLC vs. breast vs. other) for a total
of 4 strata.

*Reviewer comment: Twenty-five patients were incorrectly classified at
the site of accrual according to their primary tumor diagnosis. This
error was captured only after central review of the Case Report Forms at
an unspecified time point.*

[\*Blinding]{.underline}

This study was open-label.

[\*Central review process]{.underline}

Radiographic data was forwarded to a central location for radiographic
review. Radiographic data were forwarded by the investigational sites to
Neuroimaging Core Laboratory

at the Cleveland Clinic Foundation for centralized radiological review.

> Neuroimaging Core Laboratory
>
> Cleveland Clinic Foundation
>
> 9500 Euclid Avenue
>
> Section of Neurology/L10
>
> Cleveland, Ohio 44195

Digital data, originals or duplicate originals of films of the magnetic
resonance imaging or

computed tomography scans obtained at baseline and at follow-up visits
were sent for

blinded central review for determination of radiographic response and
progression in the brain.

Central Laboratory Facilities:

> RSR13 Assays in Plasma and Red Blood Cells (RBCs)
>
> Analytical Development Corporation
>
> 4405 N Chestnut Street
>
> Colorado Springs, CO 80907

Routine Clinical Laboratory Tests:

> Covance Central Laboratory Services SA
>
> Rue Moise-Marcinhes 7
>
> 1217 Meyrin, Geneva
>
> Switzerland
>
> Covance Central Laboratory Services
>
> 8211 Scicor Drive
>
> Indianapolis, IN 46214-2942
>
> Sonic Clinical Trials
>
> 95 Epping Road
>
> North Ryde, NSW 2113
>
> Australia

[\*Protocol violations]{.underline}

A total of 202 exemptions were granted for protocol violations that
occurred during the course of the study. A total of 151 exemptions were
granted for failure to comply with protocol-defined time windows.
Protocol deviations were defined *a priori* as violations in
eligibility, disallowed medications, dosing violations, and patients who
should have been withdrawn from the study but were not. Decisions to
enroll patients who failed to meet all eligibility criteria were made on
a

case-by-case basis:

-    Five patients in the Control arm were enrolled although they had
    received chemotherapy or hormonal therapy \< 7 days prior to start
    of WBRT. According to the sponsor, neurological symptoms in theses
    patients indicated immediate need for whole brain radiation
    treatment. Three patients (2 in the Control arm and 1 in the RSR13
    arm) were enrolled although their liver function tests were
    exclusionary. Elevations in ALT in 2 of the 3 patients were the
    result of metastases extending to the liver. In the third patient,
    elevated ALT was determined to be a temporary response to a previous
    biopsy under general anesthesia.

-    Two patients (both in the Control arm) were enrolled although they
    had received another investigational treatment within the previous
    month. Previous treatment had failed in both patients and
    neurological symptoms in these patients indicated immediate need for
    WBRT.

-   One patient was enrolled in the Control arm although FEV1 was 47%.
    This finding was determined a minor deviation since FVC was 62% and
    both resting and exercise SpO2 measurements were 94%.

-   One patient was enrolled in the RSR13 arm with a screening Hgb
    reported at 9.9 g/dL by a local laboratory and as 10.0 g/dL by
    central laboratory.

*Reviewer comments: The five patients not meeting eligibility criteria
because of prior chemotherapy or hormonal therapy within 7 days of RT
day encompass the administration of 5-fluorouracil 6 days prior to RT
day 1 (pt. \# 1026), vinorelbine 5 days prior to RT day 1 (pt. \# 3021),
herceptin (pt. \# 3077), letrozole (pt. \# 3085), and gemcitabine (pt.
\# 4041). All five were in the control arm.*

*The 3 patients not meeting eligibility criteria because of inadequate
hepatic function involved patient \# 1052 (elevated ALT was attributed
to recent biopsy of melanoma under general anesthesia- control arm),
patient \# 4007 (elevated ALT attributed to widespread metastases to the
liver- control arm), and patient# 2016 (ALT value elevated, but value
not reported -- control arm).*

*Patient \# 2012 and 4058 (both in the control arm) were given other
investigational agents within 28 days prior to RT day 1: 2012 had been
involved in a phase 2 study prior to entry, and \# 4058 had been in a
prior phase 3 experimental vaccine therapy for melanoma when this
patient developed brain metastases.*

*Patient \# 2006 (control arm) had a screening FEV1 below 50%, but FVC
was 62% and resting and exercise SpO2 measurements were 94%.*

  ---------------------------------------------- ------ ------ ----------
                                                               

  ---------------------------------------------- ------ ------ ----------

**Table 8: Ineligible Patients Identified by Blinded Central Review of
Scans**

(Derived from table10.5, Final Study Report)

  ----------------- ----------------- ----------------- -----------------
  Reason Ineligible Primary Site      Control Patient   RSR13 Patient \#
                                      \#                

  Leptomeningeal    NSCLC             2163              2025
  mets                                                  

                                      2069              2101

                                      2190              2263

                                      2227              

                                      1043              

                    Breast            3065              3016

                                      3092              3072

                                      3068              

                    Other             4055              4103

                                      4088              

                                      4108              

                                      4040              

  No measurable     NSCLC             2048              
  brain                                                 

  lesions (after                                        
  resection)                                            

                    Breast            1020              

                                      1025              

  Small cell lung   Other             4012              
  cancer                                                

  Dural disease     Breast            3015              
  ----------------- ----------------- ----------------- -----------------

*Reviewer comment: The table above identifies the patients found
ineligible after central review of scans. Patients were required to have
measurable disease for enrollment according to the protocol.
Furthermore, patients with leptomeningeal metastases, dural disease or
small cell lung cancer were ineligible according to protocol criteria.*

[\*Enrollment]{.underline}

**Table 8** lists the regions of accrual to both arms of the study. The
top 4 accrual sites were Sheerbrooke, Canada (34), Phoenix, AZ (30),
Tucson, AZ (41), and Cleveland, OH (36).

**Table 9** lists the number of investigational sites per country.

**Table 9: Number of Patients Enrolled in Each Region by Primary Site
Subpopulation and Treatment** Arm (ROW = rest of world)

+-----------------+-----------------+-----------------+-----------------+
| **Region**      | **Primary       | **Control**     | **RSR13**       |
|                 | Site**          |                 |                 |
|                 |                 | **(N=267)**     | **(N=271)**     |
|                 |                 |                 |                 |
|                 |                 | **N(%)**        | **N(%)**        |
+-----------------+-----------------+-----------------+-----------------+
| Canada          | NSCLC           | 56(21.0)        | 52(19.2)        |
|                 |                 |                 |                 |
|                 | Breast          | 11(4.1)         | 9(3.3)          |
|                 |                 |                 |                 |
|                 | Other           | 16(6.0)         | 17(6.3)         |
|                 |                 |                 |                 |
|                 | Total           | 83(31.1)        | 78(28.8)        |
+-----------------+-----------------+-----------------+-----------------+
| ROW             | NSCLC           | 30(11.2)        | 31(11.4)        |
|                 |                 |                 |                 |
|                 | Breast          | 14(5.2)         | 15(5.5)         |
|                 |                 |                 |                 |
|                 | Other           | 14(5.2)         | 14(5.2)         |
|                 |                 |                 |                 |
|                 | Total           | 58(21.7)        | 60(22.1)        |
+-----------------+-----------------+-----------------+-----------------+
| USA             | NSCLC           | 65(24.3)        | 65(24.0)        |
|                 |                 |                 |                 |
|                 | Breast          | 30(11.2)        | 36(13.3)        |
|                 |                 |                 |                 |
|                 | Other           | 31(11.6)        | 32(11.8)        |
|                 |                 |                 |                 |
|                 | Total           | 126(47.2)       | 133(49.1)       |
+-----------------+-----------------+-----------------+-----------------+

(Derived form table 10.1, Final Study Report)

**Table 10: Number of Investigational Sites Per Country**

  ----------------------------------- -----------------------------------
  **COUNTRY**                         **NUMBER OF INVESTIGATIONAL SITES**

  United States                       40

  Canada                              15

  Australia                           4

  Hungary                             4

  Belgium                             3

  Germany                             3

  Israel                              3

  France                              3

  Italy                               2

  Scotland                            2

  Spain                               2

  England                             1
  ----------------------------------- -----------------------------------

(Derived from table 6.1, Final Study report)

[\*Baseline Demographics]{.underline}

**Table** **11: Demographic Variables**

![](media/image1.png){width="6.497222222222222in" height="4.29375in"}

(Derived from table 2.7.3.3.1, Summary of Clinical Efficacy)

**Table 12. Reviewer's Description of Tumor Histology**

+-----------------------+-----------------------+-----------------------+
| **Histology**         | **Control**           | **RSR13**             |
|                       |                       |                       |
|                       | **267 patients**      | **271 patients**      |
|                       |                       |                       |
|                       | **N(%)**              | **N(%)**              |
+-----------------------+-----------------------+-----------------------+
| Lung                  | 151(56)               | 148(55)               |
|                       |                       |                       |
| Breast                | 55(20)                | 60(22)                |
|                       |                       |                       |
| \*Other:              | 61(23)                | 63(23)                |
|                       |                       |                       |
| Melanoma              | 16(6)                 | 22(8)                 |
|                       |                       |                       |
| Colorectal            | 10(4)                 | 9(3)                  |
|                       |                       |                       |
| Renal cell            | 6(2)                  | 10(4)                 |
+-----------------------+-----------------------+-----------------------+

\*Predominant histology of "other" category.

*Reviewer comment: The demographic variables and primary tumor
histological types for patients enrolled in this study were evenly
distributed between the two treatment arms.*

**Table 13: Distribution of Controlled and Uncontrolled Primary Tumors
Between Treatment Arms**

  ------------- ----------- ------------- -------------- ------------ --------------
                            **Control**                  **RSR13**    

  **Primary**   **N(%)**    Controlled    Uncontrolled   Controlled   Uncontrolled

  **Site**                  N(%)          N(%)           N(%)         N(%)

  Breast        115(21)     18(27)        37(18)         19(26)       41(21)

  NSCLC         299( 56)    32(48)        119(60)        30(42)       118(59)

  Other         124(23)     17(25)        44(22)         23(32)       40(20)

  Total         538         67            200            72           199
  ------------- ----------- ------------- -------------- ------------ --------------

*Reviewer comment: The distribution of patients with controlled and
uncontrolled primary tumors were even except within the "other"
histological subgroup in which the RSR13 arm contained more controlled
primary tumors than those in the control arm.*

**Table 14: Distribution of Breast Histology Between Treatment Arms**

+-----------------+-----------------+-----------------+-----------------+
| **Primary       | **N(%)**        | **Control**     | **RSR13**       |
| Site**          |                 |                 |                 |
|                 |                 | **N(%)**        | **N(%)**        |
+-----------------+-----------------+-----------------+-----------------+
| Breast:         | 92(80)          | 46(84)          | 46(77)          |
|                 |                 |                 |                 |
| Infiltrating    | 4(3)            | 1(1)            | 3(5)            |
| ductal:         |                 |                 |                 |
|                 | 19(17)          | 8(15)           | 11(18)          |
| Infiltrating    |                 |                 |                 |
| lobular:        |                 |                 |                 |
|                 |                 |                 |                 |
| Other:          |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| Total           | 115             | 55              | 60              |
+-----------------+-----------------+-----------------+-----------------+

*Reviewer comment: The various breast histological subtypes were evenly
distributed between the two treatment arms.*

**Table 15: Distribution of KPS Score, Type of Treatment for Primary
Malignancy, and Surgical Resection Across Treatment Arms.**

+-----------------------+-------+-------+-------+-------+-------+-------+
| **Parameter**         | *     |       |       | **RS  |       |       |
|                       | *Cont |       |       | R13** |       |       |
|                       | rol** |       |       |       |       |       |
+-----------------------+-------+-------+-------+-------+-------+-------+
|                       | **NS  | **Bre | **Ot  | **NS  | **Bre | **Ot  |
|                       | CLC** | ast** | her** | CLC** | ast** | her** |
|                       |       |       |       |       |       |       |
|                       | N=151 | N=55  | N=61  | N=148 | N=60  | N=63  |
|                       |       |       |       |       |       |       |
|                       | \%    | \%    | \%    | \%    | \%    | \%    |
+-----------------------+-------+-------+-------+-------+-------+-------+
| KPS:                  | 57    | 56    | 43    | 57    | 60    | 59    |
|                       |       |       |       |       |       |       |
| 90 -- 100             | 43    | 44    | 57    | 43    | 40    | 41    |
|                       |       |       |       |       |       |       |
| \< 90                 |       |       |       |       |       |       |
+-----------------------+-------+-------+-------+-------+-------+-------+
| Prior Treatment of    | 25    | 91    | 54    | 20    | 88    | 68    |
| the Primary           |       |       |       |       |       |       |
| Malignancy:           | 32    | 64    | 21    | 25    | 50    | 11    |
|                       |       |       |       |       |       |       |
| surgical resection    | 38    | 80    | 36    | 35    | 78    | 43    |
|                       |       |       |       |       |       |       |
| radiation Therapy     | 0     | 56    | 2     | 1     | 45    | 2     |
|                       |       |       |       |       |       |       |
| chemotherapy          |       |       |       |       |       |       |
|                       |       |       |       |       |       |       |
| hormonal Therapy      |       |       |       |       |       |       |
+-----------------------+-------+-------+-------+-------+-------+-------+
| Surgical Resection of | 9     | 7     | 20    | 6     | 3     | 16    |
| Brain metastases      |       |       |       |       |       |       |
+-----------------------+-------+-------+-------+-------+-------+-------+

*Reviewer Comment: The NSCLC and Breast subgroups of the control arm had
more radiation therapy as prior treatment of the primary malignancy than
the corresponding subgroups in the RSR13 arm. This was also noted for
hormonal therapy in the breast subgroup.*

**Table 16: Reviewer's Table Demonstrating the Distribution of KPS in
the Breast Subgroup**

+-----------------------+-----------------------+-----------------------+
| **KPS**               | **Control (N=55)**    | **RSR13 (N=60)**      |
|                       |                       |                       |
|                       | **N(%)**              | **N(%)**              |
+-----------------------+-----------------------+-----------------------+
| 60                    | 0                     | 1(2)                  |
+-----------------------+-----------------------+-----------------------+
| 70                    | 9(16)                 | 9(15)                 |
+-----------------------+-----------------------+-----------------------+
| 80                    | 15(27)                | 14(23)                |
+-----------------------+-----------------------+-----------------------+
| 90                    | 24(44)                | 28(47)                |
+-----------------------+-----------------------+-----------------------+
| 100                   | 7(13)                 | 8(13)                 |
+-----------------------+-----------------------+-----------------------+

*Reviewer comment: The distribution of KPS score was even in both
treatment arms. This appears to be the case whether KPS is viewed as two
categories or as five categories.*

**Table 17: Summary of Prior Treatment by Treatment Arm (Breast
Subpopulation)**

+-----------------+-----------------+-----------------+-----------------+
| **Location of   | **Treatment**   | **Breast Cancer |                 |
| Malignancy**    |                 | Subpopulation** |                 |
+-----------------+-----------------+-----------------+-----------------+
|                 |                 | **Control = 55  | **RSR13 = 60    |
|                 |                 | patients**      | patients**      |
|                 |                 |                 |                 |
|                 |                 | **N(%)**        | **N(%)**        |
+-----------------+-----------------+-----------------+-----------------+
| Primary         | Surgical        | 50(91)          | 54(90)          |
| malignancy      | resection       |                 |                 |
|                 |                 | 39(71)          | 39(65)          |
|                 | Radiation       |                 |                 |
|                 | Therapy         | 48(87)          | 57(95)          |
|                 |                 |                 |                 |
|                 | Chemotherapy    | 34(62)          | 32(53)          |
|                 |                 |                 |                 |
|                 | Hormonal        |                 |                 |
|                 | therapy         |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| Extracranial    | Surgical        | 9(16)           | 6(10)           |
| metastases      | resection       |                 |                 |
|                 |                 | 14(25)          | 17(28)          |
|                 | Radiation       |                 |                 |
|                 | Therapy         | 30(55)          | 32(53)          |
|                 |                 |                 |                 |
|                 | Chemotherapy    | 13(24)          | 7(12)           |
|                 |                 |                 |                 |
|                 | Hormonal        |                 |                 |
|                 | Therapy         |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| Brain           | Surgical        | 4(7)            | 2(3)            |
| metastases      | resection       |                 |                 |
+-----------------+-----------------+-----------------+-----------------+

*Reviewer comment: There were some differences in the distribution of
patients exposed to prior treatment of extracranial metastases in the
breast cancer subgroup, the most notable of which appear to be in prior
hormonal therapy. The number of patients in each subgroup is too small
to make a statistical judgment.*

**Table 18: Number of Brain Lesions According to Baseline Scans (ITT
Population)**

+-----------------+-----------------+-----------------+-----------------+
| **Number of     | **N**           | **Control**     | **RSR13**       |
| Brain Lesions** |                 |                 |                 |
|                 |                 | **N(%)**        | **N(%)**        |
+-----------------+-----------------+-----------------+-----------------+
| 1               | 98              | 53(26)          | 45(17)          |
+-----------------+-----------------+-----------------+-----------------+
| 2-3             | 162             | 81(31)          | 81(31)          |
+-----------------+-----------------+-----------------+-----------------+
| \>3             | 266             | 127(49)         | 139(52)         |
+-----------------+-----------------+-----------------+-----------------+
| Total           | 526             | 261             | 265             |
+-----------------+-----------------+-----------------+-----------------+

*Reviewer comment: Although the incidence of brain lesions appear evenly
distributed between the control and RSR13 arms in the ITT population
(Table 18), this did not seem to be the case for the breast subgroup or
"other" subgroup (Table 19).*

**Table 19: Number of Brain Lesions by Primary Site of Disease in Each
Treatment Group**

+-----------+-----------+-----------------------+-----------------------+
| **Primary | **Number  | **Control**           | **RSR13**             |
| Site**    | of brain  |                       |                       |
|           | mets**    | **N(%)**              | **N(%)**              |
+-----------+-----------+-----------------------+-----------------------+
| Breast    | 1         | 7(13)                 | 13(22)                |
|           |           |                       |                       |
| (N=114)   | 2-3       | 9(16)                 | 14(24)                |
|           |           |                       |                       |
|           | \>3       | 40(71)                | 31(53)                |
+-----------+-----------+-----------------------+-----------------------+
| Sub-total |           | 56                    | 58                    |
+-----------+-----------+-----------------------+-----------------------+
| NSCLC     | 1         | 35(23)                | 24(16)                |
|           |           |                       |                       |
| (N=298)   | 2-3       | 51(34)                | 53(36)                |
|           |           |                       |                       |
|           | \>3       | 64(43)                | 71(48)                |
+-----------+-----------+-----------------------+-----------------------+
| Sub-total |           | 150                   | 148                   |
+-----------+-----------+-----------------------+-----------------------+
| Other     | 1         | 11(20)                | 8(14)                 |
|           |           |                       |                       |
| (N=114)   | 2-3       | 21(38)                | 14(24)                |
|           |           |                       |                       |
|           | \>3       | 23(42)                | 37(63)                |
+-----------+-----------+-----------------------+-----------------------+
| Sub-total |           | 55                    | 59                    |
+-----------+-----------+-----------------------+-----------------------+
| Total     |           | 261                   | 265                   |
| (526)     |           |                       |                       |
+-----------+-----------+-----------------------+-----------------------+

(Derived from primary.xpt and scans.xpt datasets)

*Reviewer's comment: The sponsor was queried about the total number of
patients in this table adding up to 526, rather than 538. The sponsor
explained 12 patients are not included for baseline scans. Nine patients
(2126, 2127, 2131, 2232, 3045, 3065, 4012, 4015, and 4113) were
categorized as "scans not done", or "scans not evaluable" and considered
as patients not evaluable since baseline information was not reliable.
The other three patient (3025, 2025, and 4040) had missing values for
baseline scan information.*

*Within the breast subpopulation, the number of patients with ≥3 brain
lesions was higher in the control arm than the RSR13 arm. In addition,
the number of patients with only one brain lesion was higher in the
treatment arm. This suggests a greater tumor burden in breast cancer
patients within the control arm than the RSR13 arm, which could
influence outcome. In the "other" subgroup, the control arm appears to
have a greater proportion of patients with 2 to 3 brain lesions.*

**EFFICACY RESULT -- SPONSOR'S ASSESSMENT**

**1.0 Primary Endpoint**

**1.1 Survival**

Overall survival was calculated from the time of randomization into the
study until death or

31 Jan 2003, whichever occurred first. All randomized patients in both
treatment arms were

followed for survival until death or for a minimum of 6 months and
patients that were still alive

were considered censored. The hazard rate was compared between treatment
arms using the

log-rank test (unadjusted for covariates).

[Log-rank Test]{.underline}

The observed MST for the Control arm was 4.47 months (n = 267) compared
to 5.26 months for

the RSR13 treatment arm (n = 271), and no statistically significant
difference was detected

between the survival distribution functions of the 2 arms using the
unadjusted log-rank test

(HR = 0.877, p = 0.1688). For all eligible patients (N = 515), the
observed MST for the Control arm was 4.37 months compared to 5.39 months
for the RSR13 arm, a difference that was not statistically significant
by log-rank test (p = 0.1549). There was also no statistically
significant difference in survival between the 2 arms for randomized
patients in the NSCLC/breast subpopulation (HR = 0.844, p = 0.1217), nor
was there a statistically significant difference for patients in Strata
1, 2, or 4 (RPA Class I patients, RPA Class II patients with NSCLC
primary, and RPA Class II patients with other primary, respectively).

The sponsor detected a significant difference between survival of the 2
arms for patients in Stratum 3 (RPA Class II patients with breast
primary; HR = 0.542, p = 0.0061). There was also a significant
difference between the 2 treatment arms in which patients with
metachronous brain metastases in the RSR13 arm had a longer MST than
metachronous patients in the Control arm (HR = 0.731, p = 0.0069).
However, there was no significant difference between the 2 treatment
arms for patients with synchronous brain metastases (HR = 1.267, p =
0.1598).

**Table 20: Summary of Applicant's Primary Analysis**

(Derived from table 14.2.2.1.1, Final Study Report)

+------------+--------+-----+--------+-----+-----+-----------+-----+
| **Po       | **Con  |     | **R    |     |     |           |     |
| pulation** | trol** |     | SR13** |     |     |           |     |
+------------+--------+-----+--------+-----+-----+-----------+-----+
|            | **     | *   | **     | *   | **H | **95%     | **  |
|            | N(%)** | *MS | N(%)** | *MS | R** | CI**      | p-v |
|            |        | T** |        | T** |     |           | alu |
|            |        |     |        |     |     |           | e** |
+------------+--------+-----+--------+-----+-----+-----------+-----+
| Patients:  | 26     | 4   | 27     | 5   | 0.  | 0.727,    | 0.1 |
|            | 7(100) | .47 | 1(100) | .26 | 877 | 1.057     | 688 |
| ITT        |        |     |        |     |     |           |     |
|            | 2      | 4   | 2      | 5   | 0.  | 0.719,    | 0.1 |
| Eligible   | 50(94) | .37 | 65(98) | .39 | 871 | 1.054     | 549 |
+------------+--------+-----+--------+-----+-----+-----------+-----+
| Breast and | 2      | 4   | 2      | 5   | 0.  | 0.680,    | 0.1 |
| Lung       | 06(77) | .47 | 08(77) | .91 | 844 | 1.047     | 217 |
+------------+--------+-----+--------+-----+-----+-----------+-----+
| Breast     | 55(21) | 4   | 60(22) | 8   | 0.  | 0.359,    | 0.0 |
|            |        | .57 |        | .67 | 552 | 0.850     | 061 |
+------------+--------+-----+--------+-----+-----+-----------+-----+
| NSCLC      | 1      | 4   | 1      | 4   | 0.  | 0.771,    | 0.9 |
|            | 51(57) | .37 | 48(55) | .94 | 991 | 1.273     | 426 |
+------------+--------+-----+--------+-----+-----+-----------+-----+
| Other      | 61(23) | 3   | 63(23) | 4   | 1.  | 0.708,    | 0.8 |
|            |        | .75 |        | .01 | 029 | 1.496     | 812 |
+------------+--------+-----+--------+-----+-----+-----------+-----+

ITT=intent to treat

MST=median survival time

*Reviewer comment: There was no significant difference in overall
survival in the intent to treat population using the logrank test. A
significant difference in overall survival was noted in the
subpopulation of breast cancer patients; however, this subpopulation was
a predefined subset of patients identified for stratification purposes
only. Any subgroup analysis of breast cancer patients or patients with
metachronous disease should be considered exploratory.*

[Analyses per SAP]{.underline}

The estimated increase in survival of patients enrolled in arm A (RSR13
arm) was based on

the assumption that RSR13 would increase the efficacy of whole brain
radiation. In this study, RSR13 was not intended to affect extra-cranial
cancers. Given concern that patients may die of progression due to
primary or metastatic extra-cranial tumors and that those deaths could
decrease overall survival time in both treatment arms, the sponsor
analyzed the survival data based on additional subsets of patients. The
log-rank test was performed on the subsets of patients with controlled
primary cancer and no extra-cranial metastases. It was anticipated that
these patients would have a higher probability of death due to
neurological progression and therefore are patients where RSR13 may have
the greatest impact on survival. Estimates of survival for treatment arm
A patients was also provided for each category of number of RSR13 doses
received: 0-6 and ≥ 7. One hundred thirty-nine patients were classified
as "Primary Disease Controlled": 67 in the Control arm and 72 in the
RSR13 arm. No statistically significant difference in survival was
detected between the treatment arms in this subset (HR = 1.006, 95% CI:
0.682-1.484). One hundred eighty patients were classified as having no
extracranial metastases: 96 in the Control arm and 84 in the RSR13 arm.
No statistically significant difference in survival was detected between
the treatment arms (HR = 1.008, 95% CI: 0.718-1.414). Two hundred
eighteen (80.4%) of the patients in the RSR13 arm received at least 7
doses of RSR13. Patients in this group had a statistically significant
increase in survival as compared to the RSR13 arm receiving fewer than 7
doses (HR = 0.636, p = 0.0060).

[Analyses for Patients with **NSCLC** as the Site of
Primary]{.underline}

The observed MST for NSCLC patients in the Control arm (n = 151) was
4.37 months compared

to 4.94 months in the RSR13 arm (n = 148), and no statistically
significant difference was

detected between the survival distribution functions of the 2 arms using
the unadjusted log-rank

test (HR = 0.991, p = 0.9426).

*Reviewer comment: This was not a prespecified analysis. At best, this
analysis can only be regarded as exploratory. As outlined in amendment
#2, a secondary analysis for the NSCLC/breast primary tumor
subpopulation was made at a later date (6/05/01), and did not
demonstrate a significant difference in survival.*

[Analyses for Patients with the **Breast** as the Site of
Primary]{.underline}

The observed MST for breast patients in the Control arm (n = 55) was
4.57 months compared to

8.67 months for the RSR13 arm (n = 60), and the sponsor reported a
significant difference between the survival distribution functions of
the 2 arms (HR = 0.552, p = 0.0061).

The sponsor also reported significant difference between the survival
distribution functions of the 2 arms for patients in Stratum 3 (RPA
Class II patients with breast primary; HR = 0.542, p = 0.0061).

*Reviewer comment: This was not a prespecified analysis. At best, this
analysis can only be regarded as exploratory. As outlined in amendment
#2, a secondary analysis for the NSCLC/breast primary tumor
subpopulation was made at a later date (6/05/01), and did not
demonstrate a significant difference in survival.*

[Analyses for Patients with **Other** Primary Site]{.underline}

The observed MST for the patients with other primary in the Control arm
(n = 61) was

3.75 months compared to 4.01 months for the RSR13 arm (n = 63), and no
statistically

significant difference was detected between the survival distribution
functions of the 2 arms

using the unadjusted log-rank test (HR = 1.029, p = 0.8812).

*Reviewer comment: This was not a prespecified analysis.*

[Cox Regression Models]{.underline}

Of the 538 randomized patients, 10 patients were excluded from the Cox
model analysis due to

missing values for baseline MRI/CT information (9 patients) and for
missing baseline weight

(1 patient). A Cox multiple regression model was run for each of the 48
possible models (every variable plus every combination of the five
variables with different possible values) for all randomized patients
and by site of primary. **Table 21** lists the 17 covariates used by the
sponsor.

**Table 21: Covariates Included in Cox Multiple Regression Models**

  -----------------------------------------------------------------------
  **Covariate**

  Site of primary\*

  KPS\*

  RPA Class\*

  Presence of extracranial mets\*

  Number of metastatic lesions\*

  Control of primary\*

  Age\*

  Presence of liver mets

  Timing of diagnosis

  Prior cranial met treatment

  High enrolling center

  Gender

  Baseline Hgb

  Altitude

  Location of center

  Dosing algorithm category

  BDP total area
  -----------------------------------------------------------------------

\*Covariates mentioned in the original protocol as important covariates
to test the relative importance of these factors for survival.

*Reviewer comment: The sponsor points out that the log-rank test does
not adjust for these 17 covariates and that there were imbalances in the
prognostic factors between the two treatment arms. After applying Cox
multiple regression models to adjust for these imbalances, the sponsor
found a statistically significant difference in survival favoring the
RSR13 arm. While some of these covariates may influence drug effect
(e.g. higher altitude causing more release of oxygen to tissue), a
literature review did not find support for the natural history of brain
metastases being altered by whether one is from a high enrolling center,
center in high altitude center, or any particular center location in
general.*

*Seven covariates (RPA class, site of primary cancer, primary tumor
control, age, presence of extracranial metastases, KPS, and number of
metastatic lesions) were alluded to in the original protocol of RT-009.
Furthermore, there is overlap of these covariates. For instance, KPS
already encompasses age and KPS.*

**For All Randomized Patients**

There was no statistically significant difference for RSR13 effect
between the treatment arms for all randomized patients when there were
no adjustments for covariates. However, the RSR13 indicator variable was
statistically significant in 100% (48/48) of the Cox models where RSR13
treatment effect was adjusted for all other covariates. According to the
Cox regression analyses, the most important non-stratification
prognostic factors (ie, those that were statistically significant in all
48 Cox models) for predicting survival were: KPS, previous treatment for
brain metastases indicator, number of extra-cranial metastases, gender,
age, and baseline Hgb. The Control arm had a higher relative frequency
of patients with the more favorable level of these covariates for all
prognostic factors except KPS. The sponsor feels that this helps to
explain why the Cox multiple regression model analyses were able to
detect a statistically significant survival advantage for patients in
the RSR13 arm compared to patients in the Control arm that the
unadjusted log-rank failed to detect.

**By Site of Primary**

In patients with breast primary, the RSR13 indicator variable was
statistically significant in

100% (48/48) of the Cox multiple regression models where RSR13 treatment
effect was adjusted

for all other covariates as well as the Cox single regression model (HR
= 0.552, p = 0.0069). In NSCLC and other primary patients, the RSR13
indicator variable was not statistically significant in any of the Cox
multiple regression models nor the Cox single regression model.

*Reviewer comment: See statistical review for further discussion of
covariate analysis.*

**2.0 Secondary Endpoints**

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

Time to radiographic tumor progression (TTRP), as determined by blinded
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 was recorded as a
competing risk when it occurred prior to diagnosed radiographic
progression.

*All Randomized Patients*

There was not a statistically significant difference in the cumulative
incidence of radiographic

progression between the Control arm and the RSR13 arm (χ^2^=0.458,
p=0.4986).

*By Site of Primary*

There was not a statistically significant difference in the cumulative
incidence of radiographic

progression between the Control arm and the RSR13 arm in the subset of
patients with NSCLC

(χ^2^=0.055, p=0.8142), breast (χ^2^= 0.063, p=0.8023), or other primary
(χ^2^=0.839, p=0.3597).

**2.2 Time to Clinical Progression in the Brain**

Time to clinical tumor progression (TTCP), was estimated for all
patients using cumulative incidence analysis and Kaplan-Meier methods
and tested between treatment arms

using Gray's, which is used for comparing the cumulative incidence of a
particular type of failure among different groups (9). Clinical
progression was defined as either neurological progression, as assessed
by the Neurological Function (NF) status score, or as neurocognitive
deterioration as measured by the Mini Mental State Examination (MMSE)
score, or as the use of subsequent therapy for brain metastases such as
radiation, surgery, and/or SRS. An increase from baseline of 1 or more
points in the NF status score indicated neurological disease
progression. Neurocognitive deterioration was defined as a decrease from
baseline in the MMSE score of 3 or more points.

*Reviewer comment: This is a composite endpoint with subjective measures
which can only be considered exploratory in this non-blinded clinical
trial. Neurological assessments such as the Neurological Function Status
Score and Mini-Mental Status Examination are of limited objectivity,
especially in the non-blinded setting. The decision as to the nature and
timing of subsequent treatment can be influenced by a number of
variables, making interpretation of this composite endpoint even more
difficult.*

*All Randomized Patients*

There was not a statistically significant difference in the cumulative
incidence of clinical

progression between the Control arm and the RSR13 arm (χ^2^=0.595,
p=0.4407).

*By Site of Primary*

There was not a statistically significant difference in the cumulative
incidence of clinical

progression between the Control arm and the RSR13 arm in the subset of
patients with NSCLC

(χ^2^=1.541, p=0.2145), breast (χ^2^=0.846, p=0.3577), or other primary
(χ^2^=0.377, p=0.5393).

**2.3 Response Rate in the Brain**

The distribution of best response in the brain was compared between
RSR13 arms using the

Cochran-Mantel-Haenszel test.

*All Randomized Patients*

Four hundred forty-five patients had a scan after the baseline scan from
which to assess

response; 216 patients in the Control arm and 229 patients in the RSR13
arm. For all randomized patients, there was not a statistically
significant difference in the distribution

of response between the treatment arms (χ^2^= 2.3839, p = 0.1226). The
point estimates of

response rate (complete plus partial response) were 37.5% in the Control
arm and 45.4% in the

RSR13 arm. The estimated increase in response rate in patients receiving
RSR13 was 7.9% with

an associated 95% confidence interval of --0.4% to 16.3% (p = 0.0609).

*Patients with NSCLC as the Site of Primary*

For patients with NSCLC primary, there was not a statistically
significant difference between the

arms in distribution of response (χ^2^ = 1.4216, p = 0.2331) . The point
estimates of response rate (CR or PR) were 37.7% in the Control arm and
45.3% in the RSR13 arm. The estimated increase in response rate in
patients receiving RSR13 was 7.5% with an associated 95% confidence
interval of --3.6% to 18.7% (p = 0.1857).

*Patients with Breast as the Site of Primary*

For patients with breast primary, there was a statistically significant
difference between the arms

in distribution of response (χ^2^= 5.8617, p = 0.0155). The point
estimates of response rate (CR or PR) were 49.1% in the Control arm and
71.7% in the RSR13 arm. The estimated increase in response rate in
patients receiving RSR13 was 22.6% with an associated 95% confidence
interval of 5.1% to 40.0% (p = 0.0112). There were 2 covariates that
were statistically significant for predicting response (CR or PR) when
logistic multiple regression was performed for breast primary patients:

RSR13 treatment effect (odds ratio = 2.622 \[95% CI: 1.157-5.942\], p =
0.0209) and patients with

a baseline KPS ≥90 versus \<90 (odds ratio = 3.806 \[95% CI:
1.680-8.624\], p = 0.0014).

For patients with breast primary, the number of patients in continuous
remission (CR or PR)

declined over time of follow-up in the Control arm (21, 11, and 11
patients at 1, 3, and 6 months,

respectively) versus the RSR13 arm (22, 26, and 20 patients at 1, 3, and
6 months,

respectively).

*Patients with Other Sites of Primary*

For patients with other sites of primary, there was not a statistically
significant difference

between the arms in distribution of response (χ^2^= 1.1994, p = 0.2735).
The point estimates of response rate (complete plus partial response)
were 26.2% in the Control arm and 20.6% in the RSR13 arm. The estimated
increase in response rate in patients receiving RSR13 was -5.6% with an
associated 95% confidence interval of -20.5% to 9.3% (p = 0.4615).

*Reviewer comment: In assessing response to treatment, the FDA has the
following concerns:*

-   *No predefined criteria for determining Best Response in the
    protocol*

-   *Confirmatory scans were not a protocol requirement*

-   *The designation of Complete Response or Partial Response was given
    regardless of the appearance of a new brain lesion.*

*Refer to section 1.2, FDA Analysis.*

**2.4 Cause of Death**

Cause of death was determined by the investigator and attributed to 1 of
3 categories: neurologic,

non-neurologic, or indistinguishable. Patients with unknown cause of
death were assigned a neurologic cause of death for calculation of all
statistical tests.

*All Randomized Patients*

Four hundred forty-one patients died by the time of data cutoff: 221 in
the Control arm and

220 in the RSR13 arm. Three patients withdrew consent and subsequently
died, and therefore, have missing values for cause of death. The
Cochran-Mantel-Haenszel test did not detect a difference in the
distribution of cause of death between the treatment arms (χ^2^ =
0.4361,

p = 0.5090). The Cochran-Mantel-Haenszel test did not detect a
difference in the distribution of cause of death between the treatment
arms in the subset of patients with NSCLC primary

(χ^2^ = 0.0562, p = 0.8127), breast primary (χ^2^ = 1.4692, p = 0.2255),
or other primary (χ^2^ = 0.0079,

p = 0.9292).

**2.5 Quality of Life**

This 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 include
WBRT day 10. KPS measurements were used to evaluate a patient's
condition. A KPS score could range from 100 (normal, no complaints, no
evidence of disease) to 0 (death), thus a decrease in score indicated a
worsening or deterioration in the patient's condition. Patients must
have had a KPS score of at least 70 to be eligible for enrollment.
Spitzer Questionnaire (SQ) scores were based on 5 questions each worth
0-2 points for a total of 10 possible points. Patients with at least 3
of the 5 questions answered were given a scaled total score equivalent
to the average score per question multiply by 5. The SQ scores at the
6-month and 1-year follow-up visits were compared to baseline for each
patient and categorized as one of the following: stable or increasing,
decreased by 1-2 points inclusive, or decreased by more than 2 points.
The distribution of SQ categories at 6-months and at 1-year was compared
between treatment arms using the Cochran-Mantel-Haenzel test.

*KPS: All Randomized Patients*

For all randomized patients, the distributions of KPS scores were
similar at all time-points

between the 2 treatment arms, and no statistically significant
difference was

detected in the distribution of KPS score categories between treatment
arms at 6 months or

1 year using the Cochran-Mantel-Haenzel test: χ^2^= 2.0318, p = 0.1540
and χ^2^ = 1.7727,

*KPS: Patients with NSCLC as the Site of Primary*

For patients with NSCLC primary, no statistically significant difference
was detected in the

distribution of KPS score categories between treatment arms at 6 months
and 1 year using the

Cochran-Mantel-Haenzel test: χ^2^= 0.2992, p = 0.5844 and χ^2^ = 0.1221,
p = 0.7268, respectively.

*KPS: Patients with Breast as the Site of Primary*

For patients with breast primary, a statistically significant difference
was detected in the

distribution of KPS score categories between treatment arms at 6 months
and 1 year using the

Cochran-Mantel-Haenzel test: χ^2^ = 8.0212, p = 0.0046 and χ^2^ =7.2717,
p = 0.0070, respectively.

The percentages of patients with breast primary in the RSR13 arm who had
a stable or an

increasing KPS score at the 6-month interval (30% \[18/60\]) was higher
than in patients with

NSCLC primary (16% \[24/148\]) and patients with other sites of primary
(11% \[7/63\]). The

percentages of Control arm patients with a stable or an increasing KPS
score were similar at

every time-point across the 3 "Site of Primary" categories but lower
than the breast patients in

the RSR13 arm.

*KPS: Patients with Other Sites of Primary*

For patients with other primary, no statistically significant difference
was detected in the

distribution of KPS score categories between treatment arms at 6 months
and 1 year using the

Cochran-Mantel-Haenzel test: χ^2^ = 0.9718, p = 0.3242 and χ^2^ =
0.2715,

*Spitzer Questionnaire: All Randomized Patients*

For all randomized patients, the distributions of SQ scores were similar
at all time-points

between the 2 treatment arms and there was not a statistically
significant

difference in the distribution of SQ scores between the treatment arms
at 6 months or 1 year

using the Cochran-Mantel-Haenzel test: χ^2^= 1.0232, p = 0.3118 and χ^2^
= 1.6712, p = 0.1961,

respectively. The percentages of patients in the Control arm who had a
stable or an increasing

SQ score at the 6-month and 1-year intervals (15% \[39/267\] and 6%
\[15/267\], respectively) were

comparable to the RSR13 arm (16% \[43/271\] and 9% \[24/271\],
respectively).

*Spitzer Questionnaire: By Site of Primary*

There was not a statistically significant difference in the distribution
of SQ scores at the 6-month

or 1-year intervals between the Control arm and the RSR13 arm in the
subset of patients with

NSCLC (χ^2^ = 1.8099, p = 0.1785 and χ^2^= 0.7259, p = 0.3942), or other
primary (χ^2^ = 0.8519,

p = 0.3560 and χ^2^ = 0.2258, p = 0.6347, respectively) and at the
6-month interval in the subset of

patients with breast primary (χ^2^= 0.2107, p = 0.6462)(chi-square and a
p-value were not

calculated at 1-year due to missing data).

**EFFICACY RESULTS -- FDA ASSESSMENT**

**1.1 Primary Endpoint -- Survival**

Of the 538 patients randomized at study entry, 23 were subsequently
labeled ineligible (refer back to table 8), leaving 515 evaluable
patients from the intent to treat population. Amendment #2 provided that
the combined results of the NSCLC and breast primary tumor subpopulation
would also be analyzed for efficacy. One-hundred-seventy-three patients
had been enrolled by the time of this amendment.

The sponsor's proposed indication for the use of RSR13 is as adjunctive
therapy to whole brain radiation therapy in the treatment of brain
metastases originating from breast cancer. The Sponsor did not find a
statistically significant difference in survival between the two
treatment arms when analyzed using the log-rank test (median survival
time: control=4.47 months vs. RSR13=5.26 months, p=0.169). There was
also no statistically significant difference in survival between the two
arms for randomized patients in the NSCLC/Breast subpopulation
(HR=0.877, p=0.1217).

The Sponsor retrospectively analyzed the collected data and noted
significant p values for overall survival in the non-prespecified breast
cancer subpopulation using the log-rank test (control arm=4.57 months
vs. 8.67 months, p-0.0061).

##### 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 22. 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 1. The efficacy analysis in the subgroup of NSCLC/Breast primary patients is presented in Table 23. The Kaplan-Meier curves for the NSCLC/Breast subgroup is presented in Figure 2. There were 331/414 deaths in this subgroup at the time of the final analysis.

**Table 22: 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 1: Kaplan-Meier Survival Curves in the ITT Population**

![](media/image2.png){width="5.491666666666666in"
height="4.031944444444444in"}

The FDA analysis confirmed the sponsor's findings that there was no
statistically significant difference in overall survival between the two
treatment arms in the intent to treat population.

**Table 23: 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 mis-classification (i.e., non-randomized subgroup);

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

^3^: unadjusted log-rank test.

**Figure 2: Kaplan-Meier Survival Curves in the Subgroup of Patients
with NSCLC/Breast Primary**

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

The FDA analysis confirmed the sponsor's findings that there was no
statistically significant difference in overall survival between the two
treatment arms in the NSCLC/Breast groups combined.

For enrollment, all patients had to have a KPS score of ≥ 70 (**Table
16**). As for prior (initial) treatment of the primary malignancy, the
distribution of surgical resections performed, radiation therapy given,
chemotherapy, and hormonal therapy administered was fairly balanced
between the two treatment arms, except in the control arm for hormonal
therapy (**Table 17**). More patients had received hormonal therapy in
the control arm of the breast cancer subpopulation.

Patients were stratified at the time of enrollment by RPA Classes I and
II to balance both treatment arms. RPA Class II patients were further
stratified by site of the primary cancer (NSCLC vs. breast vs. other).
When these results were analyzed using the log-rank test, no
statistically significant difference in overall survival was observed
between treatment arms. After study completion, a statistically
significant difference was observed in the subgroup of breast cancer
patients. However, this was a subgroup established for stratification
purposes, not as a prespecified endpoint to test survival as a
hypothesis in this specific subgroup. The finding in the breast
subpopulation can only be considered exploratory at this time. **Table
24** reveals the exploratory survival analysis in the subgroup of
patients with primary breast cancer. The International Conference on
Harmonisation -- Guideline for Industry, section 11.4.2.8 (Examination
of Subgroups), states that subgroup analyses "are not intended to
'salvage' an otherwise nonsupportive study but may suggest hypotheses
worth examining in other studies or be helpful in refining labeling
information, patient selection, or dose escalation. When there is a
prior hypothesis of a differential effect in a particular subgroup, this
hypothesis and its assessment should be part of the planned statistical
analyses." Please see the statistical review for further discussion.

**Table 24: 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

The sponsor used the Cox multiple regression model to adjust for
potential imbalances within the two treatment arms. A reference is given
to Akazawa et al. (6), highlighting the regression model's ability to
adjust for the imbalance of prognostic factors between two treatment
groups. Such a strategy is not intended to be used as a substitute when
the primary analysis has failed according to the log-rank test.

**Table 21** listed the seventeen covariates identified by the sponsor
as potential imbalances between the control and RSR13 treatment groups.
Only seven covariates (site of primary, KPS, RPA class, presence of
extracranial metastases, number of metastatic lesions, control of
primary malignancy, and age) were mentioned in Version 1 of RT-009.
Furthermore, there is overlap of these covariates. For instance, KPS
already encompasses age and KPS. Again, although covariates such as a
high enrolling center and center location may influence the quality of
clinical trial conducted, no data is available to support the notion
that patients with brain metastases from high enrolling centers have
more favorable outcomes than those enrolled from lower enrolling
centers. Furthermore, while a high altitude may influence release of
drug such as RSR13 to tissue, there is no supportive evidence that
patients with brain metastases have more favorable outcomes based on the
altitude at which they live.

The FDA has concerns over the existence of imbalances in the number of
brain lesions between the two treatment arms in the breast subgroup as
presented in **Table 19**. It appears the control arm had a higher
percentage of patients with three or more documented brain lesions (71%
in the control arm versus 53% in the RSR13 arm). This suggests a greater
tumor burden in patients on the control arm within the breast subgroup
that were already destined to have a shorter survival when compared to
patients with fewer and possibly smaller brain lesions.

As for subsequent treatments - defined as any form of palliative therapy
administered after exposure to RSR13, the distribution of surgery,
radiation therapy, chemotherapy, hormonal therapy, stereotactic
procedures, other research studies, unknown therapies, and no further
treatment -- several imbalances were noted as outlined under **Tables
25** through **32**. **Tables 25** through **27** focuses on the Intent
To Treat population broken down by subsequent treatment of extracranial
metastases, primary malignancy, and brain metastases. **Tables 28**
through **30** focuses on the Breast subpopulation broken down by
subsequent treatment of extracranial metastases, primary malignancy, and
brain metastases. **Table 31** and **Table 32** combines subsequent
treatment of extracranial metastases and primary malignancy into the
category of Systemic Treatment for simplification.

**Table 25: Intent to Treat Population- Subsequent Treatment of**
Extracranial Metastases

+-----------------------+-----------------------+-----------------------+
| **Treatment Type**    | **Control**           | **RSR13**             |
|                       |                       |                       |
|                       | **(267 patients)**    | **(271 patients)**    |
|                       |                       |                       |
|                       | **N(%)**              | **N(%)**              |
+-----------------------+-----------------------+-----------------------+
| Surgical resection    | 7(3)                  | 4(1)                  |
+-----------------------+-----------------------+-----------------------+
| Radiation therapy     | 47(18)                | 51(19)                |
+-----------------------+-----------------------+-----------------------+
| Chemotherapy          | 37(14)                | 39(14)                |
+-----------------------+-----------------------+-----------------------+
| Hormonal therapy      | 7(3)                  | 10(4)                 |
+-----------------------+-----------------------+-----------------------+
| Stereotactic          | 0                     | 0                     |
| radiosurgery          |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Other research study  | 2(1)                  | 0                     |
+-----------------------+-----------------------+-----------------------+
| Other therapy         | 13(5)                 | 18(7)                 |
+-----------------------+-----------------------+-----------------------+
| Unknown               | 0                     | 0                     |
+-----------------------+-----------------------+-----------------------+
| No treatment          | 113(42)               | 124(46)               |
+-----------------------+-----------------------+-----------------------+

The distribution of subsequent treatment types for extracranial
metastases was even in both treatment arms in the intent to treat
population.

**Table 26: Intent to Treat Population- Subsequent Treatment of**
Primary Malignancy

+-----------------------+-----------------------+-----------------------+
| **Treatment Type**    | **Control**           | **RSR13**             |
|                       |                       |                       |
|                       | **(267 patients)**    | **(271 patients)**    |
|                       |                       |                       |
|                       | **N(%)**              | **N(%)**              |
+-----------------------+-----------------------+-----------------------+
| Surgical resection    | 2(\<1)                | 4(1)                  |
+-----------------------+-----------------------+-----------------------+
| Radiation therapy     | 39(15)                | 48(18)                |
+-----------------------+-----------------------+-----------------------+
| Chemotherapy          | 62(23)                | 76(28)                |
+-----------------------+-----------------------+-----------------------+
| Hormonal therapy      | 7(3)                  | 14(5)                 |
+-----------------------+-----------------------+-----------------------+
| Stereotactic          | 0                     | 0                     |
| radiosurgery          |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Other research study  | 4(1)                  | 3(1)                  |
+-----------------------+-----------------------+-----------------------+
| Other therapy         | 8(3)                  | 2(1)                  |
+-----------------------+-----------------------+-----------------------+
| Unknown               | 0                     | 0                     |
+-----------------------+-----------------------+-----------------------+
| No treatment          | 161(60)               | 153(56)               |
+-----------------------+-----------------------+-----------------------+

In general, subsequent treatment type (of the primary malignancy) were
evenly distributed in the two study arms. Whether the numerically
increased percentage of patients receiving chemotherapy in the RSR13 arm
(23% vs. 28%) is of significance is difficult to assess.

**Table 27: Intent to Treat Population- Subsequent Treatment of** Brain
Metastases

+-----------------------+-----------------------+-----------------------+
| **Treatment Type**    | **Control**           | **RSR13**             |
|                       |                       |                       |
|                       | **(267 patients)**    | **(271 patients)**    |
|                       |                       |                       |
|                       | **N(%)**              | **N(%)**              |
+-----------------------+-----------------------+-----------------------+
| Surgical resection    | 9(3)                  | 4(1)                  |
+-----------------------+-----------------------+-----------------------+
| Radiation therapy     | 8(3)                  | 11(4)                 |
+-----------------------+-----------------------+-----------------------+
| Chemotherapy          | 7(3)                  | 3(1)                  |
+-----------------------+-----------------------+-----------------------+
| Hormonal therapy      | 0                     | 0                     |
+-----------------------+-----------------------+-----------------------+
| Stereotactic          | 13(5)                 | 18(7)                 |
| radiosurgery          |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Other research study  | 0                     | 0                     |
+-----------------------+-----------------------+-----------------------+
| Other therapy         | 0                     | 0                     |
+-----------------------+-----------------------+-----------------------+
| Unknown               | 0                     | 1(\<1)                |
+-----------------------+-----------------------+-----------------------+
| No treatment          | 236(88)               | 234(86)               |
+-----------------------+-----------------------+-----------------------+

The distribution of subsequent treatment types (for brain metastases)
was even in both arms.

**Table 28: Breast Subpopulation- Subsequent Treatment of** Extracranial
Metastases

+-----------------------+-----------------------+-----------------------+
| **Treatment Type**    | **Control**           | **RSR13**             |
|                       |                       |                       |
|                       | **(55 patients)**     | **(60 patients)**     |
|                       |                       |                       |
|                       | **N(%)**              | **N(%)**              |
+-----------------------+-----------------------+-----------------------+
| Surgical resection    | 3(5)                  | 1(2)                  |
+-----------------------+-----------------------+-----------------------+
| Radiation therapy     | 11(20)                | 16(27)                |
+-----------------------+-----------------------+-----------------------+
| Chemotherapy          | 16(30)                | 21(35)                |
+-----------------------+-----------------------+-----------------------+
| Hormonal therapy      | 6(11)                 | 9(15)                 |
+-----------------------+-----------------------+-----------------------+
| Stereotactic          | 0                     | 0                     |
| radiosurgery          |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Other research study  | 0                     | 0                     |
+-----------------------+-----------------------+-----------------------+
| Other therapy         | 11(20)                | 12(20)                |
+-----------------------+-----------------------+-----------------------+
| Unknown               | 0                     | 0                     |
+-----------------------+-----------------------+-----------------------+
| No treatment          | 24(44)                | 21(35)                |
+-----------------------+-----------------------+-----------------------+

Subsequent treatment of extracranial metastases in the breast
subpopulation with radiation therapy, chemotherapy, or hormonal therapy
was numerically greater in the RSR13 arm. It is difficult to assess the
significance of this finding given the small number of patients
involved.

**Table 29: Breast Subpopulation-** Subsequent Treatment of Primary
Malignancy

+-----------------------+-----------------------+-----------------------+
| **Treatment Type**    | **Control**           | **RSR13**             |
|                       |                       |                       |
|                       | **(55 patients)**     | **(60 patients)**     |
|                       |                       |                       |
|                       | **N(%)**              | **N(%)**              |
+-----------------------+-----------------------+-----------------------+
| Surgical resection    | 1(2)                  | 1(2)                  |
+-----------------------+-----------------------+-----------------------+
| Radiation therapy     | 2(4)                  | 2(5)                  |
+-----------------------+-----------------------+-----------------------+
| Chemotherapy          | 11(20)                | 12(20)                |
+-----------------------+-----------------------+-----------------------+
| Hormonal therapy      | 7(13)                 | 12(20)                |
+-----------------------+-----------------------+-----------------------+
| Stereotactic          | 0                     | 0                     |
| radiosurgery          |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Other research study  | 0                     | 0                     |
+-----------------------+-----------------------+-----------------------+
| Other therapy         | 1(2)                  | 1(2)                  |
+-----------------------+-----------------------+-----------------------+
| Unknown               | 0                     | 0                     |
+-----------------------+-----------------------+-----------------------+
| No treatment          | 35(64)                | 36(60)                |
+-----------------------+-----------------------+-----------------------+

Subsequent treatment of the primary malignancy with hormonal therapy was
numerically greater in the RSR13 treatment arm compared to control*.*

**Table 30: Breast Subpopulation-** Subsequent Treatment of Brain
Metastases

+-----------------------+-----------------------+-----------------------+
| **Treatment Type**    | **Control**           | **RSR13**             |
|                       |                       |                       |
|                       | **(55 patients)**     | **(60 patients)**     |
|                       |                       |                       |
|                       | **N(%)**              | **N(%)**              |
+-----------------------+-----------------------+-----------------------+
| Surgical resection    | 1(2)                  | 1(2)                  |
+-----------------------+-----------------------+-----------------------+
| Radiation therapy     | 1(2)                  | 2(3)                  |
+-----------------------+-----------------------+-----------------------+
| Chemotherapy          | 2(4)                  | 1(2)                  |
+-----------------------+-----------------------+-----------------------+
| Hormonal therapy      | 0                     | 0                     |
+-----------------------+-----------------------+-----------------------+
| Stereotactic          | 4(7)                  | 3(5)                  |
| radiosurgery          |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Other research study  | 0                     | 0                     |
+-----------------------+-----------------------+-----------------------+
| Other therapy         | 0                     | 0                     |
+-----------------------+-----------------------+-----------------------+
| Unknown               | 0                     | 0                     |
+-----------------------+-----------------------+-----------------------+
| No treatment          | 49(89)                | 54(90)                |
+-----------------------+-----------------------+-----------------------+

The distribution of subsequent treatment types for brain metastases was
even in both arms of the study.

**Table 31: Breast Subpopulation: Subsequent Systemic Treatment
(Extracranial Metastases and for Primary Malignancy)**

+-----------------------+-----------------------+-----------------------+
| **Treatment Type**    | **Control**           | **RSR13**             |
|                       |                       |                       |
|                       | **(55 patients)**     | **(60 patients)**     |
|                       |                       |                       |
|                       | **N(%)**              | **N(%)**              |
+-----------------------+-----------------------+-----------------------+
| Surgical resection    | 4(7)                  | 2(3)                  |
+-----------------------+-----------------------+-----------------------+
| Radiation therapy     | 13(24)                | 18(30)                |
+-----------------------+-----------------------+-----------------------+
| Chemotherapy          | 25(45)                | 32(53)                |
+-----------------------+-----------------------+-----------------------+
| Hormonal therapy      | 13(24)                | 18(30)                |
+-----------------------+-----------------------+-----------------------+
| Stereotactic          | 0                     | 0                     |
| radiosurgery          |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Other research study  | 0                     | 0                     |
+-----------------------+-----------------------+-----------------------+
| Other therapy         | 11(20)                | 13(22)                |
+-----------------------+-----------------------+-----------------------+
| Unknown               | 0                     | 0                     |
+-----------------------+-----------------------+-----------------------+
| No treatment          | 46(84)                | 45(75)                |
+-----------------------+-----------------------+-----------------------+

Subsequent exposure to radiation therapy, chemotherapy, and hormonal
therapy were more frequent in the RSR13 arm. The percentage of patients
having no further systemic therapy in the breast subpopulation was lower
in the RSR13 treatment arm.

**Table 32:** Intent to Treat Population: Subsequent Systemic Treatment
(Extracranial Metastases and for Primary Malignancy)

+-----------------------+-----------------------+-----------------------+
| **Treatment Type**    | **Control**           | **RSR13**             |
|                       |                       |                       |
|                       | **(267 patients)**    | **(271 patients)**    |
|                       |                       |                       |
|                       | **N(%)**              | **N(%)**              |
+-----------------------+-----------------------+-----------------------+
| Surgical resection    | 9(3)                  | 8(3)                  |
+-----------------------+-----------------------+-----------------------+
| Radiation therapy     | 81(30)                | 89(33)                |
+-----------------------+-----------------------+-----------------------+
| Chemotherapy          | 91(34)                | 105(39)               |
+-----------------------+-----------------------+-----------------------+
| Hormonal therapy      | 14(5)                 | 20(7)                 |
+-----------------------+-----------------------+-----------------------+
| Stereotactic          | 0                     | 0                     |
| radiosurgery          |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Other research study  | 5(2)                  | 3(1)                  |
+-----------------------+-----------------------+-----------------------+
| Other therapy         | 20(7)                 | 24(9)                 |
+-----------------------+-----------------------+-----------------------+
| Unknown               | 0                     | 0                     |
+-----------------------+-----------------------+-----------------------+
| No treatment          | 207(77)               | 202(74)               |
+-----------------------+-----------------------+-----------------------+

Within the intent to treat population, the distribution of subsequent
systemic therapy types was even between both arms of the study.

Cause of death was to be determined by the investigator and documented
on the individual CRF

according to 1 of 3 categories:

-    **Neurologic cause of death**: The patient had stable systemic
    disease and progressive disease in the brain.

-    **Non-neurologic cause of death**: death was not caused by
    progressive brain disease; the death was further attributed to
    systemic cancer if extracranial progression occurred (primary or
    extracranial metastases), or to other causes including unknown.

-    **Indistinguishable cause of death**: Death could have been caused
    by documented progressive disease in the brain and/or by documented
    extracranial progression.

**Table 33** illustrates the distribution of neurologic and
non-neurologic causes of death in the treatment arms. Neurologic causes
of death included cerebral edema, neurological deterioration, and
convulsions. The non-neurologic causes of death included pneumonia,
acute renal failure, cachexia, and pulmonary embolus. These findings
suggest that the majority of breast cancer patients with brain
metastases died of non-neurologic causes of death, causes that were not
influenced by RSR13. Furthermore, a notable proportion of patients died
of causes that were indistinguishable.

**Table 33: Cause of Death - Neurologic vs. Non-neurologic**

+-----------------+-----------------+-----------------+-----------------+
| **Cause of      | **Control**     | **RSR13**       | **Total**       |
| Death**         |                 |                 |                 |
|                 | **N(%)**        | **N(%)**        | **N(%)**        |
+-----------------+-----------------+-----------------+-----------------+
| Neurologic      | 34(13)          | 36(13)          | 70(13)          |
+-----------------+-----------------+-----------------+-----------------+
| Non-neurologic  | 128(48)         | 128(47)         | 256(47)         |
+-----------------+-----------------+-----------------+-----------------+
| In              | 58(22)          | 53(19)          | 111(20)         |
| distinguishable |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| Alive/NA        | 47(18)          | 53(19)          | 100(18)         |
+-----------------+-----------------+-----------------+-----------------+
| Unknown         | 0               | 1               | 1               |
+-----------------+-----------------+-----------------+-----------------+
| Total           | 267             | 271             | 538             |
+-----------------+-----------------+-----------------+-----------------+

**1.2 Secondary Endpoint - Response Rates in the Brain**

> **Table 34: Reported Response Rates in the Brain According to Sponsor
> (ITT)**

+--------------------+------------------------+------------------------+
| **Response**       | **Control**            | **RSR13**              |
|                    |                        |                        |
|                    | **267 patients**       | **271 patients**       |
|                    |                        |                        |
|                    | **N(%)**               | **N(%)**               |
+--------------------+------------------------+------------------------+
| CR                 | 16(6)                  | 28(10)                 |
+--------------------+------------------------+------------------------+
| PR                 | 84(31)                 | 95(35)                 |
+--------------------+------------------------+------------------------+
| Cr+PR              | 100(37) CI: 0.32, 0.44 | 123(45) CI: 0.39, 0.52 |
+--------------------+------------------------+------------------------+

**Table 34** shows the response rates in the brain within the intent to
treat population according to the sponsor's analysis.

As already stated in this review, the FDA has concerns regarding this
analysis. First, the method for determining Best Response was not given
in the protocol. The sponsor replied to a query dated 2-22-04 that Best
Response was determined by selecting the maximal response for a patient,
starting at the 1-month follow-up visit and following overtime until
progressive disease or subsequent treatment of brain metastases (or
death) occurred. This is explained further in **Table 35**.

**Table 35: Method of Determining Best Response (Sponsor's Table)**

![](media/image4.png){width="6.498611111111111in"
height="1.2743055555555556in"}

As already stated in this review, the appearance of a new brain
parenchymal lesion during or proceeding the treatment was recorded in
RT-009, but was not considered a sign of progression. **Table 36**
removes four patients (three in the control arm and one in the RSR13
arm) labeled as a CR or PR on the same date as documentation of a new
brain lesion. The percentages of actual CR's and PR's do not change.

> **Table 36: Response Rates in the Brain** According to FDA Analysis

+--------------------+------------------------+------------------------+
| **Response**       | **Control**            | **RSR13**              |
|                    |                        |                        |
|                    | **267 patients**       | **271 patients**       |
|                    |                        |                        |
|                    | **N(%)**               | **N(%)**               |
+--------------------+------------------------+------------------------+
| CR                 | 15(6)                  | 27(10)                 |
+--------------------+------------------------+------------------------+
| PR                 | 82(31)                 | 95(35)                 |
+--------------------+------------------------+------------------------+
| CR+PR              | 97(36) CI: 0.31, 0.42  | 122(45) CI: 0.39, 0.51 |
+--------------------+------------------------+------------------------+

The sponsor stated in response to our query that confirmatory imaging
was not required according to the protocol; however, they provided
estimates of confirmed responses as illustrated in **Table 37**.
Confirmation of response was assessed by comparing the response of the
first scan after the best response to the best response. If the response
was the same as best response, response was considered confirmed.

**Table 37**: Confirmed Best Response in the Brain According to
Sponsor\*\^

+----------+---------+---------+---------+---------+---------+---------+
| **RE     | **CO    |         |         | **      |         |         |
| SPONSE** | NTROL** |         |         | RSR13** |         |         |
|          |         |         |         |         |         |         |
|          | **267   |         |         | **271   |         |         |
|          | PAT     |         |         | PAT     |         |         |
|          | IENTS** |         |         | IENTS** |         |         |
|          |         |         |         |         |         |         |
|          | *       |         |         | N(%)    |         |         |
|          | *N(%)** |         |         |         |         |         |
+----------+---------+---------+---------+---------+---------+---------+
| Best /   | NSCLC   | Breast  | Other   | NSCLC   | Breast  | Other   |
| C        |         |         |         |         |         |         |
| onfirmed | 151(56) | 55(20)  | 61(23)  | 148(55) | 60(22)  | 63(23)  |
+----------+---------+---------+---------+---------+---------+---------+
| CR / CR  | 8(5)    | 3(5)    | 1(2)    | 12(8)   | 4(6)    | 1(1)    |
|          |         |         |         |         |         |         |
| CR / PR  | 1(1)    | 2(4)    | 0(0)    | 5(3)    | 3(5)    | 0(0)    |
|          |         |         |         |         |         |         |
| PR / PR  | 22(14)  | 6(11)   | 3(5)    | 19(13)  | 18(30)  | 7(11)   |
+----------+---------+---------+---------+---------+---------+---------+
| Total    | 31(20)  | 11(20)  | 4(6)    | 36(24)  | 25(42)  | 8(12)   |
+----------+---------+---------+---------+---------+---------+---------+

> (Table provided by sponsor)
>
> \*Assessed by comparing the response of the first scan after best
> response to the best response. If the response was the same as best,
> response was considered confirmed.

\^Median time to confirmation \~ 2.3 months

Because confirmatory imaging studies were not required, it is difficult
to interpret the findings shown in **Table 37**. Furthermore, the FDA
cannot adequately assess duration of response due to the lack of
confirmatory scans. Given that both oxygen and radiation therapy were
part of the treatment in both arms and given the issues discussed above,
there is uncertainty as to the contribution of RSR13 to tumor response.
Therefore, it is not likely that response rate in the brain could be
used as a surrogate to predict clinical benefit in this case.

**1.3 Other Secondary Endpoints**

There were no statistically significant findings in Time to Radiographic
Tumor Progression in the Brain and Time to Clinical Tumor Progression in
the Brain.

-   Cause of Death

This is discussed under section 1.1.

+-----------------------------------------------------------------------+
| > **RT-008**:                                                         |
|                                                                       |
| **A PHASE 2 STUDY TO EVALUATE THE EFFICACY AND SAFETY OF RSR13        |
| ADMINISTERED TO PATIENTS RECEIVING STANDARD CRANIAL RADIATION THERAPY |
| FOR BRAIN METASTASES**                                                |
+-----------------------------------------------------------------------+

**PROTOCOL REVIEW**

**Table 38: Summary of Protocol Amendments**

![](media/image5.png){width="6.0625in" height="4.354166666666667in"}

  ---------- ----------- ----------- ------------------------------------
  (Derived                           
  from Table                         
  9.4, Final                         
  Study                              
  Report                             
  RT-008)                            

                                     

                                     

                                     

                                     
  ---------- ----------- ----------- ------------------------------------

**1.0 Objectives**

-   Evaluate overall median survival time (MST), response rate (CR and
    PR in the brain), and time to tumor progression in the brain in
    patients after receiving daily IV doses of 100 mg/kg RSR13
    administered over 30 minutes with standard WBRT for brain
    metastases.

-   Evaluate the safety of daily IV doses of 100 mg/kg RSR13
    administered over 30 minutes to patients receiving standard WBRT for
    brain metastases.

-   Determine the PK/PD profile of daily IV doses of 100 mg/kg RSR13
    administered over 30 minutes in this patient population.

**1.1 Survival**

Survival time was defined as the period from Radiation Therapy (RT) day
1 to death. All patients in this study were followed for survival until
death or for a minimum of 24 months.

**1.2 Response Rate in the Brain**

Response was determined based upon evaluation of each patient's MRI or
CT.

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

Time to tumor progression was defined as the time from RT day 1 to
documented disease progression.

**2.0 Eligibility Criteria**

-   Patients must have been at least 18 years of age.

-   Patients with histologically or cytologically confirmed breast,
    NSCLC primary carcinoma, melanoma, GU, or GI primary carcinomas. The
    type of primary carcinoma may have included the following: invasive
    ductal or invasive lobular adenocarcinoma of the breast; or large
    cell carcinoma, adenocarcinoma (including bronchoalveolar
    carcinoma), squamous or epidermoid carcinoma of the lung; or any
    melanoma, GU, or GI carcinoma.

-   Patients must have had either histologically or cytologically
    confirmed brain metastases or radiographic studies consistent with
    brain metastases and a histologically or cytologically confirmed
    malignancy as defined above. If no obvious primary cancer was seen,
    then a histological diagnosis consistent with a breast, NSCLC,
    melanoma, GU, or GI primary was sufficient for entry.

-   KPS ≥ 70.

-   Patients must have met the RTOG criteria for RPA Class I or Class
    II.

-   Patients must have had no prior treatment for brain metastases with
    RT, surgical resection, chemotherapy, hormonal therapy,
    immunotherapy, or biologic agents. Corticosteroid therapy was
    allowed.

-   Patients must not have received chemotherapy within 1 week before
    the start of RT. Patients may not have received chemotherapy during
    RT and RSR13 administration in the study.

-   Patients must have had a baseline resting SpO2 ≥ 90% on room air.

-   Patients must have had adequate hematologic, hepatic, and renal
    function as defined by:

-   WBC count ≥ 2,000 cells/mm^3^, hemoglobin ≥ 10 g/dL, platelet count
    ≥ 100,000 cells/mm^3^, bilirubin ≤ 2.0 mg/dL, alkaline phosphatase
    and transaminases ≤ times the upper limit of normal, and creatinine
    ≤ 2.0 mg/dL.

-   Patients must not have used any investigational drug, biologic, or
    device within 3 weeks before study initiation.

-   Patients who had a pulmonary condition that may have compromised
    oxygen loading in the lungs (eg, significant intrathoracic tumor
    involvement, COPD, interstitial lung disease, pulmonary embolism)
    must have met the following requirements: a) adequate pulmonary
    function tests as defined by forced vital capacity (FVC) and forced
    expiratory volume in 1 second (FEV1) ≥ 60% of normal for that
    patient's age, height, and race; and b) an exercise SpO2 on room air
    ≥ 90%.

-   Patients, if female and not post menopausal (\>12 months since last
    menses) or surgically sterile, must have had a negative serum
    beta-human chorionic gonadotropin pregnancy test, must not have been
    breast-feeding, and must have been practicing a medically acceptable
    contraceptive regimen.

**3.0 Treatment Plan**

The patient population consisted of patients with brain metastases who
were scheduled to receive a standard 2-week course of WBRT.

A total of 69 patients were enrolled into the study: 12 RPA Class I and
57 RPA Class II patients.

Patients were enrolled from 17 investigational sites during the period
from 24 Feb 1998 to

28 May 1999. The first patient consent was received on 24 Feb 1998, the
date the final RSR13

treatment was administered occurred on 16 Jun 1999, and the date of the
last initial (1-month)

follow-up was 26 July 1999. All patients in this study were followed for
survival until death or

for a minimum of 24 months. Data were transferred to RTOG as of 23 Jul
2001. This date was

used as the censoring date for analysis purposes. As of that date, 3
patients remained alive and

each had been followed for a minimum of 24 months. The database for the
study was locked as

of 23 Apr 2002.

Patients were stratified upon enrollment into RTOG RPA Class I or II
because of the very

different expected survival between classes (MSTs of 7.1 and 4.2 months
for Classes I and II,

respectively). Separate sample size calculations were performed by
stratum: planned enrollment

was 54 RPA Class I and 50 RPA Class II patients to reach 51 and 48
evaluable patients,

respectively. Study enrollment was closed shortly after the Class II
enrollment target was met; at

that time only 12 Class I patients had been enrolled. Enrollment of RPA
Class I patients

proceeded slowly because of the smaller proportion of Class I patients
(20%) compared to

Class II patients (65%) in the overall population of brain metastases
patients.4 In addition,

potential Class I participants often received surgery, SRS, or a
different RT regimen, all of

which would preclude their participation. Of the 69 patients enrolled,
55 patients completed

evaluations through the 1-month follow-up visit. Of these 55 patients,
there were 4 patients who

stopped receiving RSR13 due to AEs. These patients continued their
participation in the study

by completing the routine follow-up evaluations.

A total of 16 patients terminated their participation in the study.
These patients terminated from the study completely as opposed to
patients who terminated RSR13 dosing and remained in the study by
completing the follow-up visits. There were 10 patients who terminated
the study during the RSR13/RT dosing phase: 7 due to AEs, 1 due to
death, 1 due to a reason specified as other, and 1 was lost to
follow-up. There were 4 patients who terminated the study after
completing the RSR13/RT dosing phase but prior to the 1-month follow-up:
3 due to death and 1 due to unsatisfactory response. Two additional
patients terminated the study early but following the initial 1-month
follow-up: 1 patient for unsatisfactory response and 1 patient for
non-compliance.

RSR13 Injection was supplied by Almedica and was tested and released
according to Allos'

specifications. RSR13 was formulated as a sterile solution for injection
and was supplied in

single-use glass bottles as 2 g of RSR13 in 100 mL of 0.225% NaCl at a
concentration of

20 mg/mL. The osmolality of 20 mg/mL RSR13 in diluent is approximately
equivalent to

0.45% NaCl (half-normal saline). The dose of RSR13 in this study was to
be 100 mg/kg (dosing

reductions permitted) infused at a concentration of 20 mg/mL through a
central venous access

device over 30 minutes. The study drug solution for IV administration
was prepared by the

pharmacist or qualified chemotherapy nurse at the study site. The RSR13
stock solution was

removed from the 100 mL glass bottles with a syringe and then passed
through a 0.8 or

5.0 micron filter, with adequate capacity, directly into a commercial
sterile infusion bag. One

filter was to have been used for each 100 mL of RSR13 stock solution.
The RSR13 infusion

solution was prepared in the sterile infusion bag within 6 hours prior
to infusion.

RSR13 was administered at a concentration of 20 mg/mL over 30 minutes
through a central

venous access device at a constant rate using a volumetric pump. If the
administration of RSR13

was interrupted or delayed, the infusion was to have been resumed but
the total infusion duration

was not to have exceeded 45 minutes.

**4.0 Treatment Modifications**

Early termination from the study by a patient may have been required due
to any of the following

circumstances:

1\. The development of a significant adverse event/toxicity due to study
participation as

determined by the investigator or the patient.

2\. The development of an intercurrent illness, condition, or procedural
complication that could

have interfered with the patient's continued participation.

3\. Voluntary patient withdrawal.

4\. The investigator or Allos felt that it was medically in the best
interest of the patient to

terminate participation in the study.

Procedures listed under 1-month follow-up/early termination in the
Schedule of Events

were to have been completed in the case of early withdrawal/termination.
The reason

for early termination was to have been recorded on the termination page
of the case report form . Patients who terminated drug dosing, but
continued to have routine follow-up visits,

were considered to have terminated dosing, but not the study.

All patients were free to withdraw from participation in this study at
any time, for any reason,

specified or unspecified, and without prejudice.

**5.0 Safety Monitoring**

**Table 39 : Schedule of procedures for RT-008**

<table>
<colgroup>
<col style="width: 21%" />
<col style="width: 9%" />
<col style="width: 5%" />
<col style="width: 4%" />
<col style="width: 4%" />
<col style="width: 4%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 4%" />
<col style="width: 4%" />
<col style="width: 4%" />
<col style="width: 9%" />
<col style="width: 10%" />
</colgroup>
<tbody>
<tr class="odd">
<td><strong>RT week</strong></td>
<td><p><strong>Minus</strong></p>
<p><strong>14 days</strong></p></td>
<td colspan="5"><strong>Week 1</strong></td>
<td colspan="5"><strong>Week 2</strong></td>
<td><strong>1 month</strong></td>
<td><strong>routine</strong></td>
</tr>
<tr class="even">
<td>RT Day</td>
<td>Screen</td>
<td>1</td>
<td>2</td>
<td>3</td>
<td>4</td>
<td>5</td>
<td>6</td>
<td>7</td>
<td>8</td>
<td>9</td>
<td>10</td>
<td>FU</td>
<td>FU</td>
</tr>
<tr class="odd">
<td>RSR13 administration</td>
<td></td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Oxygen administration</td>
<td></td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Brain CT/MRI</td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>PFT/exercise SpO2</td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Pulse oximetry</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Physical exam</td>
<td>X</td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>X</td>
<td>X</td>
<td>X</td>
</tr>
<tr class="odd">
<td>CXR</td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Neurological Assessment</td>
<td>X</td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>X</td>
<td>X</td>
<td>X</td>
</tr>
<tr class="odd">
<td>MMSE</td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>X</td>
<td>X</td>
<td>X</td>
</tr>
<tr class="even">
<td>KPS</td>
<td>X</td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>X</td>
<td>X</td>
<td>X</td>
</tr>
<tr class="odd">
<td><p>Hematology/coags/</p>
<p>chemistry</p></td>
<td>X</td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>X</td>
<td>X</td>
<td></td>
</tr>
<tr class="even">
<td>Urine</td>
<td>X</td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>X</td>
<td>X</td>
<td></td>
</tr>
<tr class="odd">
<td>PKPD</td>
<td></td>
<td></td>
<td></td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>X</td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
</tbody>
</table>

**6.0 Response Evaluation**

CR was defined as a disappearance of all brain lesions seen on CT scans
or MRI for at least 1 month with stable or decreasing steroid dose. PR
required at least a 50% decrease in all lesions for at least 1 month
with a stable or decreasing steroid dose. A response of Stable Disease
was defined as any lesion with shrinkage less than 50% or growth less
than 25% (includes all lesions with no change in growth). Disease
progression was defined as any lesion in the brain enlarged by more than
25% with a stable or increased steroid dose, any new lesion, or clinical
deterioration with a stable scan image. For measurable disease, standard
biperpendicular diameters of the 2-dimensional tumor image at maximum
dimension were applied. For patients with more than one lesion in the
brain, all lesions must have demonstrated a decrease in size with a
stable or decreasing steroid dose to meet the criteria for CR or PR.

**7.0 Statistical Methods**

The primary objective of this study was to estimate the median survival
time (MST) of patients with brain metastases treated with RSR13 and RT.
Since MST for patients with brain metastases may be influenced by
prognostic factors, sample sizes were calculated for each of the RPA
classes addressed in this study. RPA Classes I and II formed the strata
for this study.

A two-sample test of significance at 0.10 (one-sided) and a detectable
improvement of at least

55% would have had a statistical power of 88% in RPA Class I with 51
evaluable patients

compared to the historical control. For RPA Class II patients, the
required sample size was

48 evaluable patients for a one-sided significance level of 0.05 and a
detectable difference of at

least 67%. The target sample sizes of 54 RPA Class I and 50 RPA Class II
patients allowed for a

5% rate of unevaluable patients. Patients who received 7 or more doses
of RSR13 were

considered evaluable, however, the criterion was not used in analyses.

No substitutions were made for missing or poor quality samples. No
formal interim analyses of study data were performed.

**TRIAL RESULTS**

[\*Informed consent]{.underline}

Each patient gave his or her written informed consent to participate in
the study prior to or

during the screening visit. The consent was witnessed, dated, and
retained as part of the study

records. A second original of the consent form was given to the patient.

[\*Randomization]{.underline}

This was an open-label study. There was no placebo control.

[\*Blinding]{.underline}

This was unblinded.

[\*Central review process]{.underline}

RSR13 Assays in Plasma and Red Blood Cells

Analytical Development Corporation

4405 N Chestnut Street

Colorado Springs, CO 80907

Pharmacodynamic (PD) Determinations

Allos Pharmacodynamic Laboratory

Virginia Biotech Research Park

800 Leigh Street, Suite 212

Richmond, VA 23219

Routine Clinical Laboratory Tests (Hematology, Chemistry, Coagulation,
and

Urinalysis Parameters)

Covance Classical Laboratory Services

8211 SciCore Drive

Indianapolis, IN 46214

Study site monitoring was conducted at regular intervals by Allos
Clinical Development staff:

Carrie VanDuym, Marilyn Craig, Margie Suhs, and Catherine Feutz.
Monitoring was also

conducted by clinical research associates (CRAs) of Endpoint Research
Limited and Health

Research Management, Inc. Monitoring was performed in accordance with
applicable

regulations and Good Clinical Practice guidelines.

Data management and analyses for the final report were provided by
Allos. The lead Data

Manager was Karen Guisinger. Adam Boyd, John Hackman, and Jim Kennedy
performed

analyses and produced tables. Allos Clinical Data Management personnel
performed a Quality

Control (QC) audit of the database for final reporting.

An analysis comparing results of this study with those of the Radiation
Therapy Oncology Group

Brain Metastases Database (RTOG BMD) was conducted by Charles Scott,
PhD, Associate

Director, Quality of Life Research, American College of Radiology; 1101
Market Street,

14th Floor; Philadelphia, PA 19107.

[\*Protocol violations]{.underline}

Major protocol deviations were defined as violations in eligibility,
disallowed medications,

dosing violations, and patients who should have been withdrawn from the
study but were not.

None of the patients with protocol deviations were excluded from
analysis.

A total of 12 patients had protocol deviations in 6 different categories
of eligibility. For the majority of these deviations, Allos granted an
exemption to allow the patient to enter the study. Only 1 patient did
not meet more than 1 eligibility criteria (Patient 224). Having prior
treatment for brain metastases was the most common violation in
eligibility.

Two patients had protocol deviations related to the requirement of
having a MRI/CT scan within

2 weeks of the projected start of RT:

-    Patient 229 had a CT scan performed 3 weeks before RT.

-    Patient 242 had an MRI scan performed 7 weeks before the start of
    RT. The deviation for Patient 242 was not discovered until after the
    patient was treated.

Two patients who had serious adverse events (SAEs) also had protocol
deviations related to SpO2 readings. Because these patients experienced
SAEs following protocol deviations

they are also being noted here:

-   Patient 101 (enrolled prior to Amendment 2) was discharged on RT day
    2 with an SpO2 of 87% while breathing supplemental oxygen at 2
    L/minute (protocol discharge criteria required SpO2 ≥ 87% while
    breathing room air). On RT day 5, the RSR13 infusion was started
    even though the patient's preinfusion SpO2 ranged from 85-89%
    (protocol required preinfusion SpO2 of ≥ 87% while breathing room
    air). This patient experienced an SAE on RT day 5 (hospitalization
    for hypotension, hypoxia, and acute renal failure), and RSR13 dosing
    was subsequently terminated.

-   Patient 215 was discharged on RT days 1, 2, and 3 with SpO2 values
    of 88%, 87%, and 74%, respectively, while breathing room air
    (following IND Safety Letter and Amendment 2, discharge SpO2 was to
    be ≥ 90% while breathing room air). On RT day 4 the patient
    experienced the first of 2 SAEs (hospitalization for nausea,
    vomiting, increased intracranial pressure, and cerebral edema). The
    second SAE occurred on RT day 5 (hospitalization for weakness,
    dizziness, and hyponatremia). In addition, the patient was
    discharged on RT day 5 with a SpO2 of 72%.

Minor protocol deviations (eg, not performing scheduled tests, taking
blood samples outside

scheduled time window, not taking scheduled blood samples) also
occurred, but were not

deemed to have affected the medical status of the patient and were
therefore not quantified.

Most exemptions related to dosing adjustments were granted to have RSR13
held on the first day

of RT due to procedural/timing difficulties with PICC line placement or
completion of laboratory

test results. Prior to Amendment 3, exemptions were also granted for
dose reductions from 100

to 75 or 50 mg/kg due to results from clinical or laboratory
assessments.

**Table 40**

(Derived from Table 10.1, Final Study Report)

![](media/image6.png){width="6.53125in" height="3.9479166666666665in"}

[\*Enrollment]{.underline}

A total of 69 patients were enrolled from 16 study centers in the United
States and one center in Canada.

[\*Baseline Demographics]{.underline}

**[Table 41: Demographic Variables]{.underline}**

+-----------------------------------+-----------------------------------+
| **Parameter**                     | **RSR13**                         |
|                                   |                                   |
|                                   | **Total N=69 patients**           |
|                                   |                                   |
|                                   | **N(%)**                          |
+-----------------------------------+-----------------------------------+
| **Sex**                           | 31(45)                            |
|                                   |                                   |
| Male                              | 38(55)                            |
|                                   |                                   |
| Female                            |                                   |
+-----------------------------------+-----------------------------------+
| **Race**                          | 62(90)                            |
|                                   |                                   |
| Caucasian                         | 5(7)                              |
|                                   |                                   |
| Black                             | 0                                 |
|                                   |                                   |
| Native American                   | 0                                 |
|                                   |                                   |
| Asian                             | 2(3)                              |
|                                   |                                   |
| Hispanic                          | 0                                 |
|                                   |                                   |
| Other                             |                                   |
+-----------------------------------+-----------------------------------+
| **Age**                           | 51(74)                            |
|                                   |                                   |
| \<65                              | 18(26)                            |
|                                   |                                   |
| ≥65                               | 55.8                              |
|                                   |                                   |
| mean                              |                                   |
+-----------------------------------+-----------------------------------+
| **Weight (kg)**                   | 73.0                              |
|                                   |                                   |
| Mean                              | 14.5                              |
|                                   |                                   |
| SD                                |                                   |
+-----------------------------------+-----------------------------------+
| **KPS Score**                     | 90                                |
|                                   |                                   |
| Median                            |                                   |
+-----------------------------------+-----------------------------------+
| **RPA Classification**            | 12(17)                            |
|                                   |                                   |
| RPS Class I                       | 33(48)                            |
|                                   |                                   |
| RPA Class II- NSCL primary        | 18(26)                            |
|                                   |                                   |
| RPA Class II- Breast primary      | 6(9)                              |
|                                   |                                   |
| RPA Class II- Other               |                                   |
+-----------------------------------+-----------------------------------+

(Derived from Table 2.7.3.3.1, Summary of Clinical Efficacy)

*Reviewer comment: Sex, age, race, and weight were comparable to those
participating with RT-009 on either treatment arm. Refer to Table 11.*

**Table 42: Distribution of RPA Class by Primary Tumor Site**

+-----------------------+-----------------------+-----------------------+
| **RPA Class**         | **Primary Tumor       | **Total N=69**        |
|                       | Histology**           |                       |
+-----------------------+-----------------------+-----------------------+
| **I**                 | NSCLC                 | 6                     |
|                       |                       |                       |
|                       | Breast                | 3                     |
|                       |                       |                       |
|                       | Other                 | 3                     |
|                       |                       |                       |
|                       | Total                 | 12                    |
+-----------------------+-----------------------+-----------------------+
| **II**                | NSCLC                 | 33                    |
|                       |                       |                       |
|                       | Breast                | 18                    |
|                       |                       |                       |
|                       | Other                 | 6                     |
|                       |                       |                       |
|                       | Total                 | 57                    |
+-----------------------+-----------------------+-----------------------+
| **All**               |                       | 69                    |
+-----------------------+-----------------------+-----------------------+

*Reviewer comment: The distribution of primary tumor histology by RPA
Class was comparable to RT-009.*

**Table 43: Distribution of Tumor Types in RT-008**

+-----------------+-----------------+-----------------+-----------------+
| **Primary       | **69 Total      | **Controlled    | **Uncontrolled  |
| Site**          | Patients**      | Primary Tumor** | Primary Tumor** |
|                 |                 |                 |                 |
|                 | **N(%)**        | **(31           | **(38           |
|                 |                 | Patients)**     | Patients)**     |
+-----------------+-----------------+-----------------+-----------------+
| Breast          | 21(30)          | 13(42)          | 8(21)           |
+-----------------+-----------------+-----------------+-----------------+
| GI              | 1(1)            | 1(3)            | 0(0)            |
+-----------------+-----------------+-----------------+-----------------+
| GU              | 3(4)            | 1(3)            | 2(5)            |
+-----------------+-----------------+-----------------+-----------------+
| Lung            | 39(56)          | 13(42)          | 26(68)          |
+-----------------+-----------------+-----------------+-----------------+
| Melanoma        | 5(7)            | 3(9)            | 2(5)            |
+-----------------+-----------------+-----------------+-----------------+

*Reviewer comment: Like RT-009, non-small cell lung cancer made up the
majority of primary tumor type, with breast being the next most common.
The distribution of tumor types was comparable to RT-009.*

**Table 44**: Distribution of Breast Histology in RT-008

+-----------------------------------+-----------------------------------+
| **Histology**                     | **N=69**                          |
|                                   |                                   |
|                                   | **N(%)**                          |
+-----------------------------------+-----------------------------------+
| Infiltrating ductal               | 16(23)                            |
+-----------------------------------+-----------------------------------+
| Infiltrating lobular              | 1(1)                              |
+-----------------------------------+-----------------------------------+
| Other                             | 4(6)                              |
+-----------------------------------+-----------------------------------+

*Reviewer comment: As is the case for RT-009, most patients had
infiltrating ductal carcinoma.*

**Table 45**: Distribution of KPS Score in RT-008

+-----------------------+-----------------------+-----------------------+
| **KPS Score**         | **All Patients**      | **Breast              |
|                       |                       | Subpopulation**       |
|                       | **(N=69)**            |                       |
|                       |                       | **(N=21)**            |
+-----------------------+-----------------------+-----------------------+
| 70                    | 15                    | 5                     |
+-----------------------+-----------------------+-----------------------+
| 80                    | 15                    | 5                     |
+-----------------------+-----------------------+-----------------------+
| 90                    | 30                    | 9                     |
+-----------------------+-----------------------+-----------------------+
| 100                   | 9                     | 2                     |
+-----------------------+-----------------------+-----------------------+

*Reviewer comment: The distribution of KPS scores was comparable to
RT-009.*

**EFFICACY RESULT -- SPONSOR'S ASSESSMENT**

Survival time was defined as the period from RT day 1 to death. All
patients in this study were

followed for survival until death or for a minimum of 24 months. The
survival results from RT-008 were compared to a separate study performed
by the RTOG BMD (Brain Metastases Database). Survival data from the RPA
Class II patients in RT-008 were compared to all patients in the RTOG
BMD.

According to the sponsor, the observed median survival time (MST) for
the overall population (N = 69) was 6.4 months. The MST for the RPA
Class I (N = 12) and RPA Class II (N = 57) groups was also 6.4 months
for each group. For RTOG BMD RPA Class II patients, median survival time
was 4.1 months (6.4 months vs. 4.1 months, p-0.0174). In RT-008, the
largest differences in MST observed in the overall population were for
the categories of best maximal response, age, baseline KPS, and number
of RSR13 doses. Patients with a best response of CR had a longer MST
than patients with a response of Stable Disease (12.2 vs 4.9 months);
patients younger than 65 years of age had a longer MST than patients 65
years or older (7.1 vs 3.2 months); patients with a baseline KPS score
of 90-100 had a longer MST than patients with a score of 70- 80 (8.5 vs
4.9 months); patients receiving 7 or more RSR13 doses had a longer MST
than patients who received less than 7 doses (6.6 vs 2.3 months). MST
appeared slightly longer when patients had a controlled disease status,
or when patients had a non-neurologic (defined as no progressive disease
in the brain) cause of death. According to the Sponsor, MST was less
affected by the covariates of gender, site of primary disease, presence
of extracranial metastases, mental status, or timing of diagnoses.

For RPA Class II patients, 2 of 7 patients (29%) who received 0-6 doses
of RSR13 exceeded the

expected MST of 4.2 months. However, 34 of 50 patients (68%) who
received 7-10 doses of RSR13 exceeded the expected MST. The differences
in MST within each category were generally as expected for the overall
population and the Class II group. The sponsor states that comparisons
between the Class I and Class II groups and conclusions regarding Class
I patients are difficult to make due to the small sample size of Class I
patients.

Best maximal response was categorized as either CR, PR, Stable Disease,
or Other. The "other" category included data from patients with
progressive disease, patients without a follow-up MRI

or CT scan, or patients that terminated the study prior to follow-up.
The sponsor feels the results of this study demonstrates that patients
with a more favorable response (CR or PR) tended to survive longer and
were more likely to remain progression-free for a longer time than
patients with a less favorable response (Stable Disease or Other).

*Reviewer comment: Although the sponsor does not directly mention
response rate in this study, 7/7 patients with CR and 8/13 patients with
PR were alive in these response categories after six months of
follow-up.*

Median time to progression in the brain was measured from the start date
of radiation therapy. The date of progressive disease is defined as the
date on which any lesion in the brain is enlarged by more than 25% with
a stable or increased steroid dose. For patients with more than one
lesion in the brain, all lesions needed to demonstrate a decrease in
size with a stable or decreasing steroid dose to meet the standard
oncology criteria of complete or partial response. Complete response was
defined as disappearance of all brain lesions seen on CT or MRI for at
least one month with a stable or decreasing steroid dose. Partial
response was defined as at least a 50% decrease in all lesion(s) with a
stable or decreasing steroid dose for at least one month. Stable disease
was defined as any lesion with shrinkage less than 50% or increase less
than 25%. Mixed responses were described as any other combination of
responses not defined above.

Standard oncology criteria for complete and partial responses, along
with stable and progressive disease was based on both measurable and
evaluable disease within the cranium. For measurable disease, standard
biperpendicular diameters of the two-dimensional tumor image at maximum
dimension was applied. This was compared to the indicator image on
repeat CT or MRI one month apart. For evaluable disease, the reference
neuro-radiologist used his/her radiographic judgment in applying the
response criteria.

*Reviewer comment: In the setting of a single arm study, it is difficult
to interpret time to event endpoints such as survival or time to
progression. Unlike RT-009, the protocol for RT-008 required
confirmation of response.*

**EFFICACY RESULTS -- FDA ASSESSMENT**

**D. Efficacy Conclusions**

Given that RT-008 was a single-arm trial, time to event endpoints such
as survival or time to progression are uninterpretable.

## IV. Review of Safety

> **A. Introduction**

RSR13 has been studied in 18 Phase 1 to Phase 3 studies. The submitted
NDA contains safety data through December 31, 2002. The data collected
from the Phase 3 study RT-009 and the Phase 2 study RT-008 provide the
safety information of RSR13 use in the target population (intent to
treat population and NSCLC/breast combined). Six-hundred-ninety-one
patients have received at least 1 dose of RSR13. A total of 535 patients
received one or more doses of RSR13 as sole adjunct to radiation
therapy. Of these, 332 received WBRT for brain metastases.

### B. Description of Patient Exposure

This section will include exposure analyses for both RT-008 and RT-009
performed by the sponsor and by the FDA.

**Table 46: Clinical Studies of RSR13 as Sole Adjunct to Radiation
Therapy**

+-----------------------+-----------------------+-----------------------+
| **Phase**             | **Study**             | **Target Population** |
+-----------------------+-----------------------+-----------------------+
| Phase 1               | RT-002                | Any solid tumor       |
|                       |                       |                       |
|                       | RT-006                | Glioblastoma          |
|                       |                       | multiforme            |
+-----------------------+-----------------------+-----------------------+
| Phase 2               | RT-007                | Glioblastoma          |
|                       |                       | multiforme            |
|                       | RT-008                |                       |
|                       |                       | Brain metastases      |
|                       | RT-010                |                       |
|                       |                       | NSCLC                 |
+-----------------------+-----------------------+-----------------------+
| Phase 3               | RT-009                | Brain metastases      |
+-----------------------+-----------------------+-----------------------+

Investigators graded adverse events outside the radiation portal using
the NCI Common Toxicity

Criteria (CTC). The European Organization for Research and Treatment of
Cancer/Radiation

Therapy Oncology Group (EORTC/RTOG) acute morbidity criteria were used
to score/grade

toxicity(ies) from RT. The criteria are relevant from day 1, the
commencement of therapy,

through day 90. Thereafter, the EORTC/RTOG Criteria of Late Effects were
utilized. In clinical study reports, NCI Common Toxicity Criteria were
incorporated into the overall WHOART adverse event profile using the
following algorithm to code severity:

Grade 1 = mild, Grade 2 = moderate, Grade 3= severe, and Grade 4 = very
severe or life

threatening.

RSR13 decreases hemoglobin oxygen-binding affinity and reduces oxygen
loading in the lungs

at ambient oxygen pressure. This pharmacodynamic effect is manifested by
a transient reduction in arterial oxygen saturation (SaO2). Patients
receiving RSR13 have predictable, dose-related, transient reductions in
SpO2 that have been managed through titration of the supplemental

oxygen. Additionally, supplemental oxygen administration was employed to
ensure a maximal

pharmacologic effect by fully saturating the hemoglobin binding sites.

In the early Phase 1 and Phase 2 studies of RSR13, the grading of the
severity of

treatment-emergent hypoxemia was arbitrary by individual investigators
and based on the

observed variances in the flow and duration of supplemental oxygen until
maintenance of a

protocol-defined SpO2 value on room air. The presence of signs and
symptoms

contemporaneously associated with hypoxemia were not consistently
included in the grading of

adverse events by the investigators. In addition, according to the
existing definition and grading

of hypoxia/hypoxemia (hypoxemia) in the NCI CTC scale, the use of
supplemental oxygen

attributes the severity of the event as Grade 4. Since all subjects
received supplemental oxygen

per protocol, an Allos-defined grading scale for hypoxemia as an adverse
event was introduced

in late Phase 2 and Phase 3 studies.

**Table 47: Criteria for Hypoxemia Grading in RT-009**

+-------------+-------------+-------------+-------------+-------------+
| Grades      |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| 0           | 1           | 2           | 3           | 4           |
+-------------+-------------+-------------+-------------+-------------+
| Normal\*    | S           | SpO2 \< 90% | Symptomatic | Decreased   |
|             | upplemental | while       | hypoxemia   | SpO2        |
|             | oxygen      | breathing   | defined as  | requiring   |
|             | required    | s           | decreased   | continuous  |
|             | \>3 hours   | upplemental | SpO2 with   | positive    |
|             | but \< 4    | oxygen @ 4  | headache,   | pressure    |
|             | hours       | L/min.      | dizziness,  | and/or      |
|             | post-end    |             | dyspnea or  | mechanical  |
|             | RSR13       | S           | h           | v           |
|             | infusion.   | upplemental | ypotension. | entilation. |
|             |             | oxygen      |             |             |
|             |             | required ≥  | P           |             |
|             |             | 4hours      | re-infusion |             |
|             |             | post-end    | SpO2 \<90%  |             |
|             |             | RSR13       | attributed  |             |
|             |             | infusion.   | to RSR13.   |             |
|             |             |             |             |             |
|             |             | Increase in | Decreased   |             |
|             |             | s           | SpO2        |             |
|             |             | upplemental | requiring   |             |
|             |             | oxygen \> 4 | hospi       |             |
|             |             | L/min       | talization. |             |
|             |             | during the  |             |             |
|             |             | RSR13       |             |             |
|             |             | infusion    |             |             |
|             |             | and/or      |             |             |
|             |             | during the  |             |             |
|             |             | 4-hours     |             |             |
|             |             | recovery    |             |             |
|             |             | period.     |             |             |
+-------------+-------------+-------------+-------------+-------------+

\*-supplemental oxygen administered ≤ 3 hours.

Two-hundred-seventy-one patients received RSR13 as an adjunct to WBRT
(30 Gy, 10 fractions over 2 weeks) and supplemental oxygen at 4 L/min.
Within each of the 4 strata, subjects were randomized 1:1 to the 2
treatment arms comprised of a 10-day course of WBRT with supplemental
oxygen ± RSR13. Subjects received RSR13 100 mg/kg IV (with dose
modifications to 75 mg/kg or 50 mg/kg) over 30 minutes daily. Safety and
tolerability were determined by assessment of the incidence, nature, and
severity of treatment-emergent adverse events; clinical assessments of
laboratory test results (hematology and serum chemistry); vital signs
(including SpO2); and physical examination findings.

*Reviewer comment: The Dose Adjustment Guidelines provided in Table 5 of
this review do not provide justification for a RSR13 dose of 50 mg/kg.
If a dose of 100 mg/kg was given and required downward titration, the
next lower dose level was given as 75 mg/kg. The guidelines indicate
that any further downward titrations from 75 mg/kg should lead to
omission of RSR13 for that day. A dose reduction to 50 mg/kg was allowed
by the investigator if clinical assessments or laboratory criteria
indicated that the patient was experiencing exaggerated pharmacological
effects or toxicities.*

In study RT-009, a total of 538 subjects were enrolled in the study and
the majority received 10 doses of WBRT (251/267 \[94%\] in the Control
arm and 252/271 \[93%\] in the RSR13 arm)*.* According to the sponsor,
263/271 (97%) patients in the RSR13 arm received at least 1 dose of
RSR13. The mean number of RSR13 doses administered was 8.4 (SD 2.6;
range 1-10 doses). The mean daily RSR13 dose was 84.5 mg/kg (SD 13.4;
range 14.6-106.7 mg/kg). The mean number of WBRT doses was 9.8 (SD 1.2;
range 0-10 doses) and the mean total WBRT dose given was 29.2 Gy (SD
3.7; range 3-30 Gy). RSR13 dosing was discontinued in 47/271 (17%)
subjects. The principle reason for study drug discontinuation was
adverse event(s).

RT-008 was a non-randomized, open-label study in subjects receiving
RSR13 as an

adjunct to WBRT. Subjects received RSR13 100 mg/kg IV (with dose
modifications to

75 mg/kg or 50 mg/kg) over 30 minutes daily with WBRT (30 Gy, 10
fractions over 2 weeks).

Safety and tolerability were determined by assessment of the incidence,
nature, and severity of

treatment-emergent adverse events; clinical assessments of laboratory
test results (hematology,

coagulation, serum chemistry, and urinalysis); vital signs (including
SpO2); physical examination

findings; and concomitant medications.

*Reviewer comment: RT-008, unlike RT-009, allowed downward titrations to
occur by 25-50% if needed.*

In study RT-008, a total of 69 subjects were enrolled in the study and
the majority received 10 doses of WBRT (3 subjects received 6, 7, and 8
RT doses, respectively). According to the sponsor, the mean number of
RSR13 doses administered was 8.9 (SD 2.1; range 1-11 doses). The mean
daily RSR13 dose was 92.8 mg/kg (SD 10.6; range 61.8-100.6 mg/kg). The
mean number of WBRT doses was 9.9 (SD 0.6; range 6-10 doses) and the
mean total WBRT dose given was 29.6 Gy (SD 2.0; range 17-30 Gy).
Overall, 40/69 subjects (58%) received the complete treatment per
protocol. RSR13 dosing was discontinued in 12/69 (17%) subjects. The
principle reason for study drug discontinuation was adverse event(s).

**Table 48: Extent of RSR13 Exposure in Patients Participating in
RT-009**

(Sponsor's Analysis)

+--------------+--------------+---------------+-----------+-----------+
| **Exposure   | *            | **Total       | **Breast  | **NSCLC** |
| Variable**   | *Statistic** | Patients      | S         |           |
|              |              | Receiving     | ubgroup** | **S       |
|              |              | RSR13**       |           | ubgroup** |
|              |              |               | **N=60**  |           |
|              |              | **N=271**     |           | **N=148** |
+--------------+--------------+---------------+-----------+-----------+
| Number of    | N            | 263           | 59        | 144       |
| RSR13 Doses  |              |               |           |           |
|              | Mean         | 8.4           | 8.0       | 8.3       |
|              |              |               |           |           |
|              | SD           | 2.6           | 3.0       | 2.6       |
|              |              |               |           |           |
|              | Min/Max      | 1/10          | 1/10      | 1/10      |
+--------------+--------------+---------------+-----------+-----------+
| RSR13 Dose   | N            | 263           | 59        | 144       |
| (mg/kg)      |              |               |           |           |
|              | Mean         | 84.5          | 84.7      | 84.6      |
|              |              |               |           |           |
|              | SD           | 13.4          | 12.9      | 13.8      |
|              |              |               |           |           |
|              | Min/Max      | 14.6/106.7    | 50/101.3  | 1         |
|              |              |               |           | 4.6/101.2 |
+--------------+--------------+---------------+-----------+-----------+
| RSR13        | N            | 262           | 59        | 143       |
| Duration     |              |               |           |           |
| (min)        | Mean         | 31.2          | 31.4      | 31.3      |
|              |              |               |           |           |
|              | SD           | 4.6           | 3.5       | 5.8       |
|              |              |               |           |           |
|              | Min/Max      | 3.0/83.0      | 27.6/47.9 | 3/83      |
+--------------+--------------+---------------+-----------+-----------+

> (Derived from Table 2.7.4.1.8, Summary of Clinical Safety)
>
> N=number of patients receiving at least 1 dose of RSR13
>
> Mean=arithmetic mean
>
> SD=standard deviation
>
> Min/Max=minimum-maximum amount

*Reviewer comment: According to the sponsor, the mean number of RSR13
doses given, dose received (mg/kg), and the duration of administration
were comparable between the overall patients and breast subgroup
receiving RSR13.*

> **Table 49: Extent of Radiation Exposure in Patients Participating in
> RT-009**
>
> **(Sponsor's Analysis)**

+-----------------+-----------------+-----------------+-----------------+
|                 | **Statistic**   | **Control**     | **RSR13**       |
|                 |                 |                 |                 |
|                 |                 | **(N=267)**     | **(N=271)**     |
+-----------------+-----------------+-----------------+-----------------+
| Number of RT    | N               | 267             | 271             |
| Doses           |                 |                 |                 |
|                 | Mean            | 9.7             | 9.6             |
|                 |                 |                 |                 |
|                 | SD              | 1.5             | 1.8             |
|                 |                 |                 |                 |
|                 | Min/Max         | 0/14            | 0/10            |
+-----------------+-----------------+-----------------+-----------------+
| Total RT Dose   | N               | 263             | 266             |
| (Gy)            |                 |                 |                 |
|                 | Mean            | 29.6            | 29.2            |
| Over 2 Week     |                 |                 |                 |
| Treatment       | SD              | 2.5             | 3.7             |
| Period          |                 |                 |                 |
|                 | Min/Max         | 9.0/35.0        | 3.0/30.0        |
+-----------------+-----------------+-----------------+-----------------+

> (Derived form Table 2.7.4.1.11, Summary of Clinical Safety)
>
> n=number of patients receiving at least 1 dose of WBRT
>
> Mean=arithmetic mean
>
> SD=standard deviation
>
> Min/Max=minimum-maximum amount

*Reviewer comment: According to the sponsor, total radiation doses given
over a two week treatment period were comparable in both arms of the
study.*

Below are the FDA analyses of RSR13 exposure, radiation exposure and
oxygen exposure.

**Table 50: Exposure of RSR13 in RT-009 (FDA Analysis)**

+-------------+-------------+-------------+-------------+-------------+
| **Exposure  | **          | **RSR13     | **Breast    | **NSCLC     |
| Variable**  | Statistic** | Arm**       | Subgroup**  | Subgroup**  |
|             |             |             |             |             |
|             |             | **(271      | **(60       | **(148      |
|             |             | patients)** | patients)** | patients)** |
+-------------+-------------+-------------+-------------+-------------+
| **Number of | N           | 263         | 59^1^       | 144^2^      |
| RSR13       |             |             |             |             |
| Doses**     | Mean        | 8.4         | 8.0         | 8.3         |
|             |             |             |             |             |
|             | SD          | 2.6         | 3.0         | 2.6         |
|             |             |             |             |             |
|             | Min/Max     | 1/10        | 1/10        | 1/10        |
+-------------+-------------+-------------+-------------+-------------+
| **RSR13     | N           | 263         | 59          | 144         |
| Dose        |             |             |             |             |
| delivered** | Mean        | 85.0        | 83.5        | 85.6        |
|             |             |             |             |             |
| **(mg/kg)** | SD          | 15.1        | 15.0        | 15.0        |
|             |             |             |             |             |
|             | Min/Max     | 13.5/166.7  | 13.5/101.4  | 14.6/101.5  |
+-------------+-------------+-------------+-------------+-------------+
| **RSR13     | N           | 262^3^      | 59          | 143^2^      |
| Duration**  |             |             |             |             |
|             | Mean        | 0.52        | 0.53        | 0.52        |
| **(hrs)**   |             |             |             |             |
|             | SD          | 0.08        | 0.08        | 0.08        |
|             |             |             |             |             |
|             | Min/Max     | 0.05/2.08   | 0.10/1.28   | 0.05/2.08   |
+-------------+-------------+-------------+-------------+-------------+

1- one patient never received RSR13 infusion. 263 patients received at
least 1 dose of RSR13

2- missing data for patients accounts for number discrepancies

3- no information on one patients from original 263

*Reviewer comment: The FDA analysis for drug exposure was similar to the
Sponsor's analysis. RSR13 exposure duration is reported in minutes in
the Sponsor's analysis and in hours in the FDA analysis.*

**Table 51: Radiation Therapy Exposure for the Intent To Treat
Population of RT-009**

**(FDA Analysis)**

+-----------------+-----------------+-----------------+-----------------+
| **Exposure      | **Statistic**   | **Control Arm** | **RSR13 Arm**   |
| Variable**      |                 |                 |                 |
|                 |                 | **(N=267)**     | **(N=271)**     |
+-----------------+-----------------+-----------------+-----------------+
| **Number of RT  | N               | 267             | 271             |
| Doses**         |                 |                 |                 |
|                 | Mean            | 9.7             | 9.6             |
|                 |                 |                 |                 |
|                 | SD              | 1.4             | 1.6             |
|                 |                 |                 |                 |
|                 | Min/Max         | 1/14            | 1/11            |
+-----------------+-----------------+-----------------+-----------------+
| **Total RT Dose | N               | 267             | 271             |
| Delivered       |                 |                 |                 |
| (Gy)**          | Mean            | 3.0             | 2.9             |
|                 |                 |                 |                 |
| **Per Day**     | SD              | 0.08            | 0.04            |
|                 |                 |                 |                 |
|                 | Min/Max         | 1/3.0           | 1.5/3.0         |
+-----------------+-----------------+-----------------+-----------------+

**Reviewer comment:** *The FDA analysis for radiation exposure was
similar to the Sponsor's analysis. Total RT dose delivered is reported
over the [two week treatment period]{.underline} in the Sponsor's
analysis and [per day]{.underline} in the FDA analysis.*

**Table 52: Radiation Therapy Exposure for the Breast and NSCLC
Subgroups in RT-009 (FDA Analysis)**

+----------------+----------------+--------+---+--------+--------+-------+
| **Exposure     | **Statistic**  | **Br   |   |        | **N    |       |
| Variable**     |                | east** |   |        | SCLC** |       |
|                |                |        |   |        |        |       |
|                |                | **N    |   |        | **N    |       |
|                |                | =115** |   |        | =299** |       |
+----------------+----------------+--------+---+--------+--------+-------+
|                |                | **Con  |   | **R    | **Con  | **RS  |
|                |                | trol** |   | SR13** | trol** | R13** |
|                |                |        |   |        |        |       |
|                |                | **     |   | **     | **N    | **N=  |
|                |                | N=55** |   | N=60** | =151** | 148** |
+----------------+----------------+--------+---+--------+--------+-------+
| **Number of RT | N              | 55     | 6 |        | 151    | 148   |
| Doses**        |                |        | 0 |        |        |       |
|                | Mean           | 9.8    |   |        | 9.8    | 9.7   |
|                |                |        | 9 |        |        |       |
|                | SD             | 1.6    | . |        | 1.0    | 1.6   |
|                |                |        | 7 |        |        |       |
|                | Min/Max        | 1/14   |   |        | 1/12   | 1/11  |
|                |                |        | 1 |        |        |       |
|                |                |        | . |        |        |       |
|                |                |        | 3 |        |        |       |
|                |                |        |   |        |        |       |
|                |                |        | 2 |        |        |       |
|                |                |        | / |        |        |       |
|                |                |        | 1 |        |        |       |
|                |                |        | 0 |        |        |       |
+----------------+----------------+--------+---+--------+--------+-------+
| **Total RT     | N              | 55     | 6 |        | 151    | 148   |
| Dose Delivered |                |        | 0 |        |        |       |
| (Gy)**         | Mean           | 3.0    |   |        | 3.0    | 3.0   |
|                |                |        | 3 |        |        |       |
|                | SD             | 0.1    | . |        | 0.1    | 0.03  |
|                |                |        | 0 |        |        |       |
|                | Min/Max        | 2      |   |        | 1      | 2.    |
|                |                | .0/3.0 | 0 |        | .0/3.0 | 5/3.0 |
|                |                |        | . |        |        |       |
|                |                |        | 1 |        |        |       |
|                |                |        |   |        |        |       |
|                |                |        | 1 |        |        |       |
|                |                |        | . |        |        |       |
|                |                |        | 5 |        |        |       |
|                |                |        | / |        |        |       |
|                |                |        | 3 |        |        |       |
|                |                |        | . |        |        |       |
|                |                |        | 0 |        |        |       |
+----------------+----------------+--------+---+--------+--------+-------+

*Reviewer comment: The number of RT doses and total RT doses delivered
seem to be comparable between the control arm and treatment arm of both
the breast and NSCLC subgroups.*

**Table 53: Oxygen Exposure for the Breast and NSCLC Subgroups in
RT-009**

**(FDA Analysis)**

+----------------+----------------+--------+---+-------+--------+---------+
| **Exposure     | **Statistic**  | **Br   |   |       | **N    |         |
| Variable**     |                | east** |   |       | SCLC** |         |
|                |                |        |   |       |        |         |
|                |                | **N    |   |       | **N    |         |
|                |                | =115** |   |       | =299** |         |
+----------------+----------------+--------+---+-------+--------+---------+
|                |                | **Con  |   | **RS  | **Con  | **      |
|                |                | trol** |   | R13** | trol** | RSR13** |
|                |                |        |   |       |        |         |
|                |                | **     |   | **N   | **N    | **      |
|                |                | N=55** |   | =60** | =151** | N=148** |
+----------------+----------------+--------+---+-------+--------+---------+
| **Total        | N              | 55     | 6 |       | 151    | 148     |
| Duration of    |                |        | 0 |       |        |         |
| O~2~           | Mean           | 1.1    |   |       | 1.2    | 2.3     |
| Delivered**    |                |        | 2 |       |        |         |
|                | SD             | 0.3    | . |       | 0.2    | 7.2     |
| **(4 L/min)    |                |        | 0 |       |        |         |
| Reported in    | Min/Max        | 0      |   |       | 0      | 0.      |
| Hours**        |                | .6/5.3 | 2 |       | .5/3.1 | 4/200.5 |
|                |                |        | . |       |        |         |
|                |                |        | 7 |       |        |         |
|                |                |        |   |       |        |         |
|                |                |        | 0 |       |        |         |
|                |                |        | . |       |        |         |
|                |                |        | 3 |       |        |         |
|                |                |        | / |       |        |         |
|                |                |        | 5 |       |        |         |
|                |                |        | 2 |       |        |         |
|                |                |        | . |       |        |         |
|                |                |        | 5 |       |        |         |
+----------------+----------------+--------+---+-------+--------+---------+

*Reviewer comment: Patients with breast or NSCLC receiving RSR13 appear
to have received a longer duration of oxygen therapy than counterparts
on the control arm. This finding brings into question whether this could
influence outcome of the treatment regimen.*

> **Table 54: Extent of RSR13 Exposure in Patients Participating in
> RT-008**

+--------------+--------------+---------------+-----------+-----------+
| **Exposure   | *            | **Total       | **Breast  | **NSCLC** |
| Variable**   | *Statistic** | Patients      | S         |           |
|              |              | Receiving     | ubgroup** | **S       |
|              |              | RSR13**       |           | ubgroup** |
|              |              |               | **N=21**  |           |
|              |              | **N=69**      |           | **N=39**  |
+--------------+--------------+---------------+-----------+-----------+
| Number of    | n            | 69            | 21        | 39        |
| RSR13 Doses  |              |               |           |           |
|              | Mean         | 8.9           | 8.0       | 9.1       |
|              |              |               |           |           |
|              | SD           | 2.1           | 2.4       | 2.1       |
|              |              |               |           |           |
|              | Min/Max      | 1/11          | 2/10      | 1/11      |
+--------------+--------------+---------------+-----------+-----------+
| RSR13 Dose   | n            | 69            | 21        | 39        |
| (mg/kg)      |              |               |           |           |
|              | Mean         | 92.8          | 93.1      | 93.3      |
|              |              |               |           |           |
|              | SD           | 10.6          | 12.1      | 9.5       |
|              |              |               |           |           |
|              | Min/Max      | 61.8/100.6    | 6         | 7         |
|              |              |               | 1.8/100.3 | 2.5/100.6 |
+--------------+--------------+---------------+-----------+-----------+
| RSR13        | n            | 69            | 21        | 39        |
| Duration     |              |               |           |           |
| (min)        | Mean         | 31.7          | 30.3      | 32.7      |
|              |              |               |           |           |
|              | SD           | 4.3           | 0.8       | 5.5       |
|              |              |               |           |           |
|              | Min/Max      | 28.6/57.3     | 29.7/32.8 | 28.6/57.3 |
+--------------+--------------+---------------+-----------+-----------+

> (Derived from Table 2.7.4.1.8, Summary of Clinical Safety)
>
> n=number of patients receiving at least 1 dose of RSR13
>
> Mean=arithmetic mean
>
> SD=standard deviation
>
> Min/Max=minimum-maximum amount

**Table 55: RSR13 Exposure in Patients Participating in RT-008**

**(FDA Analysis**)

+--------------+--------------+---------------+-----------+-----------+
| **Exposure   | *            | **Total       | **Breast  | **NSCLC** |
| Variable**   | *Statistic** | Patients      | S         |           |
|              |              | Receiving     | ubgroup** | **S       |
|              |              | RSR13**       |           | ubgroup** |
|              |              |               | **N=21**  |           |
|              |              | **N=69**      |           | **N=39**  |
+--------------+--------------+---------------+-----------+-----------+
| **Number of  | N            | 69            | 21        | 39        |
| RSR13        |              |               |           |           |
| Doses**      | Mean         | 10.0          | 9.9       | 10.1      |
|              |              |               |           |           |
|              | SD           | 0.4           | 0.2       | 0.5       |
|              |              |               |           |           |
|              | Min/Max      | 8/12          | 9/10      | 8/12      |
+--------------+--------------+---------------+-----------+-----------+
| **RSR13 Dose | N            | 69            | 21        | 39        |
| (mg/kg)**    |              |               |           |           |
|              | Mean         | 92.6          | 93.4      | 93.1      |
|              |              |               |           |           |
|              | SD           | 12.1          | 13.5      | 11.3      |
|              |              |               |           |           |
|              | Min/Max      | 47.8/105.0    | 4         | 5         |
|              |              |               | 7.8/102.7 | 0.1/105.0 |
+--------------+--------------+---------------+-----------+-----------+
| **RSR13      | N            | 69            | 21        | 39        |
| Duration     |              |               |           |           |
| (hrs)**      | Mean         | 0.5           | 0.5       | 0.5       |
|              |              |               |           |           |
|              | SD           | 0.1           | 0.04      | 0.1       |
|              |              |               |           |           |
|              | Min/Max      | 0.3/1.0       | 0.3/0.8   | 0.42/1.0  |
+--------------+--------------+---------------+-----------+-----------+

*Reviewer comment: Patients in RT-008 were more likely to complete 10
days of therapy than those in RT-009, where the mean number of doses
given was 8. Patients also received a higher dose of RSR13 in RT-008
than RT-009 (92.6 mg/kg vs. 85 mg/kg). Refer to **Table 50**.*

> **Table 56**: Extent of Radiation Exposure in Patients Participating
> in RT-008

+-----------------------+-----------------------+-----------------------+
| **Exposure Variable** | **Statistic**         | **N=69**              |
+-----------------------+-----------------------+-----------------------+
| Number of RT Doses    | N                     | 69                    |
|                       |                       |                       |
|                       | Mean                  | 9.9                   |
|                       |                       |                       |
|                       | SD                    | 0.6                   |
|                       |                       |                       |
|                       | Min/Max               | 6/10                  |
+-----------------------+-----------------------+-----------------------+
| Total RT Dose (Gy)    | n                     | 69                    |
|                       |                       |                       |
|                       | Mean                  | 29.6                  |
|                       |                       |                       |
|                       | SD                    | 2.0                   |
|                       |                       |                       |
|                       | Min/Max               | 17.0/30.0             |
+-----------------------+-----------------------+-----------------------+

> (Derived form Table 2.7.4.1.11, Summary of Clinical Safety)
>
> n=number of patients receiving at least 1 dose of
>
> Mean=arithmetic mean
>
> SD=standard deviation
>
> Min/Max=minimum-maximum amount

*Reviewer comment: The exposure to radiation therapy was comparable in
RT-008 to that in RT-009. Refer to **Table 51**.*

**Table 57: Radiation Therapy Exposure for the Breast and NSCLC
Subgroups in RT-008 (FDA Analysis)**

+-------------+-------------+-------------+-------------+-------------+
| **Exposure  | **          | **N=69      | **Breast    | **NSCLC     |
| Variable**  | Statistic** | Patients**  | Subgroup**  | Subgroup**  |
|             |             |             |             |             |
|             |             |             | **(N=21)**  | **(N=39)**  |
+-------------+-------------+-------------+-------------+-------------+
| **Total RT  | N           | 69          | 21          | 39          |
| Dose        |             |             |             |             |
| Delivered** | Mean        | 3.0         | 3.0         | 1.6         |
|             |             |             |             |             |
| **(Gy)**    | SD          | 0.03        | 0.05        | 0.9         |
|             |             |             |             |             |
|             | Min/Max     | 2.5/3.0     | 2.5/3.0     | 0.8/9.2     |
+-------------+-------------+-------------+-------------+-------------+

*Reviewer comment: Radiation exposure was comparable in the Breast
subgroup in RT-009 (control arm and RSR13 arm) and RT-008. There was
greater radiation exposure in the NSCLC subgroup in RT-009 when compared
to the NSCLC patients participating in RT-008.*

**Table 58: Oxygen Exposure for the RT008 (FDA Analysis**)

+-----------------+-----------------+--------+-----------+-----------+
| **Exposure      | **Statistic**   | **     | **Breast  | **NSCLC   |
| Variable**      |                 | N=69** | S         | S         |
|                 |                 |        | ubgroup** | ubgroup** |
|                 |                 |        |           |           |
|                 |                 |        | *         | *         |
|                 |                 |        | *(N=21)** | *(N=39)** |
+-----------------+-----------------+--------+-----------+-----------+
| **Total         | N               | 69     | 21        | 39        |
| Duration of     |                 |        |           |           |
| O~2~            | Mean            | 1.6    | 1.8       | 1.6       |
| Delivered**     |                 |        |           |           |
|                 | SD              | 1.1    | 1.6       | 0.9       |
| **(4 L/min)**   |                 |        |           |           |
|                 | Min/Max         | 0.     | 0.7/18.9  | 0.8/9.2   |
|                 |                 | 7/18.9 |           |           |
+-----------------+-----------------+--------+-----------+-----------+

*Reviewer comment: There was more oxygen exposure in the RSR13 treatment
arm of RT-009 than in NSCLC patients participating in RT-008. Refer to
**Table 53**.*

**C. Adverse Events**

**Treatment-emergent Adverse Events: Sponsor and FDA
Analysis/Critique.**

**Table 59** represents the sponsor's assessment of treatment --
emergent adverse events in RT-008 and RT-009. Given the lack of a
comparison arm in RT-008, the emphasis here is on RT-009.

**Table 59**

**(Derived from Sponsor's Table 2.7.4.2.9)**

![](media/image7.png){width="4.6875in" height="6.21875in"}

**Table 59 (continued)**

![](media/image8.png){width="4.625in" height="5.53125in"}

The sponsor's results were verified by FDA analysis. The most commonly
occurring treatment-emergent adverse events in the intent to treat
population were alopecia, radiation dermatitis, headache, nausea,
vomiting, fatigue, hypoxemia, hypotension, anemia, and taste perversion.
The following treatment-emergent adverse events were encountered more
commonly in the RSR13 treatment arm: headache, nausea, vomiting,
hypoxemia, hypotension, anemia, and taste perversion.

**Table 60** reproduces the majority of treatment-emergent adverse
events reported in RT-009. Nine patients were not evaluable for safety
because they never received according to the sponsor.

 

**Table 60: FDA Analysis Treatment-emergent Adverse Events Reported by
Subgroup in ≥5% of RSR13-treated Patients in RT-009**

+------------+--------+--------+--------+--------+--------+--------+
| **WHOART** | **Con  |        |        | **R    |        |        |
|            | trol** |        |        | SR13** |        |        |
| **Body     |        |        |        |        |        |        |
| System     |        |        |        |        |        |        |
| Total      |        |        |        |        |        |        |
| Preferred  |        |        |        |        |        |        |
| Term**     |        |        |        |        |        |        |
+------------+--------+--------+--------+--------+--------+--------+
|            | **N    | **Br   | **O    | **N    | **Br   | **O    |
|            | SCLC** | east** | ther** | SCLC** | east** | ther** |
|            |        |        |        |        |        |        |
|            | **(    | **     | **     | **     | **     | **     |
|            | N(%)** | N(%)** | N(%)** | N(%)** | N(%)** | N(%)** |
+------------+--------+--------+--------+--------+--------+--------+
| **N**      | *      | **54** | **59** | *      | **60** | **63** |
|            | *150** |        |        | *145** |        |        |
+------------+--------+--------+--------+--------+--------+--------+
| Fatigue    | 64(43) | 24(44) | 26(44) | 73(50) | 32(53) | 26(41) |
+------------+--------+--------+--------+--------+--------+--------+
| Edema      | 20(13) | 3(6)   | 6(10)  | 27(19) | 2(3)   | 8(13)  |
| peripheral |        |        |        |        |        |        |
+------------+--------+--------+--------+--------+--------+--------+
| pain       | 20(13) | 5(9)   | 1(2)   | 11(7)  | 6(10)  | 7(11)  |
+------------+--------+--------+--------+--------+--------+--------+
| asthenia   | 19(13) | 7(13)  | 12(20) | 8(5)   | 1(2)   | 2(3)   |
+------------+--------+--------+--------+--------+--------+--------+
| Fever      | 14(9)  | 3(6)   | 0      | 12(8)  | 6(10)  | 5(8)   |
+------------+--------+--------+--------+--------+--------+--------+
| Back pain  | 10(7)  | 6(11)  | 3(5)   | 11(7)  | 4(5)   | 5(8)   |
+------------+--------+--------+--------+--------+--------+--------+
| Chest pain | 12(8)  | 0      | 1(2)   | 18(12) | 6(10)  | 2(3)   |
+------------+--------+--------+--------+--------+--------+--------+
| Weight     | 10(7)  | 3(6)   | 7(12)  | 10(7)  | 2(3)   | 3(5)   |
| decrease   |        |        |        |        |        |        |
+------------+--------+--------+--------+--------+--------+--------+
| Leg pain   | 8(5)   | 2(4)   | 1(2)   | 3(1)   | 1(2)   | 4(6)   |
+------------+--------+--------+--------+--------+--------+--------+
| Weight     | 2(1)   | 3(6)   | 3(6)   | 9(6)   | 1(2)   | 2(3)   |
| increase   |        |        |        |        |        |        |
+------------+--------+--------+--------+--------+--------+--------+
| Rigors     | 5(3)   | 1(2)   | 1(2)   | 9(6)   | 1(2)   | 2(3)   |
+------------+--------+--------+--------+--------+--------+--------+
| Nausea     | 46(31) | 14(26) | 20(34) | 58(4)  | 39(65) | 27(43) |
+------------+--------+--------+--------+--------+--------+--------+
| Vomiting   | 27(18) | 7(13)  | 11(19) | 47(32) | 31(52) | 24(38) |
+------------+--------+--------+--------+--------+--------+--------+
| Anorexia   | 35(23) | 3(6)   | 6(10)  | 32(22) | 4(7)   | 7(11)  |
+------------+--------+--------+--------+--------+--------+--------+
| Dyspepsia  | 24(16) | 3(6)   | 6(10)  | 14(10) | 4(7)   | 5(8)   |
+------------+--------+--------+--------+--------+--------+--------+
| Mouth dry  | 3(2)   | 4(7)   | 3(5)   | 6(4)   | 2(3)   | 4(6)   |
+------------+--------+--------+--------+--------+--------+--------+
| Abdominal  | 9(6)   | 4(7)   | 9(15)  | 11(7)  | 5(8)   | 5(8)   |
| pain       |        |        |        |        |        |        |
+------------+--------+--------+--------+--------+--------+--------+
| Diarrhea   | 4(3)   | 2(4)   | 3(5)   | 10(7)  | 7(12)  | 3(5)   |
+------------+--------+--------+--------+--------+--------+--------+
| Headache   | 47(31) | 15(28) | 24(41) | 57(39) | 35(58) | 34(54) |
+------------+--------+--------+--------+--------+--------+--------+
| Dizziness  | 27(18) | 6(11)  | 7(12)  | 30(21) | 14(23) | 14(22) |
+------------+--------+--------+--------+--------+--------+--------+
| Confusion  | 11(7)  | 2(4)   | 5(9)   | 12(8)  | 4(7)   | 7(11)  |
+------------+--------+--------+--------+--------+--------+--------+
| C          | 4(3)   | 1(2)   | 4(7)   | 8(5)   | 4(7)   | 8(13)  |
| onvulsions |        |        |        |        |        |        |
+------------+--------+--------+--------+--------+--------+--------+
| P          | 7(5)   | 0      | 0      | 10(7)  | 5(8)   | 3(5)   |
| aresthesia |        |        |        |        |        |        |
+------------+--------+--------+--------+--------+--------+--------+
| Gait       | 5(3)   | 1(2)   | 1(2)   | 8(5)   | 1(2)   | 1(1)   |
| abnormal   |        |        |        |        |        |        |
+------------+--------+--------+--------+--------+--------+--------+
| Ataxia     | 11(7)  | 1(2)   | 1(2)   | 3(1)   | 1(2)   | 4(6)   |
+------------+--------+--------+--------+--------+--------+--------+
| Speech     | 4(3)   | 1(2)   | 1(2)   | 1(1)   | 2(3)   | 4(6)   |
| disorder   |        |        |        |        |        |        |
+------------+--------+--------+--------+--------+--------+--------+
| Tremor     | 8(5)   | 2(4)   | 5(8)   | 8(5)   | 1(2)   | 0      |
+------------+--------+--------+--------+--------+--------+--------+
| Alopecia   | 78(52) | 25(46) | 26(41) | 80(55) | 30(50) | 26(41) |
+------------+--------+--------+--------+--------+--------+--------+
| Radiation  | 34(23) | 13(24) | 19(32) | 35(24) | 12(20) | 22(35) |
| dermatitis |        |        |        |        |        |        |
+------------+--------+--------+--------+--------+--------+--------+
| Rash       | 5(3)   | 1(2)   | 4(7)   | 14(10) | 6(10)  | 2(3)   |
+------------+--------+--------+--------+--------+--------+--------+
| Pruritus   | 1(1)   | 1(2)   | 1(2)   | 3(1)   | 3(5)   | 2(3)   |
+------------+--------+--------+--------+--------+--------+--------+
| Hypoxia    | 8(5)   | 2(4)   | 0      | 62(43) | 23(38) | 24(38) |
+------------+--------+--------+--------+--------+--------+--------+
| Dyspnea    | 30(20) | 4(7)   | 3(5)   | 22(15) | 4(7)   | 4(6)   |
+------------+--------+--------+--------+--------+--------+--------+
| Coughing   | 18(12) | 6(11)  | 6(10)  | 23(16) | 5(8)   | 6(9)   |
+------------+--------+--------+--------+--------+--------+--------+
| Pneumonia  | 10(7)  | 0      | 2(3)   | 12(8)  | 2(3)   | 6(9)   |
+------------+--------+--------+--------+--------+--------+--------+
| Somnolence | 9(6)   | 4(7)   | 6(10)  | 13(3)  | 2(3)   | 8(13)  |
+------------+--------+--------+--------+--------+--------+--------+
| Depression | 7(5)   | 1(2)   | 3(5)   | 3(1)   | 1(2)   | 7(11)  |
+------------+--------+--------+--------+--------+--------+--------+
| Anxiety    | 11(7)  | 1(2)   | 4(7)   | 14(10) | 5(8)   | 4(6)   |
+------------+--------+--------+--------+--------+--------+--------+
| Muscle     | 22(15) | 8(15)  | 9(15)  | 18(12) | 7(12)  | 11(17) |
| weakness   |        |        |        |        |        |        |
+------------+--------+--------+--------+--------+--------+--------+
| Arthralgia | 9(6)   | 5(9)   | 4(7)   | 12(8)  | 5(8)   | 5(8)   |
+------------+--------+--------+--------+--------+--------+--------+
| D          | 11(7)  | 3(6)   | 2(3)   | 14(10) | 0      | 2(3)   |
| ehydration |        |        |        |        |        |        |
+------------+--------+--------+--------+--------+--------+--------+
| Acute      | 0      | 0      | 1(2)   | 4(3)   | 0      | 4(6)   |
| renal      |        |        |        |        |        |        |
| failure    |        |        |        |        |        |        |
+------------+--------+--------+--------+--------+--------+--------+
| Creatinine | 0      | 0      | 0      | 5(3)   | 4(7)   | 2(3)   |
| blood      |        |        |        |        |        |        |
| increased  |        |        |        |        |        |        |
+------------+--------+--------+--------+--------+--------+--------+
| Vision     | 15(10) | 4(7)   | 3(5)   | 11(7)  | 7(12)  | 5(8)   |
| a          |        |        |        |        |        |        |
| bnormality |        |        |        |        |        |        |
+------------+--------+--------+--------+--------+--------+--------+
| H          | 3(2)   | 0      | 0      | 23(16) | 7(12)  | 6(9)   |
| ypotension |        |        |        |        |        |        |
+------------+--------+--------+--------+--------+--------+--------+
| Hy         | 4(3)   | 3(6)   | 3(6)   | 2(1)   | 3(5)   | 1(1)   |
| pertension |        |        |        |        |        |        |
+------------+--------+--------+--------+--------+--------+--------+
| Anemia     | 9(6)   | 2(4)   | 3(5)   | 17(12) | 5(8)   | 11(17) |
+------------+--------+--------+--------+--------+--------+--------+
| T          | 8(5)   | 1(2)   | 1(2)   | 11(7)  | 6(10)  | 3(5)   |
| achycardia |        |        |        |        |        |        |
+------------+--------+--------+--------+--------+--------+--------+
| Thromb     | 3(2)   | 0      | 0      | 5(3)   | 2(3)   | 3(5)   |
| ocytopenia |        |        |        |        |        |        |
+------------+--------+--------+--------+--------+--------+--------+
| Taste      | 4(3)   | 4(7)   | 3(5)   | 17(12) | 7(12)  | 4(6)   |
| perversion |        |        |        |        |        |        |
+------------+--------+--------+--------+--------+--------+--------+
| Gluco      | 3(2)   | 2(4)   | 2(4)   | 10(7)  | 5(8)   | 3(5)   |
| corticoids |        |        |        |        |        |        |
| increased  |        |        |        |        |        |        |
+------------+--------+--------+--------+--------+--------+--------+

Few discrepancies were encountered. For example, 10 cases of pneumonia
were reported in the NSCLC subgroup in the control arm according to FDA
analysis, while 7 cases of pneumonia were reported in this same subgroup
according to the sponsor's analysis. Pneumonia was recorded in two body
systems in the sponsor's analysis (Respiratory and Resistance Mechanism
Disorders). The FDA reported preferred term irrespective of body system.
Furthermore, three patients of the nine that were not evaluable for
safety had records included in some of the datasets, but not others.
This may account for some of the slight differences in the numeric value
for a given adverse event.

The following treatment-emergent adverse events varied by one or two
patients between the FDA analysis and Sponsor's analysis in the control
arm of RT-009: abdominal pain, facial edema, weight increase, rigors,
speech disorder, tremor, paresthesia, disease progression, urinary tract
infection, and hypertension

### 

Grade 3 and 4 Adverse Events Encountered in RT-009 and RT-008 are
reviewed below. **Tables 61** through **65** represent the sponsor's
analysis of these events. The FDA analysis was very similar. Any
difference in outcome are discussed below.

**Table 61**

**(Derived from Sponsor's Table 2.7.4.2.13)**

![](media/image9.png){width="5.28125in" height="5.666666666666667in"}

**Table 61 (continued)**

![](media/image10.png){width="4.34375in" height="4.135416666666667in"}

The most common Grade 3 adverse events encountered in RT-009 were
headache, nausea, vomiting, dyspnea, hypoxemia, and muscle weakness.
Hypoxemia and headache occurred most frequently in the RSR13 treatment
arm.

The following Grade 3 adverse events differed by only one to two
patients between the FDA analysis and Sponsor analysis: headache,
convulsions, anorexia, dyspnea, hypertension, dehydration, hypokalemia,
and hyponatremia. These differences were noted in the control arm. Two
cases of acute renal failure occurred in the RSR13 treatment arm (Grade
3).

**Table 62**

**(Derived from Sponsor's Table 2.7.4.2.15)**

![](media/image11.png){width="5.197916666666667in"
height="5.145833333333333in"}

**Table 62 (continued)**

![](media/image12.png){width="5.197916666666667in"
height="6.739583333333333in"}

**Table 62 (continued)**
![](media/image13.png){width="5.197916666666667in" height="2.5625in"}

The most frequently observed Grade 3 adverse event by subgroup were
fatigue, nausea, vomiting, constipation, abdominal pain, headache,
hypoxia, dyspnea, pneumonia, muscle weakness, hyperglycemia, and disease
progression.

Nausea, vomiting, headache, and hypoxia were more common in the RSR13

treatment arm. Constipation, abdominal pain, dyspnea, muscle weakness,
hyperglycemia, and disease progression were more common in the control
arm.

Again, the differences noted between the FDA analysis and Sponsor's
analysis were only by one or two patients. These included anorexia,
headache, convulsions, cerebral edema, dyspnea, pneumonia, dehydration,
hypokalemia, and hypertension.

**Table 63**

**(Derived from Sponsor's Table 2.7.3.2.14)**

![](media/image14.png){width="4.927083333333333in"
height="6.385416666666667in"}

**Table 63 (continued)**

![](media/image15.png){width="4.489583333333333in"
height="5.947916666666667in"}

Grade 4 events were few, but included dyspnea, pneumonia, and acute
renal failure. Five patients in the RSR13 treatment arm had acute renal
failure compared with one patient in the control arm.

There were no discrepancies in the number of patients with Grade 4
adverse events between the FDA analysis and the Sponsor's analysis.

**Table 64**

**(Derived from Sponsor's Table 2.7.4.2.16)**
![](media/image16.png){width="5.166666666666667in" height="6.59375in"}

**Table 64 (continued)**

![](media/image17.png){width="5.0625in" height="6.572916666666667in"}

**Table 64 (continued)**

![](media/image18.png){width="5.15625in" height="2.9166666666666665in"}

In the RSR13 treatment group, four patients in the "other" subgroup and
one patient with NSCLC had acute renal failure. In the control arm, one
patient in the "other" subgroup developed acute renal failure. The
majority of Grade 4 events recorded in all subgroups included
convulsions, coma, aphasia, stupor, hemiplegia, neurolgia, paralysis,
peripheral neuropathy, dyspnea, pneumonia, pulmonary edema, respiratory
insufficiency, dehydration, hypokalemia, diabetes mellitus, and ketosis.

Only headache and muscle weakness differed between the FDA analysis and
Sponsor's analysis, again by only one patient for each adverse event.