![](media/image1.wmf){width="3.497916666666667in" height="2.80625in"}

**ONCOLOGIC DRUGS ADVISORY COMMITTEE BRIEFING DOCUMENT**

Efaproxiral (RSR13) as an Adjunct to Whole Brain Radiation Therapy for
the Treatment of Brain Metastases Originating from Breast Cancer

**AVAILABLE FOR PUBLIC DISCLOSURE WITHOUT REDACTION**

**TABLE OF CONTENTS**

[1.0 introduction 6](#introduction)

[1.1 Indication 6](#indication)

[1.2 Current Therapy for Brain Metastases
6](#current-therapy-for-brain-metastases)

[1.3 Allosteric Modification of Hemoglobin
7](#allosteric-modification-of-hemoglobin)

[1.4 Mechanism of Action of RSR13 9](#mechanism-of-action-of-rsr13)

[2.0 Background 10](#background)

[2.1 Clinical Development of RSR13 10](#clinical-development-of-rsr13)

[2.2 Clinical Pharmacology and Metabolism
13](#clinical-pharmacology-and-metabolism)

[2.2.1 Clinical Pharmacology Studies 13](#clinical-pharmacology-studies)

[2.2.2 Results from Pharmacokinetic/Pharmacodynamic Studies and RSR13
Dose Selection
13](#results-from-pharmacokineticpharmacodynamic-studies-and-rsr13-dose-selection)

[3.0 Pivotal Phase 3 STUDY FOR the Treatment of patients with Brain
Metastases (RSR13 RT‑009)
18](#pivotal-phase-3-study-for-the-treatment-of-patients-with-brain-metastases-rsr13-rt009)

[3.1 Study Design 18](#study-design)

[3.1.1 Study Endpoints 19](#study-endpoints)

[3.1.2 Prespecified Plans for Analysis of Results
20](#prespecified-plans-for-analysis-of-results)

[3.1.3 Protocol Amendments 21](#protocol-amendments)

[3.2 Patient Demographics, Baseline Characteristics and Efficacy Results
21](#patient-demographics-baseline-characteristics-and-efficacy-results)

[3.2.1 Patient Demographics and Baseline Characteristics
21](#patient-demographics-and-baseline-characteristics)

[3.2.2 Dosing 24](#dosing)

[3.2.3 Efficacy Results 25](#efficacy-results)

[4.0 Supportive Phase 2 STudy For the Treatment of patients with Brain
Metastases (RSR13 RT‑008)
51](#supportive-phase-2-study-for-the-treatment-of-patients-with-brain-metastases-rsr13-rt008)

[4.1 Study Design 51](#study-design-1)

[4.2 Demography and Baseline Characteristics of Patients with Brain
Metastases in RT‑008
51](#demography-and-baseline-characteristics-of-patients-with-brain-metastases-in-rt008)

[4.3 Dosing 53](#dosing-1)

[4.4 Efficacy Results 53](#efficacy-results-1)

[4.5 Comparison of Results from Studies RT-008 and RT-009
55](#comparison-of-results-from-studies-rt-008-and-rt-009)

[5.0 Safety 56](#safety)

[5.1 Studies Evaluated for Safety of RSR13 as an Adjunct to WBRT in
Patients with Brain Metastases from Breast Cancer
56](#studies-evaluated-for-safety-of-rsr13-as-an-adjunct-to-wbrt-in-patients-with-brain-metastases-from-breast-cancer)

[5.2 Extent of Exposure 56](#extent-of-exposure)

[5.2.1 RSR13 Exposure 56](#rsr13-exposure)

[5.2.2 RT Exposure 58](#rt-exposure)

[5.3 Safety in the Pivotal Phase 3 Efficacy Study, RT‑009
58](#safety-in-the-pivotal-phase-3-efficacy-study-rt009)

[5.4 Summary of Adverse Events 58](#summary-of-adverse-events)

[5.5 Overall Incidence of Adverse Events
59](#overall-incidence-of-adverse-events)

[5.6 Incidence of RSR13 Treatment‑related Adverse Events
60](#incidence-of-rsr13-treatmentrelated-adverse-events)

[5.7 Incidence of Grade 3 and 4 Adverse Events
61](#incidence-of-grade-3-and-4-adverse-events)

[5.8 Deaths 63](#deaths)

[5.9 Adverse Events Identified as Significant Components of the RSR13
Safety Profile
64](#adverse-events-identified-as-significant-components-of-the-rsr13-safety-profile)

[5.10 Concomitant Medications 64](#concomitant-medications)

[5.11 Relationship of Adverse Events to Dose, Dose Regimen, and
Treatment Duration
65](#relationship-of-adverse-events-to-dose-dose-regimen-and-treatment-duration)

[5.12 Summary of RSR13 Safety Profile
65](#summary-of-rsr13-safety-profile)

[6.0 Conclusions 66](#conclusions)

[7.0 References 68](#references)

List of Tables

[Table 1.1 Recursive Partitioning Analyses (RPA) Radiation Therapy
Oncology Group (RTOG) 6](#__RefHeading___Toc68333957)

[Table 1.2 Results of Randomized Studies of WBRT for the Treatment of
Brain Metastases 7](#__RefHeading___Toc68333958)

[Table 2.1 Completed and Ongoing RSR13 Oncology Studies
11](#__RefHeading___Toc68333959)

[Table 2.2 RSR13 Studies That Have Provided PK and/or PD Data for the
Oncology Indication 13](#__RefHeading___Toc68333960)

[Table 2.3 RSR13 Dose, PK, and PD Data^a^
16](#__RefHeading___Toc68333961)

[Table 3.1 Description of the Secondary Endpoints in Study RT‑009
19](#__RefHeading___Toc68333962)

[Table 3.2 Assumptions for the Primary Endpoint
20](#__RefHeading___Toc68333963)

[Table 3.3 Prespecified Cox Model Baseline Covariates in Study RT-009
20](#__RefHeading___Toc68333964)

[Table 3.4 Summary of Protocol Amendments for Study RT‑009
21](#__RefHeading___Toc68333965)

[Table 3.5 Ineligible Patients Identified by Blinded Central Review of
Scans 22](#__RefHeading___Toc68333966)

[Table 3.6 Summary of Demographic Data in Control and RSR13 Treated
Patients, Efficacy Oncology Studies 23](#__RefHeading___Toc68333967)

[Table 3.7 Tumor History and Extent of Disease by Treatment Arm in Study
RT‑009 24](#__RefHeading___Toc68333968)

[Table 3.8 Dosing Guidelines by Protocol Version
24](#__RefHeading___Toc68333969)

[Table 3.9 Number of WBRT and RSR13 Doses Received by Treatment Arm,
Study RT‑009 25](#__RefHeading___Toc68333970)

[Table 3.10 Distribution of Prognostic Factors by Treatment Group, All
Eligible Patients in Study RT‑009 29](#__RefHeading___Toc68333971)

[Table 3.11 Treatment Effect Correcting for Imbalances, All Eligible
Patients^a^ 30](#__RefHeading___Toc68333972)

[Table 3.12 Distribution of Prognostic Factors by Treatment Group,
Eligible NSCLC/breast Patients in Study RT‑009
32](#__RefHeading___Toc68333973)

[Table 3.13 Treatment Effect Correcting for Imbalances, All Eligible
NSCLC/breast Patients^a^ 33](#__RefHeading___Toc68333974)

[Table 3.14 Covariate Analysis for Breast Cancer Patients in Study
RT‑009 36](#__RefHeading___Toc68333975)

[Table 3.15 Subsequent Therapies in Patients with Breast Cancer Primary
in Study RT‑009 37](#__RefHeading___Toc68333976)

[Table 3.16 Survival by Investigator Site for Breast Cancer Patients in
Study RT‑009 37](#__RefHeading___Toc68333977)

[Table 3.17 Seven Covariates Most Predictive of Survival by Treatment
Group in Study RT‑009, All Randomized Patients
39](#__RefHeading___Toc68333978)

[Table 3.18 RSR13 Treatment Effect Correcting for Imbalances^a^
39](#__RefHeading___Toc68333979)

[Table 3.19 Survival by Stratum for All Randomized Patients
40](#__RefHeading___Toc68333980)

[Table 3.20 Survival by Best Response for All Patients in Study RT‑009
43](#__RefHeading___Toc68333981)

[Table 3.21 Survival by Best Response for NSCLC/Breast Patients in Study
RT‑009 43](#__RefHeading___Toc68333982)

[Table 3.22 Survival by Best Response for Patients with Breast Cancer
Primary in Study RT‑009 44](#__RefHeading___Toc68333983)

[Table 3.23 Confirmed Response Rate (CR+PR)
44](#__RefHeading___Toc68333984)

[Table 3.24 Differences between RSR13 and Control Arms by Endpoint for
All Randomized Patients (N = 538) 45](#__RefHeading___Toc68333985)

[Table 3.25 Differences between RSR13 and Control Arms by Endpoint for
All Randomized NSCLC/breast Patients (N = 414)
45](#__RefHeading___Toc68333986)

[Table 3.26 Differences between RSR13 and Control Arms by Endpoint for
All Randomized Patients with Breast Cancer Primary (N = 115)
46](#__RefHeading___Toc68333987)

[Table 3.27 Percentage of Patients who Received Dose Adjustments in
Studies RT‑008 and RT‑009 47](#__RefHeading___Toc68333988)

[Table 3.28 Body Weight in Study RT‑009 by Body Weight Category, Gender,
and Primary Site 48](#__RefHeading___Toc68333989)

[Table 3.29 RSR13 RBC Concentrations (μg/mL) in Study RT‑009, by Weight
Category and Primary Site 48](#__RefHeading___Toc68333990)

[Table 3.30 RSR13 Treatment Effect by Weight Group for NSCLC Patients in
Study RT‑009 48](#__RefHeading___Toc68333991)

[Table 3.31 Response Rate by Exposure Group for NSCLC Patients in Study
RT‑009 49](#__RefHeading___Toc68333992)

[Table 4.1 Summary of Demographic Data in Control and RSR13 Treated
Patients in RT‑008 52](#__RefHeading___Toc68333993)

[Table 4.2 Tumor History by RPA Class for RSR13 Treated Patients in
RT‑008 53](#__RefHeading___Toc68333994)

[Table 4.3 Survival Data RTOG Brain Metastases Database Class II
Patients versus RSR13 Class II Patients 54](#__RefHeading___Toc68333995)

[Table 4.4 Survival Data RTOG Brain Metastases Database (Exact Matches)
versus RSR13 Class II Patients 54](#__RefHeading___Toc68333996)

[Table 4.5 Survival in RPA Class II Breast Cancer Patients, Studies
RT‑008 and RT‑009 55](#__RefHeading___Toc68333997)

[Table 5.1 Extent of RSR13 Exposure for All Patients Undergoing RT for
Treatment of Solid Tumors of Different Types, Multiple Dose RSR13
Radiation Oncology Studies 57](#__RefHeading___Toc68333998)

[Table 5.2 Extent of RSR13 Exposure in Patients with Primary Breast
Cancer Undergoing WBRT for Treatment of Brain Metastases (Studies RT‑008
and RT‑009) 58](#__RefHeading___Toc68333999)

[Table 5.3 Adverse Events Occurring in \>10% of Patients in Either
Treatment arm Regardless of Causality, Study RT‑009
60](#__RefHeading___Toc68334000)

[Table 5.4 RSR13‑related Adverse Events Occurring in \>10% of Patients
in Study RT‑009 60](#__RefHeading___Toc68334001)

[Table 5.5 Grade 3 Adverse Events Occurring in ≥3% of Patients in Either
Treatment arm Regardless of Causality, Study RT‑009
61](#__RefHeading___Toc68334002)

[Table 5.6 Grade 4 Adverse Events Occurring in \>1 Patient in Either
Treatment arm Regardless of Causality, Study RT‑009
62](#__RefHeading___Toc68334003)

[Table 5.7 RSR13 Treatment‑related Grade 4 Adverse Events by Site of
Primary, Study RT‑009 62](#__RefHeading___Toc68334004)

[Table 5.8 Summary of Deaths (Number/Percentage of Patients) by
Treatment Arm 63](#__RefHeading___Toc68334005)

[Table 5.9 Summary of Deaths Considered by the Investigator to Have a
Possible, Probable, or Definite Relationship to Study Drug
64](#__RefHeading___Toc68334006)

[Table 5.10 Overall Incidence of Treatment‑emergent Adverse
Events/Adverse Event Categories Identified as Significant or Likely
Components of RSR13 Safety Profile Regardless of Causality, Study RT‑009
64](#__RefHeading___Toc68334007)

List of Figures

[Figure 1.1 Oxygen Equilibrium Curve for Human Whole Blood
8](#__RefHeading___Toc68334008)

[Figure 2.1 Oxygen Equilibrium Curve for Human Whole Blood and the
Relationship of p50 and the Hill Coefficient
14](#__RefHeading___Toc68334009)

[Figure 2.2 RBC RSR13 Concentration versus p50 for Patients who Received
RSR13 at 100 mg/kg in Study RT‑002 15](#__RefHeading___Toc68334010)

[Figure 2.3 Correlation of RSR13 Pharmacokinetics/Pharmacodynamics
16](#__RefHeading___Toc68334011)

[Figure 3.1 Kaplan‑Meier Survival Curve for All Eligible Patients
28](#__RefHeading___Toc68334012)

[Figure 3.2 Kaplan‑Meier Survival Curve for All Eligible NSCLC/breast
Patients RSR13 Arm (N = 203) versus Control Arm (N = 194)
31](#__RefHeading___Toc68334013)

[Figure 3.3 Kaplan‑Meier Survival Curve for All Eligible NSCLC/breast
Patients RSR13 Arm (N = 203) versus Control Arm (N = 194)
34](#__RefHeading___Toc68334014)

[Figure 3.4 Kaplan‑Meier Survival Curve for All Randomized Patients with
Breast Cancer Primary RSR13 Arm (N = 60) versus Control Arm (N = 55)
35](#__RefHeading___Toc68334015)

[Figure 3.5 Kaplan‑Meier Survival Curve for All Randomized Patients
RSR13 Arm (N = 271) versus Control Arm (N = 267)
38](#__RefHeading___Toc68334016)

[Figure 3.6 Kaplan‑Meier Survival Curve for All Randomized NSCLC/breast
Patients RSR13 Arm (N = 208) versus Control Arm (N = 206)
41](#__RefHeading___Toc68334017)

[Figure 3.7 Kaplan‑Meier Survival Curve for All Randomized Patients with
NSCLC Primary RSR13 Arm (N = 148) versus Control Arm (N = 151)
42](#__RefHeading___Toc68334018)

LIST OF ABBREVIATIONS

  --------------- -------------------------------------------------------
  2,3‑DPG         2,3‑diphosphoglycerate

  μg              microgram

  μm              micrometer

  μM              micromolar

  ASCO            american Society of Clinical Oncology

  ASTRO           american Society for Therapeutic Radiology and Oncology

  BCNU            carmustine, 1,3-bis (2-chloroethyl)-1-nitrosourea

  BMD             brain metastases database

  CI              confidence interval

  cm              centimeter

  C~max~          maximum concentration

  CNS             central nervous system

  CO~2~           carbon dioxide

  CR              complete response

  CT              computed tomography

  CVAD            central venous access device

  CYP2C9          hepatic microsomal cytochrome P450 enzyme

  CYP3A4          hepatic microsomal cytochrome P450 enzyme

  dL              deciliter

  g               gram

  GBM             glioblastoma multiforme

  Gy              Gray

  H^+^            hydrogen

  Hgb             hemoglobin

  HR              hazard ratio

  hr              hour

  HW              high body weight

  ICH             International Committee on Harmonization

  IND             Investigational New Drug

  IV              intravenous

  kg              kilogram

  KPS             Karnofsky Performance Status

  L               liter

  LW              low body weight

  Max             maximum

  mg              milligram

  Min             minimum

  min             minute

  mL              milliliter

  mM              millimolar

  mm              millimeter

  mmHg            millimeter of mercury

  MMSE            Mini‑mental State Examination

  MRI             magnetic resonance image

  MST             median survival time

  n or N          number

  *n*             Hill coefficient

  N/A             not applicable

  NABTT           New Approaches to Brain Tumor Therapy

  NaCl            sodium chloride

  NCI             National Cancer Institute

  NDA             New Drug Application

  NF              neurological Function

  nm              nanometer

  NSCLC           non-small cell lung cancer

  OEC             oxygen equilibrium curve

  p50             pressure of oxygen which results in 50% saturation of
                  hemoglobin

  PD              pharmacodynamic or progressive disease

  PF              progression-free

  pH              negative logarithm of the hydrogen ion concentration in
                  the blood

  PK              pharmacokinetic

  pO~2~           partial pressure of oxygen

  PR              partial response

  QOL             quality of life

  RBC             red blood cell, erythrocyte

  RPA             recursive partitioning analysis

  RSR13           RSR13 Injection

  RSR13AG         RSR13 acylglucuronide

  RT              radiation therapy

  RTOG            Radiation Therapy Oncology Group

  SAP             statistical analysis plan

  SD              standard deviation or stable disease

  SO~2~           oxygen saturation

  SpO~2~          arterial oxygen saturation measured by pulse oximetry

  SRS             stereotactic radiosurgery

  TRT             thoracic radiation therapy

  WBRT            whole brain radiation therapy

  WHOART          World Health Organization Adverse Reaction Thesaurus
  --------------- -------------------------------------------------------

# introduction

## Indication

Registration is being sought for RSR13 (efaproxiral sodium) as an
adjunct to whole brain radiation therapy (WBRT) for the treatment of
brain metastases originating from breast cancer. Standard treatment for
brain metastases consists of irradiation of the whole brain once a day,
Monday through Friday, for 2 weeks. RSR13 is infused through a central
venous access device (CVAD) at a dose of 75‑100 mg/kg/day over
30 minutes with supplemental oxygen, with each of 10 fractions of WBRT
administered within 30 minutes of end‑infusion.

## Current Therapy for Brain Metastases

It has been estimated that in the United States, between 80,000 and
170,000 individuals develop brain metastases each year, and up to 35,000
of these are patients with breast cancer.^1,\ 2^ In addition, the
incidence of brain metastases originating from breast cancer is rising
due to the following: 1) longer survival resulting from earlier
diagnosis, 2) better systemic therapy for extracranial disease, and 3) a
higher detection rate due to improved neuroimaging techniques. Standard
treatment for symptomatic lesions consists of corticosteroids and WBRT,
which will relieve symptoms and temporarily improve neurological
function in a majority of patients.^2,\ 3^ In addition to WBRT and
steroids (eg, dexamethasone), current management of patients with brain
metastases includes anticonvulsant medication, surgical resection,
stereotactic radiosurgery, and chemotherapy. WBRT is currently the
principal nonsurgical means to achieve local control and has been shown
to improve survival to approximately 4.5 months as well as
improve/stabilize neurologic function. The current standard for WBRT is
30 Gy over 10 fractions (2 weeks).

Analysis of a large database compiled by the Radiation Therapy Oncology
Group (RTOG) indicated that the overall prognosis for patients with
brain metastases remains poor with a median survival time (MST) of
4.4 months (Table 1.1).^4^ The results of this analysis showed that this
patient population is heterogeneous with respect to prognostic factors
and outcome. Despite the standard use of WBRT, the overall prognosis for
patients with brain metastases has not changed over the last 25 years
(Table 1.2).

[]{#__RefHeading___Toc68333957 .anchor}Table 1.1\
Recursive Partitioning Analyses (RPA) Radiation Therapy Oncology Group
(RTOG)

  ----------------- ----------------- ----------------- -----------------
  **Variable**      **Class I**       **Class II**      **Class III**

  **KPS**           ≥70               ≥70               \<70

  **Primary         Controlled and    Uncontrolled      \-\--
  Status**          \<65 years of age and/or ≥65 years  
                    and Brain only    of age and/or     
                                      extracranial      
                                      metastases        

  **Age (years)**                                       

  **Extracranial                                        
  Disease**                                             

  **%**             20                65                15

  **Survival        7.1               4.2               2.3
  (months)**                                            
  ----------------- ----------------- ----------------- -----------------

Source: Gaspar et al, 1997

[]{#__RefHeading___Toc68333958 .anchor}Table 1.2\
Results of Randomized Studies of WBRT for the Treatment of Brain
Metastases

+------------------+----+---------------------------+----------------+
| **Study (Year    | *  | **WBRT Treatment Arms**   | **MST          |
| Published)**     | *N |                           | (months)**     |
|                  | ** | **Total Gy/Number of      |                |
|                  |    | Fractions**               |                |
+------------------+----+---------------------------+----------------+
| Harwood et al    | 1  | 30/10 vs 10/1             | 4.0‑4.3        |
| (1977)^5^        | 01 |                           |                |
+------------------+----+---------------------------+----------------+
| Kurtz et al      | 2  | 30/10 vs 50/20            | 3.9‑4.2        |
| (1981)^6^        | 55 |                           |                |
+------------------+----+---------------------------+----------------+
| Borgelt et al    | 1  | 10/1 vs 30/10 vs 40/20    | 4.2‑4.8        |
| (1981)^7^        | 38 |                           |                |
+------------------+----+---------------------------+----------------+
| Borgelt et al    | 64 | 12/2 vs 20/5              | 2.8‑3.0        |
| (1981)^7^        |    |                           |                |
+------------------+----+---------------------------+----------------+
| Chatani et al    | 70 | 30/10 vs 50/20            | 3.0‑4.0        |
| (1985)^8^        |    |                           |                |
+------------------+----+---------------------------+----------------+
| Haie-Meder et al | 2  | 18/3 vs 36/6 vs 43/13     | 4.25.3         |
| (1993)^9^        | 16 |                           |                |
+------------------+----+---------------------------+----------------+
| Murray et al     | 4  | 54.4/34 vs 30/10          | 4.5            |
| (1997)^10^       | 45 |                           |                |
+------------------+----+---------------------------+----------------+

The efficacy of radiation therapy (RT) is affected by the extent of
oxygenation in the tumor. Hypoxic tumors are more resistant to cell
damage by radiation;^11^ therefore, tumor hypoxia adversely affects the
clinical prognosis of the patient receiving RT.^12-15^ Oxygen
measurements in human tumors have confirmed tumor hypoxia in
glioblastoma multiforme (GBM),^16^ brain metastases,^16,\ 17^ squamous
cell carcinomas of the uterine cervix^18^ and head and neck,^19^ and
breast carcinoma.^20^ Because hypoxic tumors are substantially more
resistant to radiation than oxygenated tumors, even small hypoxic
fractions in a tumor may limit the overall therapeutic effect of RT and
increase the probability that some tumor cells will survive RT. Several
clinical studies have demonstrated that tumors with a low median pO~2~
(partial pressure of oxygen) have a higher in‑field failure rate after
RT. When compared to well oxygenated tumors of similar size and stage,
patients with tumors of the uterine cervix have been found to have an
increased recurrence rate if the median pO~2~ is less than 10 mmHg.^18^
This effect has also been demonstrated in head and neck cancer.^19^

## Allosteric Modification of Hemoglobin

Hemoglobin is a tetrameric protein comprised of 2 pairs of symmetrically
related α- and β‑globin chains. Each hemoglobin molecule is capable of
binding 4 oxygen molecules. The percentage of oxygen‑binding sites of
hemoglobin bound with oxygen defines the fractional oxygen saturation
and the oxygen content of the solution. The percent saturation is
determined by the concentration of oxygen and the oxygen affinity of the
binding site. Since oxygen is a gas, its concentration is described by
the pO~2~ (measured in mmHg) it produces in solution. The
hemoglobin‑oxygen saturation at any given pO~2~ is graphically
represented as an Oxygen Equilibrium Curve (OEC) (Figure 1.1). The pO~2~
that results in 50% saturation of hemoglobin is identified as the p50.
Thus, the p50 defines the position of the OEC. For example, a high p50
indicates a decreased affinity for oxygen and rightward shift of the
OEC; a low p50 indicates an increased affinity for oxygen and a leftward
shift of the OEC. An additional parameter in the description of the
shift in OEC is the Hill coefficient (*n*), which is a numeric estimate
of a change in the slope of the OEC. Both p50 and *n* are estimated by
nonlinear regression using the following equation: SO~2~ = 100/(1 +
(p50/pO~2~)*^n^*).

[]{#__RefHeading___Toc68334008 .anchor}Figure 1.1\
Oxygen Equilibrium Curve for Human Whole Blood

![](media/image2.wmf){width="4.575694444444444in"
height="3.1527777777777777in"}

Allosteric modifiers of hemoglobin are molecules that alter the
conformational structure of hemoglobin, and thus, modify the oxygen
affinity of hemoglobin. Naturally occurring allosteric modifiers of
hemoglobin include hydrogen ions (H^+^), carbon dioxide (CO~2~), and
organic phosphates, the most important of which for human hemoglobin is
2,3‑diphosphoglycerate (2,3‑DPG). These natural molecules shift the OEC
of hemoglobin to modulate oxygen availability in the tissues under
various physiological conditions. Both acidosis and increased
temperature cause a rightward shift of the OEC, resulting in an enhanced
release of oxygen to the tissues. Acute altitude acclimation and anemia
result in increased production of 2,3‑DPG, again resulting in increased
tissue oxygenation.

In the 1980s, 2 antilipidemic drugs were found to bind to hemoglobin
resulting in a conformational change leading to a decrease of the
affinity of hemoglobin for oxygen. The net effect was increasing the
release of oxygen to tissues. In searching for a drug to treat sickle
cell anemia, Abraham et al^21^ discovered that the antilipidemic drug
clofibric acid lowered the oxygen affinity of hemoglobin solutions.
Later, Perutz et al^22^ reported that another antilipidemic drug,
bezafibrate, was much more effective. However, the potency of these
antilipidemic drugs as allosteric modifiers of hemoglobin was inadequate
for clinical use, due to dose‑limiting toxicity at levels required to
achieve a significant allosteric effect. Dr. Abraham\'s group
subsequently designed and synthesized new allosteric modifiers using a
structure-based drug design approach that combined the disciplines of
x‑ray crystallography, computer assisted drug design, and chemical
synthesis. This research effort resulted in the identification of RSR13.

## Mechanism of Action of RSR13

RSR13 is a synthetic allosteric modifier of hemoglobin, the first of
this new class of pharmaceutical agents. RSR13 is a small molecule that
binds noncovalently in the central water cavity of the hemoglobin
tetramer and reduces hemoglobin oxygen‑binding affinity. By facilitating
the release of oxygen from hemoglobin, RSR13 causes an increase in whole
blood p50 (pO~2~ for 50% hemoglobin saturation), and an increase in
tissue pO~2~. RSR13 emulates the function of natural allosteric
modifiers of hemoglobin (H^+^, CO~2~, and 2,3‑DPG). The RSR13
therapeutic strategy of enhancing oxygen unloading from hemoglobin to
tissue emulates and amplifies physiological tissue oxygenation. This
approach has broad clinical applicability in indications characterized
by tissue hypoxia including the use of RSR13 as an adjunct to RT. By
reducing the oxygen‑binding affinity of hemoglobin, RSR13 can enhance
the oxygenation of hypoxic tumors. By this mechanism, RSR13 acts as a
radiation sensitizer.

Nonclinical studies have shown that RSR13 is a potent allosteric
modifier of hemoglobin and is capable of increasing the pO~2~ of blood
in vitro and in vivo. In vivo RSR13 increases tumor oxygenation and
enhances the effectiveness of RT on hypoxic tumors. Data from
pharmacology studies have demonstrated that RSR13 decreases hemoglobin
oxygen‑binding affinity, increases tumor oxygenation, and decreases the
tumor hypoxic fraction. The studies also demonstrated that these effects
of enhancing tumor oxygenation result in a selective augmentation of
radiation toxicity to the hypoxic tumor while not affecting radiation
toxicity to non‑tumor tissue such as bone marrow or skin. In addition,
studies have shown that RSR13 does not possess direct cytotoxicity.

The fact that RSR13 does not have to enter the cancer cells to increase
the tumor sensitivity to RT is an essential differentiation from other
pharmacologic attempts to improve the efficacy of cancer therapy. This
is especially relevant in the setting of metastatic brain tumors, where
the blood brain barrier acts to exclude or impede the entry of chemical
agents into the brain parenchyma. Oxygen readily diffuses across the
blood brain barrier and the cancer cell membrane to decrease tumor
hypoxia and thereby increase the effectiveness of RT.

The goal of adjunctive RSR13 therapy is to achieve maximal
concentrations of oxygen in the tumor during administration of WBRT in
order to decrease the hypoxic fraction of tumors and increase the tumor
sensitivity to WBRT. The maximum pharmacodynamic effect of RSR13 occurs
at the end of RSR13 infusion; therefore, the timing of administration
for the WBRT fraction should be within 30 minutes of RSR13
administration. To optimize tumor oxygen delivery and ensure sufficient
arterial oxygenation during the period when oxygen affinity is reduced
by RSR13, patients receive supplemental oxygen via nasal cannula.
Supplemental oxygen is initiated prior to RSR13 infusion, administered
continuously during each RSR13 infusion, and continued during WBRT until
a protocol defined time‑point.

# Background

## Clinical Development of RSR13

RSR13 has been studied for the treatment of cancer patients in
15 Phase 1 to Phase 3 clinical studies under oncology Investigational
New Drug (IND) 48,171. RSR13 has been studied in patients with GBM,
brain metastases, and locally advanced, unresectable non-small cell lung
cancer (NSCLC) (Table 2.1).

[]{#__RefHeading___Toc68333959 .anchor}Table 2.3\
Completed and Ongoing RSR13 Oncology Studies

+-------+-----+---------------------------------+------------+-------+
| **    | **  | **Study Title**                 | **RSR13    | **Sta |
| Study | N** |                                 | dose       | tus** |
| Num   |     |                                 | (mg/kg)**  |       |
| ber** |     |                                 |            |       |
+=======+=====+=================================+============+=======+
| R     | 20  | A Phase 1b Study to Evaluate    | 75, 100    | Comp  |
| T‑002 |     | the Safety and Tolerance of     |            | lete; |
|       |     | Multiple Daily Intravenous      |            | Rep   |
|       |     | Doses of RSR13 Administered to  |            | orted |
|       |     | Patients Receiving Concurrent   |            |       |
|       |     | Radiation Therapy               |            |       |
+-------+-----+---------------------------------+------------+-------+
| R     | 12  | A Phase 2 Study to Evaluate the | *RSR13*:   | Comp  |
| T‑004 |     | Effects of a Single Intravenous | 100        | lete; |
|       |     | Infusion of RSR13 on Tumor      |            | Rep   |
|       |     | Oxygenation in Patients with    | *Placebo:* | orted |
|       |     | Tumors Amenable to Oxygen       | 0.45% NaCl |       |
|       |     | Determination Measurements      |            |       |
+-------+-----+---------------------------------+------------+-------+
| R     | 19  | A Phase 1b Study to Evaluate    | 100        | Comp  |
| T‑006 |     | the Safety and Tolerance of     |            | lete; |
|       |     | Repetitive Daily Intravenous    |            | Rep   |
|       |     | Doses of RSR13 Administered to  |            | orted |
|       |     | Patients Receiving Cranial      |            |       |
|       |     | Radiation Therapy for           |            |       |
|       |     | Glioblastoma Multiforme         |            |       |
+-------+-----+---------------------------------+------------+-------+
| R     | 50  | A Phase 2 Study to Evaluate the | 100        | Comp  |
| T‑007 |     | Efficacy and Safety of          |            | lete; |
|       |     | Repetitive Daily Intravenous    |            | Rep   |
|       |     | Doses of RSR13 Administered to  |            | orted |
|       |     | Patients Receiving Cranial      |            |       |
|       |     | Radiation Therapy for           |            |       |
|       |     | Glioblastoma Multiforme         |            |       |
+-------+-----+---------------------------------+------------+-------+
| RT    | 67  | A Companion Phase 2 Study to    | 100        | Comp  |
| ‑007b |     | Evaluate the Efficacy and       |            | lete; |
|       |     | Safety of Repetitive Daily      |            | Rep   |
|       |     | Intravenous Doses of RSR13      |            | orted |
|       |     | Administered to Patients        |            |       |
|       |     | Receiving Cranial Radiation     |            |       |
|       |     | Therapy for Glioblastoma        |            |       |
|       |     | Multiforme                      |            |       |
+-------+-----+---------------------------------+------------+-------+
| R     | 69  | A Phase 2 Study to Evaluate the | 100 with   | Comp  |
| T‑008 |     | Efficacy and Safety of RSR13    | dose       | lete; |
|       |     | Administered to Patients        | reductions | Rep   |
|       |     | Receiving Standard Cranial      | to 75\     | orted |
|       |     | Radiation Therapy for Brain     | or 50      |       |
|       |     | Metastases                      | allowed    |       |
+-------+-----+---------------------------------+------------+-------+
| R     | 538 | A Phase 3 Randomized,           | *RSR13:*   | Comp  |
| T‑009 |     | Open‑Label, Comparative Study   | 100 with   | lete; |
|       |     | of Standard Whole Brain         | dose       | Rep   |
|       |     | Radiation Therapy, With or      | reduction  | orted |
|       |     | Without RSR13, in Patients with | to 75      |       |
|       |     | Brain Metastases                | allowed    |       |
|       |     |                                 |            |       |
|       |     |                                 | *Control*: |       |
|       |     |                                 | No RSR13/  |       |
|       |     |                                 | no placebo |       |
+-------+-----+---------------------------------+------------+-------+
| R     | 51  | A Phase 2 Study of Induction    | 75 with    | Comp  |
| T‑010 |     | Chemotherapy with Paclitaxel    | dose       | lete; |
|       |     | and Carboplatin Followed by     | adjustment | Rep   |
|       |     | Radiation Therapy with RSR13    | to 50 or   | orted |
|       |     | for Locally Advanced Inoperable | 100        |       |
|       |     | Non‑Small Cell Lung Cancer      | allowed    |       |
+-------+-----+---------------------------------+------------+-------+
| R     | 70  | A Phase 1/2 Study to Evaluate   | 25‑100 to  | Study |
| T‑012 | ^a^ | the Safety, Tolerance, and      | determine  | On    |
|       |     | Efficacy of RSR13 (Efaproxiral) | maximum    | going |
|       |     | Administered to Patients        | tolerated  |       |
|       |     | Receiving a Course of Cisplatin | dose       |       |
|       |     | and Radiation Therapy for       |            |       |
|       |     | Locally Advanced Carcinoma of   |            |       |
|       |     | the Cervix                      |            |       |
+-------+-----+---------------------------------+------------+-------+
| C     | 70  | A Phase 1/2 Study to Evaluate   | 25‑100 to  | Study |
| T‑001 | ^a^ | the Safety and Tolerance of     | determine  | On    |
|       |     | Escalating Doses of RSR13       | maximum    | going |
|       |     | (Efaproxiral) Administered with | tolerated  |       |
|       |     | a Fixed Dose of BCNU Every 6    | dose       |       |
|       |     | Weeks in Patients with          |            |       |
|       |     | Recurrent Malignant Glioma      |            |       |
+-------+-----+---------------------------------+------------+-------+
|       |     |                                 |            |       |
+-------+-----+---------------------------------+------------+-------+
| R     | 22  | A Phase 1 Open-label Study of   | 50‑75 to   | Study |
| T‑014 | ^a^ | RSR13 (efaproxiral) and         | determine  | On    |
|       |     | Supplemental Oxygen with        | maximum    | going |
|       |     | Concurrent Paclitaxel,          | tolerated  |       |
|       |     | Carboplatin, and Thoracic       | dose       |       |
|       |     | Radiation Therapy in Patients   |            |       |
|       |     | with Locally Advanced,          |            |       |
|       |     | Unresectable (Stage IIIA/IIIB)  |            |       |
|       |     | Non‑small Cell Lung Cancer      |            |       |
+-------+-----+---------------------------------+------------+-------+
| R     | 360 | A Phase 3 Randomized,           | *RSR13:*   | Study |
| T‑016 | ^a^ | Open‑Label Comparative Study of | 100 with   | On    |
|       |     | Standard Whole Brain Radiation  | dose       | going |
|       |     | Therapy with Supplemental       | reduction  |       |
|       |     | Oxygen, with or without         | to 75      |       |
|       |     | Concurrent RSR13 (efaproxiral), | allowed    |       |
|       |     | in Women with Brain Metastases  |            |       |
|       |     | from Breast Cancer              | *Control*: |       |
|       |     |                                 | No RSR13/  |       |
|       |     |                                 | no placebo |       |
+-------+-----+---------------------------------+------------+-------+

N: total number of patients enrolled

^a^Number of patients planned

Two studies were designed to provide efficacy data for the use of RSR13
as an adjunct to WBRT plus supplemental oxygen in the treatment of
patients with brain metastases: the Phase 2 study, RSR13 RT‑008,^23^ and
the Phase 3 study, RSR13 RT‑009. The main goal of concurrent
administration of RSR13 and WBRT plus supplemental oxygen in the
treatment of brain metastases was to show improvements in survival and
response rate. The Phase 2 (RT‑008) survival analyses were prospectively
designed per protocol to be compared to the survival results of the RTOG
Brain Metastases Database (BMD). Findings indicated that RSR13 improves
the efficacy of WBRT plus supplemental oxygen in patients with brain
metastases.

In view of the encouraging results of RT‑008 and the high unmet medical
need for effective treatment in patients with brain metastases, the
Phase 3 study (RT‑009) was designed to test the hypothesis that the
addition of RSR13 to WBRT plus supplemental oxygen would improve
survival and response rate when compared to WBRT plus supplemental
oxygen alone. Patients receiving daily intravenous (IV) doses of RSR13
with supplemental oxygen administered immediately prior to standard WBRT
were compared to patients receiving daily standard WBRT with
supplemental oxygen (without a placebo). The patient groups analyzed in
this study included the predefined co‑primary populations of all
eligible patients and eligible patients with NSCLC/breast cancer
primary. Additional analyses by stratum and by primary tumor type were
performed (NSCLC, breast, and other primary tumor types). In both
co‑primary populations, RT‑009 showed a decreased risk of death
associated with RSR13 compared to the control when analyzed by Cox
multiple regression model. In addition, with additional follow‑up, an
improvement in survival was observed in eligible NSCLC/breast primary
patients. It was apparent, however, that these results were in large
part driven by the treatment effect observed in patients with breast
cancer. In these patients, a significant difference in survival (using
log‑rank and Cox multiple regression model) favoring RSR13 as an adjunct
to WBRT plus supplemental oxygen (MST, 8.7 months) versus WBRT plus
supplemental oxygen alone (MST, 4.6 months) was observed. These results
were supported by the response rate improvement in RT‑009 as well as
evidence from RT‑008 in the same patient population. Based on these
results, Allos Therapeutics, Inc. submitted the New Drug Application
(NDA) for RSR13 as an adjunct to WBRT for brain metastases in patients
with breast cancer.

## Clinical Pharmacology and Metabolism

### Clinical Pharmacology Studies

The clinical pharmacology results in this section were based on studies
with RSR13 doses of 10‑100 mg/kg, administered by constant‑rate, IV
infusions over 30‑60 minutes, with RT administered within 30 minutes of
end‑infusion. The descriptions of dosing for the 9 clinical studies are
summarized in Table 2.2.

[]{#__RefHeading___Toc68333960 .anchor}Table 2.4\
RSR13 Studies That Have Provided PK and/or PD Data for the Oncology
Indication

  -------------- --------------------------------------------------------
  **Study        **Description of Dosing**
  Number**       

  HV‑001         A single dose, dose-escalation study (10‑100 mg/kg) in
                 healthy young male and female patients

  HV‑003         A single dose study to evaluate the mass balance of a
                 single 75 mg/kg IV dose of RSR13 to healthy male and
                 female patients\`

  RT‑002         A multiple dose, dose- and schedule-escalation study in
                 cancer patients receiving palliative RT, utilizing doses
                 of 75‑100 mg/kg for up to 5 days per week for 2 weeks,
                 10 total doses.

  RT‑004         A single RSR13 dose study to evaluate the effect of a
                 single 100 mg/kg IV dose of RSR13 on tumor oxygenation.

  RT‑006         A repetitive dose, schedule-escalation study in patients
                 receiving a 6‑week course of cranial RT for GBM,
                 utilizing 100 mg/kg dose every other day versus every
                 day for a total of either 15 or 30 doses

  RT‑007         A repetitive dose study in patients receiving a 6‑week
                 course of cranial RT for GBM, utilizing RSR13 100 mg/kg
                 dose for a total of 30 doses

  RT‑008         A repetitive dose study in patients receiving a 2‑week
                 course of cranial RT for brain metastases secondary to
                 breast, NSCLC, melanoma, genitourinary or
                 gastrointestinal primary cancer, utilizing RSR13
                 75‑100 mg/kg dose (with dose modifications to 50 mg/kg
                 or omission) for a total of 10 doses

  RT‑009         A repetitive dose study in patients receiving a 2‑week
                 course of cranial RT for brain metastases secondary to
                 breast, NSCLC, melanoma, genitourinary or
                 gastrointestinal primary cancer, utilizing 75‑100 mg/kg
                 dose (with dose modifications to 50 mg/kg or omission)
                 for a total of 10 doses

  RT‑010         A repetitive dose study in patients undergoing a
                 6‑7 week course TRT for NSCLC (subsequent to 2 cycles
                 paclitaxel and carboplatin 3 weeks apart) utilizing
                 RSR13 75 mg/kg with dose adjustments to 50 or 100 mg/kg
  -------------- --------------------------------------------------------

### Results from Pharmacokinetic/Pharmacodynamic Studies and RSR13 Dose Selection

The goal in dosing RSR13 is to shift the hemoglobin‑oxygen dissociation
in order to maximize the potential oxygen concentration gradient to
facilitate diffusion of oxygen into the tumor; therefore, the greater
the shift in p50 the greater the oxygen dissociation. However, RSR13
also affects the *n* (Hill coefficient). This combination of effects is
illustrated in Figure 2.1. The progressive increase in p50 and decrease
in *n* causes the curve on the left to flatten forming the curve on the
right. The impact of the flattening is that it becomes more difficult to
saturate hemoglobin with oxygen in the pulmonary circulation, even with
supplemental oxygen. Therefore, based on the competing effects on
hemoglobin‑oxygen‑binding affinity, it was determined that a target
shift in p50 of 10 mmHg provided for oxygen dissociation, while still
allowing sufficient cooperativity to assure sizable saturation in the
pulmonary circulation, in order to provide the greatest oxygen gradient
to enhance tumor oxygenation and radiation sensitization.

[]{#__RefHeading___Toc68334009 .anchor}Figure 2.2\
Oxygen Equilibrium Curve for Human Whole Blood and the Relationship of
p50 and the Hill Coefficient

![](media/image3.wmf)

The first clinical study of RSR13, HV‑001, was a randomized,
double-blind, placebo‑controlled, single‑center, partial crossover study
employing single, sequential, ascending RSR13 doses administered by IV
infusion to 19 healthy subjects (16 male, 3 female). RSR13
pharmacokinetics (PK) was evaluated at 4 of the 5 ascending doses of
10 (kinetics not measured at this dose), 25, 50, 75, and 100 mg/kg. The
predefined pharmacodynamic endpoint was a p50 shift of 10 mmHg and was
consistently achieved at a dose of 100 mg/kg. Therefore, it was
concluded that the doses necessary to achieve a p50 shift of 10 mmHg
could be administered to healthy volunteers.

Study RT‑002 followed as the first study with RSR13 as an adjunct to RT
in cancer patients. RT‑002 was a non‑randomized, open‑label,
multi-center study in which RSR13 was administered with supplemental
oxygen immediately prior to RT in patients with histologically or
cytologically proven malignancy refractory to, or not amenable to,
curative anticancer therapy. Patients were to receive a 2‑3 week course
of palliative RT. RSR13 was administered by constant‑rate, IV infusion
at doses of 75 or 100 mg/kg over 60 minutes. The first RSR13 dose was
started on or before the patient's fourth radiation treatment. The
objectives of the study were to evaluate the safety/tolerability of
escalating the RSR13 dose, as well as to determine the PK/PD profile.
The pharmacodynamic (PD) endpoint of the study was a targeted increase
in p50 of 10 mmHg. The results of the study showed RSR13 concentration
in red blood cells (RBCs) correlates strongly with the PD activity
(Figure 2.2). The effect of RSR13 in oncology patients was the same as
the effect in healthy volunteers.

[]{#__RefHeading___Toc68334010 .anchor}Figure 2.3\
RBC RSR13 Concentration versus p50 for Patients who Received RSR13 at
100 mg/kg in Study RT‑002

(Kavanagh et al., 2001)

![](media/image4.png){width="5.280555555555556in"
height="3.827777777777778in"}

Further data supporting the correlation of RSR13 dose, PK and PD data
are presented in Table 2.3 and Figure 2.3.^23-30^ The data are from all
RSR13 studies with PK/PD data obtained at both 75 and 100 mg/kg (HV‑001,
RT‑002, RT‑008, and RT‑010). The data show that an RSR13 dose of
100 mg/kg can produce RSR13 RBC concentrations that correlate with the
desired p50 shift. Figure 2.3 demonstrates 1) that increasing RSR13 RBC
concentration correlates with increasing p50, and 2) to achieve the
desired PD effect, an RSR13 RBC concentration of at least 483 μg/mL in
RBCs has to be reached.

[]{#__RefHeading___Toc68333961 .anchor}Table 2.5\
RSR13 Dose, PK, and PD Data^a^

  ---------------------- ------- ------------- ----------- --------------- ---------
  **Population (study    **N**   **Infusion    **Dose      **Mean RSR13    **Mean
  identification)**              Duration      (mg/kg)**   concentration   p50
                                 (minutes)**               in RBCs         Shift**
                                                           (μg/mL)\***     

  Healthy subjects       24      60            75          450             9.3
  (HV‑001)^29-31^                                                          

                                               100         513             11.9

  Patients with solid    20      60            75          333             5.7
  tumors of different                                                      
  types (RT‑002)^27^                                                       

                                               100         459             8.1

  Brain metastases       69      30            75          453             10.7
  (RT‑008)^23^                                                             

                                               100         536             11.3

  NSCLC (RT‑010)^24-26^  47      30            75          419             8.1

                                               100         547             11.0
  ---------------------- ------- ------------- ----------- --------------- ---------

N: number of patients who received at least 1 RSR13 dose

Mean maximum concentration (C~max~) occurring at end-infusion

^a^Correlation includes studies in which the
pharmacokinetic/pharmacodynamic data were obtained at doses of 75 and
100 mg/kg.

[]{#__RefHeading___Toc68334011 .anchor}Figure 2.4\
Correlation of RSR13 Pharmacokinetics/Pharmacodynamics

![](media/image5.wmf)

#### RSR13 Clinical Pharmacokinetic Summary

The PK of RSR13 were **consistent** across all studies and the PK
results at therapeutic doses are summarized below:

-   Low mean clearance (\<1 mL/min/kg).

-   Low steady-state volume of distribution (\<0.2 L/kg).

-   Plasma protein binding is ∼95% and saturable.

-   Saturable plasma protein binding increases the RBC/plasma
    concentration ratio, presumably by permitting relatively more
    unbound drug to penetrate the RBCs.

-   Terminal exponential half‑lives ∼5.6 hours and 4.5 hours in plasma
    and RBCs, respectively.

-   All metabolism occurs via conversion (conjugation) to acyl
    glucuronide (RSR13AG), a saturable metabolic process.

-   RSR13 is eliminated predominantly via renal excretion (83%)
    (HV‑003). RSR13 is excreted as intact RSR13 or as RSR13AG, through
    passive filtration and saturable and active tubular secretion.

-   Minimal drug accumulation occurs on once daily administration for
    5 consecutive days.

#### RSR13 Clinical Pharmacodynamic Summary

The PD activity of RSR13 (increase in p50) was **consistent** across all
studies and corresponds with the pharmacokinetics of RSR13. The PD
results at therapeutic doses are summarized below:

-   The key PD measurement of RSR13 activity is the partial pressure of
    oxygen which results in a 50% saturation of hemoglobin (p50).

-   RSR13 concentration in RBCs strongly correlates with the PD activity
    (Figures 2.2 and 2.3).

-   RSR13 dosing is not based on achieving steady‑state, but rather is
    necessary only for a period of time needed to administer the RT.

-   All PD activity derives from intact RSR13; RBCs are impervious to
    RSR13AG, presumably due to its hydrophilic nature.

#### RSR13 Dose Justification

Studies showed that an increase in p50 of 10 mmHg provided for oxygen
dissociation while still allowing sufficient cooperativity to assure
sizable saturation in the pulmonary circulation. This should provide
adequate oxygen gradient to enhance tumor oxygenation and radiation
sensitization. Studies HV‑001 and RT‑002 determined that a dose of
100 mg/kg was feasible, well tolerated, and consistently achieved an
RSR13 concentration in RBCs that correlated with the desired PD effect.

# Pivotal Phase 3 STUDY FOR the Treatment of patients with Brain Metastases (RSR13 RT‑009)

## Study Design

Study RT‑009 was a randomized, open‑label, comparative, multi‑center,
efficacy, safety, and PK study in patients receiving a standard 2‑week
course of WBRT for brain metastases with RSR13 (RSR13 arm) or without
RSR13 (Control arm). Patients in both treatment arms were randomized to
receive WBRT, 30 Gy in 10 daily fractions of 3.0 Gy, as well as
supplemental oxygen at 4 L/min via nasal cannula beginning 35 minutes
prior to, during, and for at least 15 minutes after completion of daily
WBRT. The RSR13‑treatment group received RSR13 at 100 or 75 mg/kg
(depending on the dosing algorithm) administered via central venous
access by volumetric pump over a 30‑minute interval no more than
30 minutes prior to each session of a 10‑day course of WBRT.

The MST for the Control arm was estimated to be 4.57 months. The
alternative hypothesis was that WBRT (plus supplemental oxygen) with
RSR13 improves survival. A sample size of 239 eligible patients per
treatment arm provided overall statistical power of 85% (assuming an
increase of MST of 35%) with a two‑sided significance value of 0.05. The
estimated sample size included the following parameters: shape parameter
of 0.0 (O'Brien and Fleming), and 27 months of accrual at 17.67 patients
per month. A minimum of 402 deaths was required for analysis of
survival. Amendment 2 added the co‑primary population of NSCLC/breast
for the survival analysis; a minimum of 308 deaths was required for
analysis.

Enrolled patients had to have histologically or cytologically confirmed
brain metastases, or radiographic studies consistent with brain
metastases. Study RT‑009 was open‑label and unblinded. The patients and
the investigative staff could not be blinded because RSR13 can produce
hypoxemia. The Control arm did not receive a placebo because RSR13 must
be administered through a CVAD.

Patients were stratified at randomization to the following:

1\. RPA Class I

2\. RPA Class II NSCLC primary

3\. RPA Class II breast primary

4\. RPA Class II with other primaries

Definitions of RPA classes are provided in Table 1.1. In study RT‑009,
each patient was centrally randomized prior to the planned commencement
of WBRT. Patients were randomized (within assigned stratum) 1:1 to the
2 treatment arms based on a modified balanced block randomization.^32^

The main eligibility criteria for inclusion are listed below.
Eligibility for enrollment was determined at the screening visit and
reassessed at baseline for confirmation. Enrollment was open to male and
female patients of any ethnic background. Females and minorities were
actively recruited for this protocol.

**Eligibility**

(1) 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.

(2) ≥18 years of age and able to provide written informed consent.

(3) No prior treatment for brain metastases with the exception of prior
    surgical resection if at least 1 measurable lesion remained; prior
    and concurrent corticosteroid therapy allowed.

(4) Adequate hematologic, renal, hepatic, and pulmonary function as
    determined by screening physical examination, pulmonary function
    tests, and laboratory measurements.

(5) Resting and exercise standard pulse oximetry (SpO~2~) while
    breathing room air ≥90%.

(6) No cytotoxic chemotherapy within 7 days prior to WBRT day 1,
    scheduled during the WBRT course or for 1 month after completion of
    WBRT.

(7) No use of any investigational drug, biologic, or device within
    4 weeks prior to WBRT day 1.

(8) Negative serum beta‑human chorionic gonadotropin pregnancy test at
    screening and practicing a medically acceptable contraceptive
    regimen, if patient a female of childbearing potential.

(9) Karnofsky performance status (KPS) ≥70.

(10) Patients must not have previously received RSR13.

### Study Endpoints

The primary endpoint was survival and the secondary efficacy endpoints
(Table 3.1) were response rate in the brain, time to radiographic tumor
progression and time to clinical tumor progression in the brain, cause
of death, and quality of life (QOL).

[]{#__RefHeading___Toc68333962 .anchor}Table 3.6\
Description of the Secondary Endpoints in Study RT‑009

+-----------------------------------+-----------------------------------+
| Response Rate in the Brain        | Scheduled radiographic            |
|                                   | assessments of indicator lesions  |
|                                   | at 1 and 3 months after RT        |
|                                   | course; every 3 months thereafter |
|                                   | compared to baseline              |
+-----------------------------------+-----------------------------------+
| Time to Radiographic Tumor        | Any treated lesion in the brain   |
| Progression in the Brain          | was enlarged by \>25%             |
+-----------------------------------+-----------------------------------+
| Time to Clinical Tumor            | Assessment was made using:        |
| Progression in the Brain          |                                   |
|                                   | > 1\. Neurologic Function (NF)    |
|                                   | > Status score                    |
|                                   | >                                 |
|                                   | > 2\. Mini‑mental State Exam      |
|                                   | > (MMSE)                          |
+-----------------------------------+-----------------------------------+
| Cause of Death                    | Determined as neurologic,         |
|                                   | non‑neurologic, or                |
|                                   | indistinguishable                 |
+-----------------------------------+-----------------------------------+
| QOL                               | KPS and Spitzer Questionnaire     |
+-----------------------------------+-----------------------------------+

### Prespecified Plans for Analysis of Results

Analysis of the primary endpoint (survival) was based on the assumptions
listed in Table 3.2.

[]{#__RefHeading___Toc68333963 .anchor}Table 3.7\
Assumptions for the Primary Endpoint

+-----------------------------------+-----------------------------------+
| RPA Class I : II                  | 20% : 80%                         |
+-----------------------------------+-----------------------------------+
| MST Control arm                   | 4.57 months                       |
+-----------------------------------+-----------------------------------+
| 35% Improvement                   | 6.17 months in the RSR13 arm      |
+-----------------------------------+-----------------------------------+
| Number of events (deaths)         | 402 All randomized patients       |
|                                   |                                   |
|                                   | 308 NSCLC/breast patients         |
|                                   |                                   |
|                                   | 6‑month minimum follow‑up         |
+-----------------------------------+-----------------------------------+

Due to the heterogeneity of these patients, and the potential for
imbalances in prognostic factors, the Cox multiple regression model was
specified in the protocol and statistical analysis plan (SAP). Table 3 3
lists all prespecified Cox model baseline covariates.

[]{#__RefHeading___Toc68333964 .anchor}Table 3.8\
Prespecified Cox Model Baseline Covariates in Study RT-009

  ----------------------------------- -----------------------------------
  Prespecified in the RT‑009 Protocol Prespecified and Added in the
                                      RT‑009 SAP

  RPA Class                           Gender

  Primary tumor type                  Hemoglobin

  Control of primary                  Presence of liver metastases

  Age                                 Size of brain metastases

  Extent of extracranial metastases   Previous resection of brain
                                      metastases

  KPS                                 Timing of diagnosis

  Number of brain metastases          Site location

                                      Site size

                                      Altitude

                                      Weight category
  ----------------------------------- -----------------------------------

Based on the literature, the anticipated 402 events are adequate to
allow for up to 40 covariates. Since only 17 covariates were specified,
the assumption for number of events per covariate was adequately
met.^33^

In Table 3.3, timing of diagnosis was defined per SAP as synchronous
(less than 30 days between diagnosis of primary and brain metastases)
versus metachronous (30 days or more between the diagnosis of primary
and brain metastases).

To ensure that results of the Cox analysis were not sensitive to the
functional form of the covariates, 5 covariates were considered in more
than one way. These included age, KPS, area of brain metastases,
hemoglobin, and altitude. This resulted in a possible 48 unique Cox
models. In addition, both the full model (all covariates in model
simultaneously) and the stepwise selection model were specified.

The SAP defined, per strict International Committee on Harmonization
(ICH) guidelines, the eligible patient population as the primary
analysis population. Efficacy analyses were also performed on all
randomized patients. In both cases, the 2 co‑primary populations were
analyzed. In addition, the results were analyzed per stratum and by site
of primary (regardless of RPA classification).

### Protocol Amendments

A total of 3 amendments were brought to the original study protocol. All
changes dealt with logistical and administrative aspects of the study or
minor clarification of wording with the exception of the following
changes summarized in Table 3.4.

[]{#__RefHeading___Toc68333965 .anchor}Table 3.9\
Summary of Protocol Amendments for Study RT‑009

+-----------------------+--------+------------------------------------+
| **Amendment (Protocol | **     | **Description of Change**          |
| Version)**            | Date** |                                    |
+-----------------------+--------+------------------------------------+
| Amendment 1 (Protocol | 02 Ma  | -   Expand MRI/CT specifications   |
| Version 2)            | r 2000 |                                    |
|                       |        | -   Omit RSR13 on any day if       |
|                       |        |     SpO~2~ \<90%                   |
+-----------------------+--------+------------------------------------+
| Amendment 2 (Protocol | 05 Ju  | -   Sample size up to 538 patients |
| Version 3)            | n 2001 |     with NSCLC/breast co‑primary   |
|                       |        |                                    |
|                       |        | -   Dose Adjustment for            |
|                       |        |     anti‑hypertensives, weight,    |
|                       |        |     and gender                     |
+-----------------------+--------+------------------------------------+
| Amendment 3 (Protocol | 09 Oc  | -   Use of Cobalt 60 allowed       |
| Version 4)            | t 2001 |                                    |
+-----------------------+--------+------------------------------------+

Based on the higher percentage of dosing terminations early on in the
course of study RT‑009 relative to RT‑008, as well as the approximate PK
target of 500 μg/mL, we modeled the RSR13 RBC concentrations at
end-infusion prior to amendment 2 using dose, gender, and weight as
independent variables. The mixed model results suggested that heavy
patients of either sex could be overdosed at 100 mg/kg. Based on the
model results, a cutoff weight for each sex that predicted an
end-infusion RBC concentration of approximately 500 μg/mL was determined
and then adjusted downward to ensure patients would not be overdosed on
their initial dose of RSR13. While this algorithm was intended to only
affect the initial dose of RSR13 for heavy patients, the practical
result was that investigators did not always increase the dose of RSR13
to 100 mg/kg after day 1 even in the absence of safety concerns, thereby
not allowing for the maximum therapeutic benefit of RSR13. In addition,
this conservative approach to RSR13 dosing was applied in many cases to
low weight patients, and when added to the existing dosing guidelines
led to higher rates of RSR13 doses held and reduced in protocol
Versions 3 and 4.

## Patient Demographics, Baseline Characteristics and Efficacy Results

### Patient Demographics and Baseline Characteristics

Patients were randomized from 82 investigational sites in 12 countries.
The first patient consent was received on 16 Feb 2000 and the date of
the last initial (1‑month) follow‑up was 24 Sep 2002. A total of
538 patients were planned (269 in each treatment arm): 538 patients
total were randomized (Control arm: 267 patients; RSR13 arm:
271 patients), and 515 met the eligibility criteria (Control arm:
250 patients; RSR13: 265 patients). Table 3.5 lists the 23 patients who
failed to meet disease specific eligibility criteria; these patients did
not conform to the basic definition of the study population. All except
1 patient with small cell lung cancer were identified through
independent central review of the scans blinded to study arm and
treatment outcome.

[]{#__RefHeading___Toc68333966 .anchor}Table 3.10\
Ineligible Patients Identified by Blinded Central Review of Scans

+-----------------------------+-----------+------------+--------------+
| **Reason Ineligible**       | **Primary | *          | **RSR13**    |
|                             | Site**    | *Control** |              |
+-----------------------------+-----------+------------+--------------+
|                             |           | **N = 17** | **N = 6**    |
+-----------------------------+-----------+------------+--------------+
| Leptomeningeal metastases   | NSCLC     | 5          | 3            |
+-----------------------------+-----------+------------+--------------+
|                             | Breast    | 3          | 2            |
+-----------------------------+-----------+------------+--------------+
|                             | Other     | 4          | 1            |
+-----------------------------+-----------+------------+--------------+
| No measurable brain lesions | NSCLC     | 1          | 0            |
|                             |           |            |              |
| (status post‑resection)     |           |            |              |
+-----------------------------+-----------+------------+--------------+
|                             | Breast    | 2          | 0            |
+-----------------------------+-----------+------------+--------------+
| Small cell lung cancer      | Other     | 1          | 0            |
+-----------------------------+-----------+------------+--------------+
| Dural disease related to    | Breast    | 1          | 0            |
| skull metastases            |           |            |              |
+-----------------------------+-----------+------------+--------------+

There were 529 patients who received at least on1 dose of
protocol‑specified study treatment (Control arm: 263 patients; RSR13
arm: 266 patients) and were therefore analyzed for safety.

Demographics are presented in Table 3.6. Overall, demographics were
similar between the 2 treatment arms but with a slight trend towards
younger patients in the Control arm.

Because body weight was a determinant for the starting dose of RSR13
after Amendment 2, analysis was performed to show body weight by gender
and primary site subpopulation. Per protocol females \>70 kg and males
\>95 kg were grouped in the high body weight (HW) category and females
≤70 kg and males ≤95 kg were classified as low body weight (LW). In the
RSR13 arm, most patients in the NSCLC primary subpopulation were LW
(83%) while in the breast primary subpopulation, only 47% of patients
were LW. Mean body weight for females in the breast primary
subpopulation was 4 kg higher than the mean body weight for females in
the NSCLC primary subpopulation and 3 kg higher than the overall mean
body weight for the subpopulation of patients with NSCLC primary. In the
Control arm, the same trend was observed.

[]{#__RefHeading___Toc68333967 .anchor}Table 3.11\
Summary of Demographic Data in Control and RSR13 Treated Patients,
Efficacy Oncology Studies

  --------------- -------------------------------------------- --------------- ---------------
  **Parameter**                                                **RT‑009        **RT‑009
                                                               Control**       RSR13**

                                                               **(N = 267)**   **(N = 271)**

  **Gender n                                                                   
  (%)**                                                                        

                  Male                                         117 (44)        118 (44)

                  Female                                       150 (56)        153 (56)

  **Race n (%)**                                                               

                  Caucasian                                    239 (90)        242 (89)

                  Black                                        12 (4)          15 (6)

                  Native American                              1               1

                  Asian                                        3 (1)           2 (1)

                  Hispanic                                     6 (2)           7 (3)

                  Other/Missing                                6 (2)           4 (2)

  **Age (years)**                                                              

                  \<65 years n (%)                             197 (74)        196 (72)

                  ≥65 years n (%)                              70 (26)         75 (28)

                  Mean                                         57.0            57.1

                  SD                                           11.0            11.1

                  Min-Max                                      2381           3087

  **Weight (kg)**                                                              

                  Mean                                         72.5            71.3

                  SD                                           17.1            15.0

                  Min-Max                                      33.0140.9      39.8122.0

                  n Missing                                    2               0

  **Weight                                                                     
  Category^a^**                                                                

                  LW                                           198 (74)        204 (75)

                  HW                                           67 (25)         67 (25)

  **Strata as                                                                  
  Randomized**                                                                 

                  Stratum 1: RPA Class I                       28 (10)         29 (11)

                  Stratum 2: RPA Class II -- NSCLC primary     132 (49)        132 (49)

                  Stratum 3: RPA Class II -- Breast cancer     51 (19)         52 (19)
                  primary                                                      

                  Stratum 4: RPA Class II -- Other primary     56 (21)         58 (21)
                  tumor type                                                   

  **Screening                                                                  
  Resting                                                                      
  SpO~2~^b^**                                                                  

                  \<96%                                        53 (20)         59 (22)

                  ≥96%                                         214 (80)        212 (78)
  --------------- -------------------------------------------- --------------- ---------------

> ^a^Two patients had missing data in the Control arm.
>
> ^b^Missing baseline resting SpO~2~ counted in the \<96% category.

Tumor history is summarized by treatment arm in Table 3.7. There were
imbalances in several important prognostic factors, all of which favored
the Control arm, including: the proportion of patients without
extracranial metastases, the proportion of patients without liver
metastases, the proportion of patients with a prior brain tumor
resection, and the time from diagnosis of primary disease to study day 1
(ie, WBRT day 1).

[]{#__RefHeading___Toc68333968 .anchor}Table 3.12\
Tumor History and Extent of Disease by Treatment Arm in Study RT‑009

+-------------------------+------------+---------------+---------------+
| **Covariate**           | **Value**  | **Control**   | **RSR13**     |
|                         |            |               |               |
|                         |            | **N = 267**   | **N = 271**   |
+-------------------------+------------+---------------+---------------+
| **RPA Class:**          | I          | 28            | 29            |
+-------------------------+------------+---------------+---------------+
|                         | II         | 239           | 242           |
+-------------------------+------------+---------------+---------------+
| **Primary Control:**    | Controlled | 67            | 72            |
+-------------------------+------------+---------------+---------------+
|                         | Un         | 200           | 199           |
|                         | controlled |               |               |
+-------------------------+------------+---------------+---------------+
| **Duration of primary   | Q1         | 1.1           | 0.9           |
| disease (months)^a^:**  |            |               |               |
+-------------------------+------------+---------------+---------------+
|                         | Q2         | 11.4          | 9.9           |
+-------------------------+------------+---------------+---------------+
|                         | Q3         | 33.8          | 28.9          |
+-------------------------+------------+---------------+---------------+
| **Presence of           | Yes        | 171           | 187           |
| extracranial            |            |               |               |
| metastases:**           |            |               |               |
+-------------------------+------------+---------------+---------------+
|                         | No         | 96            | 84            |
+-------------------------+------------+---------------+---------------+
| **Prior treatment for   | Yes        | 29            | 21            |
| brain metastases:**     |            |               |               |
+-------------------------+------------+---------------+---------------+
|                         | No         | 238           | 250           |
+-------------------------+------------+---------------+---------------+
| **Liver metastases:**   | Yes        | 42            | 54            |
+-------------------------+------------+---------------+---------------+
|                         | No         | 225           | 217           |
+-------------------------+------------+---------------+---------------+

> ^a^Q1, Q2, and Q3 represent the first, second, and third quartiles,
> respectively

### Dosing

The selection of the RSR13 doses administered 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 (including 69 patients with
brain metastases) received repetitive daily RSR13 infusions prior to RT.
Based on these background data, the starting dose in this present study
was 75 or 100 mg/kg.

The changes in the initial RSR13 dose received as a result of
Amendment 2 (Protocol Version 3) are summarized in Table 3.8.

[]{#__RefHeading___Toc68333969 .anchor}Table 3.13\
Dosing Guidelines by Protocol Version

  ------------ ---------------------- -------------- --------- --------------------------
               **Protocol Versions 1  **Protocol               
               and 2**                Versions 3 and           
                                      4**                      

  **SpO~2~     RSR13 held             RSR13 held               
  \<90%**                                                      

  **SpO~2~     RSR13 administered at  RSR13                    
  90%-92%**    75 mg/kg               administered             
                                      at 75 mg/kg              

  **SpO~2~     RSR13 administered at  The following            
  ≥93%**       100 mg/kg              weight and               
                                      gender                   
                                      guideline was            
                                      used:                    

                                                     Males     \- If weight ≤95 kg,
                                                               administer 100 mg/kg RSR13

                                                               \- If weight \> 95 kg,
                                                               administer 75 mg/kg RSR13

                                                     Females   \- If weight ≤70 kg,
                                                               administer 100 mg/kg RSR13

                                                               \- If weight \> 70 kg,
                                                               administer 75 mg/kg RSR13
  ------------ ---------------------- -------------- --------- --------------------------

Under Protocol Versions 3 and 4, if a patient was administered
anti‑hypertensive medications the patient received RSR13 at 75 mg/kg.

Reasons for dose reductions for Protocol Versions 1‑4 can be summarized
as follows:

1.  Supplemental oxygen was administered for \>3 hours

2.  Nausea and/or vomiting ≥Grade 2

3.  Hypotension

4.  Hypoxemia requiring treatment after discharge

5.  Room air SpO~2~ 90%‑92% with ≥93% on previous day

The number of RSR13 doses and the mean RSR13 dose administered during
the study are summarized in Table 3.9. Fifty‑two percent (141/271) of
RSR13‑treated patients received the entire RSR13 course of 10 doses. The
majority of patients (80%, 218/271) received 7 or more RSR13 doses, and
only 13% (34/271) of patients received ≤4 RSR13 doses. RSR13 did not
affect the delivery of WBRT.

[]{#__RefHeading___Toc68333970 .anchor}Table 3.14\
Number of WBRT and RSR13 Doses Received by Treatment Arm, Study RT‑009

+-----------------+-----------------+-----------------+-----------------+
| **Number of     | **Control**     | **RSR13**       |                 |
| Doses**         |                 |                 |                 |
|                 | **N = 267**     | **N = 271**     |                 |
+-----------------+-----------------+-----------------+-----------------+
|                 | **WBRT**        | **WBRT**        | **RSR13**       |
|                 |                 |                 |                 |
|                 | **N** **(%)**   | **N (%)**       | **n (%)**       |
+-----------------+-----------------+-----------------+-----------------+
| **0**           | 4 (1)           | 5 (2)           | 8 (3)           |
+-----------------+-----------------+-----------------+-----------------+
| **1‑6**         | 6 (2)           | 9 (3)           | 45 (17)         |
+-----------------+-----------------+-----------------+-----------------+
| **7‑9**         | 3 (1)           | 3 (1)           | 77 (28)         |
+-----------------+-----------------+-----------------+-----------------+
| **10**          | 254 (95)        | 254 (94)        | 141 (52)        |
+-----------------+-----------------+-----------------+-----------------+
| **Mean**        | 9.9             | 9.8             | 8.4             |
+-----------------+-----------------+-----------------+-----------------+

### Efficacy Results

The study RT‑009 efficacy results are organized as follows:

> Section 3.2.3.1 Overview of Key Efficacy Findings
>
> Section 3.2.3.2 Primary Endpoint: Survival
>
> Section 3.2.3.3 Secondary Endpoint: Response Rate in the Brain
>
> Section 3.2.3.4 Other Secondary Endpoints
>
> Section 3.2.3.5 Differences between NSCLC and Breast Patients
>
> Section 3.2.3.6 Efficacy Conclusions

#### Overview of Key Efficacy Findings

**Key Efficacy Findings Overall:**

-   38% increase in MST and an 18% reduction in risk of death observed
    in the co‑primary population of eligible NSCLC/breast patients (HR
    \[hazard ratio\] = 0.82, p = 0.07, unadjusted log‑rank) in the
    per‑protocol January 2003 analysis. This estimate became more
    precise with the additional follow‑up conducted in January
     2004 (HR = 0.82, p = 0.05, unadjusted log‑rank).

-   13% reduction in risk of death observed in the co‑primary population
    of all eligible patients (January 2003 analysis: HR = 0.87,
    p = 0.16, unadjusted log‑rank; January 2004 analysis: HR = 0.87,
    p = 0.13, unadjusted log‑rank).

-   24% reduction in risk of death observed in both co‑primary
    populations after correcting for the imbalances in prognostic
    factors via the prespecified Cox multiple regression model (p = 0.01
    and p = 0.02 in all eligible and all eligible NSCLC/breast
    co-primary populations, respectively).

-   Survival advantage due to RSR13 driven by the patients with breast
    primary; 45% reduction in risk of death observed in these patients
    (HR = 0.55, p \<0.01, unadjusted log‑rank).

-   Survival advantage due to RSR13 in co‑primary NSCLC/breast
    population as well as breast primary patients supported by increased
    response rate (Control vs RSR13 response rate: 41% vs 53%
    \[p = 0.01\] in NSCLC/breast patients and 49% vs 72% \[p = 0.02\] in
    breast patients).

**Key Efficacy Findings in Breast Cancer Patients:**

-   90% improvement in MST (4.6 vs 8.7 months, HR = 0.55, 95% confidence
    interval (CI): 0.35, 0.85)

-   Consistent treatment effect on response rate and QOL

-   Treatment arms well‑balanced by prespecified covariates and
    subsequent therapy

#### Primary Endpoint: Survival

The SAP specified that the primary survival analysis was to be performed
using the unadjusted log-rank test on 2 populations: all eligible
patients and all eligible NSCLC/breast patients. In addition, the
protocol stated that analysis of all randomized patients in the 2
co-primary populations and an analysis by stratum would be performed.
Furthermore, to correct for potential imbalances in prognostic factors
between the treatment arms, a Cox model was fully prespecified in the
SAP.

For the original data analyses, overall survival was calculated from the
time of randomization into the study until death or 31 Jan 2003,
whichever occurred first. At the time of this survival analysis, there
were a total of 441 deaths in the entire patient population and 331 in
the NSCLC/breast population. A survival follow‑up was conducted with
survival data until January 2004, which provided an additional 12 months
of data. At this update, there were a total of 496 deaths in the entire
patient population and 377 in the NSCLC/breast population.

The RT‑009 study protocol and the SAP specified log-rank as the primary
statistical test to be applied to the survival analyses, but an argument
can be made that the log‑rank test is not the most appropriate tool to
analyze the survival results of study RT‑009. It has been demonstrated
in simulation studies, and verified in study RT‑009, that for
heterogeneous samples a simple log‑rank test can yield misleading
results.^35^ In addition, slight imbalances in known prognostic factors
can bias treatment comparisons as reviewed by Sather et al^36^ and by
Altman et al.^37^

For all of the covariates listed in Table 3.3, the proportional hazards
assumption underlying the Cox multiple regression models was examined
and verified using a nonparametric kernel smoothing plot of the
hazards.^34^ Notably, the hazard functions generally declined with time.
A deviance residual plot showed that the results of the analysis were
robust with respect to outliers. Furthermore, the RSR13 estimates were
consistent regardless of the functional form of the covariates as
outlined in Section 3.1.2.

Unless otherwise noted, all survival analysis results represent the
analysis at the protocol specified time, conducted using follow‑up
through January 2003.

##### Survival in All Eligible Patients

The observed MST for the Control arm (N = 250) was 4.4 months compared
to 5.4 months for the RSR13 arm (N = 265) (Figure 3.1). This treatment
effect translated into a hazard ratio of 0.87 via the unadjusted
log‑rank test (p = 0.16) and a hazard ratio of 0.76 via the prespecified
Cox multiple regression model utilizing all covariates simultaneously
(p \<0.01). The reason for the discrepancy between the 2 tests is
primarily due to the imbalance in important prognostic factors between
the 2 treatment arms; namely, KPS, and the presence of extracranial
metastases (Table 3.10). Beginning with a Cox model that included only
treatment arm, Table 3.11 shows how adding covariates one‑at‑a‑time
based on their statistical significance in the full Cox model affects
the RSR13 treatment effect estimate. After adjusting for the imbalances
in KPS and presence of extracranial metastases, the 2 most significant
covariates in the full Cox model, the RSR13 treatment effect has a
p‑value of 0.03.

[]{#__RefHeading___Toc68334012 .anchor}Figure 3.5\
Kaplan‑Meier Survival Curve for All Eligible Patients

RSR13 Arm (N = 265) versus Control Arm (N = 250)

![](media/image2.wmf)

[]{#__RefHeading___Toc68333971 .anchor}Table 3.15\
Distribution of Prognostic Factors by Treatment Group, All Eligible
Patients in Study RT‑009

+------------------------------+------------+------------+------------+
| **Covariate**                | **Value**  | *          | **RSR13**  |
|                              |            | *Control** |            |
|                              |            |            | **(        |
|                              |            | **(        | N = 265)** |
|                              |            | N = 250)** |            |
|                              |            |            | **%**      |
|                              |            | **%**      |            |
+------------------------------+------------+------------+------------+
| **Primary Site**             | NSCLC      | 58         | 55         |
+------------------------------+------------+------------+------------+
|                              | Breast     | 20         | 22         |
+------------------------------+------------+------------+------------+
|                              | Other      | 22         | 23         |
+------------------------------+------------+------------+------------+
| **Age**                      | \<65 years | 73         | 72         |
+------------------------------+------------+------------+------------+
|                              | ≥65 years  | 27         | 28         |
+------------------------------+------------+------------+------------+
| **Baseline KPS**             | 100        | 16         | 13         |
+------------------------------+------------+------------+------------+
|                              | 90         | 37         | 46         |
+------------------------------+------------+------------+------------+
|                              | 80         | 31         | 23         |
+------------------------------+------------+------------+------------+
|                              | 70         | 16         | 17         |
+------------------------------+------------+------------+------------+
| **Gender**                   | Female     | 56         | 56         |
+------------------------------+------------+------------+------------+
|                              | Male       | 44         | 44         |
+------------------------------+------------+------------+------------+
| **Control of**               | Controlled | 24         | 26         |
|                              |            |            |            |
| **primary cancer**           |            |            |            |
+------------------------------+------------+------------+------------+
|                              | Un         | 76         | 74         |
|                              | controlled |            |            |
+------------------------------+------------+------------+------------+
| **RPA Class**                | I          | 10         | 11         |
+------------------------------+------------+------------+------------+
|                              | II         | 90         | 89         |
+------------------------------+------------+------------+------------+
| **Number of sites of**       | 0          | 36         | 31         |
|                              |            |            |            |
| **extracranial metastases**  |            |            |            |
+------------------------------+------------+------------+------------+
|                              | 1 to 2     | 46         | 48         |
+------------------------------+------------+------------+------------+
|                              | ≥3         | 18         | 22         |
+------------------------------+------------+------------+------------+
| **Presence of**              | Yes        | 16         | 20         |
|                              |            |            |            |
| **liver metastases**         |            |            |            |
+------------------------------+------------+------------+------------+
|                              | No         | 84         | 80         |
+------------------------------+------------+------------+------------+
| **Number of**                | 1          | 20         | 17         |
|                              |            |            |            |
| **brain metastases** ^a^     |            |            |            |
+------------------------------+------------+------------+------------+
|                              | 2 to 3     | 32         | 30         |
+------------------------------+------------+------------+------------+
|                              | \>3        | 47         | 52         |
+------------------------------+------------+------------+------------+
| **Sum of**                   | \          | 25         | 26         |
|                              | <250 mm^2^ |            |            |
| **Bidimensional**            |            |            |            |
|                              |            |            |            |
| **products of lesions** ^a^  |            |            |            |
+------------------------------+------------+------------+------------+
|                              | 250‑       | 46         | 50         |
|                              | 1000 mm^2^ |            |            |
+------------------------------+------------+------------+------------+
|                              | \>1000     | 28         | 23         |
|                              | mm^2^      |            |            |
+------------------------------+------------+------------+------------+
| **Timing of**                | Me         | 68         | 67         |
|                              | tachronous |            |            |
| **Diagnosis**                |            |            |            |
+------------------------------+------------+------------+------------+
|                              | S          | 32         | 33         |
|                              | ynchronous |            |            |
+------------------------------+------------+------------+------------+
| **Prior cranial tumor        | Yes        | 10         | 8          |
| resection**                  |            |            |            |
+------------------------------+------------+------------+------------+
|                              | No         | 90         | 92         |
+------------------------------+------------+------------+------------+
| **Baseline hemoglobin**      | \<12 g/dL  | 16         | 17         |
+------------------------------+------------+------------+------------+
|                              | ≥12 g/dL   | 84         | 83         |
+------------------------------+------------+------------+------------+
| **Site location**            | USA        | 47         | 50         |
+------------------------------+------------+------------+------------+
|                              | Canada     | 32         | 29         |
+------------------------------+------------+------------+------------+
|                              | ROW        | 21         | 21         |
+------------------------------+------------+------------+------------+
| **Altitude at**              | \          | 86         | 87         |
|                              | <2000 feet |            |            |
| **treatment site**           |            |            |            |
+------------------------------+------------+------------+------------+
|                              | ≥2000 feet | 14         | 13         |
+------------------------------+------------+------------+------------+
| **Weight per dosing**        | High       | 26         | 25         |
|                              | weight     |            |            |
| **adjustment algorithm**     |            |            |            |
+------------------------------+------------+------------+------------+
|                              | Low weight | 74         | 75         |
+------------------------------+------------+------------+------------+

> ^a^Five patients with missing data

[]{#__RefHeading___Toc68333972 .anchor}Table 3.16\
Treatment Effect Correcting for Imbalances, All Eligible Patients^a^

  ------------------------------------------------------- ---------------
  **Covariates in Cox Model**                             **RSR13
                                                          Effect**

  \-\--                                                   HR = 0.87,
                                                          p = 0.16

  KPS                                                     HR = 0.86,
                                                          p = 0.12

  KPS, Number of Extracranial Metastases                  HR = 0.81,
                                                          p = 0.03

  KPS, Number of Extracranial Metastases, Prior resection HR = 0.80,
                                                          p = 0.02

  KPS, Number of Extracranial Metastases, Prior           HR = 0.78,
  resection, Gender                                       p = 0.01

  KPS, Number of Extracranial Metastases, Prior           HR = 0.79,
  resection, Gender, Breast Primary                       p = 0.02

  KPS, Number of Extracranial Metastases, Prior           HR = 0.79,
  resection, Gender, Breast Primary, Age Group            p = 0.01
  ------------------------------------------------------- ---------------

^a^Last row contains all covariates that were statistically significant
(p \<0.05)

For the initial survival data analyses, overall survival was calculated
from the time of randomization into the study until death or
31 Jan 2003, whichever occurred first. The survival results were updated
through January 2004. There were 474 deaths in the updated survival
data. The unadjusted hazard ratio for the updated survival data was
0.87 (95% CI: 0.72, 1.05) and the Cox multiple regression HR was 0.79
(95% CI: 0.65, 0.95).

##### Survival in All Eligible Patients in the NSCLC/breast Population

The observed MST for the Control arm (N = 194) was 4.4 months compared
to 6.0 months for the RSR13 arm (N = 203) (Figure 3.2). This treatment
effect translated into a hazard ratio of 0.82 via the unadjusted
log-rank test (p = 0.07) and a hazard ratio of 0.76 via the prespecified
Cox multiple regression model utilizing all covariates simultaneously
(p = 0.02). The reason the Cox multiple regression model results in a
lower p‑value is primarily due to the slight imbalance in important
prognostic factors between the 2 treatment arms; namely, KPS and prior
brain tumor resection ( Table 3.12). Beginning with a Cox model that
included only treatment arm, Table 3.13 shows how adding covariates
one‑at‑a‑time based on their statistical significance in the full Cox
model affects the RSR13 treatment effect estimate. After adjusting for
KPS and presence of extracranial metastases, the 2 most significant
covariates in the full Cox model, the RSR13 treatment effect has a
p‑value of 0.03.

[]{#__RefHeading___Toc68334013 .anchor}Figure 3.6\
Kaplan‑Meier Survival Curve for All Eligible NSCLC/breast Patients\
RSR13 Arm (N = 203) versus Control Arm (N = 194)

![](media/image2.wmf)

[]{#__RefHeading___Toc68333973 .anchor}Table 3.17\
Distribution of Prognostic Factors by Treatment Group, Eligible
NSCLC/breast Patients in Study RT‑009

+-----------------------+-------------+--------------+----------------+
| **Covariate**         | **Value**   | **Control    | **RSR13**      |
|                       |             | (N = 194)**  |                |
|                       |             |              | **(N = 203)**  |
|                       |             | **%**        |                |
|                       |             |              | **%**          |
+-----------------------+-------------+--------------+----------------+
| **Primary Site**      | NSCLC       | 75           | 71             |
+-----------------------+-------------+--------------+----------------+
|                       | Breast      | 25           | 29             |
+-----------------------+-------------+--------------+----------------+
| **Age**               | \<65 years  | 72           | 72             |
+-----------------------+-------------+--------------+----------------+
|                       | ≥65 years   | 28           | 28             |
+-----------------------+-------------+--------------+----------------+
| **Baseline KPS**      | 100         | 16           | 13             |
+-----------------------+-------------+--------------+----------------+
|                       | 90          | 39           | 47             |
+-----------------------+-------------+--------------+----------------+
|                       | 80          | 28           | 24             |
+-----------------------+-------------+--------------+----------------+
|                       | 70          | 16           | 17             |
+-----------------------+-------------+--------------+----------------+
| **Gender**            | Female      | 62           | 61             |
+-----------------------+-------------+--------------+----------------+
|                       | Male        | 38           | 39             |
+-----------------------+-------------+--------------+----------------+
| **Control of**        | Controlled  | 23           | 23             |
|                       |             |              |                |
| **primary cancer**    |             |              |                |
+-----------------------+-------------+--------------+----------------+
|                       | U           | 77           | 77             |
|                       | ncontrolled |              |                |
+-----------------------+-------------+--------------+----------------+
| **RPA Class**         | I           | 10           | 11             |
+-----------------------+-------------+--------------+----------------+
|                       | II          | 90           | 89             |
+-----------------------+-------------+--------------+----------------+
| **Number of sites     | 0           | 37           | 36             |
| of**                  |             |              |                |
|                       |             |              |                |
| **extracranial        |             |              |                |
| metastases**          |             |              |                |
+-----------------------+-------------+--------------+----------------+
|                       | 1 to 2      | 46           | 46             |
+-----------------------+-------------+--------------+----------------+
|                       | ≥3          | 18           | 17             |
+-----------------------+-------------+--------------+----------------+
| **Presence of**       | Yes         | 15           | 15             |
|                       |             |              |                |
| **liver metastases**  |             |              |                |
+-----------------------+-------------+--------------+----------------+
|                       | No          | 85           | 85             |
+-----------------------+-------------+--------------+----------------+
| **Number of**         | 1           | 21           | 18             |
|                       |             |              |                |
| **brain metastases**  |             |              |                |
| ^a^                   |             |              |                |
+-----------------------+-------------+--------------+----------------+
|                       | 2 to 3      | 30           | 32             |
+-----------------------+-------------+--------------+----------------+
|                       | \>3         | 48           | 49             |
+-----------------------+-------------+--------------+----------------+
| **Sum of**            | \<250 mm^2^ | 25           | 26             |
|                       |             |              |                |
| **bidimensional**     |             |              |                |
|                       |             |              |                |
| **products of         |             |              |                |
| lesions** ^a^         |             |              |                |
+-----------------------+-------------+--------------+----------------+
|                       | 250         | 46           | 48             |
|                       | ‑1000 mm^2^ |              |                |
+-----------------------+-------------+--------------+----------------+
|                       | \           | 29           | 25             |
|                       | >1000 mm^2^ |              |                |
+-----------------------+-------------+--------------+----------------+
| **Timing of**         | M           | 67           | 63             |
|                       | etachronous |              |                |
| **Diagnosis**         |             |              |                |
+-----------------------+-------------+--------------+----------------+
|                       | Synchronous | 33           | 37             |
+-----------------------+-------------+--------------+----------------+
| **Prior cranial tumor | Yes         | 8            | 5              |
| resection**           |             |              |                |
+-----------------------+-------------+--------------+----------------+
|                       | No          | 92           | 95             |
+-----------------------+-------------+--------------+----------------+
| **Baseline            | \<12 g/dL   | 16           | 13             |
| hemoglobin**          |             |              |                |
+-----------------------+-------------+--------------+----------------+
|                       | ≥12 g/dL    | 84           | 87             |
+-----------------------+-------------+--------------+----------------+
| **Site location**     | USA         | 45           | 49             |
+-----------------------+-------------+--------------+----------------+
|                       | Canada      | 34           | 30             |
+-----------------------+-------------+--------------+----------------+
|                       | ROW         | 21           | 21             |
+-----------------------+-------------+--------------+----------------+
| **Altitude at**       | \<2000 ft   | 86           | 89             |
|                       |             |              |                |
| **treatment site**    |             |              |                |
+-----------------------+-------------+--------------+----------------+
|                       | ≥2000 ft    | 14           | 11             |
+-----------------------+-------------+--------------+----------------+
| **Weight per dosing** | High weight | 26           | 28             |
|                       |             |              |                |
| **adjustment          |             |              |                |
| algorithm**           |             |              |                |
+-----------------------+-------------+--------------+----------------+
|                       | Low weight  | 74           | 72             |
+-----------------------+-------------+--------------+----------------+

> ^a^Three patients with missing data

[]{#__RefHeading___Toc68333974 .anchor}Table 3.18\
Treatment Effect Correcting for Imbalances, All Eligible NSCLC/breast
Patients^a^

  ------------------------------------------------------- ---------------
  **Covariates in Cox Model**                             **RSR13
                                                          Effect**

  \-\--                                                   HR = 0.82,
                                                          p = 0.07

  KPS                                                     HR = 0.80,
                                                          p = 0.05

  KPS, Number of Extracranial Metastases                  HR = 0.78,
                                                          p = 0.03

  KPS, Number of Extracranial Metastases, Age             HR = 0.78,
                                                          p = 0.03

  KPS, Number of Extracranial Metastases, Age, Prior      HR = 0.77,
  resection                                               p = 0.02

  KPS, Number of Extracranial Metastases, Age, Prior      HR = 0.75,
  resection, Gender                                       p = 0.01
  ------------------------------------------------------- ---------------

^a^Last row contains all covariates that were statistically significant
(p \<0.05)

There were 361 deaths in the survival data updated through January 2004.
The unadjusted hazard ratio for the updated survival data was
0.82 (95% CI: 0.66, 1.00) and the Cox adjusted HR was 0.77
(95% CI: 0.62, 0.95). Importantly, the difference in survival for the
co-primary population of eligible patients with NSCLC/breast cancer
reaches p = 0.05 before correcting for the imbalances in prognostic
factors, as shown by Figure 3.3. Also, the results of the unadjusted
log‑rank and Cox multiple regression model are roughly consistent
(HR = 0.82, p = 0.05 vs HR = 0.77, p = 0.02, respectively).

[]{#__RefHeading___Toc68334014 .anchor}Figure 3.7\
Kaplan‑Meier Survival Curve for All Eligible NSCLC/breast Patients\
RSR13 Arm (N = 203) versus Control Arm (N = 194)

January 2004

![](media/image2.wmf)

##### Survival in Patients with Breast Cancer

Based on the survival difference between treatment arms in the survival
data for all eligible NSCLC/breast patients, and due to the fact that
breast cancer patients represent a distinct population, we then analyzed
the results of all breast cancer patients to determine if there was a
different treatment effect in the 2 tumor types comprising this
co‑primary population; namely, NSCLC and breast.

In the breast cancer patients, the observed MST for the Control arm
(N = 55) was 4.6 months compared to 8.7 months for the RSR13 arm
(N = 60) (Figure 3.4). This treatment effect translated into a hazard
ratio of 0.55 via the unadjusted log‑rank test (p \<0.01) and a hazard
ratio of 0.51 via the prespecified Cox multiple regression model
utilizing all covariates simultaneously (p \<0.01).

[]{#__RefHeading___Toc68334015 .anchor}Figure 3.8\
Kaplan‑Meier Survival Curve for All Randomized Patients with Breast
Cancer Primary\
RSR13 Arm (N = 60) versus Control Arm (N = 55)

![](media/image2.wmf)

As stated in the Cox single regression model (as well as above), a
highly statistically significant difference could be determined for
RSR13 effect between the treatment arms without adjustments for
covariates (p \<0.01). Patients who received RSR13 had a 45% reduction
in the likelihood of death at a given time‑point than patients in the
Control arm (HR = 0.55, 95% CI: 0.35, 0.85).

The analysis in Table 3.14 shows consistent results for breast cancer
primary patients across all prespecified covariates.

[]{#__RefHeading___Toc68333975 .anchor}Table 3.19\
Covariate Analysis for Breast Cancer Patients in Study RT‑009

+-------------------+----------+----+------+---+-----+---------------+
| **Covariate**     | *        | *  |      | * |     | **Hazard      |
|                   | *Value** | *C |      | * |     | Ratio**       |
|                   |          | on |      | R |     |               |
|                   |          | tr |      | S |     | **(95% CI)**  |
|                   |          | ol |      | R |     |               |
|                   |          | ** |      | 1 |     |               |
|                   |          |    |      | 3 |     |               |
|                   |          |    |      | * |     |               |
|                   |          |    |      | * |     |               |
+-------------------+----------+----+------+---+-----+---------------+
|                   |          | *  | **M  | * | *   |               |
|                   |          | *% | ST** | * | *MS |               |
|                   |          | ** |      | % | T** |               |
|                   |          |    |      | * |     |               |
|                   |          |    |      | * |     |               |
+-------------------+----------+----+------+---+-----+---------------+
| **Age**           | \<       | 82 | 6.05 | 8 | 10  | 0.55 (0.34,   |
|                   | 65 years |    |      | 0 | .48 | 0.90)         |
+-------------------+----------+----+------+---+-----+---------------+
|                   | ≥        | 18 | 2.78 | 2 | 5   | 0.35 (0.12,   |
|                   | 65 years |    |      | 0 | .70 | 0.98)         |
+-------------------+----------+----+------+---+-----+---------------+
| **Baseline KPS**  | 90 - 100 | 56 | 7.29 | 6 | 10  | 0.58 (0.32,   |
|                   |          |    |      | 0 | .64 | 1.05)         |
+-------------------+----------+----+------+---+-----+---------------+
|                   | \<90     | 44 | 2.79 | 4 | 5   | 0.52 (0.28,   |
|                   |          |    |      | 0 | .70 | 0.98)         |
+-------------------+----------+----+------+---+-----+---------------+
| **Control of**    | co       | 33 | 6.42 | 3 | 11  | 0.54 (0.23,   |
|                   | ntrolled |    |      | 2 | .33 | 1.26)         |
+-------------------+----------+----+------+---+-----+---------------+
| **primary         | unco     | 67 | 4.47 | 6 | 7   | 0.53 (0.32,   |
| cancer**          | ntrolled |    |      | 8 | .26 | 0.87)         |
+-------------------+----------+----+------+---+-----+---------------+
| **RPA Class**     | I        | 11 | 1    | 1 | 25  | 0.37 (0.07,   |
|                   |          |    | 2.94 | 3 | .72 | 2.01)         |
+-------------------+----------+----+------+---+-----+---------------+
|                   | II       | 89 | 4.47 | 8 | 7   | 0.56 (0.36,   |
|                   |          |    |      | 7 | .03 | 0.88)         |
+-------------------+----------+----+------+---+-----+---------------+
| **Number of sites | 0        | 15 | 9.36 | 1 | 9   | 0.81 (0.18,   |
| of**              |          |    |      | 2 | .69 | 3.67)         |
+-------------------+----------+----+------+---+-----+---------------+
| **extracranial    | 1 to 2   | 45 | 4.57 | 5 | 7   | 0.62 (0.34,   |
| metastases**      |          |    |      | 7 | .26 | 1.12)         |
+-------------------+----------+----+------+---+-----+---------------+
|                   | ≥3       | 40 | 4.24 | 3 | 7   | 0.45 (0.22,   |
|                   |          |    |      | 2 | .33 | 0.94)         |
+-------------------+----------+----+------+---+-----+---------------+
| **Presence of**   | Yes      | 35 | 3.52 | 3 | 6   | 0.43 (0.21,   |
|                   |          |    |      | 5 | .90 | 0.88)         |
+-------------------+----------+----+------+---+-----+---------------+
| **liver           | No       | 65 | 6.49 | 6 | 8   | 0.64 (0.37,   |
| metastases**      |          |    |      | 5 | .67 | 1.10)         |
+-------------------+----------+----+------+---+-----+---------------+
| **Number of**     | 1        | 9  | 4.99 | 2 | 10  | 0.36 (0.11,   |
|                   |          |    |      | 2 | .48 | 1.19)         |
+-------------------+----------+----+------+---+-----+---------------+
| **brain           | 2 to 3   | 16 | 1    | 2 | Not | 0.65 (0.22,   |
| metastases**      |          |    | 0.81 | 2 | est | 1.93)         |
+-------------------+----------+----+------+---+-----+---------------+
|                   | \>3      | 73 | 4.39 | 5 | 7   | 0.54 (0.32,   |
|                   |          |    |      | 7 | .00 | 0.92)         |
+-------------------+----------+----+------+---+-----+---------------+
| **Sum of**        | \<2      | 13 | 2.66 | 2 | 13  | 0.18 (0.06,   |
|                   | 50 mm^2^ |    |      | 8 | .21 | 0.54)         |
+-------------------+----------+----+------+---+-----+---------------+
| **Bidimensional** | 250‑10   | 53 | 6.11 | 4 | 5   | 0.98 (0.55,   |
|                   | 00 mm^2^ |    |      | 8 | .03 | 1.76)         |
+-------------------+----------+----+------+---+-----+---------------+
| **products of     | \>10     | 33 | 4.27 | 2 | 10  | 0.40 (0.17,   |
| lesions**         | 00 mm^2^ |    |      | 3 | .51 | 0.95)         |
+-------------------+----------+----+------+---+-----+---------------+
| **Timing of**     | meta     | 96 | 4.47 | 9 | 8   | 0.54 (0.35,   |
|                   | chronous |    |      | 7 | .67 | 0.84)         |
+-------------------+----------+----+------+---+-----+---------------+
| **Diagnosis**     | syn      | 4  | 8.84 | 3 | 7   | 0.62 (0.06,   |
|                   | chronous |    |      |   | .85 | 7.00)         |
+-------------------+----------+----+------+---+-----+---------------+
| **Prior treatment | Yes      | 7  | 8.05 | 3 | 5   | 2.06 (0.29,   |
| for**             |          |    |      |   | .75 | 14.83)        |
+-------------------+----------+----+------+---+-----+---------------+
| **brain           | No       | 93 | 4.47 | 9 | 9   | 0.52 (0.33,   |
| metastases**      |          |    |      | 7 | .00 | 0.80)         |
+-------------------+----------+----+------+---+-----+---------------+
| **Mental status** | abnormal | 7  | 3.06 | 1 | 7   | 0.27 (0.06,   |
|                   |          |    |      | 5 | .03 | 1.25)         |
+-------------------+----------+----+------+---+-----+---------------+
|                   | Normal   | 93 | 4.99 | 8 | 9   | 0.53 (0.34,   |
|                   |          |    |      | 5 | .69 | 0.85)         |
+-------------------+----------+----+------+---+-----+---------------+
| **Baseline        | \        | 27 | 4.30 | 2 | 8   | 0.35 (0.14,   |
| hemoglobin**      | <12 g/dL |    |      | 2 | .67 | 0.85)         |
+-------------------+----------+----+------+---+-----+---------------+
|                   | ≥12 g/dL | 73 | 5.03 | 7 | 9   | 0.61 (0.37,   |
|                   |          |    |      | 8 | .69 | 1.01)         |
+-------------------+----------+----+------+---+-----+---------------+
| **Site location** | USA      | 55 | 5.85 | 6 | 8   | 0.51 (0.29,   |
|                   |          |    |      | 0 | .67 | 0.91)         |
+-------------------+----------+----+------+---+-----+---------------+
|                   | Canada   | 20 | 4.01 | 1 | 9   | 0.39 (0.14,   |
|                   |          |    |      | 5 | .69 | 1.10)         |
+-------------------+----------+----+------+---+-----+---------------+
|                   | ROW      | 25 | 4.39 | 2 | 5   | 0.75 (0.30,   |
|                   |          |    |      | 5 | .03 | 1.86)         |
+-------------------+----------+----+------+---+-----+---------------+
| **Altitude at**   | \        | 89 | 4.99 | 9 | 8   | 0.58 (0.37,   |
|                   | <2000 ft |    |      | 2 | .67 | 0.90)         |
+-------------------+----------+----+------+---+-----+---------------+
| **treatment       | ≥2000 ft | 11 | 3.48 | 8 | 25  | 0.36 (0.07,   |
| site**            |          |    |      |   | .72 | 1.91)         |
+-------------------+----------+----+------+---+-----+---------------+
| **Weight per      | High     | 35 | 8.31 | 5 | 9   | 0.65 (0.34,   |
| dosing**          | weight   |    |      | 3 | .69 | 1.26)         |
+-------------------+----------+----+------+---+-----+---------------+
| **adjustment      | Low      | 62 | 4.27 | 4 | 7   | 0.49 (0.27,   |
| algorithm**       | weight   |    |      | 7 | .15 | 0.89)         |
+-------------------+----------+----+------+---+-----+---------------+

Subsequent therapy is a known factor influencing the survival outcome in
studies including patients with primary breast cancer. Importantly, both
the Control and RSR13 arms were balanced for types of subsequent
treatments (Table 3.15).

[]{#__RefHeading___Toc68333976 .anchor}Table 3.20\
Subsequent Therapies in Patients with Breast Cancer Primary in Study
RT‑009

+-------------------------------+------------------+------------------+
| **Type of Therapy**           | **Control**      | **RSR13**        |
|                               |                  |                  |
|                               | **N = 55**       | **N = 60**       |
+-------------------------------+------------------+------------------+
| **Any systemic n**            | 36               | 41               |
|                               |                  |                  |
| **Any systemic %**            | 65%              | 68%              |
|                               |                  |                  |
| **Median time to therapy      | 0.7              | 1.0              |
| (months)**                    |                  |                  |
+-------------------------------+------------------+------------------+
| **Brain surgery n**           | 1                | 1                |
|                               |                  |                  |
| **Brain surgery %**           | 2%               | 2%               |
|                               |                  |                  |
| **Median time to therapy      | 3.1              | 22.0             |
| (months)**                    |                  |                  |
+-------------------------------+------------------+------------------+
| **SRS for brain n**           | 4                | 3                |
|                               |                  |                  |
| **SRS for brain %**           | 7%               | 5%               |
|                               |                  |                  |
| **Median time to therapy      | 4.8              | 5.6              |
| (months)**                    |                  |                  |
+-------------------------------+------------------+------------------+

Comparable survival benefits in favor of RSR13 were seen for the 6
highest enrolling study sites, which enrolled 43% of the breast cancer
patients (HR = 0.46; 95% CI: 0.23, 0.93) and the remaining 34 study
sites (HR = 0.63; 95% CI: 0.36, 1.11) (Table 3.16). Notably, the
survival benefit for the 6 highest enrolling sites was statistically
significant and the benefit for the remaining sites neared significance.

[]{#__RefHeading___Toc68333977 .anchor}Table 3.21\
Survival by Investigator Site for Breast Cancer Patients in Study RT‑009

+-----------------+------------+------------+-------------------------+
| **Site No.**    | **Number   |            | **Survival Hazard Ratio |
|                 | of         |            | (95% CI**)              |
|                 | Deaths/**  |            |                         |
|                 |            |            |                         |
|                 | **Number   |            |                         |
|                 | of         |            |                         |
|                 | Patients** |            |                         |
+-----------------+------------+------------+-------------------------+
|                 | *          | **RSR13**  |                         |
|                 | *Control** |            |                         |
+-----------------+------------+------------+-------------------------+
| **Top 6 sites** | 22 / 26    | 14 / 24    | 0.462 (0.23, 0.93)      |
|                 | (85%)      | (58%)      |                         |
+-----------------+------------+------------+-------------------------+
| **Remaining     | 25 / 29    | 25 / 36    | 0.633 (0.36, 1.11)      |
| 34 sites**      | (86%)      | (69%)      |                         |
+-----------------+------------+------------+-------------------------+
| **All Sites**   | 47 / 55    | 39 / 60    | 0.552 (0.36, 0.85)      |
|                 | (86%)      | (65%)      |                         |
+-----------------+------------+------------+-------------------------+

To formally test for a differing effect between NSCLC patients and
breast primary patients in the eligible NSCLC/breast co-primary
population, an interaction test was performed. The results of this
partial likelihood ratio test show that the effect in the breast primary
patients is substantially larger than in the NSCLC patients
(χ^2^~ ~= 8.46, p = 0.01). This statistical result implies that the
population of breast cancer patients should be considered on their own.
Although we recognize that the sample size of this population represents
21% (115/538) of the entire RT‑009 study population, we believe the
highly significant survival benefit achieved in patients with primary
breast cancer deems these results relevant for analysis.

##### Survival in Additional Subpopulations

###### Survival in All Randomized Patients

Per ICH guidelines, analysis for all patients randomized was also
performed. However, due to the large discrepancy in survival times for
the ineligible patients between treatment arms (MST Control arm vs RSR13
arm: 5.9 vs 3.3 months, respectively), the treatment effect estimates
for all randomized patients may not be appropriate. The observed MST for
the Control arm (N = 267) was 4.5 months compared to 5.3 months for the
RSR13 arm (N = 271) (Figure 3.5). This treatment effect translated into
a hazard ratio of 0.88 via the unadjusted log-rank test (p = 0.17) and a
hazard ratio of 0.75 via the prespecified Cox multiple regression model
utilizing all covariates simultaneously (p \<0.01).

[]{#__RefHeading___Toc68334016 .anchor}Figure 3.9\
Kaplan‑Meier Survival Curve for All Randomized Patients\
RSR13 Arm (N = 271) versus Control Arm (N = 267)

![](media/image2.wmf)

Of the 17 prespecified covariates that were analyzed for imbalances in
study RT‑009 between the Control and RSR13 arms, there were 7 covariates
that predicted outcome and they are summarized in Table 3.17. There were
no covariate imbalances that favored the RSR13 arm. The following
covariates favored the Control arm: KPS, prior treatment for brain
metastases, number of extracranial metastases, and to a lesser degree,
age.

[]{#__RefHeading___Toc68333978 .anchor}Table 3.22\
Seven Covariates Most Predictive of Survival by Treatment Group in Study
RT‑009, All Randomized Patients

+--------------+------+--------+-------+--------------+--------------+
| *            | *    | **Con  | **RS  | **Predictive |              |
| *Covariate** | *Lev | trol** | R13** | Effect (on   |              |
|              | el** |        |       | Survival)**  |              |
|              |      | *      | **(   |              |              |
|              |      | *(N =  | N = 2 |              |              |
|              |      | 267)** | 71)** |              |              |
|              |      |        |       |              |              |
|              |      | **N    | **N   |              |              |
|              |      |  (%)** | (%)** |              |              |
+--------------+------+--------+-------+--------------+--------------+
|              |      |        |       | **HR**       | **           |
|              |      |        |       |              | p‑value^a^** |
+--------------+------+--------+-------+--------------+--------------+
| **Baseline   | **1  | 4      | 34    | ≤70 vs 80    |              |
| KPS**        | 00** | 3 (16) |  (13) | vs 90 vs 100 |              |
|              |      |        |       |              |              |
|              | **   | 10     | 124   |              |              |
|              | 90** | 0 (37) |  (46) |              |              |
|              |      |        |       |              |              |
|              | **   | 8      | 64    |              |              |
|              | 80** | 0 (30) |  (24) |              |              |
|              |      |        |       |              |              |
|              | ≤**  | 4      | 49    |              |              |
|              | 70** | 4 (16) |  (18) |              |              |
+--------------+------+--------+-------+--------------+--------------+
|              |      |        |       | 0.72         | \<0.0001     |
+--------------+------+--------+-------+--------------+--------------+
| **Prior      | **Y  | 2      | 2     | No vs Yes    |              |
| Treatment    | es** | 9 (11) | 1 (8) |              |              |
| for Brain    |      |        |       |              |              |
| Mets**       | **   | 23     | 250   |              |              |
|              | No** | 8 (89) |  (92) |              |              |
+--------------+------+--------+-------+--------------+--------------+
|              |      |        |       | 0.44         | \<0.0001     |
+--------------+------+--------+-------+--------------+--------------+
| **N. of      | *    | 9      | 84    | 0 v          |              |
| E            | *0** | 6 (36) |  (31) | s 1‑2 vs \>2 |              |
| xtra‑cranial |      |        |       |              |              |
| Mets**       | **1  | 12     | 128   |              |              |
|              | -2** | 4 (46) |  (47) |              |              |
|              |      |        |       |              |              |
|              | **\  | 4      | 59    |              |              |
|              | >2** | 7 (18) |  (22) |              |              |
+--------------+------+--------+-------+--------------+--------------+
|              |      |        |       | 1.42         | 0.0001       |
+--------------+------+--------+-------+--------------+--------------+
| **Gender**   | **   | 15     | 153   | Fe           |              |
|              | Fema | 0 (56) |  (56) | male vs Male |              |
|              | le** |        |       |              |              |
|              |      | 11     | 118   |              |              |
|              | **Ma | 7 (44) |  (44) |              |              |
|              | le** |        |       |              |              |
+--------------+------+--------+-------+--------------+--------------+
|              |      |        |       | 1.43         | 0.002        |
+--------------+------+--------+-------+--------------+--------------+
| **Breast     | **Y  | 5      | 60    | No vs Yes    |              |
| Primary**    | es** | 5 (21) |  (22) |              |              |
|              |      |        |       |              |              |
|              | **   | 21     | 211   |              |              |
|              | No** | 2 (79) |  (78) |              |              |
+--------------+------+--------+-------+--------------+--------------+
|              |      |        |       | 0.61         | 0.003        |
+--------------+------+--------+-------+--------------+--------------+
| **Age        | **\< | 19     | 196   | \<65 vs ≥65  |              |
| Group**      | 65** | 7 (74) |  (72) |              |              |
|              |      |        |       |              |              |
|              | **≥  | 7      | 75    |              |              |
|              | 65** | 0 (26) |  (28) |              |              |
+--------------+------+--------+-------+--------------+--------------+
|              |      |        |       | 1.41         | 0.004        |
+--------------+------+--------+-------+--------------+--------------+
| **Log        | **Me | 2.599  | 2.588 | Lo           |              |
| (Baseline    | an** |        |       | g (Hgb) vs L |              |
| Hgb)**       |      | 0.116  | 0.112 | og (Hgb) + 1 |              |
|              | **   |        |       |              |              |
|              | SD** |        |       |              |              |
+--------------+------+--------+-------+--------------+--------------+

^a^p‑values represent the mean of p‑values from the 48 Cox models; the
covariates were statistically significant in all 48 models.

Beginning with a Cox model that included only treatment arm, Table 3.18
shows how adding covariates one‑at‑a‑time, based on their statistical
significance in the full Cox model, affects the RSR13 treatment effect
estimate. After adjusting for KPS, prior brain tumor resection, and
presence of extracranial metastases, the 3 most significant covariates
in the full Cox model, the RSR13 treatment effect has a p‑value of 0.03.

[]{#__RefHeading___Toc68333979 .anchor}Table 3.23\
RSR13 Treatment Effect Correcting for Imbalances^a^

  ------------------------------------------------------- ---------------
  **Covariates in Cox Model**                             **RSR13
                                                          Effect**

  \-\--                                                   HR = 0.88,
                                                          p = 0.17

  KPS                                                     HR = 0.86,
                                                          p = 0.11

  KPS, Prior resection                                    HR = 0.83,
                                                          p = 0.05

  KPS, Prior resection, Number of Extracranial Metastases HR = 0.81,
                                                          p = 0.03

  KPS, Prior resection, Number of Extracranial            HR = 0.79,
  Metastases, Gender                                      p = 0.02

  KPS, Prior resection, Number of Extracranial            HR = 0.80,
  Metastases, Gender, Breast Primary                      p = 0.02

  KPS, Prior resection, Number of Extracranial            HR = 0.79,
  Metastases, Gender, Breast Primary, Age Group           p = 0.02

  KPS, Prior resection, Number of Extracranial            HR = 0.78,
  Metastases, Gender, Breast Primary, Age Group, Baseline p = 0.01
  Hgb                                                     
  ------------------------------------------------------- ---------------

^a^Last row contains all covariates that were statistically significant
(p \<0.05)

We conclude then that when adjusted for imbalances in prognostic
variables by the use of a Cox model, the results of study RT‑009 show a
clear and compelling statistically significant difference in survival in
favor of the patients that received RSR13 over the Control arm.

The survival results are presented by stratum in Table 3.19.

[]{#__RefHeading___Toc68333980 .anchor}Table 3.24\
Survival by Stratum for All Randomized Patients

+--------+---------------+------------------+---------------+---------+
| **Str  | **Control     | **RSR13          | **RSR13       |         |
| atum** | (N = 267)**   | (N = 271)**      | Effect**      |         |
|        |               |                  |               |         |
|        | **MST         | **MST (months)** |               |         |
|        | (months)**    |                  |               |         |
+--------+---------------+------------------+---------------+---------+
|        |               |                  | **HR          | **p‑    |
|        |               |                  | (95% CI)**    | value** |
+--------+---------------+------------------+---------------+---------+
| **1**  | 7.0           | 4.2              | 1.06 (0.54,   | 0.86    |
|        |               |                  | 2.09)         |         |
|        | (n = 24)      | (n = 22)         |               |         |
+--------+---------------+------------------+---------------+---------+
| **2**  | 4.1           | 5.3              | 0.93 (0.72,   | 0.60    |
|        |               |                  | 1.21)         |         |
|        | (n = 136)     | (n = 133)        |               |         |
+--------+---------------+------------------+---------------+---------+
| **3**  | 4.5           | 7.3              | 0.54 (0.35,   | \<0.01  |
|        |               |                  | 0.85)         |         |
|        | (n = 50)      | (n = 56)         |               |         |
+--------+---------------+------------------+---------------+---------+
| **4**  | 3.7           | 3.9              | 1.07 (0.73,   | 0.73    |
|        |               |                  | 1.57)         |         |
|        | (n = 57)      | (n = 60)         |               |         |
+--------+---------------+------------------+---------------+---------+

######  Survival in All Randomized Patients in the NSCLC/breast Population: 

The observed MST for the Control arm (N = 206) was 4.5 months compared
to 5.9 months for the RSR13 arm (N = 208) (Figure 3.6). This treatment
effect translated into a hazard ratio of 0.84 via the unadjusted
log‑rank test (p = 0.12) and a hazard ratio of 0.76 via the prespecified
Cox multiple regression model utilizing all covariates simultaneously
(p = 0.02).

[]{#__RefHeading___Toc68334017 .anchor}Figure 3.10\
Kaplan‑Meier Survival Curve for All Randomized NSCLC/breast Patients\
RSR13 Arm (N = 208) versus Control Arm (N = 206)

![](media/image2.wmf)

###### Survival in Patients with NSCLC

The observed MST for the Control arm (N = 151) was 4.4 months compared
to 4.9 months for the RSR13 arm (N = 148) (Figure 3.7). This treatment
effect translated into a hazard ratio of 0.99 via the unadjusted
log‑rank test (p = 0.94) and a hazard ratio of 0.86 via the prespecified
Cox multiple regression model utilizing all covariates simultaneously
(p = 0.26). The reasons for the difference in efficacy results between
the NSCLC and breast cancer populations are outlined in Section 3.2.3.5.

[]{#__RefHeading___Toc68334018 .anchor}Figure 3.11\
Kaplan‑Meier Survival Curve for All Randomized Patients with NSCLC
Primary\
RSR13 Arm (N = 148) versus Control Arm (N = 151)

![](media/image2.wmf)

#### Secondary Endpoint: Response Rate in the Brain

##### Response Rate in the Brain for All Randomized Patients

Best maximal response was determined from magnetic resonance image (MRI)
or computed tomography (CT) scans performed at baseline, initial
follow‑up 1 month after WBRT day 10, 3 months after WBRT day 10, and
every 3 months thereafter until progression. A central, independent
radiologic review blinded to treatment arm and outcome was conducted for
all scans by the Neuroimaging Core Laboratory (Cleveland Clinic). The
point estimates of response rate (complete plus partial response) were
37.5% in the Control arm and 45.4% in the RSR13 arm (Table 3.20). The
estimated increase in response rate in patients receiving RSR13 was 7.9%
with an associated 95% CI of --0.4% to 16.3% (p = 0.06). Furthermore,
10% of patients in the RSR13 arm had a complete response (CR) as best
response compared to 6% in the Control arm.

[]{#__RefHeading___Toc68333981 .anchor}Table 3.25\
Survival by Best Response for All Patients in Study RT‑009

+-----------+-----------+-------------+-------------+----------------+
|           | **        |             | **RSR13**   |                |
|           | Control** |             |             |                |
|           |           |             | **          |                |
|           | **(N      |             | (N = 271)** |                |
|           |  = 267)** |             |             |                |
|           |           |             | **n (%)**   |                |
|           | **n (%)** |             |             |                |
+-----------+-----------+-------------+-------------+----------------+
|           | N (%)     | MST         | n (%)       | MST            |
+-----------+-----------+-------------+-------------+----------------+
| **CR**    | 16 (6)    | 10.02       | 28 (10)     | \-\--          |
+-----------+-----------+-------------+-------------+----------------+
| **PR**    | 84 (31)   | 6.57        | 95 (35)     | 7.62           |
+-----------+-----------+-------------+-------------+----------------+
| **SD**    | 83 (31)   | 4.37        | 72 (27)     | 4.21           |
+-----------+-----------+-------------+-------------+----------------+
| **PD**    | 33 (12)   | 5.59        | 34 (13)     | 5.32           |
+-----------+-----------+-------------+-------------+----------------+
| **        | 51 (19)   | 1.31        | 42 (15)     | 1.23           |
| Missing** |           |             |             |                |
+-----------+-----------+-------------+-------------+----------------+

##### Response Rate in the Brain for All Randomized Patients in the NSCLC/breast Population

The point estimates of response rate (complete plus partial response)
were 40.8% in the Control arm and 52.9% in the RSR13 arm (Table 3.21).
The estimated increase in response rate in patients receiving RSR13 was
12.1% with an associated 95% CI of 2.5% to 21.7% (p = 0.01).
Furthermore, 13% of patients in the RSR13 arm had a CR as best response
compared to 7% in the Control arm.

[]{#__RefHeading___Toc68333982 .anchor}Table 3.26\
Survival by Best Response for NSCLC/Breast Patients in Study RT‑009

+--------------+-----------+--------------+-----------+--------------+
|              | **        |              | **RSR13** |              |
|              | Control** |              |           |              |
|              |           |              | **(N      |              |
|              | **(N      |              |  = 208)** |              |
|              |  = 206)** |              |           |              |
|              |           |              | **n (%)** |              |
|              | **n (%)** |              |           |              |
+--------------+-----------+--------------+-----------+--------------+
|              | n (%)     | MST          | n (%)     | MST          |
+--------------+-----------+--------------+-----------+--------------+
| **CR**       | 15 (7)    | 10.02        | 27 (13)   | \-\--        |
+--------------+-----------+--------------+-----------+--------------+
| **PR**       | 69 (33)   | 6.28         | 83 (40)   | 7.69         |
+--------------+-----------+--------------+-----------+--------------+
| **SD**       | 64 (31)   | 4.58         | 57 (27)   | 4.37         |
+--------------+-----------+--------------+-----------+--------------+
| **PD**       | 20 (10)   | 5.77         | 15 (7)    | 5.39         |
+--------------+-----------+--------------+-----------+--------------+
| **Missing**  | 38 (18)   | 1.30         | 26 (13)   | 1.51         |
+--------------+-----------+--------------+-----------+--------------+

##### Response Rate in the Brain for All Patients with Breast Cancer

A total of 102 patients had a scan after treatment from which to assess
response; 47 patients in the Control arm and 55 patients in the RSR13
arm (Table 3.22). The point estimates of response rate (complete plus
partial response) 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 = 0.01). Furthermore, 13% of patients in the RSR13 arm had a CR as
best response compared to 9% in the Control arm. For patients in
Stratum 3, the estimated increase in response rate in patients receiving
RSR13 was 21.6% with an associated 95% confidence interval of 3.3% to
40.0%.

[]{#__RefHeading___Toc68333983 .anchor}Table 3.27\
Survival by Best Response for Patients with Breast Cancer Primary in
Study RT‑009

+-------------+------------+------------+---------------+------------+
|             | *          |            | **RSR13**     |            |
|             | *Control** |            |               |            |
|             |            |            | **(N = 60)**  |            |
|             | **         |            |               |            |
|             | (N = 55)** |            |               |            |
+-------------+------------+------------+---------------+------------+
|             | n (%)      | MST        | n (%)         | MST        |
+-------------+------------+------------+---------------+------------+
| **CR**      | 5 (9)      | 8.94       | 8 (13)        | \-\--      |
+-------------+------------+------------+---------------+------------+
| **PR**      | 22 (40)    | 5.62       | 35 (58)       | 10.48      |
+-------------+------------+------------+---------------+------------+
| **SD**      | 15 (27)    | 3.84       | 12 (20)       | 3.96       |
+-------------+------------+------------+---------------+------------+
| **PD**      | 5 (9)      | 4.99       | 0             | \-\--      |
+-------------+------------+------------+---------------+------------+
| **Missing** | 8 (15)     | 2.87       | 5 (8)         | 0.99       |
+-------------+------------+------------+---------------+------------+

##### Confirmed Response Rate

Confirmation of response was not required per protocol; however, many
patients had additional follow‑up scans a minimum of 4 weeks after the
initial determination of response. An additional analysis was conducted
to support this endpoint. Confirmed responses were those responses that
were identified as either CR or partial response (PR) on 2 consecutive
scans at least 4 weeks apart. The results of this analysis show a
statistically significant improvement in confirmed response rate (CR+PR)
for patients in the RSR13 arm compared to patients in the Control arm
for both co‑primary populations as well as for breast cancer patients
(Table 3.23).

[]{#__RefHeading___Toc68333984 .anchor}Table 3.28\
Confirmed Response Rate (CR+PR)

  ------------------------ --------------- --------------- ---------------
                           **Control**     **RSR13**       **p‑value**

  **All Randomized         17%             25%             0.02
  Patients**                                               

  **NSCLC/breast           20%             29%             0.03
  Patients**                                               

  **Breast Cancer          21%             41%             \<0.01
  Patients**                                               
  ------------------------ --------------- --------------- ---------------

#### Other Secondary Endpoints

Tables 3.24, 3.25, and 3.26 summarize the differences in secondary
endpoints between RSR13 and Control arms for all randomized patients
(N = 538), for all randomized NSCLC/breast patients (N = 414), and all
randomized patients with breast cancer primary (N = 115), respectively.

[]{#__RefHeading___Toc68333985 .anchor}Table 3.29\
Differences between RSR13 and Control Arms by Endpoint for All
Randomized Patients (N = 538)

+----------------------------------------+---------+---------+---------+
| **Endpoint**                           | **Co    | **      | **p‑    |
|                                        | ntrol** | RSR13** | value** |
|                                        |         |         |         |
|                                        | **(N =  | **(N =  |         |
|                                        |  267)** |  271)** |         |
+----------------------------------------+---------+---------+---------+
| **QOL**                                |         |         |         |
+----------------------------------------+---------+---------+---------+
| > **KPS (% stable/improving at         | 18%     | 24%     | \<      |
| > 3 months)**                          |         |         | 0.01^a^ |
+----------------------------------------+---------+---------+---------+
| > **Spitzer Questionnaire (%           | 21%     | 23%     | 0.06^a^ |
| > stable/improving at 3 months)**      |         |         |         |
+----------------------------------------+---------+---------+---------+
| **Cause of Death (% Neurologic)^b^**   | 15      | 17      | 0.51    |
+----------------------------------------+---------+---------+---------+
| **Time to clinical progression (% PF   | 64      | 72      | 0.44    |
| at 3 months)**                         |         |         |         |
+----------------------------------------+---------+---------+---------+
| **Time to radiographic progression (%  | 85      | 84      | 0.50    |
| PF at 3 months)**                      |         |         |         |
+----------------------------------------+---------+---------+---------+

PF = progression‑free

^a^Cochran‑Mantel‑Haenszel test with time (1, 3, 6, and 12 months) as
strata

^b^Percent of all patients that died

[]{#__RefHeading___Toc68333986 .anchor}Table 3.30\
Differences between RSR13 and Control Arms by Endpoint for All
Randomized NSCLC/breast Patients (N = 414)

+---------------------------------------+---------+---------+---------+
| **Endpoint**                          | **Co    | **      | **p‑    |
|                                       | ntrol** | RSR13** | value** |
|                                       |         |         |         |
|                                       | **(N =  | **(N =  |         |
|                                       |  206)** |  208)** |         |
+---------------------------------------+---------+---------+---------+
| **QOL**                               |         |         |         |
+---------------------------------------+---------+---------+---------+
| > **KPS (% stable/improving at 3      | 19      | 26      | \<      |
| > months)**                           |         |         | 0.01^a^ |
+---------------------------------------+---------+---------+---------+
| > **Spitzer Questionnaire (%          | 22      | 26      | 0.01^a^ |
| > stable/improving at 3 months)**     |         |         |         |
+---------------------------------------+---------+---------+---------+
| **Cause of Death (% Neurologic) ^b^** | 16      | 18      | 0.38    |
+---------------------------------------+---------+---------+---------+
| **Time to clinical progression (% PF  | 65      | 75      | 0.21    |
| at 3 months)**                        |         |         |         |
+---------------------------------------+---------+---------+---------+
| **Time to radiographic progression (% | 89      | 90      | 0.88    |
| PF at 3 months)**                     |         |         |         |
+---------------------------------------+---------+---------+---------+

PF = progression-free

^a^Cochran-Mantel-Haenszel test with time (1, 3, 6, and 12 months) as
strata

^b^Percent of all patients that died

[]{#__RefHeading___Toc68333987 .anchor}Table 3.31\
Differences between RSR13 and Control Arms by Endpoint for All
Randomized Patients with Breast Cancer Primary (N = 115)

+----------------------------------------+---------+---------+---------+
| **Endpoint**                           | **Co    | **      | **p‑    |
|                                        | ntrol** | RSR13** | value** |
|                                        |         |         |         |
|                                        | **(N    | **(N    |         |
|                                        | = 55)** | = 60)** |         |
+----------------------------------------+---------+---------+---------+
| **QOL**                                |         |         |         |
+----------------------------------------+---------+---------+---------+
| > **KPS (% stable/improving at         | 18      | 35      | \<      |
| > 3 months)**                          |         |         | 0.01^a^ |
+----------------------------------------+---------+---------+---------+
| > **Spitzer Questionnaire (%           | 24      | 37      | 0.01^a^ |
| > stable/improving at 3 months)**      |         |         |         |
+----------------------------------------+---------+---------+---------+
| **Cause of Death (% Neurologic) ^b^**  | 17      | 21      | 0.23    |
+----------------------------------------+---------+---------+---------+
| **Time to clinical progression (% PF   | 86      | 91      | 0.36    |
| at 3 months)**                         |         |         |         |
+----------------------------------------+---------+---------+---------+
| **Time to radiographic progression (%  | 90      | 98      | 0.80    |
| PF at 3 months)**                      |         |         |         |
+----------------------------------------+---------+---------+---------+

PF = progression-free

^a^Cochran-Mantel-Haenszel test with time (1, 3, 6, and 12 months) as
strata

^b^Percent of all patients that died

The treatment effect of RSR13 in several of the secondary endpoints was
inconclusive. For time to radiographic progression and time to clinical
progression, too much censoring resulted in low power. Images were only
assessed every 3 months. Therefore, most patients that died did not have
an opportunity to have a brain scan to detect progression (or lack
thereof) in the brain. Due to the low number of events for this
endpoint, the statistical test was inconclusive. In addition, there were
too many competing risks (eg, systemic death) to accurately determine
time to radiographic and clinical progression. Cause of death was
difficult to accurately determine and there was a high variability in
assessment between sites.

#### Differences between NSCLC and Breast Patients 

The reasons why RSR13 as an adjunct to WBRT had a larger treatment
effect in patients with breast cancer and brain metastases are many and
may include the following: radiobiology, growth fraction, and effect of
subsequent therapy. However, the principle reason why RSR13 had a larger
treatment effect in breast cancer patients was likely due to differences
in dosing between NSCLC and breast cancer patients. PK studies have
revealed that patients with breast cancer were more effectively dosed
than patients with NSCLC and this is discussed in Section 3.2.3.5.1.

##### Differences in Dosing

A critical determinant of RSR13 PK and RSR13 exposure is the patient's
body weight category. The volume of distribution for RSR13 is the
intravascular compartment, but RSR13 is dosed based on actual body
weight, which does not correlate well with intravascular volume. For
example, a lean 60 kg patient may have a volume of distribution roughly
equal to a 90 kg patient who has a higher percentage of body fat. If
both patients receive a 100 mg/kg dose of RSR13, there will be a higher
concentration of RSR13 in RBCs in the 90 kg patient versus the 60 kg
patient.

In order to completely determine the impact of dosing throughout the
course of the treatment in study RT‑009, it is important to summarize
Amendment 2 of the study protocol (Protocol Version 3), which was
implemented 05 Jun 2001. According to Amendment 2 the following patients
would receive a lower starting dose of RSR13 (75 mg/kg instead of
100 mg/kg):

-   Patients receiving anti‑hypertensives

-   Patients with a prior nephrectomy

-   HW females (body weight over 70 kg)

-   HW males (body weight over 95 kg)

The intent of Amendment 2 (Protocol Version 3) was to decrease the
starting dose of RSR13 in HW patients to reduce the likelihood of
terminations. Prior to this amendment, there was already a higher
percentage of patients with dose adjustments in study than in study
RT‑008 (Table 3.27). After this amendment, there was an increase in the
percentage of study RT‑009 patients receiving RSR13 who had a starting
dose at a reduced dose level, both in patients with NSCLC and in breast
cancer patients, compared to Protocol Versions 1 and 2. Half of the
patients with breast cancer and 41% of the patients with NSCLC received
a starting dose of RSR13 of 75 mg/kg, instead of 100 mg/kg, which
compares to 4% and 16% before Protocol Version 3.

[]{#__RefHeading___Toc68333988 .anchor}Table 3.32\
Percentage of Patients who Received Dose Adjustments in Studies RT‑008
and RT‑009

+-------------------------+--------------+--------------+--------------+
| **Primary Site**        | **Study**    |              |              |
+-------------------------+--------------+--------------+--------------+
|                         | **RT‑008**   | **RT‑009**   | **RT‑009**   |
|                         |              |              |              |
|                         | **%**        | **Ve         | **Ve         |
|                         |              | rsions 1,2** | rsions 3,4** |
|                         |              |              |              |
|                         |              | **%**        | **%**        |
+-------------------------+--------------+--------------+--------------+
| **NSCLC**               | N = 39       | N = 61       | N = 87       |
|                         |              |              |              |
| **Initial Dose          | 8            | 16           | 41           |
| \<100 mg/kg**           |              |              |              |
|                         | 13           | 20           | 16           |
| **Drug Terminated**     |              |              |              |
|                         | 15           | 27           | 43           |
| **Doses Held**          |              |              |              |
|                         | 31           | 45           | 52           |
| **Doses Reduced**       |              |              |              |
+-------------------------+--------------+--------------+--------------+
| **Breast Cancer**       | N = 21       | N = 26       | N = 34       |
|                         |              |              |              |
| **Initial Dose          | 0            | 4            | 50           |
| \<100 mg/kg**           |              |              |              |
|                         | 33           | 31           | 15           |
| **Drug Terminated**     |              |              |              |
|                         | 24           | 38           | 36           |
| **Doses Held**          |              |              |              |
|                         | 33           | 62           | 48           |
| **Doses Reduced**       |              |              |              |
+-------------------------+--------------+--------------+--------------+

As stated above, body weight category is a critical determinant of RSR13
PK and RSR13 exposure, and therefore, differences in weight across
populations are likely to influence outcome. Using the weight cut‑off
specified in Amendment 2 of study RT‑009, Table 3.28 shows the frequency
of HW and LW patients across primary tumor type for both genders. The
percentage of LW patients is much lower in patients with breast cancer
primary than in patients with NSCLC primary (47% vs 83%, respectively).
Furthermore, the mean weight of female patients with NSCLC primary was
lower than the mean weight of female patients with breast cancer primary
(57.4 vs 61.3 kg, respectively).

[]{#__RefHeading___Toc68333989 .anchor}Table 3.33\
Body Weight in Study RT‑009 by Body Weight Category, Gender, and Primary
Site

+-------------+--------+--------+--------+--------+--------+--------+
| **Primary   | **We   |        |        |        |        |        |
| Site and    | ight** |        |        |        |        |        |
| Gender**    |        |        |        |        |        |        |
+-------------+--------+--------+--------+--------+--------+--------+
|             | *      |        |        | **     |        |        |
|             | *Low** |        |        | High** |        |        |
+-------------+--------+--------+--------+--------+--------+--------+
|             | **     | **%**  | *      | **     | **%**  | *      |
|             | Number |        | *Mean  | Number |        | *Mean  |
|             | of     |        | (kg)** | of     |        | (kg)** |
|             | Sam    |        |        | Sam    |        |        |
|             | ples** |        |        | ples** |        |        |
+-------------+--------+--------+--------+--------+--------+--------+
| **NSCLC**   | 71     | 89     | 72.6   | 9      | 11     | 105.8  |
|             |        |        |        |        |        |        |
| > **Male**  | 52     | 76     | 57.4   | 16     | 24     | 81.2   |
| >           |        |        |        |        |        |        |
| >           | 123    | 83     | 66.2   | 25     | 17     | 90.0   |
|  **Female** |        |        |        |        |        |        |
|             |        |        |        |        |        |        |
| **Total**   |        |        |        |        |        |        |
+-------------+--------+--------+--------+--------+--------+--------+
| **Breast**  | 28     | 47     | 61.3   | 32     | 53     | 83.6   |
|             |        |        |        |        |        |        |
| >           |        |        |        |        |        |        |
|  **Female** |        |        |        |        |        |        |
+-------------+--------+--------+--------+--------+--------+--------+

As detailed in Table 3.29, LW patients had lower RSR13 RBC compared with
HW patients. Furthermore, the mean RSR13 RBC concentration determined in
LW NSCLC patients receiving 75 mg/kg is 430 μg/ml. This concentration
would be expected to result in a suboptimal p50 shift, according to data
detailed in Section 2.0. A similar dose of RSR13 in LW breast cancer
patients resulted in a mean RSR13 concentration in RBCs of 493 μg/ml.
This concentration would be sufficient to consistently produce a
p50 shift near the desired 10 mmHg.

[]{#__RefHeading___Toc68333990 .anchor}Table 3.34\
RSR13 RBC Concentrations (μg/mL) in Study RT‑009, by Weight Category and
Primary Site

+------------+-------------+-------------+-------------+-------------+
| **Primary  | **Low Body  |             | **High Body |             |
| Site and   | Weight**    |             | Weight**    |             |
| Dose       |             |             |             |             |
| (mg/kg)**  |             |             |             |             |
+------------+-------------+-------------+-------------+-------------+
|            | **Number of | **Median    | **Number of | **Median    |
|            | Samples**   | Conc        | Samples**   | Conc        |
|            |             | entration** |             | entration** |
+------------+-------------+-------------+-------------+-------------+
| **NSCLC**  | 58          | 430         | 14          | 554         |
|            |             |             |             |             |
| **75**     | 108         | 556         | 22          | 736         |
|            |             |             |             |             |
| **100**    |             |             |             |             |
+------------+-------------+-------------+-------------+-------------+
| **Breast** | 13          | 493         | 16          | 505         |
|            |             |             |             |             |
| **75**     | 24          | 635         | 26          | 708         |
|            |             |             |             |             |
| **100**    |             |             |             |             |
+------------+-------------+-------------+-------------+-------------+

Further evidence that LW NSCLC patients were dosed ineffectively is
evident if results are analyzed by weight group (Table 3.30). This shows
a clear treatment effect in HW NSCLC patients (HR = 0.75 vs 1.06
\[neutral\], respectively).

[]{#__RefHeading___Toc68333991 .anchor}Table 3.35\
RSR13 Treatment Effect by Weight Group for NSCLC Patients in Study
RT‑009

  ----------------------- ----------------------- -----------------------
  **Weight Group**        **Response Rate         **Survival HR
                          Improvement (95% CI)**  (95% CI)**

  **Low Body Weight**     7% (-6%, 19%)           1.06 (0.79, 1.40)

  **High Body Weight**    12% (-14%, 38%)         0.75 (0.42, 1.35)
  ----------------------- ----------------------- -----------------------

When the results in NSCLC patients are adjusted by dosing and PK
(Table 3.31), it is evident that if RSR13 doses are administered
effectively, NSCLC patients can derive benefit from RSR13. NSCLC
patients with ≥7 doses of RSR13 and with ≥7 successful doses (a
successful dose is one that results in an RSR13 concentration in RBCs of
at least 483 mg/mL) had a greater response rate and twice as many NSCLC
patients with a best response of CR versus Control patients who received
≥7 doses. In addition, for patients with ≥7 doses of RSR13 and with
≥7 successful doses, 57% of NSCLC patients were responders. However, 43%
of NSCLC patients with ≥7 doses of RSR13 but with \<7 successful doses
were responders and 30% of NSCLC patients with \<7 doses of RSR13 were
responders. It is important to note that the NSCLC patients with
≥7 doses of RSR13 but with \<7 successful doses received the same amount
of drug as the NSCLC patients with ≥7 doses of RSR13 and with
≥7 successful doses, but the latter had higher (ie, successful) RSR13
RBC concentrations than the former and there is a clear difference in
response rate between the 2 groups.

[]{#__RefHeading___Toc68333992 .anchor}Table 3.36\
Response Rate by Exposure Group for NSCLC Patients in Study RT‑009

+----------+-----------+-----------+-----------+-----------+-----------+
| **Best   | **        | **        | **RSR13** | **RSR13** | **RSR13** |
| Re       | Control** | Control** |           |           |           |
| sponse** |           |           | **\<      | **≥       | **≥       |
|          | **\<      | **≥       | 7 Doses** | 7 Doses** | 7 Doses** |
|          | 7 Doses** | 7 Doses** |           |           |           |
|          |           |           |           | **        | *         |
|          | **WBRT**  | **WBRT**  |           | \<7 Doses | *≥7 Doses |
|          |           |           |           | Suc       | Suc       |
|          |           |           |           | cessful** | cessful** |
+----------+-----------+-----------+-----------+-----------+-----------+
|          | **        | **(N      | **(       | **(       | **(       |
|          | (N = 4)** |  = 147)** | N = 30)** | N = 65)** | N = 53)** |
|          |           |           |           |           |           |
|          | **%**     | **%**     | **%**     | **%**     | **%**     |
+----------+-----------+-----------+-----------+-----------+-----------+
| **CR**   | 0         | 7         | 10        | 12        | 15        |
+----------+-----------+-----------+-----------+-----------+-----------+
| **PR**   | 0         | 32        | 20        | 31        | 42        |
+----------+-----------+-----------+-----------+-----------+-----------+
| **SD**   | 0         | 33        | 23        | 35        | 28        |
+----------+-----------+-----------+-----------+-----------+-----------+
| **PD**   | 0         | 10        | 3         | 11        | 13        |
+----------+-----------+-----------+-----------+-----------+-----------+
| **U      | 100       | 18        | 43        | 11        | 2         |
| nknown** |           |           |           |           |           |
+----------+-----------+-----------+-----------+-----------+-----------+

##### Dosing Conclusions 

-   Dose adjustments from 100 mg/kg to 75 mg/kg have a greater impact on
    LW patients

-   A higher percentage of the NSCLC patients were LW compared with the
    breast cancer patients

-   Based on the PK results we conclude that the LW patients with NSCLC
    were underdosed, and when the results in NSCLC patients are analyzed
    taking into account drug exposure there is a clear RSR13 treatment
    effect in NSCLC patients

#### Efficacy Conclusions

The results of study RT‑009 confirm the hypothesis that RSR13 enhances
the efficacy of WBRT in patients with brain metastases. Study RT‑009
showed an improvement in survival in 1 of the 2 co‑primary populations
(Eligible NSCLC/breast cancer patients). This result reached statistical
significance with additional follow up and it is supported by the fact
that RSR13 produced a statistically significant improvement in the
response rate in the brain in this population. In addition, when the
results of study RT‑009 are analyzed by the prespecified Cox multiple
regression model, the results of the study in both prespecified
co-primary populations show a 24% reduction in the risk of death due to
RSR13.

The results of study RT‑009 are driven by the large treatment effect in
the breast cancer population. In these patients we observed a clinically
meaningful prolongation in survival due to RSR13. This improvement in
survival is supported by the significant increase in response rate in
the brain produced by the addition of RSR13. Improved QOL measures were
also observed in the breast cancer patients that received RSR13.

# Supportive Phase 2 STudy For the Treatment of patients with Brain Metastases (RSR13 RT‑008)

## Study Design

RT‑008 was a non‑randomized, open‑label, multi‑center, efficacy, safety,
and PK/PD study of patients receiving RSR13 as adjunct to a conventional
2‑week course of WBRT for brain metastases. Planned enrollment was
104 patients, 54 with RTOG RPA of prognostic factors criteria for
Class I and 50 with RTOG RPA Class II brain metastases. The objectives
of RT‑008 were to evaluate overall MST (primary endpoint), 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. Patients
received WBRT, 30 Gy in 10 fractions of 3.0 Gy each, preceded by RSR13,
50‑100 mg/kg IV over 30 minutes via a CVAD. Patients also received
supplemental oxygen at 4 L/minute via nasal cannula for at least
5 minutes before the start of RSR13 administration. Oxygen was
administered continuously during each RSR13 infusion and WBRT treatment
until the patient's SpO~2~ on room air was stable at ≥90%.

Survival data were analyzed using unadjusted log‑rank test, Kaplan‑Meier
estimates, and a multivariable Cox proportional hazards regression model
with baseline characteristics and study group as factors. In a separate
protocol-specified analysis, survival results from the Class II patients
in this study were compared to the RTOG BMD. In addition, a comparison
of survival data (with a stratified Cox model) was also conducted for
Class II patients who were case‑matched exactly (exact‑matched controls)
by KPS, primary tumor site, status of extracranial metastases, status of
primary tumor, and age (within 5 years) to patients from the RTOG BMD.

## Demography and Baseline Characteristics of Patients with Brain Metastases in RT‑008

Patients were enrolled from 17 investigational sites during the period
from 24 Feb 1998 to 28 May 1999. Actual enrollment/analysis included
12 Class I and 57 Class II patients. Study enrollment was closed shortly
after the Class II enrollment target was met; at that time only
12 Class I patients had been enrolled. A total of 12 RPA Class I
patients, 33 RPA Class II patients with NSCLC primary, 18 RPA Class II
patients with breast cancer primary, and 6 RPA Class II patients with
other types of primary were enrolled. Demographics are presented in
Table 4.1.

[]{#__RefHeading___Toc68333993 .anchor}Table 4.37\
Summary of Demographic Data in Control and RSR13 Treated Patients in
RT‑008

  ---------------- -------------------------------------------------- -----------------
  **Parameter**                                                       **RT‑008 RSR13**

                                                                      **(N = 69)**

  **Sex n (%)**                                                       []{.mark}

  []{.mark}        Male                                               31 (45)

                   Female                                             38 (55)

  **Race n (%)**                                                      

                   Caucasian                                          62 (90)

                   Black                                              5 (7)

                   Native American                                    0 (0)

                   Asian                                              0 (0)

                   Hispanic                                           2 (3)

                   Other                                              0 (0)

  **Age (years)**                                                     

                   \<65 years n (%)                                   51 (74)

                   ≥65 years n (%)                                    18 (26)

                   Mean                                               55.8

                   SD                                                 10.4

                   Min-Max                                            37‑76

  **Weight (kg)**                                                     

                   Mean                                               73.0

                   SD                                                 14.5

                   Min-Max                                            38.6‑129.1

                   n Missing                                          0

  **RPA                                                               
  Classification n                                                    
  (%)**                                                               

                   RPA Class I                                        12 (17)

                   RPA Class II -- NSCLC primary                      33 (48)

                   RPA Class II -- Breast cancer primary              18 (26)

                   RPA Class II -- Other primary tumor type           6 (9)

  **Screening                                                         
  Resting                                                             
  SpO~2~^a^**                                                         

                   \<96%                                              17 (25)

                   ≥96%                                               52 (75)
  ---------------- -------------------------------------------------- -----------------

> ^a^Missing baseline resting SpO~2~ counted in the \<96% category.

The median duration of primary disease was similar for Class I and
Class patients; however, Class II patients with primary breast cancer
had a longer median duration of primary disease than patients with other
types of primary disease (Table 4.2). The duration of NSCLC was shorter
than other types of primary disease (particularly in Class II patients)
due to the fact that most patients with NSCLC had synchronous
metastases. The median duration of primary disease in RPA Class II
patients with breast cancer primary was similar between studies RT‑008
and RT‑009 (43.0 vs 43.4 months, respectively).

[]{#__RefHeading___Toc68333994 .anchor}Table 4.38\
Tumor History by RPA Class for RSR13 Treated Patients in RT‑008

  --------- ----------- ------- ---------- -------------- ------------ ------------------ ------------ ----------
  **RPA     **Primary   **n**   **Median   **Controlled   **Median     **Extra-cranial\   **Median     **Median
  Class**   Disease**           Age        Primary\       Duration of  Mets\              Duration of  Baseline
                                (years)\   No/Yes**       Primary\     No/Yes**^a^        Brain Mets   KPS**
                                **                        Disease                         (months)**   
                                                          (months)**                                   

  I         NSCLC       6       56.5       0/6            11.5         6/0                0.2          90

            Breast      3       42.0       0/3            12.8         3/0                0.1          90

            Other       3       53.0       0/3            14.3         3/0                0.4          90

            Total       12      52.5       0/12           12.3         12/0               0.2          90

  II        NSCLC       33      61.0       26/7           0.8          14/19              0.4          90

            Breast      18      49.5       8/10           43.0         0/18               0.2          90

            Other       6       61.0       4/2            27.2         1/5                0.7          80

            Total       57      56.0       38/19          12.4         15/42              0.3          90

  All                   69      55.0       38/31          12.3         27/42              0.3          90
  --------- ----------- ------- ---------- -------------- ------------ ------------------ ------------ ----------

^a^Extracranial metastases were not documented in Class I patients (per
definition).

## Dosing

The original study protocol specified an RSR13 dose of 100 mg/kg,
however the protocol was later amended (Amendment 3) to allow for RSR13
dose reductions to 75 or 50 mg/kg (or withholding of doses) if clinical
assessments or laboratory criteria indicated that the patient was
experiencing exaggerated pharmacological effects. However, as presented
in Table 3.27, there were fewer dose reductions in study RT‑008 than in
study RT‑009.

## Efficacy Results

The observed Kaplan‑Meier estimate of MST for the overall RSR13‑treated
population was 6.4 months and the MST for the Class I and II groups was
also 6.4 months for each group. After 6 months of follow-up, 51% (35/69)
of all RT‑008 patients were alive and 33% (23/69) were alive and free of
intracranial progression. Extracranial progression was experienced by
61% (42/69) of all patients by the end of the follow‑up period
(\>24 months).

KPS measurements demonstrated that approximately 6 months after the
start of treatment the majority of living patients had an acceptable
performance status. At the 5‑7 month period 70% (16/23) of living
patients with KPS scores available had little or no change from baseline
in their KPS score. MMSE measurements demonstrated that approximately 6
months after the start of treatment the mental state of the majority of
living patients was stable or improved from baseline.

Patients with a CR or PR survived longer and remained free of
intracranial progression for a longer time than patients with a response
of SD. In addition, patients with a CR or PR were more likely to have
maintained their neurological function status from baseline to follow‑up
than patients with a response of SD or Other.

Patients in the RT‑008 Class II group (n = 57) had statistically
significantly improved survival compared to the RTOG BMD (n = 1070;
p = 0.017). The observed Kaplan‑Meier MST for the Class II group was
6.4 months (95% CI: 4.4‑9.0 months), compared to 4.1 months
(CI: 3.8‑4.5 months) for the RTOG BMD control group (Table 4.3). Based
on a Cox multiple‑regression model analysis, the risk of death was
reduced by 22% for patients in the Class II group versus patients in the
RTOG BMD (p = 0.098).

[]{#__RefHeading___Toc68333995 .anchor}Table 4.39\
Survival Data\
RTOG Brain Metastases Database Class II Patients versus RSR13 Class II
Patients

  ------------------ -------------------- -------------- -------------------- --------------
                     **All Patients**                                         

                     **RTOG BMD                          **RSR13 Class II**   
                     Class II**                                               

  **Time (Months)**  **% Alive**          **No. at       **% Alive**          **No. at
                                          Risk**                              Risk**

  0                  100                  1070           100                  57

  6                  35                   376            51                   29

  12                 15                   157            23                   13

  18                 6                    66             12                   7

  24                 3                    30             11                   6

  **Median**         4.1 months                          6.4 months           

  **Dead/Total**     1049/1070                           54/57                

  **p-value**        0.017                                                    

  **95% CI**         \[3.8-4.5 months\]                  \[4.4-9.0 months\]   
  ------------------ -------------------- -------------- -------------------- --------------

A subset of Class II patients (n = 38) in the study could be
case-matched exactly by KPS, primary tumor site, extent of metastases,
status of primary tumor, and age (within 5 years) to patients from the
RTOG BMD (n = 38). As shown in Table 4.4, using exact case‑matched
RTOG BMD controls, the difference in survival was even more significant
(p = 0.0060) than in the overall comparison, with MST at 7.3 months
(CI: 4.6‑10.9 months) versus 3.4 months (CI: 1.7‑5.0 months).

[]{#__RefHeading___Toc68333996 .anchor}Table 4.40\
Survival Data\
RTOG Brain Metastases Database (Exact Matches) versus RSR13 Class II
Patients

  ------------------ -------------------- -------------- --------------------- --------------
                     **All Patients**                                          

                     **RTOG BMD                          **RSR13 Class II**    
                     Class II**                                                

  **Time (Months)**  **% Alive**          **No. at       **% Alive**           **No. at
                                          Risk**                               Risk**

  0                  100                  38             100                   38

  6                  21                   8              58                    22

  12                 8                    3              24                    9

  18                 3                    1              13                    5

  24                 3                    1              13                    5

  **Median**         3.4 months                          7.3 months            

  **Dead/Total**     38/38                               36/38                 

  **p-value**        0.0060                                                    

  **95% CI**         \[1.7‑5.0 months\]                  \[4.6‑10.9 months\]   
  ------------------ -------------------- -------------- --------------------- --------------

A stratified Cox model, with each case-matched pair (RTOG BMD:RSR13) as
a stratum, and study group as the only independent factor was also used
to estimate RSR13 treatment effect. For the case-matched controls
(n = 38), there was a 54% reduction in the risk of death for patients
who received RSR13/RT versus RTOG BMD patients (p = 0.0267).

## Comparison of Results from Studies RT-008 and RT-009

Table 4.5 demonstrates that the efficacy results are consistent between
studies RT‑008 and RT‑009 and add further support to the validity of the
treatment effect in study RT‑009 patients with breast cancer primary.

[]{#__RefHeading___Toc68333997 .anchor}Table 4.41\
Survival in RPA Class II Breast Cancer Patients, Studies RT‑008 and
RT‑009

+-----------------+-----------------+-----------------+-----------------+
| **Study and     | **Control MST   | **RSR13 MST     | **p‑value**     |
| Analysis**      | (months)**      | (months)**      |                 |
+-----------------+-----------------+-----------------+-----------------+
| **RT‑008**      | 5.4             | 9.7             | 0.54            |
|                 |                 |                 |                 |
|                 | (n = 113)       | (n = 18)        |                 |
+-----------------+-----------------+-----------------+-----------------+
| **RT‑008: RTOG  | 4.9             | 7.9             | 0.03            |
| Case Matching** |                 |                 |                 |
|                 | (n = 12)        | (n = 12)        |                 |
+-----------------+-----------------+-----------------+-----------------+
| **RT‑009        | 4.5             | 7.0             | 0.01            |
| Stratum 3**     |                 |                 |                 |
|                 | (n = 49)        | (n = 52)        |                 |
+-----------------+-----------------+-----------------+-----------------+

# Safety

## Studies Evaluated for Safety of RSR13 as an Adjunct to WBRT in Patients with Brain Metastases from Breast Cancer

Development of the RSR13 safety profile specific to the indication of
WBRT for brain metastases from breast cancer is based upon data obtained
in 7 Phase 1‑3, radiation oncology studies that employed multiple-dose
regimens of RSR13 as sole adjunct to RT. The 7 studies are RT‑002,
RT‑006, RT‑007, RT‑007b, RT‑008, RT‑009, and RT‑010.

Data obtained in the controlled Phase 3 study, RT‑009, and that of the
Phase 2 study, RT‑008, provided the pivotal evaluation of the RSR13
safety profile in the target population of patients with brain
metastases.

## Extent of Exposure

### RSR13 Exposure

A total of 535 patients have received at least 1 dose of RSR13 as sole
adjunct to RT. Table 5.1 summarizes the overall exposure for patients in
the safety population, which was comprised of patients from the
7 oncology studies that employed multiple dose regimens of RSR13 as sole
adjunct to RT. A total of 547 patients were enrolled in these studies,
538 patients were assigned to the RSR13 arm, and 535 patients received
at least 1 dose of RSR13. Various RT regimens were utilized across all
multiple dose RT studies. The number of RT and RSR13 doses varied
substantially between studies (10‑32 treatments); therefore, exposure to
RSR13 as part of a 10‑day treatment regimen with standard WBRT for the
treatment of brain metastases in the proposed indication is presented
separately. The exposure to RSR13 varied across RT studies with a mean
number of daily doses ranging from 5.8‑26.8 and the mean daily dose
ranging from 77.7‑98.3 mg/kg. The duration of infusion was approximately
60 minutes in 2 studies (RT‑002 and RT‑006) and approximately 30 minutes
in all other studies. A total of 80 patients with brain metastases
originating from breast cancer have received at least 1 dose of RSR13
(studies RT‑009 and RT‑008).

[]{#__RefHeading___Toc68333998 .anchor}Table 5.42\
Extent of RSR13 Exposure for All Patients Undergoing RT\
for Treatment of Solid Tumors of Different Types, Multiple Dose RSR13
Radiation Oncology Studies

  ---------------------------------- ---------------- ----------------------
                                                      **All RSR13**

                                                      **(Total = 547)^a^**

  Number of RSR13 Doses              n ^b^            535

                                     Mean             13.9

                                     SD               2.6

                                     Min‑Max          1‑34

  RSR13 Dose (mg/kg)                 n ^b^            535

                                     Mean             88.6

                                     SD               13.6

                                     Min‑Max          1.9‑106.7

  RSR13 Duration (min)               n ^b^            534

                                     Mean             33.2

                                     SD               8.6

                                     Min‑Max          3.0‑83.0
  ---------------------------------- ---------------- ----------------------

> ^a^Total: This denominator includes patients undergoing WBRT\
> for brain metastases in studies RT‑008 and RT‑009, in addition\
> to treated patients in RT‑002, RT‑006, RT‑007/7b, and RT‑010.
>
> ^b^n: Total number of patients treated with RSR13 (ie, received\
> at least 1 dose RSR13)

When analyzing only patients in studies RT‑008 and RT‑009, the overall
exposure to RSR13 in patients undergoing WBRT for treatment of brain
metastases demonstrated the consistency of treatment in this patient
population. The mean numbers of daily doses were 8.9 in study RT‑008 and
8.4 in study RT‑009; the mean daily dose was 92.8 and 84.5 mg/kg,
respectively. The decrease in the daily RSR13 dose of study RT‑009
compared to study RT‑008 was due was due to implementation of dosing
adjustment guidelines in study RT‑009. These guidelines were expanded in
Amendment 2 of the protocol to calculate starting dose and subsequent
dosing adjustments according to body weight and gender to decrease the
frequency and severity of treatment‑emergent adverse events in females
and patients with high body weight.

The overall exposure of RSR13 in patients with brain metastases from
breast cancer was consistent across study RT‑008 and the RSR13 arm of
studynRT‑009 (Table 5.2). The mean number of doses in patients with
brain metastases from breast cancer was 8 in both studies, and the mean
daily dose was 93.1 mg/kg in study RT‑008 and 84.7 mg/kg in the RSR13
arm of study RT‑009.

[]{#__RefHeading___Toc68333999 .anchor}Table 5.43\
Extent of RSR13 Exposure in Patients with Primary Breast Cancer\
Undergoing WBRT for Treatment of Brain Metastases\
(Studies RT‑008 and RT‑009)

  ---------------------- ---------- ------------ ------------- -------------
                                    **RT‑008     **RT‑009      **All RSR13
                                    (Breast)**   (Breast RSR13 ^a^\
                                                 arm)**        (Breast)**

                                                               

  Number of RSR13 Doses  n^b^       21           59^c^         80

                         Mean       8.0          8.0           8.0

                         SD         2.4          3.0           2.8

                         Min‑Max    2/10         1/10          1/10

  RSR13 Dose (mg/kg)     n^b^       21           59^c^         80

                         Mean       93.1         84.7          86.9

                         SD         12.1         12.9          13.2

                         Min‑Max    61.8/100.3   50/101.3      50/101.3

  RSR13 Duration (min)   n^b^       21           59^c^         80

                         Mean       30.3         31.4          31.1

                         SD         0.8          3.5           3.1

                         Min‑Max    29.7/52.8    27.6/47.9     27.6/47.9
  ---------------------- ---------- ------------ ------------- -------------

> Mean: arithmetic mean
>
> SD: standard deviation
>
> Min‑Max: minimum‑maximum amount
>
> ^a^All RSR13 includes all patients with primary breast cancer in
> studies RT‑008 and RT‑009.
>
> ^b^n: Total number of patients treated with RSR13 (ie, received at
> least 1 dose RSR13)\
> ^c^Of the 60 patients with primary breast cancer enrolled in the RSR13
> arm, 1 patient\
> did not receive RSR13.

### RT Exposure

RSR13 as an adjunct to WBRT did not adversely affect the delivery of
planned RT. When patients that received RT alone were compared to
patients who received RT with RSR13 in studies RT‑008 and RT‑009, there
was no difference in the mean number of RT doses administered
(9.9 \[SD = 0.6\] vs 9.6 \[SD = 1.6\], respectively) or in the mean
total RT dose administered (29.6 Gy \[SD = 2.0\] vs 29.3 Gy
\[SD = 3.4\], respectively).

## Safety in the Pivotal Phase 3 Efficacy Study, RT‑009

## Summary of Adverse Events

Overall, 95.8% (252/263) of the patients in the Control arm and
98.1% (261/266) of the patients in the RSR13 arm experienced at least
1 treatment‑emergent adverse event. While the overall incidences of
treatment‑emergent adverse events were comparable in the 2 treatment
arms, the most commonly reported treatment‑emergent adverse events in
the RSR13 arm were headache and nausea, both reported in 45% (120/266)
of RSR13‑treated patients, and the most frequently reported
treatment-emergent adverse event in the Control arm was fatigue reported
in 39% (102/263) of Control patients.

The overall occurrence of Grade 3 or 4 adverse events in RSR13‑treated
patients was essentially equivalent to that observed in Control
patients. However, the most commonly reported Grade 3 adverse event in
RSR13‑treated patients was hypoxemia, reported in 11% (29/266) of
patients; no Grade 4 hypoxemia was reported. The most commonly reported
Grade 3 or 4 adverse event in Control patients was disease progression,
reported in 8% (20/263) of patients.

Serious adverse event reports were submitted for 39% (204/529) of
patients overall (42% \[110/263\] in the Control arm and 35% \[94/266\]
in the RSR13 arm). Of these reports, events in 23% (22/266) of
RSR13 treated patients were determined by the investigator to be study
drug related.

Death was the reason for early termination from the study in 59 patients
(32 in the Control arm and 27 in the RSR13 arm). Three deaths were
attributed a possible causal link to RSR13 by the investigator (cause of
death reported as pneumonia in 1 patient with NSCLC primary, disease
progression in 1 patient with breast primary, and acute renal failure in
1 patient with other primary, in this case malignant melanoma).

## Overall Incidence of Adverse Events

The most commonly reported adverse events (\>40%) in the RSR13 arm were
alopecia, fatigue, headache, nausea, and transient hypoxemia
(Table 5.3). The most commonly reported adverse events (\>40%) in the
Control arm were alopecia and fatigue.

[]{#__RefHeading___Toc68334000 .anchor}Table 5.44\
Adverse Events Occurring in \>10% of Patients in Either Treatment arm
Regardless of Causality, Study RT‑009

+-----------------------------------+----------------+----------------+
| **Adverse Event**                 | **Control**    | **RSR13**      |
|                                   |                |                |
|                                   | **(N = 263)**  | **(N = 266)**  |
|                                   |                |                |
|                                   | **%**          | **%**          |
+-----------------------------------+----------------+----------------+
| Alopecia                          | 49             | 51             |
+-----------------------------------+----------------+----------------+
| Fatigue                           | 43             | 49             |
+-----------------------------------+----------------+----------------+
| Headache                          | 33             | 47             |
+-----------------------------------+----------------+----------------+
| Nausea                            | 30             | 47             |
+-----------------------------------+----------------+----------------+
| Hypoxemia                         | 4              | 41             |
+-----------------------------------+----------------+----------------+
| Vomiting                          | 17             | 38             |
+-----------------------------------+----------------+----------------+
| Radiation dermatitis              | 25             | 26             |
+-----------------------------------+----------------+----------------+
| Disease progression               | 26             | 17             |
+-----------------------------------+----------------+----------------+
| Constipation                      | 16             | 22             |
+-----------------------------------+----------------+----------------+
| Dizziness                         | 15             | 22             |
+-----------------------------------+----------------+----------------+
| Perioral symptoms (during         | N/A            | 21             |
| infusion)                         |                |                |
+-----------------------------------+----------------+----------------+
| Moniliasis                        | 20             | 16             |
+-----------------------------------+----------------+----------------+
| Anorexia                          | 17             | 16             |
+-----------------------------------+----------------+----------------+
| Insomnia                          | 18             | 14             |
+-----------------------------------+----------------+----------------+
| Muscle weakness                   | 15             | 14             |
+-----------------------------------+----------------+----------------+
| Peripheral edema                  | 11             | 14             |
+-----------------------------------+----------------+----------------+
| Cough                             | 11             | 13             |
+-----------------------------------+----------------+----------------+
| Dyspepsia                         | 13             | 9              |
+-----------------------------------+----------------+----------------+
| Asthenia                          | 14             | 4              |
+-----------------------------------+----------------+----------------+
| Hypotension                       | 1              | 14             |
+-----------------------------------+----------------+----------------+
| Anemia                            | 5              | 12             |
+-----------------------------------+----------------+----------------+
| Dyspnea                           | 14             | 11             |
+-----------------------------------+----------------+----------------+
| Taste perversion                  | 4              | 11             |
+-----------------------------------+----------------+----------------+

## Incidence of RSR13 Treatment‑related Adverse Events

Overall, the most commonly reported RSR13‑related adverse event was
hypoxemia reported in 40% (106/266) of RSR13‑treated patients
(Table 5.4). The other most common adverse events determined to be RSR13
treatment‑related (\>30%) were nausea, vomiting, and headache
(36% \[96/266\], 31% \[82/266\], and 33% \[88/266\], respectively).

[]{#__RefHeading___Toc68334001 .anchor}Table 5.45\
RSR13‑related Adverse Events Occurring in \>10% of Patients in Study
RT‑009

+-------------------------------------------+--------------------------+
| **Adverse Event**                         | **RSR13**                |
|                                           |                          |
|                                           | **(N = 266)**            |
|                                           |                          |
|                                           | **%**                    |
+-------------------------------------------+--------------------------+
| Hypoxemia                                 | 40                       |
+-------------------------------------------+--------------------------+
| Nausea                                    | 36                       |
+-------------------------------------------+--------------------------+
| Headache                                  | 33                       |
+-------------------------------------------+--------------------------+
| Vomiting                                  | 31                       |
+-------------------------------------------+--------------------------+
| Fatigue                                   | 21                       |
+-------------------------------------------+--------------------------+
| Perioral symptoms (during infusion)       | 20                       |
+-------------------------------------------+--------------------------+
| Dizziness                                 | 14                       |
+-------------------------------------------+--------------------------+
| Hypotension                               | 11                       |
+-------------------------------------------+--------------------------+

## Incidence of Grade 3 and 4 Adverse Events

The majority of treatment‑emergent adverse events were Grade 1 (mild) to
Grade 2 (moderate) in severity in both treatment arms.

Hypoxemia was reported as a Grade 3 (severe) adverse event in
11% (29/266) of patients in the RSR13 arm and 2% (5/263) of patients in
the Control arm (Table 5.5). The other most commonly reported Grade 3
adverse events (\>5% in either treatment arm) were headache, reported in
7% of RSR13-treated patients, and disease progression and dyspnea,
reported in 7% and 6% of Control patients, respectively. Grade 3 adverse
events occurring in 5% of patients in either treatment arm included
nausea and vomiting in the RSR13 arm and muscle weakness in the Control
arm.

[]{#__RefHeading___Toc68334002 .anchor}Table 5.46\
Grade 3 Adverse Events Occurring in ≥3% of Patients in Either Treatment
arm Regardless of Causality, Study RT‑009

+-----------------------------------+------------------+---------------+
| **Adverse Event**                 | **Control**      | **RSR13**     |
|                                   |                  |               |
|                                   | **(N = 263)**    | **(N = 266)** |
|                                   |                  |               |
|                                   | **%**            | **%**         |
+-----------------------------------+------------------+---------------+
| Hypoxemia                         | 2                | 11            |
+-----------------------------------+------------------+---------------+
| Disease progression               | 7                | 4             |
+-----------------------------------+------------------+---------------+
| Headache                          | 3                | 7             |
+-----------------------------------+------------------+---------------+
| Nausea                            | 3                | 5             |
+-----------------------------------+------------------+---------------+
| Vomiting                          | 3                | 5             |
+-----------------------------------+------------------+---------------+
| Fatigue                           | 3                | 4             |
+-----------------------------------+------------------+---------------+
| Constipation                      | 4                | 3             |
+-----------------------------------+------------------+---------------+
| Pneumonia                         | 2                | 3             |
+-----------------------------------+------------------+---------------+
| Muscle weakness                   | 5                | 2             |
+-----------------------------------+------------------+---------------+
| Dyspnea                           | 6                | 2             |
+-----------------------------------+------------------+---------------+

Overall Grade 4 adverse events (considered by the investigator to be
life threatening) were reported at comparable frequencies in the
2 treatment arms: reported in 11% (28/263) of Control patients and in
12% (33/266) of RSR13‑treated patients. In both treatment arms, disease
progression was the most frequently occurring Grade 4 adverse event:
reported in 6% of patients in both arms (15/263 Control patients and
16/266 RSR13‑treated patients) (Table 5.6). All other Grade 4 adverse
events occurred in 1 or 2 patients in both treatment arms with the
exception of Grade 4 headache and Grade 4 fatigue (both reported in
3 patients in the Control arm) and Grade 4 acute renal failure (reported
in 3 patients in the RSR13 arm).

[]{#__RefHeading___Toc68334003 .anchor}Table 5.47\
Grade 4 Adverse Events Occurring in \>1 Patient in Either Treatment arm
Regardless of Causality, Study RT‑009

+------------------------------------+-----------------+---------------+
| **Adverse Event**                  | **Control**     | **RSR13**     |
|                                    |                 |               |
|                                    | **(N = 263)**   | **(N = 266)** |
|                                    |                 |               |
|                                    | **%**           | **%**         |
+------------------------------------+-----------------+---------------+
| Disease progression                | 13              | 11            |
+------------------------------------+-----------------+---------------+
| Dyspnea                            | 2               | 2             |
+------------------------------------+-----------------+---------------+
| Pulmonary embolism                 | 1               | 2             |
+------------------------------------+-----------------+---------------+
| Acute renal failure                | 0.4             | 2             |
+------------------------------------+-----------------+---------------+
| Headache                           | 1               | 1             |
+------------------------------------+-----------------+---------------+
| Convulsions                        | 1               | 1             |
+------------------------------------+-----------------+---------------+
| Pneumonia                          | 0               | 2             |
+------------------------------------+-----------------+---------------+
| Pain                               | 0.4             | 1             |
+------------------------------------+-----------------+---------------+
| Respiratory insufficiency          | 0.4             | 1             |
+------------------------------------+-----------------+---------------+
| Condition aggravated               | 1               | 0.4           |
+------------------------------------+-----------------+---------------+
| Coma                               | 1               | 0.4           |
+------------------------------------+-----------------+---------------+
| Fatigue                            | 1               | 0             |
+------------------------------------+-----------------+---------------+
| Intracranial hemorrhage            | 1               | 0             |
+------------------------------------+-----------------+---------------+
| Pericardial effusion               | 1               | 0             |
+------------------------------------+-----------------+---------------+
| Vomiting                           | 0               | 1             |
+------------------------------------+-----------------+---------------+
| Medication error                   | 0               | 1             |
+------------------------------------+-----------------+---------------+
| Hypotension                        | 0               | 1             |
+------------------------------------+-----------------+---------------+
| Hyperglycemia                      | 1               | 0             |
+------------------------------------+-----------------+---------------+
| Hypokalemia                        | 1               | 0             |
+------------------------------------+-----------------+---------------+
| Myocardial infarction              | 1               | 0             |
+------------------------------------+-----------------+---------------+

Grade 4 adverse events that were judged related to RSR13 treatment are
summarized by tumor type in Table 5.7.

[]{#__RefHeading___Toc68334004 .anchor}Table 5.48\
RSR13 Treatment‑related Grade 4 Adverse Events by Site of Primary, Study
RT‑009

+---------------+------------+------------+------------+------------+
| **Adverse     | **NSCLC**  | **Breast** | **Other**  | **All**    |
| Event**       |            |            |            |            |
|               | **(        | **         | **         | **(        |
|               | N = 144)** | (N = 60)** | (N = 62)** | N = 266)** |
|               |            |            |            |            |
|               | **%**      | **%**      | **%**      | **%**      |
+---------------+------------+------------+------------+------------+
| Acute renal   | 0          | 0          | 5          | 1          |
| failure       |            |            |            |            |
+---------------+------------+------------+------------+------------+
| Vomiting      | 1          | 0          | 0          | 0.4        |
+---------------+------------+------------+------------+------------+
| Stupor        | 1          | 0          | 0          | 0.4        |
+---------------+------------+------------+------------+------------+
| Pneumonia     | 1          | 0          | 0          | 0.4        |
+---------------+------------+------------+------------+------------+
| Hypotension   | 0          | 0          | 2          | 0.4        |
+---------------+------------+------------+------------+------------+
| Tachycardia   | 0          | 0          | 2          | 0.4        |
+---------------+------------+------------+------------+------------+
| Creatinine    | 0          | 0          | 2          | 0.4        |
| blood         |            |            |            |            |
| increased     |            |            |            |            |
+---------------+------------+------------+------------+------------+
| Oliguria      | 0          | 0          | 2          | 0.4        |
+---------------+------------+------------+------------+------------+
| Disease       | 0          | 2          | 0          | 0.4        |
| progression   |            |            |            |            |
+---------------+------------+------------+------------+------------+
| Deafness      | 1          | 0          | 0          | 0.4        |
+---------------+------------+------------+------------+------------+

## Deaths

Based on the patient population being studied and the stage of disease,
it was anticipated that the majority of patients would progress and
ultimately die of their underlying disease. Through the 1‑month
follow‑up, disease progression was reported as cause of death in
33/263 (13%) patients in the Control arm versus 26/266 (10%) patients in
the RSR13 arm (Table 5.8).

The most common cause of death other than disease progression in both
treatment arms was pneumonia (Table 5.8) which was reported in
3 patients in the Control arm (all with NSCLC primary) and 5 patients in
the RSR13 arm (2 patients with NSCLC primary, 1 patient with primary
renal cell carcinoma, 1 patient with primary ovarian cancer, and
1 patient with primary colorectal cancer). An additional patient in the
Control arm died as a result of *Pneumocystis carinii* pneumonia
(Patient 4062); however, this event was coded by the World Health
Organization Adverse Reaction Thesaurus (WHOART) Body System criteria
according to the type infection rather than site of infection with this
specific organism.

[]{#__RefHeading___Toc68334005 .anchor}Table 5.49\
Summary of Deaths (Number/Percentage of Patients) by Treatment Arm

  --------------------------------------------- --------------- ---------------
  **Cause of Death**                            **Control**     **RSR13**

                                                **(N = 263)**   **(N = 266)**

                                                **%**           **%**

  Disease progression                           13              10

  Pneumonia                                     1               2

  Respiratory insufficiency                     0               1

  Edema cerebral                                0               0.4

  Neurologic deterioration                      0.4             0.4

  Convulsions                                   0.4             0

  Renal failure acute                           0.4             1

  Condition aggravated                          1               0.4

  Cachexia                                      0.4             0

  Anorexia                                      0.4             0.4

  Cardiac arrest                                0               0.4

  Dehydration                                   0.4             0.4

  Diabetes mellitus aggravated                  0.4             0

  Somnolence                                    0.4             0.4

  Cerebrovascular disorder                      0.4             0.4

  Cerebral hemorrhage                           0.4             0

  Embolism pulmonary                            0.4             0

  Left ventricular dysfunction                  0.4             0

  Pneumocystis carinii infection                0.4             0

  Sepsis                                        0.4             0

  Stevens Johnson syndrome                      0.4             0
  --------------------------------------------- --------------- ---------------

Three deaths were attributed as having a "possible" causal link to the
study drug by the investigator (Table 5.9).

[]{#__RefHeading___Toc68334006 .anchor}Table 5.50\
Summary of Deaths Considered by the Investigator to Have a Possible,
Probable, or Definite Relationship to Study Drug

  ----------- ---------------- ----------- ---------- -------------------------------
  **Patient   **Gender/Age**   **Primary   **Allos    **WHOART Preferred Term
  \#**                         Site**      SAE \#**   (Verbatim)**

  1023        Male/63          NSCLC       0302       Pneumonia (pneumonia)

  3040        Female/71        Breast      0301       Disease progression (disease
                                                      progression)

  4084        Male/49          Other^a^    0398       Renal failure acute (acute
                                                      renal failure)
  ----------- ---------------- ----------- ---------- -------------------------------

> ^a^ Malignant melanoma

## Adverse Events Identified as Significant Components of the RSR13 Safety Profile

Eight treatment‑emergent adverse events or adverse event categories were
identified as components of the RSR13 safety profile. Factors considered
in this determination were the incidence of the event, attribution to
study treatment, mechanism of action of the investigative product, and
evaluation of safety data in study RT‑009. Table 5.10 lists the adverse
events/categories and the incidence of these events in study RT‑009, as
well as for all patients who were randomized to the RSR13 arm in all
studies.

[]{#__RefHeading___Toc68334007 .anchor}Table 5.51\
Overall Incidence of Treatment‑emergent Adverse Events/Adverse Event
Categories Identified as Significant or Likely Components of RSR13
Safety Profile Regardless of Causality, Study RT‑009

+-------------------------+--------------+--------------+--------------+
| **Adverse Event**       | **Control**  | **RSR13**    | **All        |
|                         |              |              | RSR13**      |
|                         | *            | *            |              |
|                         | *(N = 263)** | *(N = 266)** | *            |
|                         |              |              | *(N = 538)** |
|                         | **%**        | **%**        |              |
|                         |              |              | **%**        |
+-------------------------+--------------+--------------+--------------+
| **Nausea**              | 30           | 47           | 52           |
+-------------------------+--------------+--------------+--------------+
| **Vomiting**            | 17           | 38           | 38           |
+-------------------------+--------------+--------------+--------------+
| **Headache**            | 33           | 47           | 51           |
+-------------------------+--------------+--------------+--------------+
| **Hypoxemia**           | 4            | 41           | 37           |
+-------------------------+--------------+--------------+--------------+
| **Dizziness**           | 15           | 22           | 25           |
+-------------------------+--------------+--------------+--------------+
| **Hypotension**         | 1            | 14           | 13           |
+-------------------------+--------------+--------------+--------------+
| **Infusion symptoms**   | 0            | 27           | 30           |
+-------------------------+--------------+--------------+--------------+
| **Rash/allergic         | 8            | 12           | 16           |
| reaction**              |              |              |              |
+-------------------------+--------------+--------------+--------------+
| **Anemia**              | 5            | 12           | 16           |
+-------------------------+--------------+--------------+--------------+
| **Renal dysfunction**   | 1            | 8            | 9            |
+-------------------------+--------------+--------------+--------------+

## Concomitant Medications

No prospective drug‑drug interaction studies have been conducted in
humans. Results of in vitro studies have indicated that RSR13 may be a
weak metabolic inhibitor of hepatic CYP2C9 and CYP3A4 isoenzymes.

In study RT‑009, drug‑drug interactions were explored with respect to
the distribution of selected treatment‑emergent adverse events by body
system, preferred term, study, selected concomitant medication, and/or
medical history. Patients receiving RSR13 with a positive history of
cardiovascular diseases or known concomitant anti‑hypertensive treatment
had a higher incidence and severity of the following treatment‑emergent
adverse events: hypoxemia, hypotension, and renal dysfunction. In study
RT‑009, the management of these events consisted of modifications of the
anti-hypertensive regimen (dose reduction, omission of doses, change in
schedule) as well as dose modifications of RSR13. With the above
modifications, the majority of patients were able to receive RSR13
throughout the planned treatment period.

## Relationship of Adverse Events to Dose, Dose Regimen, and Treatment Duration

RSR13 is dosed on a mg/kg body weight basis. RSR13 binds to hemoglobin
and the compartment of drug distribution is represented by the total
blood volume of the patient. However, the total blood volume does not
increase proportionally with body weight. Within gender, patients with a
higher body weight received higher total doses on a mg/kg basis while
their total blood volume was more comparable to patients at lower
weight. Female patients generally achieved higher concentrations of
RSR13 in plasma and RBCs. Female patients with a weight over 70 kg and
males with a weight over 95 kg demonstrated a higher incidence of RSR13
treatment‑related adverse events leading to the implementation of
dosing‑adjustment guidelines. The guidelines included these weights as
cut‑off values for the determination of starting dose and subsequent
doses of RSR13. The dosing-adjustment guidelines also took into
consideration the patient\'s adverse event profile when the starting
dose or subsequent dosing was determined.

## Summary of RSR13 Safety Profile

1.  Safety data from over 500 RSR13‑treated oncology patients indicate
    an acceptable safety profile for RSR13

2.  Eight adverse events have been identified as components of the RSR13
    safety profile

3.  There was a consistent incidence of the adverse events identified as
    components of the RSR13 safety profile between the RSR13 arm in
    study RT‑009 and safety data from 535 oncology patients who received
    at least 1 dose of RSR13

# Conclusions

RSR13 is the first of a new class of agents, allosteric modifiers of
hemoglobin. The goal of the initial clinical study of RSR13 (HV‑001) was
to administer a dose of RSR13 sufficient to induce the desired PD
endpoint, increasing whole blood p50 by 10 mmHg. Following HV‑001, the
first study of RSR13 in patients with cancer receiving RT (RT‑002) was
conducted. RT‑002 confirmed the feasibility of administering doses of
RSR13 sufficient to reach the desired PD endpoint and, together with the
previous study (HV‑001) and subsequent studies (RT‑008 and RT‑010),
confirmed the strong correlation between RSR13 concentration in the RBC
and p50 shift. Based on these studies, a dose of RSR13 of
75‑100 mg/kg/day was identified as optimal for further testing, and was
the dose selected for patients with brain metastases enrolled in the
pivotal Phase 3 study (Study RT‑009). Study RT‑009 was the culmination
of 10 years of clinical development of RSR13 as a radiation sensitizer.
As such, it represents the first successful randomized study of a
non‑cytotoxic radiation sensitizer in patients with any solid tumor.

The prognosis of patients with brain metastases has not changed for the
past 2 decades. The administration of WBRT has been shown to increase
survival and to delay neurologic progression, but since its
introduction, no meaningful improvement in the outcome of these patients
has been realized. While some selected patients benefit from resection
or stereotactic radiosurgery (SRS), the majority of patients with brain
metastases are not candidates for either of these interventions.
Furthermore, the use of SRS does not eliminate the need for WBRT, as
randomized studies have shown that the addition of WBRT to SRS is
superior to SRS alone. Lack of progress for these patients is evidenced
by the results of the Control Arm of study RT‑009 which showed an MST of
4.6 months, almost identical compared to the MST of patients in the RTOG
BMD treated over the last 25 years.

The results of study RT‑009 demonstrate that RSR13 as an adjunct to WBRT
can improve the outcome of patients with brain metastases without
adversely affecting their QOL. Despite the fact that the primary
analysis for survival in the two co‑primary populations of study RT‑009
revealed a difference in survival that did not reach statistical
significance by unadjusted log-rank, several pieces of evidence confirm
the activity of RSR13 in this setting:

1.  The analysis of survival in the NSCLC/Breast cancer co‑primary
    population revealed a 38% improvement in MST due to RSR13 (MST:
    Control 4.4 months versus RSR13 Arm 6.0 months) with a strong trend
    towards statistical significance (p = 0.07, unadjusted log‑rank).
    The primary analysis of survival for study RT‑009 took place after a
    prespecified number of events had occurred and with a minimum
    follow‑up of 6 months. When these results are analyzed with an
    additional follow‑up of 12 months, the comparison between the arms
    in the NSCLC/Breast co‑primary population reaches significance
    (p=0.05).

2.  Imbalances in the relative frequency of prognostic factors favoring
    the Control arm require the use of a Cox multiple regression model
    to accurately assess the treatment effect in study RT‑009. There is
    ample support in the literature for the use of a Cox model in this
    setting, and in fact, the protocol and the SAP specified that a Cox
    multiple regression analysis would be conducted as part of the
    statistical analysis of this study. All covariates included in the
    model were prespecified, the Cox model was run for each of
    48 possible combinations of covariates, and the RSR13 indicator
    variable was statistically significant in 48/48 of the models (mean
    HR = 0.76). We therefore conclude that when adjusted for imbalances
    in prognostic variables using a Cox model, the results of study
    RT‑009 demonstrated a statistically significant difference in
    survival in favor of the patients that received RSR13 over the
    Control arm.

3.  While the results of study RT‑009 as a whole showed evidence of
    activity for RSR13 across tumor types, these results were in large
    part driven by the treatment effect observed in patients with brain
    metastases originating from breast cancer. Thus, we analyzed the
    results in this population separately. The results of the study in
    this population reveal:

    a.  Clinically meaningful improvement in survival (4.6 months
        compared to 8.7 months).

    b.  The reduction in the risk of death produced by RSR13 in breast
        cancer patients was highly consistent whether analyzed by
        unadjusted log‑rank (HR = 0.55) or by Cox multiple regression
        (HR = 0.51).

    c.  Significant improvement in response rate by unadjusted log‑rank.

    d.  Stable or improved QOL measurements.

    e.  Consistent Treatment Effect: When primary breast cancer patients
        were analyzed according to 16 prespecified covariates, the RSR13
        treatment‑effect was consistent across all covariate subgroups.

4.  While the results in patients with NSCLC were not what we expected,
    analyses of the dosing, and adjustment of the results for adequate
    dosing and favorable ("successful") pharmacokinetics, strongly
    suggest that if dosed adequately, these patients should derive
    benefit from the addition of RSR13 to WBRT.

5.  RSR13 is aimed at increasing survival by improving local control.
    The clearest evidence supporting the principle that RSR13 improves
    the effectiveness of WBRT comes from the statistically significant
    improvement in response rate observed in the co-primary population
    of patients with NSCLC/breast cancer. A trend towards significance
    was also seen in the co‑primary population of all randomized
    patients. It is important to point out that response was associated
    with longer survival, both in studies RT‑008 and in RT‑009, in the
    latter, independently of study arm.

The results of study RT‑009 confirmed what previous studies with RSR13
had suggested: RSR13 is safe when administered to cancer patients as an
adjunct to RT. This is supported by the low frequency of Grade 3‑4
adverse events in study RT‑009.

The most characteristic adverse event observed with RSR13 is transient
hypoxemia. This is a direct result of the PD effect of the drug and it
is associated with its activity as a radiation sensitizer. It is
important to stress the fact that 73% of all patients in study RT‑009
who experienced hypoxemia as an adverse event were asymptomatic and the
only treatment required was supplemental oxygen.

In conclusion, RSR13 represents not only the first non‑cytotoxic
radiation sensitizer to demonstrate a survival benefit, but also the
first clinically meaningful advance since the introduction of WBRT for
patients with brain metastases originating from breast cancer and who
are candidates for WBRT.

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