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

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TABLE OF CONTENTS

1.0          introduction.. 6

1.1       Indication. 6

1.2       Current Therapy for Brain Metastases. 6

1.3       Allosteric Modification of Hemoglobin. 7

1.4       Mechanism of Action of RSR13. 9

2.0          Background.. 10

2.1       Clinical Development of RSR13. 10

2.2       Clinical Pharmacology and Metabolism.. 13

2.2.1    Clinical Pharmacology Studies. 13

2.2.2    Results from Pharmacokinetic/Pharmacodynamic Studies and RSR13 Dose Selection. 13

3.0          Pivotal Phase 3 STUDY FOR the Treatment of patients with Brain Metastases (RSR13 RT‑009). 18

3.1       Study Design. 18

3.1.1    Study Endpoints. 19

3.1.2    Prespecified Plans for Analysis of Results. 20

3.1.3    Protocol Amendments. 21

3.2       Patient Demographics, Baseline Characteristics and Efficacy Results. 21

3.2.1    Patient Demographics and Baseline Characteristics. 21

3.2.2    Dosing. 24

3.2.3    Efficacy Results. 25

4.0          Supportive Phase 2 STudy For the Treatment of patients with Brain Metastases (RSR13 RT‑008). 51

4.1       Study Design. 51

4.2       Demography and Baseline Characteristics of Patients with Brain Metastases in RT‑008. 51

4.3       Dosing. 53

4.4       Efficacy Results. 53

4.5       Comparison of Results from Studies RT-008 and RT-009. 55

5.0          Safety.. 56

5.1       Studies Evaluated for Safety of RSR13 as an Adjunct to WBRT in Patients with Brain Metastases from Breast Cancer. 56

5.2       Extent of Exposure. 56

5.2.1    RSR13 Exposure. 56

5.2.2    RT Exposure. 58

5.3       Safety in the Pivotal Phase 3 Efficacy Study, RT‑009. 58

5.4       Summary of Adverse Events. 58

5.5       Overall Incidence of Adverse Events. 59

5.6       Incidence of RSR13 Treatment‑related Adverse Events. 60

5.7       Incidence of Grade 3 and 4 Adverse Events. 61

5.8       Deaths. 63

5.9       Adverse Events Identified as Significant Components of the RSR13 Safety Profile. 64

5.10     Concomitant Medications. 64

5.11     Relationship of Adverse Events to Dose, Dose Regimen, and Treatment Duration. 65

5.12     Summary of RSR13 Safety Profile. 65

6.0          Conclusions. 66

7.0          References. 68

List of Tables

Table 1.1 Recursive Partitioning Analyses (RPA) Radiation Therapy Oncology Group (RTOG). 6

Table 1.2 Results of Randomized Studies of WBRT for the Treatment of Brain Metastases. 7

Table 2.1 Completed and Ongoing RSR13 Oncology Studies. 11

Table 2.2 RSR13 Studies That Have Provided PK and/or PD Data for the Oncology Indication. 13

Table 2.3 RSR13 Dose, PK, and PD Dataa 16

Table 3.1 Description of the Secondary Endpoints in Study RT‑009. 19

Table 3.2 Assumptions for the Primary Endpoint 20

Table 3.3 Prespecified Cox Model Baseline Covariates in Study RT-009. 20

Table 3.4 Summary of Protocol Amendments for Study RT‑009. 21

Table 3.5 Ineligible Patients Identified by Blinded Central Review of Scans. 22

Table 3.6 Summary of Demographic Data in Control and RSR13 Treated Patients, Efficacy Oncology Studies. 23

Table 3.7 Tumor History and Extent of Disease by Treatment Arm in Study RT‑009. 24

Table 3.8 Dosing Guidelines by Protocol Version. 24

Table 3.9 Number of WBRT and RSR13 Doses Received by Treatment Arm, Study RT‑009. 25

Table 3.10 Distribution of Prognostic Factors by Treatment Group, All Eligible Patients in Study RT‑009. 29

Table 3.11 Treatment Effect Correcting for Imbalances, All Eligible Patientsa 30

Table 3.12 Distribution of Prognostic Factors by Treatment Group, Eligible NSCLC/breast Patients in Study RT‑009. 32

Table 3.13 Treatment Effect Correcting for Imbalances, All Eligible NSCLC/breast Patientsa 33

Table 3.14 Covariate Analysis for Breast Cancer Patients in Study RT‑009. 36

Table 3.15 Subsequent Therapies in Patients with Breast Cancer Primary in Study RT‑009. 37

Table 3.16 Survival by Investigator Site for Breast Cancer Patients in Study RT‑009. 37

Table 3.17 Seven Covariates Most Predictive of Survival by Treatment Group in Study RT‑009, All Randomized Patients. 39

Table 3.18 RSR13 Treatment Effect Correcting for Imbalancesa 39

Table 3.19 Survival by Stratum for All Randomized Patients. 40

Table 3.20 Survival by Best Response for All Patients in Study RT‑009. 43

Table 3.21 Survival by Best Response for NSCLC/Breast Patients in Study RT‑009. 43

Table 3.22 Survival by Best Response for Patients with Breast Cancer Primary in Study RT‑009. 44

Table 3.23 Confirmed Response Rate (CR+PR). 44

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

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

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

Table 3.27 Percentage of Patients who Received Dose Adjustments in Studies RT‑008 and RT‑009. 47

Table 3.28 Body Weight in Study RT‑009 by Body Weight Category, Gender, and Primary Site. 48

Table 3.29 RSR13 RBC Concentrations (mg/mL) in Study RT‑009, by Weight Category and Primary Site. 48

Table 3.30 RSR13 Treatment Effect by Weight Group for NSCLC Patients in Study RT‑009. 48

Table 3.31 Response Rate by Exposure Group for NSCLC Patients in Study RT‑009. 49

Table 4.1 Summary of Demographic Data in Control and RSR13 Treated Patients in RT‑008. 52

Table 4.2 Tumor History by RPA Class for RSR13 Treated Patients in RT‑008. 53

Table 4.3 Survival Data RTOG Brain Metastases Database Class II Patients versus RSR13 Class II Patients. 54

Table 4.4 Survival Data RTOG Brain Metastases Database (Exact Matches) versus RSR13 Class II Patients. 54

Table 4.5 Survival in RPA Class II Breast Cancer Patients, Studies RT‑008 and RT‑009. 55

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

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

Table 5.3 Adverse Events Occurring in >10% of Patients in Either Treatment arm Regardless of Causality, Study RT‑009. 60

Table 5.4 RSR13‑related Adverse Events Occurring in >10% of Patients in Study RT‑009. 60

Table 5.5 Grade 3 Adverse Events Occurring in ³3% of Patients in Either Treatment arm Regardless of Causality, Study RT‑009. 61

Table 5.6 Grade 4 Adverse Events Occurring in >1 Patient in Either Treatment arm Regardless of Causality, Study RT‑009. 62

Table 5.7 RSR13 Treatment‑related Grade 4 Adverse Events by Site of Primary, Study RT‑009. 62

Table 5.8 Summary of Deaths (Number/Percentage of Patients) by Treatment Arm.. 63

Table 5.9 Summary of Deaths Considered by the Investigator to Have a Possible, Probable, or Definite Relationship to Study Drug. 64

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

List of Figures

Figure 1.1 Oxygen Equilibrium Curve for Human Whole Blood. 8

Figure 2.1 Oxygen Equilibrium Curve for Human Whole Blood and the Relationship of p50 and the Hill Coefficient 14

Figure 2.2 RBC RSR13 Concentration versus p50 for Patients who Received RSR13 at 100 mg/kg in Study RT‑002. 15

Figure 2.3 Correlation of RSR13 Pharmacokinetics/Pharmacodynamics. 16

Figure 3.1 Kaplan‑Meier Survival Curve for All Eligible Patients. 28

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

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

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

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

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

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

 

LIST OF ABBREVIATIONS

2,3‑DPG

2,3‑diphosphoglycerate

mg

microgram

mm

micrometer

mM

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

Cmax

maximum concentration

CNS

central nervous system

CO2

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

pO2

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

SO2

oxygen saturation

SpO2

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

 

1.0                introduction

1.1                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.

1.2                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).

Table 1.1
Recursive Partitioning Analyses (RPA) Radiation Therapy Oncology Group (RTOG)

Variable

Class I

Class II

Class III

KPS

³70

³70

<70

Primary Status

Controlled and <65 years of age and Brain only

Uncontrolled and/or ³65 years of age and/or extracranial metastases

---

Age (years)

Extracranial Disease

%

20

65

15

Survival (months)

7.1

4.2

2.3

Source: Gaspar et al, 1997

Table 1.2
Results of Randomized Studies of WBRT for the Treatment of Brain Metastases

Study (Year Published)

N

WBRT Treatment Arms

Total Gy/Number of Fractions

MST (months)

Harwood et al (1977)5

101

30/10 vs 10/1

4.0‑4.3

Kurtz et al (1981)6

255

30/10 vs 50/20

3.9‑4.2

Borgelt et al (1981)7

138

10/1 vs 30/10 vs 40/20

4.2‑4.8

Borgelt et al (1981)7

64

12/2 vs 20/5

2.8‑3.0

Chatani et al (1985)8

70

30/10 vs 50/20

3.0‑4.0

Haie-Meder et al (1993)9

216

18/3 vs 36/6 vs 43/13

4.25.3

Murray et al (1997)10

445

54.4/34 vs 30/10

4.5

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 cervix18 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 pO2 (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 pO2 is less than 10 mmHg.18  This effect has also been demonstrated in head and neck cancer.19

1.3                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 pO2 (measured in mmHg) it produces in solution.  The hemoglobin‑oxygen saturation at any given pO2 is graphically represented as an Oxygen Equilibrium Curve (OEC) (Figure 1.1).  The pO2 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: SO2 = 100/(1 + (p50/pO2)n).

Figure 1.1
Oxygen Equilibrium Curve for Human Whole Blood

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 (CO2), 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 al21 discovered that the antilipidemic drug clofibric acid lowered the oxygen affinity of hemoglobin solutions.  Later, Perutz et al22 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. 

1.4                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 (pO2 for 50% hemoglobin saturation), and an increase in tissue pO2.  RSR13 emulates the function of natural allosteric modifiers of hemoglobin (H+, CO2, 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 pO2 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.

2.0                Background

2.1                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).

Table 2.1
Completed and Ongoing RSR13 Oncology Studies

Study Number

N

Study Title

RSR13 dose (mg/kg)

Status

RT‑002

20

A Phase 1b Study to Evaluate the Safety and Tolerance of Multiple Daily Intravenous Doses of RSR13 Administered to Patients Receiving Concurrent Radiation Therapy

75, 100

Complete; Reported

RT‑004

12

A Phase 2 Study to Evaluate the Effects of a Single Intravenous Infusion of RSR13 on Tumor Oxygenation in Patients with Tumors Amenable to Oxygen Determination Measurements

RSR13: 100

Placebo: 0.45% NaCl

Complete; Reported

RT‑006

19

A Phase 1b Study to Evaluate the Safety and Tolerance of Repetitive Daily Intravenous Doses of RSR13 Administered to Patients Receiving Cranial Radiation Therapy for Glioblastoma Multiforme

100

Complete; Reported

RT‑007

50

A Phase 2 Study to Evaluate the Efficacy and Safety of Repetitive Daily Intravenous Doses of RSR13 Administered to Patients Receiving Cranial Radiation Therapy for Glioblastoma Multiforme

100

Complete; Reported

RT‑007b

67

A Companion Phase 2 Study to Evaluate the Efficacy and Safety of Repetitive Daily Intravenous Doses of RSR13 Administered to Patients Receiving Cranial Radiation Therapy for Glioblastoma Multiforme

100

Complete; Reported

RT‑008

69

A Phase 2 Study to Evaluate the Efficacy and Safety of RSR13 Administered to Patients Receiving Standard Cranial Radiation Therapy for Brain Metastases

100 with dose reductions to 75
or 50 allowed

Complete; Reported

RT‑009

538

A Phase 3 Randomized, Open‑Label, Comparative Study of Standard Whole Brain Radiation Therapy, With or Without RSR13, in Patients with Brain Metastases

RSR13: 100 with dose reduction to 75 allowed

Control: No RSR13/ no placebo

Complete; Reported

RT‑010

51

A Phase 2 Study of Induction Chemotherapy with Paclitaxel and Carboplatin Followed by Radiation Therapy with RSR13 for Locally Advanced Inoperable Non‑Small Cell Lung Cancer

75 with dose adjustment to 50 or 100 allowed

Complete; Reported

RT‑012

70a

A Phase 1/2 Study to Evaluate the Safety, Tolerance, and Efficacy of RSR13 (Efaproxiral) Administered to Patients Receiving a Course of Cisplatin and Radiation Therapy for Locally Advanced Carcinoma of the Cervix

25‑100 to determine maximum tolerated dose

Study Ongoing

CT‑001

70a

A Phase 1/2 Study to Evaluate the Safety and Tolerance of Escalating Doses of RSR13 (Efaproxiral) Administered with a Fixed Dose of BCNU Every 6 Weeks in Patients with Recurrent Malignant Glioma

25‑100 to determine maximum tolerated dose

Study Ongoing

 

RT‑014

22a

A Phase 1 Open-label Study of RSR13 (efaproxiral) and Supplemental Oxygen with Concurrent Paclitaxel, Carboplatin, and Thoracic Radiation Therapy in Patients with Locally Advanced, Unresectable (Stage IIIA/IIIB) Non‑small Cell Lung Cancer

50‑75 to determine maximum tolerated dose

Study Ongoing

RT‑016

360 a

A Phase 3 Randomized, Open‑Label Comparative Study of Standard Whole Brain Radiation Therapy with Supplemental Oxygen, with or without Concurrent RSR13 (efaproxiral), in Women with Brain Metastases from Breast Cancer

RSR13: 100 with dose reduction to 75 allowed

Control: No RSR13/ no placebo

Study Ongoing

N: total number of patients enrolled

aNumber 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.

2.2                Clinical Pharmacology and Metabolism

2.2.1           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. 

Table 2.2
RSR13 Studies That Have Provided PK and/or PD Data for the Oncology Indication

Study Number

Description of Dosing

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

2.2.2           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.

Figure 2.1
Oxygen Equilibrium Curve for Human Whole Blood and the Relationship of p50 and the Hill Coefficient

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.

Figure 2.2
RBC RSR13 Concentration versus p50 for Patients who Received RSR13 at 100 mg/kg in Study RT‑002

(Kavanagh et al., 2001)

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 mg/mL in RBCs has to be reached.

Table 2.3
RSR13 Dose, PK, and PD Dataa

Population (study identification)

N

Infusion Duration (minutes)

Dose (mg/kg)

Mean RSR13 concentration in RBCs (mg/mL)*

Mean p50 Shift

Healthy subjects (HV‑001)29-31

24

60

75

450

9.3

100

513

11.9

Patients with solid tumors of different types (RT‑002)27

20

60

75

333

5.7

100

459

8.1

Brain metastases (RT‑008)23

69

30

75

453

10.7

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 (Cmax) occurring at end-infusion

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

Figure 2.3
Correlation of RSR13 Pharmacokinetics/Pharmacodynamics

2.2.2.1      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.

2.2.2.2      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.

2.2.2.3      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.

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

3.1                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)    ³18 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 (SpO2) while breathing room air ³90%.

(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) ³70.

(10) Patients must not have previously received RSR13.

3.1.1           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).

Table 3.1
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 Progression in the Brain

Any treated lesion in the brain was enlarged by >25%

Time to Clinical Tumor Progression in the Brain

Assessment was made using:

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

3.1.2           Prespecified Plans for Analysis of Results

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

Table 3.2
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.

Table 3.3
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). 

3.1.3           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. 

 

Table 3.4
Summary of Protocol Amendments for Study RT‑009

Amendment (Protocol Version)

Date

Description of Change

Amendment 1 (Protocol Version 2)

02 Mar 2000

·        Expand MRI/CT specifications

·        Omit RSR13 on any day if SpO2 <90%

Amendment 2 (Protocol Version 3)

05 Jun 2001

·        Sample size up to 538 patients with NSCLC/breast co‑primary

·        Dose Adjustment for anti‑hypertensives, weight, and gender

Amendment 3 (Protocol Version 4)

09 Oct 2001

·        Use of Cobalt 60 allowed

 

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 mg/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 mg/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.

3.2                Patient Demographics, Baseline Characteristics and Efficacy Results

3.2.1           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.

Table 3.5
Ineligible Patients Identified by Blinded Central Review of Scans

Reason Ineligible

Primary Site

Control

RSR13

 

 

N = 17

N = 6

Leptomeningeal metastases

NSCLC

5

3

Breast

3

2

Other

4

1

No measurable brain lesions

(status post‑resection)

NSCLC

1

0

Breast

2

0

Small cell lung cancer

Other

1

0

Dural disease related to skull metastases

Breast

1

0

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.

Table 3.6
Summary of Demographic Data in Control and RSR13 Treated Patients, Efficacy Oncology Studies

Parameter

RT‑009 Control

RT‑009 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)

 

³65 years  n (%)

70 (26)

75 (28)

 

Mean

57.0

57.1

 

SD

11.0

11.1

 

Min-Max

23¾81

30¾87

Weight (kg)

 

 

 

Mean

72.5

71.3

 

SD

17.1

15.0

 

Min-Max

33.0¾140.9

39.8¾122.0

 

n Missing

2

0

Weight Categorya

 

 

 

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 primary

51 (19)

52 (19)

 

Stratum 4: RPA Class II – Other primary tumor type

56 (21)

58 (21)

Screening Resting SpO2b

 

 

 

<96%

53 (20)

59 (22)

 

³96%

214 (80)

212 (78)

aTwo patients had missing data in the Control arm.

bMissing baseline resting SpO2 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).

Table 3.7
Tumor History and Extent of Disease by Treatment Arm in Study RT‑009

Covariate

Value

Control

N = 267

RSR13

N = 271

RPA Class:

I

28

29

II

239

242

Primary Control:

Controlled

67

72

Uncontrolled

200

199

Duration of primary disease (months)a:

Q1

1.1

0.9

Q2

11.4

9.9

Q3

33.8

28.9

Presence of extracranial metastases:

Yes

171

187

No

96

84

Prior treatment for brain metastases:

Yes

29

21

No

238

250

Liver metastases:

Yes

42

54

No

225

217

aQ1, Q2, and Q3 represent the first, second, and third quartiles, respectively

3.2.2           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.

Table 3.8
Dosing Guidelines by Protocol Version

 

Protocol Versions 1 and 2

Protocol Versions 3 and 4

SpO2 <90%

RSR13 held

RSR13 held

SpO2 90%-92%

RSR13 administered at 75 mg/kg

RSR13 administered at 75 mg/kg

SpO2 ³93%

RSR13 administered at 100 mg/kg

The following 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 ³Grade 2

(3)       Hypotension

(4)       Hypoxemia requiring treatment after discharge

(5)       Room air SpO2 90%‑92% with ³93% 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.

Table 3.9
Number of WBRT and RSR13 Doses Received by Treatment Arm, Study RT‑009

Number of Doses

Control

N = 267

RSR13

N = 271

WBRT

N (%)

WBRT

N (%)

RSR13

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

3.2.3           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

3.2.3.1      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

3.2.3.2      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 al36 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.

3.2.3.2.1     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. 

Figure 3.1
Kaplan‑Meier Survival Curve for All Eligible Patients

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

 

Table 3.10
Distribution of Prognostic Factors by Treatment Group, All Eligible Patients in Study RT‑009

Covariate

Value

Control

(N = 250)

%

RSR13

(N = 265)

%

Primary Site

NSCLC

58

55

Breast

20

22

Other

22

23

Age

<65 years

73

72

³65 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

primary cancer

Controlled

24

26

Uncontrolled

76

74

RPA Class

I

10

11

II

90

89

Number of sites of

extracranial metastases

0

36

31

1 to 2

46

48

³3

18

22

Presence of

liver metastases

Yes

16

20

No

84

80

Number of

brain metastases a

1

20

17

2 to 3

32

30

>3

47

52

Sum of

Bidimensional

products of lesions a

<250 mm2

25

26

250‑1000 mm2

46

50

>1000 mm2

28

23

Timing of

Diagnosis

Metachronous

68

67

Synchronous

32

33

Prior cranial tumor resection

Yes

10

8

No

90

92

Baseline hemoglobin

<12 g/dL

16

17

³12 g/dL

84

83

Site location

USA

47

50

Canada

32

29

ROW

21

21

Altitude at

treatment site

<2000 feet

86

87

³2000 feet

14

13

Weight per dosing

adjustment algorithm

High weight

26

25

Low weight

74

75

aFive patients with missing data

Table 3.11
Treatment Effect Correcting for Imbalances, All Eligible Patientsa

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 resection, Gender

HR = 0.78, p = 0.01

KPS, Number of Extracranial Metastases, Prior resection, Gender, Breast Primary

HR = 0.79, p = 0.02

KPS, Number of Extracranial Metastases, Prior resection, Gender, Breast Primary, Age Group

HR = 0.79, p = 0.01

aLast 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).

3.2.3.2.2     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. 

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

Table 3.12
Distribution of Prognostic Factors by Treatment Group, Eligible NSCLC/breast Patients in Study RT‑009

Covariate

Value

Control (N = 194)

%

RSR13

(N = 203)

%

Primary Site

NSCLC

75

71

Breast

25

29

Age

<65 years

72

72

³65 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

primary cancer

Controlled

23

23

Uncontrolled

77

77

RPA Class

I

10

11

II

90

89

Number of sites of

extracranial metastases

0

37

36

1 to 2

46

46

³3

18

17

Presence of

liver metastases

Yes

15

15

No

85

85

Number of

brain metastases a

1

21

18

2 to 3

30

32

>3

48

49

Sum of

bidimensional

products of lesions a

<250 mm2

25

26

250‑1000 mm2

46

48

>1000 mm2

29

25

Timing of

Diagnosis

Metachronous

67

63

Synchronous

33

37

Prior cranial tumor resection

Yes

8

5

No

92

95

Baseline hemoglobin

<12 g/dL

16

13

³12 g/dL

84

87

Site location

USA

45

49

Canada

34

30

ROW

21

21

Altitude at

treatment site

<2000 ft

86

89

³2000 ft

14

11

Weight per dosing

adjustment algorithm

High weight

26

28

Low weight

74

72

aThree patients with missing data

Table 3.13
Treatment Effect Correcting for Imbalances, All Eligible NSCLC/breast Patientsa

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 resection

HR = 0.77, p = 0.02

KPS, Number of Extracranial Metastases, Age, Prior resection, Gender

HR = 0.75, p = 0.01

aLast 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). 

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

January 2004

3.2.3.2.3     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). 

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

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. 

Table 3.14
Covariate Analysis for Breast Cancer Patients in Study RT‑009

Covariate

Value

Control

RSR13

Hazard Ratio

(95% CI)

%

MST

%

MST

Age

<65 years

82

6.05

80

10.48

0.55 (0.34, 0.90)

 

³65 years

18

2.78

20

5.70

0.35 (0.12, 0.98)

Baseline KPS

90 - 100

56

7.29

60

10.64

0.58 (0.32, 1.05)

 

<90

44

2.79

40

5.70

0.52 (0.28, 0.98)

Control of

controlled

33

6.42

32

11.33

0.54 (0.23, 1.26)

primary cancer

uncontrolled

67

4.47

68

7.26

0.53 (0.32, 0.87)

RPA Class

I

11

12.94

13

25.72

0.37 (0.07, 2.01)

 

II

89

4.47

87

7.03

0.56 (0.36, 0.88)

Number of sites of

0

15

9.36

12

9.69

0.81 (0.18, 3.67)

extracranial metastases

1 to 2

45

4.57

57

7.26

0.62 (0.34, 1.12)

 

³3

40

4.24

32

7.33

0.45 (0.22, 0.94)

Presence of

Yes

35

3.52

35

6.90

0.43 (0.21, 0.88)

liver metastases