A Phase II Study of RRx-001 in Platinum Refractory/Resistant Small Cell Carcinoma, EGFR TKI Resistant EGFR+ T790M Negative Non-Small Cell Lung Cancer, High Grade Neuroendocrine Tumors and Resistant/Refractory Ovarian Cancer Prior to Re-administration of Platinum Based Doublet Regimens (QUADRUPLE THREAT)
Phase: PHASE2
Conditions: Small Cell Carcinoma, Carcinoma, Non-Small-Cell Lung, Neuroendocrine Tumors, Ovarian Epithelial Cancer
Sponsor: EpicentRx, Inc.

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 1 of 99 
CLINICAL STUDY PROTOCOL 
 
Protocol No. 
RRx001-211-01 
Product 
RRx-001 
Title: 
RRx-001 in patients with small cell carcinoma, high-grade 
neuroendocrine carcinoma, EGFR mutation positive non-
small cell lung cancer, ovarian cancer (including Malignant 
Mixed Mullerian Tumor (MMMT) of the ovary or uterus) 
previously treated with a platinum-based regimen 
(QUADRUPLE THREAT) 
Development Phase 
IND #: 
Phase 2 
107,674 
Version: 
Original 
October 7, 2014 
Amendment No.  
Date: 
Amendment 10 
July 20, 2018 
Sponsor: 
EpicentRx, Inc. 
11099 North Torrey Pines Rd, Suite 160 
La Jolla, CA 92037 
Sponsor’s Medical Contact: 
Bryan Oronsky, M.D. 
Chief Medical Officer 
11099 North Torrey Pines Rd, Suite 160 
La Jolla, CA 92037 
Tel: 408-569-3202 
Email: boronsky@epicentrx.com 
Study Medical Monitor: 
Bryan Oronsky, M.D.  
This document contains proprietary and confidential information of EpicentRx. Acceptance of this document constitutes agreement by the 
recipient that no previously unpublished information contained herein will be published or disclosed without the prior written approval of 
EpicentRx with the exception that this document may be disclosed to study personnel under your supervision who need to know the contents for 
conducting the study and appropriate Institutional Review Boards (IRBs)/Independent Ethics Committees (IEC) under the condition that the 
personnel have agreed to keep this information confidential. The foregoing shall not apply to disclosure required by governmental regulations or 
laws; however, EpicentRx shall be promptly notified of any such disclosure. 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 2 of 99 
INVESTIGATOR AGREEMENT PAGE 
 
EpicentRx, Inc. 
 
Protocol No. RRx001-211-01  
RRx-001 in patients with small cell carcinoma, high-grade neuroendocrine carcinoma, 
EGFR mutation positive non-small cell lung cancer, ovarian cancer (including Malignant 
Mixed Mullerian Tumor (MMMT) of the ovary or uterus) previously treated with a 
platinum-based regimen (QUADRUPLE THREAT) 
July 20, 2018 
 
 
 
 
I will provide copies of the protocol, any subsequent protocol amendments and access to all 
information provided by the Sponsor to the study personnel under my supervision. I will discuss 
this material with them to ensure that they are fully informed about the investigational drug and 
the study protocol. 
 
I agree to conduct this clinical trial according to the attached protocol, except when mutually 
agreed to in writing. I also agree to conduct this study in compliance with all federal, state and 
local regulations, as well as with the requirements of the appropriate Institutional Review Board 
and any other institutional requirements. 
 
 
 
Principal Investigator 
 
Date 
Printed Name: 
 
 
 
Institution: 
 
 
 
 
 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 3 of 99 
PROTOCOL APPROVAL PAGE 
 
 
TITLE:  
RRx-001 in patients with small cell carcinoma, high-grade neuroendocrine 
carcinoma, EGFR mutation positive non-small cell lung cancer, ovarian 
cancer (including Malignant Mixed Mullerian Tumor (MMMT) of the ovary 
or uterus) previously treated with a platinum-based regimen (QUADRUPLE 
THREAT) 
 
 
SPONSOR: 
 
EpicentRx, Inc. 
11099 North Torrey Pines Rd, Suite 160 
La Jolla, CA 92037 
 
 
 
 
 
 
20 JUL 2018 
 
 
Bryan Oronsky, M.D. 
        Date  
 
 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 4 of 99 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ...................................................................................................7 
1 
STUDY SCHEMAS ........................................................................................................9 
1.1 
Treatment Schemas [SCC, EOC, NET, NSCLC] ..........................................................9 
2 
STUDY SUMMARY ..................................................................................................... 13 
3 
BACKGROUND AND RATIONALE .......................................................................... 19 
3.1 
Background ................................................................................................................ 19 
3.2 
RRx-001 as a Tumor-Associated Macrophage Targeting Agent with Tumor 
Sensitizing Properties ................................................................................................. 24 
3.3 
Clinical Experience with RRx-001 .............................................................................. 24 
3.4 
Rationale .................................................................................................................... 34 
4 
STUDY OBJECTIVES ................................................................................................. 35 
4.1 
Primary Objectives ..................................................................................................... 35 
4.2 
Secondary Objectives ................................................................................................. 35 
4.3 
Exploratory Objectives ............................................................................................... 35 
4.4 
Endpoints ................................................................................................................... 35 
5 
STUDY DESIGN ........................................................................................................... 38 
5.1 
Description of the Study ............................................................................................. 38 
5.2 
Administrative Structure ............................................................................................. 39 
5.3 
Compliance with Laws and Regulations ..................................................................... 39 
6 
MATERIALS AND METHODS .................................................................................. 39 
6.1 
Study Population ........................................................................................................ 39 
6.2 
Study Treatment ......................................................................................................... 39 
6.3 
Concomitant and Excluded Therapies ......................................................................... 49 
6.4 
Study Assessments ..................................................................................................... 49 
6.5 
Patient Discontinuation ............................................................................................... 52 
6.6 
Study Discontinuation ................................................................................................ 52 
7 
STATISTICAL METHODS OF DATA ANALYSIS .................................................. 53 
7.1 
Study Design .............................................................................................................. 53 
7.2 
Efficacy Variables ...................................................................................................... 55 
7.3 
Safety Variables ......................................................................................................... 57 
7.4 
Statistical and Analytical Methods .............................................................................. 57 
7.5 
Power Considerations and Sample Size Determination ............................................... 58 
7.6 
Interim Analysis and Data Monitoring ........................................................................ 58 
7.7 
Institutional Review Board ......................................................................................... 59 
7.8 
Data Quality Assurance .............................................................................................. 59 
8 
ASSESSMENT OF SAFETY........................................................................................ 60 
8.1 
Specification of Safety Variables ................................................................................ 60 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 5 of 99 
8.2 
Methods and Timing for Assessing and Recording Safety Variables ........................... 61 
8.3 
Reporting Requirements for Adverse Events ............................................................... 64 
8.4 
Type and Duration of Follow-Up of Patients After Adverse Events ............................ 66 
9 
SPONSOR AND INVESTIGATOR REQUIREMENTS ............................................ 67 
9.1 
Study Initiation ........................................................................................................... 67 
9.2 
Informed Consent ....................................................................................................... 67 
9.3 
Institutional Review Board Approval .......................................................................... 68 
9.4 
Study Monitoring Requirements ................................................................................. 68 
9.5 
Data Collection ........................................................................................................... 68 
9.6 
Study Medication Accountability ................................................................................ 69 
9.7 
Disclosure of Data ...................................................................................................... 69 
9.8 
Retention of Records .................................................................................................. 69 
10 
REFERENCES.............................................................................................................. 70 
11 
APPENDICES ............................................................................................................... 75 
Appendix A. Response evaluation criteria in solid tumors ..................................................... 75 
Appendix B. ECOG performance status scale ........................................................................ 85 
Appendix D. Visual Analogue Fatigue Scale ......................................................................... 86 
Appendix F. Imaging Collection for Independent Review: .................................................... 87 
Appendix G. Schedules of Assessments ................................................................................ 88 
 
 
List of Tables 
Table 1: 
Treatment Emergent Adverse Events (TEAEs) Considered Related to Study Drug RRx-
001 in Decreasing Order of Frequency ................................................................................ 27 
Table 2: 
Pharmacokinetic Properties for RRx-001-GSH vs Dose. Values are shown ± SD ................ 29 
Table 3: 
RRx-001 Regimen Premedication Description .................................................................... 40 
Table 4: 
Dose Modifications for RRx-001 Administration ................................................................ 43 
Table 5: 
Dose Delays / Modifications based on Absolute Neutrophil Count: Platinum Doublets........ 44 
Table 6: 
Dose Delays / Modifications based on Platelet Count: Platinum Doublets ........................... 45 
Table 7: 
Platinum Therapies - Adverse Event Dose Modifications: Non-Hematological .................... 46 
Table 8: 
Dose Modifications for Hepatic Impairment: Nab-Paclitaxel (Abraxane)............................. 46 
Table 9: 
Dose Modifications for neurologic and hematologic adverse drug reactions: Nab-
Paclitaxel (Abraxane) ......................................................................................................... 47 
Table 10: 
Permanent Dose Reductions for Hematologic and Neurologic Drug Reactions in 
NSCLC: Nab-Paclitaxel (Abraxane) ................................................................................... 47 
Table 11: 
Etoposide Dose Modifications for Renal Function............................................................... 48 
Table 12: 
Adverse Event Grading (Severity) Scale ............................................................................. 62 
 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 6 of 99 
List of Figures 
Figure 1: 
Platinum resistance definition by Gynecologic Oncology Group (GOG) ............................. 23 
Figure 2: 
Left: Plot of AvgAUCinf for Day 1 and Day 22/50 against dose. Right: Plot of 
AvgCmax for Day 1 and Day 22/50 against dose. ............................................................... 30 
Figure 3: 
Adhesion of RRx-001-Modified Red Blood Cells (Blue Arrows) to the Tumor 
Vasculature Leading to Vaso-Occlusion. The Orange Arrows Indicate Presence of the 
RBCs in the Tumor Parenchyma. ........................................................................................ 31 
Figure 4: 
Appearance of Vacuolation (Foamy Cell Changes) (Orange Arrows) Seen Over Time 
in Serial Biopsies of the Tumor an RRx-001-Treated Patient on QUADRUPLE 
THREAT ............................................................................................................................ 31 
Figure 5: 
In Vivo Experiment Demonstrating RRx-001-Induced Polarization of Tumor 
Associated Macrophages..................................................................................................... 32 
Figure 6: 
Three Step Macrophage-Mediated Anti-Tumor Mechanism of Action ................................. 32 
Figure 7: 
Preclinical Evidence of Chemoprotection.  RRx-001 Treated Mice Prior to Treatment 
with Cisplatin ..................................................................................................................... 33 
Figure 8: 
Hemoglobin Concentration, Platelets, and WBC Counts Significantly Reduced in Mice 
Pretreated with RRx-001 ..................................................................................................... 34 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 7 of 99 
LIST OF ABBREVIATIONS 
AABB 
American Association of Blood Banks 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BID 
Twice a day 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CFI 
Chemotherapy Free Interval 
CMH 
Cochran-Mantel-Haenszel Test 
CMP 
Comprehensive Metabolic Panel 
CPT 
Cold Pressor Test 
CR 
Complete Response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose Limiting Toxicity 
ECOG 
Eastern Cooperative Oncology Group 
EOC 
Epithelial Ovarian Cancer 
ES-SCLC 
Extensive Stage Small Cell Lung Cancer 
FDG 
Fluorodeoxyglucose 
FMP 
Family Member Prefix 
GI 
Gastrointestinal 
GU 
Genitourinary 
HCC 
Hepatocellular Carcinoma 
HGNEC 
Extrapulmonary High Grade Neuroendocrine Tumors 
HRPP 
Human Research Protections Program 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
miRNA 
MicroRNA 
MMMT 
Malignant Mixed Mullerian Tumor 
MRI 
Magnetic Resonance Imaging 
MRN 
Medical Record Number 
NCI 
National Cancer Institute 
NSCLC 
Non-Small Cell Lung Cancer 
NYHA 
New York Heart Association 
OS 
Overall Survival 
PET 
Positron Emission Tomography 
PFS 
Progression Free Survival 
PD 
Progressive Disease 
PLD 
Pegylated Liposomal Doxorubicin 
p.o. 
per os/by mouth/orally 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 8 of 99 
PR 
Partial Response 
PS 
Phosphatidylserine 
PT 
Prothrombin Time 
q.d. 
quaque die/every day 
RBC 
Red Blood Cell 
rEOC 
Resistant/Refractory Epithelial Ovarian Cancer 
rSCLC 
Resistant/Refractory Small Cell Lung Cancer 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
SCLC 
Small Cell Lung Cancer 
SCC 
Small Cell Carcinoma 
SD 
Stable Disease 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SPGT 
Serum Glutamic Pyruvic Transaminase 
SSN 
Social Security Number 
TAM 
Tumor Associated Macrophages 
T790M 
Threonine (amino acid position 790) Methionine 
TEAE 
Treatment Emergent Adverse Events 
TFI 
Treatment-Free Interval 
TKI 
Tyrosine Kinase Inhibitor 
ULN 
Upper Limit of Normal 
VAS 
Visual Analog Scale 
WBC 
White Blood Cells 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 9 of 99 
1 STUDY SCHEMAS 
1.1 Treatment Schemas [SCC, EOC, NET, NSCLC]  
SCC 
 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 10 of 99 
EOC 
 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 11 of 99 
NET 
 
 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 12 of 99 
NSCLC 
 
 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 13 of 99 
2 STUDY SUMMARY 
Title: 
RRx-001 in patients with small cell carcinoma, high-grade neuroendocrine carcinoma, EGFR 
mutation positive non-small cell lung cancer, ovarian cancer (including Malignant Mixed 
Mullerian Tumor (MMMT) of the ovary or uterus) previously treated with a platinum-based 
regimen (QUADRUPLE THREAT) 
Descriptive Title: 
RRx-001 for Sensitization/Resensitization to Platinum Based Chemotherapy in Gynecologic, 
Thoracic, and Extrathoracic Malignancies in Patients Who Previously Received and 
Eventually Progressed on or after a Platinum Doublet Regimen 
Phase: 
Phase 2 Study 
Methodology: 
The study is designed to explore the potential of the epigenetic and tumor associated 
macrophage (TAM)-targeting agent RRx-001 to sensitize patients who previously received 
and now have progressed on a platinum based doublet regimen. This is an open label study 
for administration of RRx-001 with autologous blood.  
Small cell carcinoma and ovarian cohort patients will be randomized to 1 of 2 treatment arms, 
respectively.  Neuroendocrine and NSCLC patients will be enrolled to single arms, 
respectively, as stated below.  
SCC cohort patients (enrolled as of Amendment 10) will be randomized (2:1) to 1 of 2 
treatment arms:  
Arm 1): RRx-001 weekly for 3 weeks followed by up to 4 cycles of platinum plus 
etoposide chemotherapy ‘rechallenge’ and then RRx-001 & platinum maintenance (for 
patients with stable disease (SD) or better at discontinuation of platinum rechallenge) 
Arm 2): Standard of Care Investigator’s Choice Control Arm, treatment options of one 
of the following: platinum plus etoposide, irinotecan or vinorelbine until progression or 
intolerable toxicity  
Ovarian cohort patients (enrolled as of Amendment 10) will be randomized (2:1) to 1 of 2 
treatment arms: 
Arm 1): RRx-001 weekly for 2 weeks followed by 2 cycles of carboplatin ‘rechallenge’ 
and then ‘maintenance’, cycling between 1 dose of RRx-001 followed by 2 cycles of 
carboplatin, which repeats until progression or intolerable toxicity 
Arm 2): Standard of Care Investigator’s Choice Control Arm, treatment options of one 
of the following: carboplatin, etoposide, doxil, gemcitabine, vinorelbine or taxane 
treatments until progression or intolerable toxicity 
Neuroendocrine cohort patients: Will receive RRx-001 weekly until progression followed 
by up to 6 cycles of platinum doublet chemotherapy. 
 Maintenance RRx-001 is given for patients with stable disease or better at 
discontinuation of platinum and administered weekly (QW) until progression.  
NSCLC cohort patients: Will receive RRx-001 weekly for 3 weeks followed by up to 6 
cycles of platinum doublet chemotherapy. 
 Maintenance RRx-001 is given for patients with stable disease or better at 
discontinuation of platinum and administered weekly (QW) until progression.  
 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 14 of 99 
Objectives: 
Primary Objective 
To evaluate Overall Survival (OS) and Overall Response Rate (ORR).  
Secondary Objectives 
• To estimate the transition probability between disease progression and disease 
amelioration attributable to resensitization   
• To estimate the mean sojourn time in a platinum sensitized state 
• To evaluate disease control rate (DCR) and PFS by RECIST v1.1 criteria in adult 
patients with advanced or metastatic SCC, NSCLC, EOC or HGNEC after re-treatment 
with platinum-based therapy following exposure to RRx-001 
• To evaluate the toxicity of RRx-001 monotherapy 
• To evaluate the toxicity of platinum-based therapy following prior exposure to these 
agents and treatment with RRx-001 monotherapy 
Exploratory Objectives 
• To investigate:  
o Circulating Tumor Cells 
o Circulating Endothelial Cells (CEP and CEC) 
o Immune Subsets 
o Epigenetic markers e.g., Protein Hyperacetylation and gene methylation 
o Status of tumor suppressors such as p53, pre and post RRx-001 
o Expression of TGF-beta and its receptor and fibrosis status pre and post dose of 
RRx-001. 
o Relative density of tumor associated macrophages in patient biopsies 
o Status of microRNAs (miRNAs) pre and post RRx-001.  
o To evaluate changes in a panel of tumor biomarkers. (i.e., CA-125 for ovarian cancer 
and chromogranin A and neuron specific enolase (NSE) for neuroendocrine tumors) 
o To evaluate the overall response rate (ORR), disease control rate (DCR) and PFS by 
immune response criteria in adult patients with advanced or metastatic SCC, NSCLC, 
EOC or HGNEC during RRx-001 treatment period 
Number of 
Patients: 
Approximately 135 (original study target), approximately 213 total (updated as of 
Amendment 10) 
Amendment 10 enrolled subjects added:  
Small Cell Carcinoma: 2:1 randomization, 26 ARM 1, 13 ARM 2; 39 additional 
Ovarian: 2:1 randomization, 26 for ARM 1, 13 for ARM 2; 39 additional patients 
Total Study Enrollment Target with Amendment 10 expansion: 135 + 78 = 213 
(approximately) 
Patient 
Population: 
Inclusion Criteria 
1. Patients must have histologically or cytologically confirmed advanced or metastatic: 
A. Resistant/Refractory Small Cell Carcinoma (SCC) patients in 3rd line or beyond that 
have previously received platinum or patients in 2nd line with platinum-refractory or 
platinum-resistant disease 
B. EGFR mutated non-small cell lung cancer (NSCLC) that has previously received a 
first line platinum doublet and all applicable EGFR TKIs 
C. Epithelial Ovarian Cancer (EOC), fallopian tube or primary peritoneal cancer and 
Malignant Mixed Mullerian Tumor (MMMT) of the ovary or uterus. Excludes other 
non-epithelial ovarian tumors and ovarian tumors with low malignant potential. 
Patients must have previously received a platinum based regimen for 
advanced/metastatic disease or have platinum resistant or refractory disease defined 
as relapse within 6 months. EOC – specific criteria: Patients who progress or have 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 15 of 99 
stable disease during first-line treatment or who relapse within 1 month are 
considered to be 'platinum-refractory'. Patients who respond to primary treatment 
and relapse within 6 months are considered 'platinum-resistant', and patients who 
relapse more than 6 months after completion of initial therapy are characterized as 
'platinum-sensitive'. Patients who relapse 6-12 months following the end of their 
initial regimen are classified as 'partially sensitive’. 
D. High-Grade Neuroendocrine Carcinoma (HGNEC), any organ of origin, including a 
pathology of neuroendocrine features, in patients previously been treated with 
chemotherapy  
i. Although neuroendocrine tumors may be classified differently based on organ of 
origin, in the context of this protocol they are defined as high grade on the basis 
of either 
1. Aggressive clinical behavior requiring previous treatment with chemotherapy 
even if histologic features such as the Ki67 index or mitotic rate corresponds 
with low or intermediate grade. 
2. Histologic features: 
a. Neuroendocrine tumors of lung origin are considered high grade if in any 
part of the tumors, there are >10 mitoses/2mm2 or 10 high power field 
(HPF). Large zones of necrosis are usually present. This includes small 
cell lung carcinoma and large cell neuroendocrine lung carcinoma. 
[SCLC will not enroll in the HGNEC cohort.] 
b. Neuroendocrine tumors of gastroenteropancreatic origin are considered 
high grade if in any part of the tumors there are either >20 mitoses/2mm2 
or 10 high power field (HPF) OR Ki67. 
2. Radiographically measurable disease by RECIST v1.1  
3. A washout period of 3-weeks from last treatment (prior to Day 1 of study).  
4. Patients must have previously received a platinum based regimen for 
advanced/metastatic disease and progressed or have platinum resistant or refractory 
disease defined as relapse within 6 months.  
5. Age ≥18 years. 
6. Life expectancy of ≥12 weeks. 
7. ECOG performance status 0-2. 
8. Participants must have adequate organ and marrow function as defined below both prior 
to administration of RRx-001 and prior to administration of platinum based regimen: 
A. Absolute neutrophil count ≥1,500/mcL 
B. Platelets ≥100,000/mcL (non-transfused platelet count) 
C. Hemoglobin ≥9 g/dL (transfused Hgb allowed) 
D. Creatinine ≤1.5 x the upper limit of normal 
E. Total bilirubin ≤2.0 x the upper limit of normal or <3.0 xULN if patient has a 
history of Gilbert’s syndrome  
F. AST (SGOT)/ALT (SGPT) ≤5 X institutional upper limit of normal if with liver 
metastases; ≤2.5 X ULN if no liver metastases 
9. Patient must consent to the access, review and analysis of previous medical and cancer 
history, including tumor archival tissue (if available) and imaging data by the sponsor or 
a third party nominated by the sponsor. 
10. Ability to understand and sign a written informed consent document. 
11. Women of child-bearing potential and men with partners of child-bearing potential must 
agree to use adequate contraception (hormonal or barrier method of birth control; 
abstinence) prior to study entry, for the duration of study participation, and for 90 days 
following completion of therapy.   
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 16 of 99 
Note: A woman of child-bearing potential is any female (regardless of sexual 
orientation, having undergone a tubal ligation, or remaining celibate by choice) who 
meets the following criteria: 
• Has not undergone a hysterectomy or bilateral oophorectomy; or 
• Has not been postmenopausal for at least 12 consecutive months 
Exclusion Criteria 
1. Receiving concurrent investigational therapy 
2. Symptomatic central nervous system metastasis (e.g., patients requiring increasing doses 
of steroids) 
3. History of needing to permanently discontinue prior platinum doublet-based regimen for 
toxicity (e.g., cisplatin causing renal impairment, ototoxicity, or severe neuropathy).   
4. Known severe hypersensitivity to the platinum agent (i.e., carboplatin or cisplatin) or 
prior partner of platinum agent (i.e., etoposide for SCC and HGNEC; nab-paclitaxel, 
paclitaxel, or pemetrexed for NSCLC; paclitaxel, pegylated liposomal doxorubicin, 
docetaxel or gemcitabine for ovarian) planned for the platinum therapy period. If the 
patient has had prior hypersensitivity reaction to the drug partner of platinum, a patient 
may enroll as long as it is acceptable to treat with platinum and one of the alternative 
chemotherapy partner agents. 
5. Any significant medical diseases or conditions, as assessed by the investigators and 
sponsor that would substantially increase the medical risks of participating in this study 
(i.e., uncontrolled diabetes, NYHA II-IV congestive heart failure, myocardial infarction 
within 6 months of study, severe chronic pulmonary disease or active uncontrolled 
infection, uncontrolled or clinically relevant pulmonary edema). 
6. Pregnant or nursing 
Statistical 
Analysis: 
Primary Efficacy Endpoints: 
OS is defined as the time from enrollment to date of death, and its analysis will be similar to 
PFS in an intent-to-treat (ITT) population.  
The Kaplan-Meier estimate of the active cohort survival curve, its median survival times 
(with 95% confidence CI) will be derived.  A hazard ratio will be estimated using the 
historical control (as a reference). The hazard ratio (HR) and its 95% CI will be calculated. 
Overall response rate (ORR) of re-introduced platinum therapy, which will be calculated as 
confirmed response (CR + PR).  
The treatment effect on ORR will be quantified using the odds ratio.  Clopper-Pearson 2-
sided 95% confidence limits will be calculated. ORR analyses will be performed for the 
Efficacy Evaluable population.  Patients who do not have measurable disease at baseline will 
be excluded from the population.  
Secondary Efficacy Endpoints: 
The transition probability between disease progression and disease amelioration attributable 
to sensitization/resensitization will be estimated. A semi-Markov chain model will be used to 
capture the transition probability matrix between disease progression states. The average time 
each patient spends in a given disease state will be estimated (mean sojourn time) and its 95% 
confidence interval derived. The expected time spent healthy (or diseased) before death will 
also be estimated. 
The analysis of PFS will be similar to OS. Patients will be followed until their date of death, 
loss to follow-up, withdrawal of consent for further follow-up for survival, or final database 
closure.  Patients who are lost-to-follow-up or are not known to have disease progression at 
the time of data-cut-off for analysis will be censored at last date shown to be alive. Patients 
who do not have any follow up since enrollment will be censored at the date of enrollment. 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 17 of 99 
Rate of Grade 3 and Grade 4 non-hematologic toxicities for reintroduced platinum based 
chemotherapy. Disease control rate (DCR) defined as the sum of complete responses (CR) + 
partial responses (PR) + stable disease (SD) between topotecan and reintroduced platinum 
therapy, the rate of Grades 3 and 4 non-hematologic toxicities between topotecan and 
reintroduced platinum based chemotherapy will be analyzed in a manner similar to ORR. 
Safety Variables: Safety data will include adverse events (AEs), serious adverse events 
(SAEs), ECOG performance status, clinical laboratory tests, vital signs and physical 
examination results.  Safety summaries will be based on the Safety Population, and presented 
by treatment group using summary tables and listings. Adverse events will be coded by 
system organ class (SOC) and preferred term using MedDRA (Version 18.1), and severity 
will be based on NCI CTCAE Grade criterion (Version 5.0).   
A Treatment Emergent Adverse Event (TEAE) is defined as an AE that was not present prior 
to treatment with study drug, but appeared following treatment or was present at treatment 
initiation, but worsened during treatment.  Incidence of TEAEs by MedDRA SOC, preferred 
term and relationship (Related/Not Related) to study drug will be summarized based on the 
safety population.  Adverse event incidence rates will be summarized using frequency and 
percentage.  Adverse event data will be descriptively evaluated by treatment disease cohort 
and for overall patients.  
Amendment 10 Statistical updates:  
General design considerations, effective as of Amendment 10:  
1. Small Cell Carcinoma: Newly enrolled patients (post Amendment 10) will be allocated 
to one of two treatment arms using a 2-to-1 randomization ratio,(approximately 26 to 
Arm 1 and 13 to Arm 2). 
The two treatment arms are as follows:  
Arm 1: RRx-001 weekly for 3 weeks followed by up to 4 cycles of platinum plus 
etoposide chemotherapy ‘rechallenge’ and then RRx-001 & platinum maintenance (for 
patients with stable disease (SD) or better at discontinuation of platinum rechallenge) 
Arm 2: Standard of Care Investigator’s Choice Control Arm, treatment options of 
platinum plus etoposide, irinotecan or vinorelbine until progression or intolerable 
toxicity 
2. Ovarian: Newly enrolled patients (post Amendment 10) will be allocated to one of two 
treatment arms using a 2-to-1 randomization ratio (approximately 26 to Arm 1 and 13 
to Arm 2). 
The two treatment arms are as follows: 
Arm 1: RRx-001 weekly for 2 weeks followed by 2 cycles of carboplatin 
‘rechallenge’ and then ‘maintenance’, cycling between 1 dose of RRx-001 followed by 
2 cycles of carboplatin, which repeats until progression or intolerable toxicity 
Arm 2: Standard of Care Investigator’s Choice Control Arm, treatment options of one 
of the following: carboplatin, etoposide, doxil, gemcitabine, vinorelbine or taxane 
treatments until progression or intolerable toxicity 
3. Neuroendocrine: The only modification with Amendment 09 forward to the existing 
treatment schedule is the addition of a RRx-001 maintenance for patients with > SD  
following discontinuation of platinum based chemotherapy (for up to 6 cycles).  
4. NSCLC: Patients enrolled post amendment 09 will receive 3 consecutive doses of 
RRx-001, after which, RRx-001 is discontinued and platinum based chemotherapy is 
started for up to 6 cycles. In addition, a RRx-001 maintenance for patients with > SD 
following discontinuation of platinum based chemotherapy (for up to 6 cycles) was 
added.  
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 18 of 99 
Sample size determination and power considerations: 
The extension stage of the study will approximately enroll 39 patients to the small cell 
carcinoma cohort and also 39 patients to the ovarian cohort. In each cohort, a 2-to-1 
randomization allocation ratio will be employed (approximately 26 in Arm 1 and 13 in Arm 
2, in each cohort). The proposed sample size modification is motivated by recent clinical 
observations arising from current study data results. This upward sample size adjustment 
should provide sufficient precision to derive estimates of responses and time-to-event 
endpoints. Inferential statistics are not the main focus of this newly proposed focus study 
extension. 
Analysis of Activity Data: 
Descriptive statistics arranged by treatment group (within each of the four cohorts) are 
planned. Graphical depiction of the statistical summaries (ORR, DCR, OS, PFS) will 
accompany the tabular formatted data results for a more complete presentation of the 
statistical findings. Specifically, Kaplan-Meier curves and estimation of time-to-event 
medians with their corresponding 95% confidence intervals will be produced. ORR and DCR 
responses will be derived and the Clopper-Pearson method will be used to derive the 
responses 95% confidence intervals. 
Standard safety data will include adverse events (AEs), serious adverse events (SAEs), ECOG 
performance scale, clinical laboratory tests, vital signs and physical examination results. 
Safety summaries will use the safety population and will be presented separately by treatment 
group (within cohort) and across all cohorts aggregated. All safety data will be presented in 
data listings.  
AEs will be coded by system organ class (SOC) and preferred term using MedDRA, version 
14.1; severity will be based on NCI CTCAE Grade (version 5.0). Incidence of TEAEs by 
MedDRA SOC, preferred term and relationship (Related/Not Related) to study drug will be 
summarized based on the safety population. Adverse event incidence rates will be 
summarized using frequency and percentage. Adverse event data will be descriptively 
evaluated by treatment arm and for overall patients. 
Study Product(s), 
Dose, Route, 
Regimen: 
RRx-001 Drug Product is supplied as a sterile solution in PEG-400. Prior to administration, 
Diluent for RRx-001, DMA, will be added to RRx-001 Drug Product to yield a solution 
containing 66% PEG-400 and 33% DMA. This solution will then be diluted to 2.0 mg/mL 
with Water for Injection (WFI).  
The dose in this trial will be 4 mg, based on ongoing evidence of activity. The dose of 4 mg 
translates to 2 mL, which will be mixed with an aliquot of autologous blood and 
anticoagulant and re-infused into the patient once a week over an expected time period of less 
than an hour. The procedure is described in detail in the latest version of the ‘Blood 
Administration Best Practices & Guidelines for IV Infusion of RRx-001 + Blood Mix’ guide. 
All doses of RRx-001 will be administered on an open-label basis.   
Following treatment with RRx-001, one of the regimens referenced in the methodology 
section will be administered. 
Duration of 
administration: 
In the absence of treatment delays due to adverse events, RRx-001 treatment may continue as 
outlined in the assigned cohort schema or until disease progression, unacceptable toxicity or 
physician discretion.  Per the standard of care, the platinum based therapy will be given for 
two cycles of therapy and, if tumor assessments show stable disease or a partial response, an 
additional two cycles of chemotherapy will be given.   
 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 19 of 99 
3 BACKGROUND AND RATIONALE 
3.1 Background 
Lung cancer is the leading cause of death among men and women in North America (Jemal, 
2009).  An estimated 172,016 subjects have been diagnosed with non small cell lung cancer 
(NSCLC) in 2009 (Jemal, 2009).  Of these subjects more than 55% will present with advanced 
stage disease (stage IV or stage IIIB) that is not amenable to curative treatment. Of the remaining 
45% that are treated with curative intent only 20% of these will undergo surgery while the 
remaining will be treated with definitive chemoradiation.  More than half of these subjects will 
relapse and eventually succumb to their disease.   
1. EGFR+ NSCLC: For EGFR-mutation-positive NSCLC patients who progress on tyrosine 
kinase inhibitors (TKIs), the most common cause (in 60% of patients) is a second site exon 
20 EGFR mutation in the kinase domain of EGFR called T790M (the “gatekeeper” 
mutation), which prevents drug from binding to the receptor. Several mutant-selective TKIs, 
including rocelitinib and osimertinib, inhibit both activating mutations as well as the T790M 
gatekeeper resistance mutation, but do not target wild type (WT) EGFR. Preliminary clinical 
results from these agents indicate high response rates with long duration in T790M+ cases of 
acquired resistance. By contrast, the optimal treatment for patients with T790M negative 
resistance to EGFR TKIs remains unclear. Histologic and molecular investigations of tumor 
tissue obtained at progression have revealed multiple mechanisms of resistance. These 
include transformation to a small cell histology or epithelial-to-mesenchymal transformation; 
amplification of other receptor tyrosine kinases including MET, HER2 and WT EGFR; and 
point mutations in downstream genes including PIK3CA and BRAF. Thus, NSCLC patients 
who have failed treatment with TKIs and whose tumors do not express the T790M mutation 
represent a group with fatal disease and unmet need. (Yu, 2013) 
The current chemotherapy standard for subjects with advanced NSCLC is one of a number of 
platinum-based doublets; however, in the United States the most commonly used 
combination is solvent-based paclitaxel (sb-paclitaxel) plus carboplatin.  The 130-nm 
albumin-bound formulation of paclitaxel (nab-paclitaxel [Abraxane]), which may reach the 
tumor microenvironment more efficiently than sb-paclitaxel, is indicated for the first-line 
treatment of locally advanced or metastatic non-small cell lung cancer, in combination with 
carboplatin, in subjects who are not candidates for curative surgery or radiation therapy 
(Desai, 2006). The median survival of all subjects with advanced NSCLC is 10-12 months 
(Carbone, 1995). The fraction of subjects who are alive one year after diagnosis has only 
increased slightly over the past decade (Carbone, 1995). Treating subjects with more than 
4 cycles of the same chemotherapy, or adding a third chemotherapy agent to the platinum-
based doublet has not improved overall survival (Carbone, 1995). Non-platinum-based 
regimens have been evaluated in several Phase II and Phase III clinical trials, showing 
similar survival rates to platinum based treatments (Rodriguez, 2000; Douillard, 2001; 
Kosmidis, 2002; Georgoulias, 2001, Alberola, 2003; Gridelli, 2003).  The EORTC-08975 
(Smit, 2003) randomized 483 subjects to three arms -- two cisplatin based regimens and one 
non-cisplatin based (paclitaxel/gemcitabine).  The response rates were similar (27.7% to 
36.6%) as was the median survival (between 6.7 months to 8.9 months), but progression free 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 20 of 99 
survival was inferior in the non-platinum based regimen.  Other studies have reported 
somewhat worse results with non-platinum combinations, therefore platinum is still 
considered a preferred agent for combination chemotherapy in fit subjects with advanced 
NSCLC. 
Second line treatment for recurrent or progressive disease includes treatment with the 
chemotherapy agents docetaxel and pemetrexed, or treatment with an oral EGFR antagonist, 
erlotinib.  Docetaxel was approved for second line treatment in 2000 after a randomized trial 
demonstrated that docetaxel at 75 mg/m2 given every 3 weeks offered a clinically meaningful 
benefit to subjects with advanced NSCLC whose disease had relapsed or progressed after 
platinum-based chemotherapy with a response rate of approximately 7% (Fossella, 2000).  
Pemetrexed was approved for second line treatment based on a non-inferiority study as 
compared to docetaxel.  Treatment with pemetrexed resulted in clinically equivalent efficacy 
outcomes, but with significantly fewer side effects compared with docetaxel in the second-
line treatment of subjects with advanced NSCLC (Hanna, 2004).  With these findings 
pemetrexed has now become increasingly used in the second line setting, and recent clinical 
trials have extended its use in first line setting for the treatment of subjects with non-
squamous cell carcinoma NSCLC (Scagliotti, 2008).  A Phase III trial compared 
pemetrexed/cisplatin to gemcitabine/cisplatin.  This trial has demonstrated an improvement 
in overall survival over the combination cisplatin/gemcitabine in subjects with 
adenocarcinoma NSCLC (12.6 vs. 10.9 months) and in large cell NSCLC (10.4 vs. 6.7 
months) (Scagliotti, 2008).   
The decision to use pemetrexed depends on the histology of NSCLC. A recent review of two 
large pemetrexed based trials have concluded that although pemetrexed is well tolerated in 
squamous cell histology subjects, pemetrexed based regimens result in a shorter overall 
survival than non-pemetrexed based regimens in treatment of recurrent squamous cell 
NSCLC (Scagliotti, 2009).  With pemetrexed being used with increased frequency in the 
first-line setting for adenocarcinoma and limiting the use of pemetrexed to non-squamous 
cell histology, the need to develop improved second line agents has become increasingly 
important.  Currently, subjects with advanced NSCLC who have progressed after 2nd-line 
treatment have limited options.  Nivolumab has recently received FDA approval for use in 
the 2nd line setting for subjects with metastatic squamous cell carcinoma who have 
progressed on or after platinum-based chemotherapy based on the results of a Phase II trial, 
and data from the Phase III CheckMate-017 trial.    
Retrospective analysis using chemotherapy for 3rd line treatment show response rates of only 
2% and median survival of 4 months (Massarelli, 2003).   
Oral agents gefitinib and erlotinib are small molecule inhibitors of the EGFR tyrosine kinase 
activity, which have demonstrated clinical benefit after failure of first line chemotherapy 
(Fukuoka, 2003; Perez-Soler, 2004).  Erlotinib was approved in 2004 for the treatment of 
subjects with locally advanced or metastatic NSCLC after the failure of one or two prior 
chemotherapy regimens with a single agent response rate of 8.3 % and a median overall 
survival of 6.3 months (Shepherd, 2005).   To date it remains the only approved third line 
therapy for NSCLC.    
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 21 of 99 
2. SCLC: In contrast to the ferment and rapidly changing status of NSCLC, in which significant 
inroads have been made with targeted agents, the small cell lung cancer landscape has 
remained, like its name, disappointingly small and static.  Small cell lung cancer (SCLC) 
accounts for about 13% (Govindan, 2006) of all lung cancers and is strongly correlated with 
a history of smoking. It is an aggressive subtype of lung cancer associated with rapid growth, 
early spread to distant sites, and distinct paraneoplastic syndromes (Kazarian, 2011), 
including hypercalcemia, Eaton-Lambert syndrome, and syndrome of inappropriate diuretic 
hormone, that is treated with chemotherapy alone in the metastatic setting. The most 
commonly used classification is the Veterans Administration Lung Study Group (VALG) 
staging system, in which the disease is subdivided into limited stage (LS) and extensive stage 
(ES) (Allen, 2008; Dowell, 2010; Drivsholm, 1999). Without treatment extensive stage small 
cell lung cancer (ES-SCLC), representing approximately two-thirds of all cases (LS-SCLC 
comprises the other one-third), is rapidly and invariably fatal within two to four months 
(Pelayo, 2009). With combination chemotherapy, the cornerstone of management (DeVore, 
1996) in subjects without localized symptoms (i.e. superior vena cava syndrome, lobar 
obstruction, or painful bone metastases), responses are dramatic but sadly short-lived: SCLC 
inevitably relapses (Hann, 2009) and relapse is associated with a median OS often <6 months 
(Davies, 2004), a survival rate which has scarcely improved over the last 40 years (Shepherd, 
2007).  
The current standard of first-line care for ES-SCLC is platinum based with a combination of 
cisplatin and etoposide (or cisplatin-irinotecan or cisplatin-topotecan) with or without 
concurrent radiation therapy, followed in general by topotecan, the sole agent with FDA 
approval specifically for the second line setting in platinum-sensitive disease and relapsed 
disease at least 45 days from the end of first-line chemotherapy. (Chan, 2013). A standard 
third line treatment is lacking although single agent paclitaxel, irinotecan, gemcitabine and 
vinorelbine are commonly tried in subjects with acceptable performance status. With relapse 
the prognosis is poor, with about a 20% to 30% response, and a median survival of weeks to 
months (Allen, 2008; Dowell, 2010; Drivsholm, 1999).  
In the case of resistant or refractory relapse classified as a progression free survival of greater 
<3 months or progression during treatment, rechallenge is not warranted whereas it is 
warranted with sensitive relapse classified as a progression free survival of greater >3 months 
(Ardizzoni, 2014) on the basis of a meta analysis by Garassino et al in which 30% of subjects 
experienced clinical benefit (i.e. stable disease + partial response) with rechallenge 
chemotherapy (Garassino, 2011).   
The ability to improve on these clinical benefit rates with an agent like RRx-001 that may 
predispose to successful platinum rechallenge represents a breakout opportunity to change 
the rules of the ‘game’ from a treatment paradigm of ‘one (or hopefully more) and done’ to 
‘if at first you succeed try and try again’ thereby permanently altering a therapeutic landscape 
that for the last four decades has remained largely stagnant.  
3. HGNEC: Unlike lung cancer, which is the second most common tumor type and the leading 
cause of cancer-related deaths among both men and women in the world (Abbasi, 2011), 
extrapulmonary high-grade neuroendocrine carcinomas (HGNECs) (Shia, 2008) are rare, 
aggressive tumors, with a poor prognosis, biologically similar to small cell lung cancer, that 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 22 of 99 
most commonly develop in the gastrointestinal (GI) and the genitourinary (GU) tracts 
(Strosberg, 2010). Since cisplatin-based regimens, especially the cisplatin and etoposide 
regimen, are the most studied and widely used in metastatic small-cell lung cancer, they have 
also been investigated in metastatic NECAs of the GI tract. The first such study by Moertel et 
al reported a response rate of 67% with response duration of 8 months and a median survival 
of 19 months (Moertel, 1991). 
A subsequent study reported a response rate of 42% with response duration of 9 months and 
a median survival of 15 months (Mitry, 1999). 
On the basis of these clinical trials, the combination of cisplatin and etoposide is 
recommended as standard first-line therapy; carboplatin and irinotecan are offered as 
substitutes for cisplatin and etoposide, respectively.  However, the optimal duration of 
chemotherapy is unknown and unclear, as is the question of whether to continue treatment 
beyond 4 cycles. While there is no data for a standard regimen in second line, retreatment 
with platinum and etoposide is an option especially if an initial response was seen and 
relapse occurred more than three months afterwards. 
4. Gynecologic Cancers: Epithelial ovarian cancer or EOC (70% of all ovarian cancers with 
stromal and germ cell tumors comprising the rest) is the fifth most lethal gynecologic 
malignancy and the leading cause of cancer deaths in women in industrialized countries 
(Jemal, 2005). Since early ovarian cancer causes minimal to no symptoms, 75% of subjects 
present with advanced disease (stage III – IV), where the five-year survival rate falls below 
25% (Rien, 2011). Malignant Mixed Mullerian Tumor (MMMT) of the ovary or uterus are 
dedifferentiated (metaplastic) epithelial tumors comprised of carcinomatous and sarcomatous 
elements arising from a single malignant clone. MMMT is also referred to as 
Carcinosarcoma and accounts for between 2 to 7.5 percent of ovarian carcinomas but is 
perhaps the most lethal of all subtypes (Seidman, 2003). These tumors tend to present in 
more advanced stages and are often large, necrotic and/or hemorrhagic. MMMT generally 
progresses rapidly and responds briefly to platinum-based chemotherapy, which portends a 
poor prognosis (Silasi, 2008), (Mano, 2007). Uterine MMMTs are generally excluded from 
endometrial clinical trials because of the belief that they are of dedifferentiated epithelial 
origin with a much more aggressive, sarcoma-like clinical behavior (Vaidya, 2006).  For this 
reason, we are including them in this cohort with their more closely related ovarian MMMT 
cousins.  
Standard initial treatment involves tumor debulking and platinum-based chemotherapy with a 
taxane derivative to which the response is high (approximately 70%), however, 60–80% will 
relapse under two years with a platinum-resistant metastatic disease that is uniformly fatal 
(Gubbels, 2010). The Gynecologic Oncology Group (GOG) adopted the definition of 
sensitivity to chemotherapy (or sensitivity to platinum) in EOC based on the interval between 
the last dose of platinum and the development of resistance (Harter 2006) (Figure 1). 
In general, progression or stable disease during first-line treatment or relapse within 1 month 
is characterized as 'platinum-refractory'. Subjects who respond to primary treatment and 
relapse within 6 months are considered 'platinum-resistant', and subjects who relapse more 
than 6 months after completion of initial therapy are characterized as 'platinum-sensitive'. 
The longer the platinum free interval (PFI) the better the chances for benefit with platinum 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 23 of 99 
re-challenge. This is especially the case for PFI longer than 12 months. Subjects that relapse 
6-12 months after the end of their initial regimen, and who are usually classified as so-called 
'partially sensitive', tend to be less responsive (Pisano, 2009). 
Figure 1: 
Platinum resistance definition by Gynecologic Oncology Group (GOG) 
Platinum sensitivity is classified as resistant, partially sensitive, or sensitive, according to the 
time elapsed since finishing first-line treatment. Probability of re-treatment response is shown. 
 
 
In the setting of platinum resistant disease, a poor prognosis population with an OS <12 months, 
no universal standard for treatment exists; single agent therapy with paclitaxel, topotecan, 
pegylated liposomal doxorubicin (PLD) and gemcitabine is generally recommended in second 
line based on some evidence of activity in Phase III trials, with overall response rates <15% and 
a median PFS of 3–4 months. (Gordon, 2004; Markman, 2006) In contrast with platin-sensitive 
recurrences, combination chemotherapy has been shown to increase toxicity without benefit 
(Ledermann, 2013). The possible exception is bevacizumab, which in the 2012 AURELIA trial, 
significantly improved the PFS in combination with an investigator’s choice of pegylated 
liposomal doxorubicin, weekly paclitaxel, or topotecan but not the overall survival. (Pujade-
Lauraine, 2014). 
RRx-001 is a small molecule administered by i.v. that selectively and with great affinity binds to 
hemoglobin and free sulfhydryl groups such as reduced glutathione present in red blood cells. 
RRx-001 modified, oxidatively stressed red blood cells exhibit conformational and biochemical 
alterations under hypoxia, which collectively may lead to adhesion to the tumor vascular 
endothelium, entrapment in the microvasculature, and engulfment by tumor associated 
macrophages (TAMs), which undergo M2 to M1 polarization. Preclinical and Phase 1 data 
suggests that RRx-001 altered DNA methylation of genes and cancer pathways restores 
sensitivity to previously failed therapies resulting in a prolonged overall survival. On this basis, 
reintroduction of platinum doublet-based therapies is mandated on progression. In addition, 
immunohistochemistry of tumor biopsies from subjects on the QUADRUPLE THREAT trial 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 24 of 99 
have revealed an influx of CD8 expressing tumor-infiltrating lymphocytes, confirming that RRx-
001 has immunotherapeutic properties (Brzezniak, 2016). 
Before co-infusion with blood, the primary adverse event related to RRx-001 was pain during 
infusion that manifested together with local venodilation (Reid, 2015), presumably due to the 
displacement of nitric oxide (NO) from its binding site on the beta Cys 93 residue on 
hemoglobin. This infusional pain that was subject to considerable inter-subject variability 
resolved within seconds to minutes after administration was stopped. In the same way that 
capsaicin evokes a sensation of burning without producing tissue damage, RRx-001, likely 
through the intermediary of nitric oxide, a well-known algetic stimulus on intravascular 
application in humans, activated nociceptors in the venous endothelium to produce pain.  
Subjects enrolled and treated on the QUADRUPLE THREAT study with RRx-001 blood mix 
has been well tolerated without any significant drug related toxicity reported.   
RRx-001 has demonstrated the capacity to reverse resistance to first and second line 
chemotherapy in selected subjects treated on the Phase I trial (Reid, 2014). Reintroduction of 
first-line platinum doublet-based therapies after treatment with RRx-001, therefore, potentially 
represents an important and highly desirable strategy to improve clinical outcomes and prolong 
survival by significantly impacting the natural histories of SCC, NSCLC, ovarian and HGNEC. 
3.2 RRx-001 as a Tumor-Associated Macrophage Targeting Agent with 
Tumor Sensitizing Properties 
RRx-001 (previously known as ABDNAZ) is a TAM-targeting agent with epigenetic and tumor-
sensitizing properties that has been investigated in a completed Phase I study at UCSD and Sarah 
Cannon Research Institute (SCRI) (Reid, 2015) and an ongoing randomized Phase 2 study vs. 
regorafenib in 3rd and 4th line colorectal cancer.  
3.3 Clinical Experience with RRx-001 
To date, RRx-001 has been studied in a single Phase 1 clinical trial (Protocol RRx001-11-01, 
Reid, 2015).  The study design was standard ‘3+3’ dose escalation cohorts based on a modified 
Fibonacci scheme.  The primary endpoint was safety and pharmacokinetics with the objective of 
defining a maximum tolerated dose (MTD) and the recommended Phase 2 dose (RP2D). 
RRx-001 was administered to subjects intravenously through a peripheral line on a weekly and 
twice-weekly schedule. 
The open-label, Phase I dose-escalating clinical trial in heavily pretreated subjects with 
refractory metastatic solid tumors investigated the safety and tolerability of RRx-001 when 
administered as monotherapy. Key inclusion criteria were histologically proven solid tumor for 
which no satisfactory therapy was available or had failed, adequate organ and hematologic 
function, ECOG performance status of ≤2 and life expectancy of at least 3 months. Key 
exclusion criteria included previous cancer therapy within 42 days of baseline visit. 26 subjects 
were enrolled and 25 subjects were treated. The treatment was continued until disease 
progression, intolerable toxicity, or subject withdrawal of consent.  
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 25 of 99 
RRx-001 was tolerated at all doses from 10-83 mg/m2 i.v. and a maximum tolerated dose was not 
reached. Twenty-five subjects received the study drug and are therefore considered evaluable for 
analysis of safety. All 25 subjects experienced at least one adverse event. Events considered 
definitely related to protocol therapy were reported in 23 of 25 subjects (92%). Inflammation 
and/or burning along the course of the injected vein were the most common AEs. Two events of 
Grade 3, infusion site pain and anxiety related to infusion site pain, were reasonably possible or 
definitely related to study drug in the opinion of the Investigator. Three subjects experienced 
adverse events or other problems leading to premature termination from the study and before an 
assessment of activity could be determined. Subject 001-002 withdrew consent due to infusion 
site reaction, 002-005 died on study due an SAE arising from a preexisting infection and 002-014 
withdrew due to an AE (bowel obstruction) that was considered to be unlikely related to RRx-
001 administration. In one subject, Grade 3 anxiety was observed associated with the localized 
pain on infusion. However, this event was not considered dose limiting, as it was transitory, and 
promptly disappeared after the infusion was discontinued. Other Grade 1 to Grade 2 related 
toxicities included infusion site tenderness, vein hardening, vein occlusion, skin discoloration 
over the site of injection, chest discomfort, cough, dyspnea and mouth tingling but the relative 
contributions of RRx-001 and malignant disease in the etiology of these toxicities is not known.  
No specific laboratory abnormalities were attributed RRx-001; any abnormalities appeared to be 
more indicative of the underlying systemic disease rather than RRx-001. No RRx-001 related 
adverse effects on the major physiological systems (cardiovascular, respiratory, hepatic, renal 
and central nervous systems) occurred in any subject. 
In contrast to standard IV administration, which is lengthy (up to 6 hours), time consuming and 
acutely painful, the RRx-001 blood mix is rapidly administered in under an hour and painless; 
hence the reason that all of the RRx-001 protocols have been converted to this method of 
administration.  
Solutions of RRx-001 for Injection were previously tested for hemolytic potential:  
Test formulations of 0 (vehicle), 0.5, 1.0, or 2.0 mg/mL RRx-001 were tested (1:1) with human 
whole blood and plasma. Hemolysis was evaluated by determining the amount of hemoglobin in 
the supernatant following incubation. Plasma compatibility was determined macroscopically. 
Formulations of 0.5, 1.0, and 2.0 mg/mL were prepared by mixing RRx-001 powder with the 
vehicle (3% DMA, 6% PEG 400 NF, and sterile WFI USP). Osmolality values were 618, 612, 
and 614 mOsm/kg for the 0.5, 1.0, and 2.0 mg/mL formulations, respectively, compared with the 
control value of 606 mOsm/kg. RRx-001 at concentrations of 0.5, 1.0, or 2.0 mg/mL or vehicle 
alone did not cause hemolysis or macroscopic changes in plasma.  
A time course following dilution of human whole blood (5 parts) to RRx-001 infusion solution 
(1 part) was followed over two hours. CBC parameters were collected at 1, 5, 15, 60 and 120 
min. At this dilution and over this time period, only mild changes in cell size were noted. No 
evidence of clotting or hemolysis was seen.   
In the Phase I study, antineoplastic activity was detected in several solid tumor types: non-small 
cell lung cancer, colorectal cancer, ovarian cancer, hepatocellular cancer, pancreatic cancer and 
head and neck cancer. One objective partial response was observed.  There was no obvious 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 26 of 99 
correlation between the antitumor activity and the dose level. After single agent therapy with 
RRx-001, four subjects became responsive to previously failed FOLFIRI, as shown by changes 
in CEA and by imaging. 
 
A further three subjects appeared to respond favorably to subsequent chemotherapy and radiation 
post RRx-001.  
3.3.1 Safety 
Twenty-five subjects were treated at 6 dose levels of 10 (n=6), 16.7 (n=3), 24.6 (n=3), 33 (n=4), 
55 (n=3), and 83 (n=6) mg/m2. RRx-001 was generally well tolerated. Adverse events were 
mostly Grades 1 and 2, with one Grade 3 infusion site pain and one Grade 3 anxiety. Pain at the 
site of injection was most common (84%), mostly Grades 1 and 2, and related to study drug 
(Table 1). RRx-001 was initially infused intravenously weekly over 20 minutes. With increasing 
doses of RRx-001, infusion site pain required increasing the infusion time up to 8 hours and 
splitting the total dose and administering RRx-001 twice-weekly at the highest dose of 
83 mg/m2.  No dose-limiting toxicities (Grade 3 infusion site pain was not considered a DLT) 
were observed in any cohort, and therefore the maximum tolerated dose was not reached. 
However, due to the infusion site pain that could be mitigated by slowing the infusion rate, 
83 mg/m2 was considered to be the maximum feasible dose when delivered over up to 8 hours.  
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 27 of 99 
Table 1: 
Treatment Emergent Adverse Events (TEAEs) Considered Related to Study 
Drug RRx-001 in Decreasing Order of Frequency 
TEAE 
Cohort 1 
(n=6) 
10 mg/m2 
Cohort 2 
(n=3) 
16.7 mg/m2 
Cohort 3 
(n=3) 
24.6 mg/m2 
Cohort 4 
(n=4) 
33 mg/m2 
Cohort 5 
(n=3) 
55 mg/m2 
Cohort 6 
(n=6) 
83 mg/m2 
Total 
(n=25) 
Infusion Site Pain 
4 
3 
1 
4* 
3 
6 
21 (84%) 
Arm Swelling/Edema 
 
1 
 
1 
2 
4 
8 (32%) 
Vein Hardening 
 
 
 
1 
1 
5 
7 (28%) 
Dyspnea/Wheezing§ 
1 
 
 
 
1 
3 
5 (20%) 
Mouth tingling/burning 
 
 
 
 
2 
2 
4 (16%) 
Anxiety 
 
 
 
 
2** 
1 
3 (12%) 
Chest Discomfort 
1 
1 
 
 
 
1 
3 (12%) 
Cough 
 
 
 
 
1 
2 
3 (12%) 
Fatigue 
 
 
 
1 
 
2 
3 (12%) 
Skin Discoloration 
 
 
 
1 
 
2 
3 (12%) 
Flushing¶ 
1 
 
 
 
 
1# 
2 (8%) 
Throat Discomfort 
 
 
 
 
 
2 
2 (8%) 
Vasodilation 
1 
 
 
1 
 
 
2 (8%) 
Vein Occlusion/DVT 
 
 
 
 
 
2 
2 (8%) 
Weakness 
 
 
 
 
2 
 
2 (8%) 
Abdominal pain upper 
1 
 
 
 
 
 
1 (4%) 
Bilateral hand 
numbness 
1# 
 
 
 
 
 
1 (4%) 
Blood Tinged Sputum 
 
 
 
 
 
1 
1 (4%) 
Decreased Respirations 
 
 
 
 
 
1 
1 (4%) 
Dizziness 
1 
 
 
 
 
 
1 (4%) 
Elevated Blood 
Pressure 
 
 
 
 
 
1 
1 (4%) 
Infusion reaction 
1 
 
 
 
 
 
1 (4%) 
Nasal discomfort 
1 
 
 
 
 
 
1 (4%) 
Runny Nose/Sinus 
Drainage 
 
 
 
 
1 
 
1 (4%) 
Site Tenderness 
 
 
 
1 
 
 
1 (4%) 
Throat irritation 
1 
 
 
 
 
 
1 (4%) 
Urinary Incontinence 
 
 
 
 
 
1 
1 (4%) 
Vasculitis 
 
 
1# 
 
 
 
1 (4%) 
Vision Changes 
 
 
 
1# 
 
 
1 (4%) 
Vomiting 
1# 
 
 
 
 
 
1 (4%) 
*1 subject had Grade 3 infusion site pain 
** 1 subject had Grade 3 anxiety 
# Outstanding queries 
§ Terms ‘Wheezing’, ‘Dyspnea’ and Dyspnea/Wheezing’ were combined 
¶ Terms ‘Flushing’ and ‘Intermittent Flushing’ were combined 
 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 28 of 99 
There were 12 serious adverse events (SAEs) reported in 10 subjects, all of which were 
considered unrelated to study drug.  The SAE terms were 1) seizures secondary to brain mets; 
2) hypercalcemia; 3) cerebral bleed; 4) increased somnolence; 5) atelectatic changes right lung 
base; 6) bilrubinemia; 7) klebsiella septicemia; 8), upper gastrointestinal bleed; 9) pleural 
effusion (two SAEs in the same subject); 10) bowel obstruction; and 11) dehydration. Overall, 
the types of serious AEs reported among this study population were consistent with the severity 
of illness and underlying disease. No ECG effects or clinically relevant RRx-001-related changes 
in vital signs or laboratory values were seen in the study.  
There were 4 deaths on study or within 30 days of last dose of study drug, all considered 
unrelated to RRx-001, and related to the subjects’ underlying malignancy. 
RRx-001 was administered through a peripheral vein. 84% of subjects across the 6 cohorts 
experienced a prominent and transient, dose-dependent forearm vasodilation and transient mild 
to moderate pain that was ameliorated with slowing of the infusion time, stopping and restarting 
the infusion at a slower rate, and concomitant administration of analgesics (short-acting opioids), 
benzodiazepines or anti-inflammatory medications such as corticosteroids as needed. 
In particular, premedication treatment with corticosteroids and ibuprofen at the day of dosing 
was found to be effective. Premedication with corticosteroids is required at every RRx-001 
administration when administering by direct IV infusion.   
Several subjects in the highest dose cohort (83 mg/m2), complained of moderately severe 
injection pain, that was inadequately addressed with adjunctive opioid analgesics and have 
received a reduced total dose or a split dosing schedule (twice-weekly). Overall, higher doses 
tend to result in a concomitant escalation in pain, which has become more severe in the later 
cohorts. At present, 83 mg/m2 is the maximum feasible dose using the current infusion rates. 
Most subjects recovered from the injection site pain and vasodilation within minutes of the 
infusion being stopped or slowed down and without sequelae; four subjects temporarily 
developed a non-tender, non-erythematous cord-like induration over the vein of injection, which 
resolved spontaneously within a few weeks. Duplex ultrasound was negative for venous 
thrombosis and in the absence of warmth, swelling, redness or tenderness, the diagnosis was 
more suggestive of focal venous dilation than superficial phlebitis.  Initially, RRx-001 was 
administered through a central IV line. However, based on complaints from one subject in the 
first cohort of an unpleasant nasopharyngeal burning sensation, which led to his (voluntary) 
discontinuation from the study, IV administration was moved to the antecubital or forearm area. 
In summary, other than localized venous dilation and pain on infusion, RRx-001 was very well 
tolerated.  The pain was dose related and resulted in attempts to slow the infusion and split the 
dose between two days within a week.  The maximum feasible dose appears to be 83 mg/m2 at 
the present time and under the present infusion conditions.  
3.3.2 Pharmacokinetics 
As part of the Phase I protocol, the pharmacokinetics of RRx-001 was investigated.  PK samples 
were taken at Day 1 and Day 50 within 15 min predose, 15 min after the start of the infusion, at 
the end of the infusion (0±1 min) then at 15±2 and 30±5 min after the end of infusion followed 
by 1, 2, 3, 4.5, 6 and 24 hours ±5 min post infusion. The 24 hour sample was taken for Day 1 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 29 of 99 
only. As part of change in cycle duration from 4 weeks to 2 weeks in Amendment 1.3, Day 50 
samples were redefined as Day 22 and the requirement for a 6 h sample on Day 22 was removed. 
Based on the available data, in Amendment 1.4, the Day 1 the 4.5 and 6 h as well as the Day 22 
samples were removed.  
The following parameters were calculated for each subject: Cmax, AUCinf, and half-life and is 
shown in Table 2. Half-life did not vary greatly across dose levels or between Day 1 and 
Day 22/50 samples and was found to be 0.46 h. The calculated average Cmax and AUCinf for 
both Day 1 and Day 22/50 for each cohort, was found to be dose dependent with the exception of 
the highest dose cohort. Figure 2 shows the plots of average AUCinf (left) and Cmax (right) for 
Day 1 and Day 22/50 against dose. These data suggest that analysis of RRx-001-GSH is 
indicative of exposure to RRx-001 for the range 10 to 55 mg/m2. However, the pharmacokinetics 
of RRx-001-GSH do not correlate well with the pharmacodynamics of RRx-001. Accordingly no 
justification for dosing decisions based upon PK information of the glutathione adduct can be 
made.  
Table 2: 
Pharmacokinetic Properties for RRx-001-GSH vs Dose. Values are shown ± SD 
Dose 
AvgCmax 
(D1) 
(ng/mL) 
AvgCmax 
(D22/50) 
(ng/mL) 
AvgAUCinf 
(D1) 
(ng*hr/mL) 
AvgAUCinf 
(D22/50) 
(ng*hr/mL) 
AvgHL 
(D1) 
(h) 
AvgHL 
(D22/50) 
(h) 
10 
136.46 ± 92 
62.7 ± 76 
88.0 ± 29 
63.2 ± 43 
0.38 ± 0.20 
0.37 ± 0.17 
16.7 
194.6 ± 86 
132.0 ± 28 
411.6 ± 180 
309.6 ± 81 
0.42 ± 0.16 
0.56 ± 0.26 
24.6 
173.0 ± 42 
127.2 ± 56 
455.1 ± 75 
378.5 ± 79 
0.47 ± 0.07 
0.51 ± 0.20 
33 
172.8 ± 124 
254.0 ± 281 
477.0 ± 292 
664.1 ± 522 
0.47 ± 0.22 
0.44 ± 0.17 
55 
408.0 ± 375 
315.3 ± 148 
1343.8 ± 779 
1063.1 ± 364 
0.42 ± 0.06 
0.42 ± 0.13 
83 
161.3 ± 73 
251.1 ± 170 
457.4 ± 192 
1217.5 ± 808 
0.60 ± 0.10 
0.45 ± 0.06 
Average 
 
 
 
 
0.46 
0.46 
Abbreviations: AvgCmax: Max. concentration, averaged over cohort; AvgAUCinf: Area under the plasma 
concentration-time curve from time zero to infinity, averaged over cohort; AvgHL: Half-life, averaged over cohort.  
 
 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 30 of 99 
Figure 2: 
Left: Plot of AvgAUCinf for Day 1 and Day 22/50 against dose. Right: Plot of 
AvgCmax for Day 1 and Day 22/50 against dose.  
 
 
An overview of relevant nonclinical information is presented below. 
3.3.3 Preclinical Studies of RRx-001 
RRx-001 is a de-energized analog of the explosive, TNAZ, the widely-used replacement for 
TNT, with a closed strained ring structural backbone called a dinitroazetidine, developed as an 
anticancer agent. 
Preclinical and clinical studies support the rationale for the clinical development of RRx-001 in 
the setting of metastatic refractory cancer both as monotherapy and in combination with standard 
cytotoxic chemotherapy. 
RRx-001 is a nitrogen oxide donor. In hamsters infused with RRx-001 through a central vein at a 
dose of 5 mg/kg vs. hamsters infused with saline as vehicle controls, significantly increased 
levels of exhaled nitric oxide in breath condensate were measured in the treated cohort during the 
infusion; these levels returned rapidly to baseline almost immediately after cessation of the 
infusion. 
With infusion into the antecubital veins, the nitric oxide dissipation effect during infusion is 
clearly visible as a network of dilated, palpable superficial veins that travel up the forearm 
proximally in the clinical trial subjects, confined to and persisting only for a distance of 8-10 
inches from the site of infusion. The discomfort of the infusion in the forearm varied greatly 
from subject to subject and did not appear to correspond to the amount of visible dilation. 
The anticancer mechanism of action is related to modification of the intracellular milieu of the 
red blood cell and repolarization of tumor associated macrophages. RRx-001 covalently binds to 
the beta Cysteine 93 residue on hemoglobin, which significantly upregulates the nitrite reductase 
activity of hemoglobin, catalyzing the conversion of the endogenous anion nitrite to nitric oxide 
under hypoxic conditions. This overproduction of NO under hypoxic conditions oxidizes the red 
blood cell, leading to the expression of phosphatidylserine (PS) and vascular cell adhesion 
molecules at the RBC surface. RBC adhesion to the tumor endothelial cells sequestrates the 
RBCs and occludes the tumor microvasculature. Macrophages, which engulf and degrade the 
adherent and PS-expressing RRx-001 RBCs, extravasate into the extravascular stroma 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 31 of 99 
(Figure 3), as demonstrated by the intracellular lipid accumulation and, consequently, foam cell 
formation or vacuolation seen on tumor biopsies (Figure 4). Engulfment of the RBCs induces 
TAM repolarization to antitumor M1 macrophages that secrete proinflammatory cytokines and 
produce free radicals (Figure 5). The secreted cytokines recruit more immune cells and the 
increased production of reactive oxygen and nitrogen species inhibit activity of the 
hypomethylating enzyme DNMT1 involved in epigenetic processes.  
Figure 3: 
Adhesion of RRx-001-Modified Red Blood Cells (Blue Arrows) to the Tumor 
Vasculature Leading to Vaso-Occlusion. The Orange Arrows Indicate 
Presence of the RBCs in the Tumor Parenchyma. 
 
 
Figure 4: 
Appearance of Vacuolation (Foamy Cell Changes) (Orange Arrows) Seen 
Over Time in Serial Biopsies of the Tumor an RRx-001-Treated Patient on 
QUADRUPLE THREAT 
 
 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 32 of 99 
Figure 5: 
In Vivo Experiment Demonstrating RRx-001-Induced Polarization of Tumor 
Associated Macrophages 
 
 
Figure 6: 
Three Step Macrophage-Mediated Anti-Tumor Mechanism of Action 
 
 
 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 33 of 99 
3.3.4 Preclinical Studies of RRx-001 (continued): Chemoprotection with Cisplatin 
The chemoprotective effect of RRx-001 was studied on cisplatin-induced nephro-, myelo- and 
genotoxicity in BALB/c mice. The mice were divided into three groups: (1) no treatment, 
(2) vehicle and cisplatin only, and (3) RRx-001 and cisplatin. RRx-001 treatment (5 mg/kg every 
other day for three days) was initiated 3 days prior to cisplatin administration. Renal dysfunction 
was evaluated biochemically by measuring the concentration of blood urea nitrogen (BUN) and 
serum creatinine. Genotoxicity was evaluated by metaphase spreads from whole bone marrow 
cells. Myelotoxicity was evaluated with measurement of serum hemoglobin, leukocyte and 
platelet concentrations.  
Cisplatin significantly elevated the levels of blood urea nitrogen, serum creatinine, and the 
kidney to body weight ratio, but pretreatment with RRx-001 significantly attenuated the 
cisplatin-induced nephrotoxicity. After administration of cisplatin, the frequency of 
chromosomal abnormalities distinctly increased. However, in mice pretreated with RRx-001, 
Consistent improvement in chromosome spreading with lower frequencies of broken metaphases 
was obtained in RRx-001-pretreated mice compared with mice injected with only cisplatin, as 
seen in the figure below. 
Figure 7: 
Preclinical Evidence of Chemoprotection.  RRx-001 Treated Mice Prior to 
Treatment with Cisplatin 
The red arrows mark gaps, breaks, or rearrangements in metaphase chromosomes. 
 
 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 34 of 99 
Figure 8: 
Hemoglobin Concentration, Platelets, and WBC Counts Significantly 
Reduced in Mice Pretreated with RRx-001 
 
 
The results suggest that RRx-001 has a protective effect against cisplatin-induced nephro-, 
myelo- and genotoxicity. 
3.4 Rationale 
Survival of SCC, NSCLC, resistant/refractory EOC/MMMT and HGNEC cancer subjects 
remains poor, and new effective and well-tolerated therapeutics for chemorefractory subjects are 
urgently needed. We propose a Phase 2 study of RRx-001 administered at a dose of 4 mg once 
weekly in SCC, NSCLC, EOC/MMMT and HGNEC subjects until progression followed by re-
administration of a platinum based regimen specific to the four tumor types outlined in the 
methodology section. To be eligible for this trial, subjects must have received platinum doublet 
therapy as standard therapy for advanced disease and now have progressive disease. 
This study design is based upon clinical experience of subjects who were treated with RRx-001 
monotherapy in the phase I setting, followed by the off-trial re-treatment with therapies that they 
may have previously failed. Two subjects, both with colorectal cancer (CRC), were noted to 
have responses both in tumor burden and CEA upon re-challenge with FOLFIRI, which they had 
each previously failed. The first subject had a 7-month duration of response. The second subject 
was restarted on FOLFIRI in 7/2013 and responded to this therapy (Reid, 2014). Two additional 
subjects, one with colorectal cancer (CRC) and one with lung cancer, both achieved prolonged 
stable responses after treatment with RRx-001 and re-challenge with a previously failed therapy: 
sorafenib and gemcitabine, respectively.  
Early data analysis in the QUADRUPLE THREAT trial demonstrated 8/13 (61%) of patients had 
been newly sensitized to platinum doublets, indicative of reversal of chemoresistance. Given the 
limited choices of subjects with advanced thoracic malignancies, this reversal of resistance, 
which in theory ‘primes’ tumors to respond subsequent chemotherapy may allow previous 
responders to derive benefit from retreatment of the same chemotherapy after previous exposure 
to RRx-001. In addition, immunohistochemical staining of HC of tumor biopsies from two 
subjects on the TRIPLE THREAT trial revealed the infiltration of cytotoxic CD3+ CD8+ 
lymphocytes. 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 35 of 99 
4 STUDY OBJECTIVES 
4.1 Primary Objectives  
To evaluate Overall Survival and Overall Response Rate 
4.2 Secondary Objectives  
1. To estimate the transition probability between disease progression and disease 
amelioration attributable to resensitization. 
2. To estimate the mean sojourn time in a platinum sensitized state 
3. To evaluate disease control rate (DCR), and PFS/MMMT. 
4. To evaluate the toxicity of platinum-based therapy following prior exposure to these 
agents and treatment with RRx-001 monotherapy. 
5. To evaluate changes in a panel of tumor biomarkers. (i.e., CA-125 for ovarian cancer 
and chromogranin A and neuron specific enolase (NSE) for neuroendocrine tumors) 
4.3 Exploratory Objectives  
To investigate: 
• Circulating Tumor Cells 
• Circulating Endothelial Cells (CEP and CEC) 
• Immune Subsets 
• Epigenetic markers e.g., Protein Hyperacetylation and gene methylation 
• Status of tumor suppressors such as p53, pre and post RRx-001 
• Expression of TGF-beta and its receptor and fibrosis status pre and post dose 
• Relative density of tumor associated macrophages in patient biopsies 
• Status of microRNAs (miRNAs) pre and post RRx-001 
4.4 Endpoints 
4.4.1 Primary Endpoints 
1. Overall Survival (OS): the time from enrollment until the time of death from any cause 
or last follow-up.  Patients will be followed clinically as outlined in the treatment 
schedule and will be followed off study for death. 
2. Overall Response Rate (ORR):  The proportion of patients who achieve a reduction in 
the sum of target lesions by 30% following the re-administration of chemotherapy. 
Radiographic assessment of disease burden will be evaluated by CT and disease RR will 
be documented using RECIST v1.1.  
 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 36 of 99 
4.4.2 Secondary Endpoints 
1. Disease Control Rates (DCR): The percentage of patients who have achieved complete 
response, partial response and stable disease (as per RECIST v1.1). 
2. Progression free survival (PFS): the time from enrollment to the time of the first 
radiographic documentation of objective progression as defined by RECIST v1.1 or death 
from any cause. 
3. Toxicity: Rate of Grade 3 and Grade 4 hematologic and non-hematologic toxicities of 
reintroduced platinum based chemotherapy. 
4. The transition probability between disease progression and disease amelioration 
attributable to sensitization/resensitization and the mean sojourn time. 
4.4.3 Exploratory Endpoints 
1. Circulating Tumor Cells: 
Peripheral blood will be collected to correlate changes in circulating tumor cells with 
clinical response. CTCs will be assessed using ferrofluidic enrichment and multi-
parameter flow cytometric detection. CTCs are identified by positive expression of 
epithelial markers and a viability marker and negative expression of hematopoietic 
markers. 
2. Circulating Endothelial Cells (CEP and CEC): 
Circulating endothelial progenitor cells (CEP) and mature circulating endothelial cells 
(CEC) will be assessed by multiparameter flow cytometry. Cells will be analyzed for 
forward and side scatter, and cells expressing hematopoietic markers will be excluded.  
Endothelial cells will be identified using co-expression of markers, such as CD31 and 
CD146 for CEC, and CD31 and CD133 for CEP. The cell populations will also be 
analyzed for viability using scatter profiles and a vital stain, such as Hoechst 33258. 
Percentages of stained cells will be determined and compared with appropriate negative 
controls. Multi-parameter flow analysis will be performed with a Miltenyi Quant 
equipped with FlowJo software, using a minimum of 500,000 events per analysis. 
3. Immune Subsets: 
The immune infiltrate will be analyzed in tumor biopsies obtained pre- and post-therapy. 
The tissue will be dissociated into single cells and assessed by multiparameter flow 
cytometry for immune subsets. The immune populations analyzed will be dependent on 
the number and viability of infiltrating immune cells.  Subsets analyzed may include 
regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSC), effector and 
exhausted CD8+ T-cells, and type II polarized macrophages (TAMs). As sample permits, 
assessment will include functional markers, i.e., PD-1, PD-L1, Tim-3, CTLA-4 and 
CD40. Peripheral blood mononuclear cells (PBMC) will be assessed using 
multiparameter flow cytometry for immune subsets including but not necessarily limited 
to Tregs, MDSC, effector and exhausted CD8+ T-cells.  Assessment will include 
functional markers, i.e., PD-1, Tim-3, CTLA-4 and/or CD40. 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 37 of 99 
4. Epigenetic markers e.g., Protein Hyperacetylation and gene methylation:  
Protein hyperacetylation pre- and post-therapy will be assessed in peripheral blood 
mononuclear cells (PBMC) using multiparameter flow cytometry. Gene acetylation and 
methylation will be carried out by PCR and IHC techniques. The impact of RRx-001 on 
the epigenetic status of genes that are closely correlated to resistance to platinum therapy 
will be studied.  
5. Status of tumor suppressors such as p53, pre and post RRx-001: 
Expression and mutational status of tumor suppressors such as p53, p21 will be studied 
by PCR and IHC techniques to see if silenced genes can be reactivated.   
6. TGF-beta and its receptor and fibrosis status:  
Radiotherapy has been shown to induce increased expression of both TGF-beta and its 
receptor, which is associated with an increase in fibrosis. Due to the pro-oxidant effect of 
RRx-001 in tumors, it is hypothesized that a similar effect may occur with RRx-001. Pre 
and post biopsy samples will be used to investigate this effect.  
7. MicroRNAs (miRNAs) relating to gene expression:  
MicroRNAs (miRNAs) are short noncoding RNAs that influence gene expression. 
Increased miRNA levels downregulate genes; conversely, decreased miRNA levels may 
result in upregulated genes. RRx-001 has been shown to decrease a specific set of 
miRNAs in the tumor that result in upregulation of type III hypersensitivity genes. 
Profiling of these perturbed miRNAs in the context of RRx-001 treatment may help to 
predict drug responses. The PAXgene blood tubes are provided to isolate miRNA and 
total RNA for analysis. 
8. The relative macrophage density:  
TAMs will be immunohistochemically labeled using a monoclonal (CD68) antibody in 
biopsy specimens from patients. CD68-positive cells will be counted with the aid of a 
microscope and expressed as TAMs/mm2. TAMs will be quantified by systematically 
screening the entire cancer area and by counting at the hot spot in a cancer area where 
macrophages accumulated at highest density in the specimens. The densities of these 
cells will scored as +, low; ++, moderate; and +++, high. 
 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 38 of 99 
5 STUDY DESIGN 
5.1 Description of the Study 
The study is designed to explore the potential tumor associated macrophage (TAM)-targeting 
agent RRx-001 to sensitize patients who previously received and now have failed a platinum 
based regimen.  
RRx-001 is administered with autologous blood once weekly followed by or in combination with 
reintroduction of platinum-based therapy according to the treatment schedule illustrated in 
Section 1.1 Treatment Schemas [SCC, EOC, NET, NSCLC] ). 
As of Amendment 10, an investigator’s choice control arm has been added to small cell 
carcinoma and ovarian enrolled patients, randomized 2:1 to 1 of 2 Arms. The investigational 
ARM 1 will enroll an additional 26 patients, with the ‘investigators choice’ control arm enrolling 
13 patients total, per patient group.  
In addition, in neuroendocrine and NSCLC cohorts, after up to 6 cycles of the reintroduced 
platinum doublet, patients with stable disease or better (>SD) start on maintenance RRx-001 
administered weekly (QW) until progression.  
5.1.1 Toxicity  
Toxicity will be graded according to the National Cancer Institute (NCI) Common Toxicity 
Criteria for Adverse Events (CTCAE) version 5.0.  
Serious and unexpected toxicity is defined as ANY Grade 3 or higher toxicity considered by 
the investigator to be possibly, probably or definitely related to the study drug, RRx-001, or to its 
potentiation of protocol defined therapy toxicity, occurring after the initial dose of RRx-001 until 
up to 30 days after discontinuation of protocol defined therapy. The following exceptions are not 
considered serious and unexpected toxicity related to RRx-001 or protocol defined therapy: 
• Grade 3 or 4 anemia, or neutropenia that resolve to ≤Grade 2 within 10 days.  Patients 
should have repeat labs within 10 days to document resolution. 
• Grade 3 or 4 thrombocytopenia without clinically significant bleeding that resolves to 
≤Grade 2 within 10 days.  Patients should have repeat labs within 10 days to document 
resolution. 
• Grade 3 or 4 leukopenia/lymphopenia without clinically significant consequences 
(i.e., infection). 
• Grade 3 nausea, vomiting or diarrhea with maximal medical support that resolves to 
≤Grade 2 within 72 hours. 
 
If 5 patients develop serious and unexpected toxicity in a particular RRx-001 cohort, which is 
thought to be directly or indirectly related to RRx-001, then enrollment in that particular cohort 
will stop. Management and dosing modifications are outlined in Section 6.2.6. 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 39 of 99 
5.2 Administrative Structure 
This trial is performed under the IND of EpicentRx, Inc.  
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of Helsinki. 
The Principal Investigator is responsible for personally overseeing the treatment of all study 
patients and assuring that all study site personnel adhere to the study protocol and all 
FDA/GCP/NCI regulations and guidelines regarding clinical trials both during and after study 
completion. 
5.3 Compliance with Laws and Regulations 
This study will be conducted according with FDA regulations, the International Conference on 
Harmonization (ICH) E6 Guideline for Good Clinical Practice (GCP), and applicable local, state, 
and federal laws. 
 
6 MATERIALS AND METHODS 
6.1 Study Population 
Patients must meet all of the Inclusion Criteria to participate in this study. 
Patients meeting any of the Exclusion Criteria at baseline will be excluded from study 
participation. 
6.2 Study Treatment 
Study treatment refers to both RRx-001 and the chosen protocol defined therapy. 
6.2.1 RRx-001 Formulation 
RRx-001 Drug Product and diluent product:  RRx-001 Drug Product is supplied as a sterile 
solution in PEG-400. Prior to administration, DMA will be added to RRx-001 Drug Product to 
yield a solution containing 66% PEG-400 and 33% DMA. This solution will then be diluted to 
2.0 mg/mL with Water for injection (WFI). Please refer to pharmacy manual for drug storage 
conditions and drug preparation instructions.  
RRx-001 is not light sensitive. The product should be used soon after dilution. RRx-001 
solutions diluted with saline are not stable and saline should not be used. The osmolality of the 
2.0 mg/mL dosing solution was determined to be 614 mOsm/kg. 
The study product is stored in a secured site with restricted access.   
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 40 of 99 
6.2.2 RRx-001 Dose, Procedure and Dose Schedule 
Treatment will be administered on an outpatient basis. Patients will receive 4 mg of RRx-001, 
premixed with the patient’s blood prior to reinfusion, in the schedule described in the Schedule 
of Assessments.  
The administration procedure of RRx-001 incorporates the use of an in-line filter ‘device’ as an 
added patient safety element; though likely unnecessary, given the patient’s own blood is being 
drawn into a syringe containing anticoagulant, where the study drug (RRx-001) is subsequently 
transferred to mix with the blood, followed by the treated blood being reinfused back into the 
patient, within approximately 15 minutes from start of blood draw, all inside a closed sterile 
assembly.  
The filter ‘device’ is a clinical use in-line blood filter and is part of an FDA approved Neonatal 
Syringe Set that is used to deliver small aliquots of whole blood. Modification was made for our 
use by the manufacturer, both to the tubing length (adding approximately 3”) and tubing ends 
(changing the previously female luer connector to a male luer connector on 1 end, and a 
removing an IV bag spike and replacing it with a male luer connector on the opposite end), thus 
making this technically ‘off label’ use.  
Appropriate in-use studies have been conducted with this filter ‘device’ and these results along 
with the following device labeling: ‘CAUTION—Investigational device for use with RRx-001. 
Limited by Federal law to investigational use under IND 107,674’ have been shared with the 
FDA by way of an information amendment submission, dated December 14, 2017. 
A description of the pretreatment regimen is further outlined in Table 3 below. Appropriate dose 
modifications are described in Section 6.2.6.  
Table 3: 
RRx-001 Regimen Premedication Description 
Agent 
Premedication 
Route 
Schedule 
RRx-001 
10 mg Dexamethasone (or equivalent dose of another 
corticosteroid) IV or PO up to 2 hours prior to 
administration of RRx-001 
IV or 
oral 
Days 1, 8 and 15 of each 
cycle 
RRx-001 
Low-Dose Aspirin 81 mg or Acetaminophen 500 mg up 
to 2 hours prior to administration of RRx-001 
Oral 
Days 1, 8 and 15 of each 
cycle 
 
The patient's identification must be verified by two people prior to starting the blood draw and 
infusion process.  Ensure that the RRx-001 and anticoagulant doses, both provided from 
pharmacy, are for the correct patient (using patient identifiers noted on labeling); that the RRx-
001 and anticoagulant are mixed with the patient's autologous blood; and that the mixture is re-
infused back to the correct patient.  DO NOT proceed with administration if any discrepancies 
are noted.  
Proper Handling: 
The methodology for administering the RRx-001 dose by premixing with the patient’s blood is 
based on procedures used in blood product transfusions.  Standard procedures for avoiding 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 41 of 99 
hemolysis will be followed. These include the use of large gauge IV needles (19g or larger 
preferred) and slow consistent rate during blood draw to avoid undue mechanical shear stress to 
red blood cells.  
Whenever blood is present during the administration procedure, handle with care and do not 
shake.  Avoid excessive temperatures, (both high and low temperatures can cause hemolysis). 
Avoid conditions that create high turbulence or trauma to the red blood cells.  
Anticoagulant & RRx-001 Doses Prepared by the Pharmacy: 
The Anticoagulant and RRx-001 doses will be prepared by the pharmacy for the clinic, where the 
patient administration procedure takes place. For details of the pharmacy procedure, please refer 
to the latest version of the pharmacy manual. 
Administration Procedure in the Clinic: 
The RRx-001 and anticoagulant doses should be properly labeled per institutional standards and 
in accordance with the latest pharmacy manual guidelines.   
Administration procedure steps should be followed carefully and can be found in the latest 
version of the ‘Blood Administration Best Practices & Guidelines for IV Infusion of RRx-001 + 
Blood Mix’.  Safety guidelines are based on procedures used in blood product transfusions.  It is 
important each step is followed in the order outlined in the guide to maintain sterility at all 
times. 
6.2.3 Protocol Defined Therapies 
Standard of care protocol defined therapies will be administered per institutional standard of care 
and in accordance with the United States Package Insert (USPI) approved by the US FDA. Any 
patient with a history of toxicity that required permanent discontinuation of any of the 
chemotherapy agents is ineligible. 
• SCC 
o ARM 1:  
 Carboplatin or cisplatin + etoposide 
o ARM 2 “investigators choice” one of the following:  
 Carboplatin or cisplatin + etoposide, irinotecan, vinorelbine  
 
• EOC: 
o ARM 1:  
 Carboplatin (single agent) 
o ARM 2 “investigators choice” one of the following:  
 Carboplatin  
 Etoposide 
 Pegylated liposomal doxorubicin 
 Taxane Treatments 
 Gemcitabine 
 Vinorelbine  
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 42 of 99 
• Neuroendocrine: 
o Carboplatin or cisplatin + etoposide 
• NSCLC: 
o Carboplatin or cisplatin + paclitaxel or 
o Carboplatin or cisplatin + nab-paclitaxel or 
o Carboplatin or cisplatin + pemetrexed 
Treatment interruption and/or dose reduction may be needed to manage suspected adverse drug 
reactions in line with standard treatment practice. Refer to the United States Package Insert 
(USPI) for dose interruption and modification instructions. Patients who previously required 
dose reduction selected treatment in the first line setting may start treatment at a reduction of the 
standard dosing, at the discretion of the investigator.    
6.2.4 Other Considerations 
The hydration for cisplatin should occur pre and post infusion and additionally, supportive 
diuretics (i.e., mannitol) may be used per investigator discretion. For those treatments considered 
highly emetogenic anti-nausea regimens will be followed per standard of care.  Hematopoietic 
growth factors may be used per standard of care. 
Hematopoietic growth factors (i.e., G- or GM-CSF).  
• The use of filgrastrim (neupogen) will be allowed for treatment of Grade 3 or 4 neutropenia 
or febrile neutropenia. Filgrastrim (neupogen) must be discontinued at least 48 h prior to 
initiation of the next dose of chemotherapy and prior to the initiation of the next cycle of 
therapy.  
• 
The use of pegfilgrastim (neulasta) will be allowed as secondary prophylaxis if there was 
evidence of Grade 3 or 4 neutropenia on a previous cycle.  
 
6.2.5 Criteria for Continuing Treatment 
Patients will be evaluated during the treatment period to determine if continued treatment is 
appropriate. If, at any time during treatment the criteria are not met, treatment will be held or the 
dose adjusted per protocol and/or per the United States Package Insert (USPI) for treatment 
parameters. 
6.2.6 Dosing Delays/Dosing Modifications: RRx-001 
Mild or moderate infusion-related reactions were reported as the most common infusion reaction 
with RRx-001 when infused directly, and these responded to a reduction in the rate of injection.  
Although mild reactions were observed when RRx-001 was infused using the Blood-Mix dosing 
procedure, if a reduction in dose is required or desired, for any reason, whether or not toxicity is 
present, it is permissible to decrease the dose from 4 mg to 2 mg.  Dose modification or drug 
discontinuation for toxicity may take place at the discretion of the Investigator and will be 
reported. If a Grade 3 or 4 study drug-related adverse event occurs after a dose reduction, RRx-
001 will be discontinued. The dose modifications are listed below in the table below.  
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 43 of 99 
Table 4: 
Dose Modifications for RRx-001 Administration 
Sequential Dose 
Modifications 
RRx-001 
Dose in mg 
RRx-001 Dose 
in mg/m2 
mL 
Infusion Time 
Frequency &  
Interval 
Initial 
4 
2.3 
2.0 
Not to exceed 
4 hours from 
extraction of blood 
Refer to  
Schedule of Assessments 
Dose reduction 
2 
1.15 
1.0 
Not to exceed 
4 hours from 
extraction of blood 
Refer to  
Schedule of Assessments  
 
6.2.7 Dosing Delays/Dosing Modifications: Platinum Based Therapy 
This section applies to treatment regimens that include the investigational agent RRx-001 as 
follows:  
• Small Cell Carcinoma ARM 1 only 
• Ovarian ARM 1 only 
• Neuroendocrine  
• Non-Small Cell Lung Cancer (NSCLC) 
For SCC (ARM2) and EOC (ARM 2), “investigator’s choice” enrolled subjects, follow standard 
of care practice in accordance with the USPI FDA package insert and investigator discretion.  
In the event that a patient previously required a dose reduction during first line treatment, the 
patient may be started on a dose reduction during the initial cycle. This will be at the discretion 
of the principal investigator. At any time during study the investigator may choose to discontinue 
the partner agent due to toxicity, maintaining the platinum based agent (as a single agent).  
Any treatment delays beyond the protocol allowed 3-week (21 day) break must be approved by 
the medical monitor.   
The following regimens are allowed as defined in the respective treatment schema:   
1) Platinum agent:  Carboplatin or Cisplatin.  Platinum agents are given per the initial approval 
by the package insert (USPI FDA).  The following starting options are:  
a) Cisplatin will be initially dosed at 60-80 mg/m2 on day 1 every 3 weeks. 
b) Carboplatin will be initially dosed at an AUC of 5-6 on day 1 every 3 weeks. 
2) For the cohorts where a second agent will be combined with platinum, the partner agent will 
be given per the initial approval by the package insert (USPI FDA). The following starting 
options are:   
a) Etoposide will be initially dosed at 80-100 mg/m2 Days 1-3 every 3 weeks 
b) Paclitaxel will be initially dosed at 175-225 mg/m2 on Day 1 of every 3 weeks.  
c) Nab-Paclitaxel will be initially dosed at 100 mg/m2 on Days 1, 8, and 15 every 3 weeks 
d) Pemetrexed will be initially dosed at 500 mg/m2 IV over 10 minutes on Day 1 every 
3 weeks for up to 6 cycles 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 44 of 99 
Table 5: 
Dose Delays / Modifications based on Absolute Neutrophil Count: Platinum 
Doublets 
ANC 
(On Day 1 of 
treatment cycle)* 
Chemotherapy 
(Platinum based doublet) 
 
ANC nadir 
Chemotherapy 
(Platinum based doublet) 
≥ 1.5 x 109/L  
Full dose 
 
Any 
No dose delays or adjustments will 
be done based on nadir ANC.  
< 1.5 x 109/L  
Hold up to 3 weeks until ANC 
are ≥ 1.5 x 109/L 
Use G-CSF support 
 
 
 
 
 
ANC 
(On Day 8 of 
treatment cycle)** 
Chemotherapy 
(Day 8 chemotherapy) 
 
ANC 
Chemotherapy 
(Day 8 chemotherapy) 
≥ 1.5 x 109/L 
Full dose 
 
Any 
No dose delays or adjustments will 
be done based on nadir ANC.  
< 1.5 x 109/L 
Hold Day 8 of treatment 
Use G-CSF support, next cycle 
 
 
 
 
 
ANC 
(On Day 15 of 
treatment cycle)*** 
Chemotherapy 
(Day 15 chemotherapy) 
 
ANC 
Chemotherapy 
(Day 15 chemotherapy) 
≥ 1.5 x 109/L  
Full dose 
 
Any 
No dose delays or adjustments will 
be done based on nadir ANC.  
< 1.5 x 109/L  
Hold Day 15 of treatment 
Use G-CSF support, next cycle 
*Dose adjustments will be based only on ANC measured on Day 1 of each cycle (samples drawn up to 3 days prior 
to cycle Day 1 are allowed). 
**Dose adjustments are only for treatment that requires Day 8 dosing of chemotherapy. 
***Dose adjustments are only for treatment that requires Day 15 dosing of chemotherapy. 
As previously mentioned, G-CSF (Filgrastim or Pegfilgrastim) will be allowed either therapeutically to allow 
recovery from Grade 3 or 4 neutropenia between cycles or as secondary prophylaxis to prevent a second episode of 
neutropenia in future cycles.  
 
 
 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 45 of 99 
Table 6: 
Dose Delays / Modifications based on Platelet Count: Platinum Doublets 
Platelets 
(On Day 1 of treatment 
cycle)* 
Chemotherapy 
(Platinum based doublet) 
 
Platelets 
Chemotherapy 
(Platinum based doublet) 
≥ 100 x 109/L  
Full dose 
 
< 25 x 109/L or 
< 50 x 109/L 
associated with 
bleeding 
Hold Chemotherapy and 
once platelets increase to ≥ 
100 x 109/L 
25% dose reduction of both 
chemotherapy agents 
>50 x 109/L but  
< 100 x 109/L 
Hold up to 3 weeks until 
platelets are ≥ 100 x 109/L, 
then full dose 
 
 
 
 
 
Platelets 
(On Day 8 of treatment 
cycle)** 
Chemotherapy 
(Day 8 chemotherapy) 
 
Platelets 
Chemotherapy 
(Day 8 chemotherapy) 
≥ 75 x 109/L  
Full dose 
 
< 25 x 109/L or 
< 50 x 109/L 
associated with 
bleeding 
Hold chemotherapy and 
next cycle will be a 25% 
dose reduction of both 
chemotherapy agents 
> 25 x 109/L but  
< 75 x 109/L 
Hold Day 8  
chemotherapy 
 
 
 
 
 
Platelets 
(On Day 15 of treatment 
cycle)*** 
Chemotherapy 
(Day 15 chemotherapy) 
 
Platelets 
Chemotherapy 
(Day 15 chemotherapy) 
≥ 75 x 109/L  
Full dose 
 
< 25 x 109/L or 
< 50 x 109/L 
associated with 
bleeding 
Hold chemotherapy and 
next cycle will be a 25% 
dose reduction of both 
chemotherapy agents 
> 25 x 109/L but  
< 75 x 109/L 
Hold Day 15  
chemotherapy 
* 
Dose adjustments will be based only on platelet count measured on day 1 of each cycle (samples drawn up to 
3 days prior to cycle day 1 are allowed). 
** Dose adjustments are only for treatment that requires Day 8 dosing of chemotherapy. 
*** Dose adjustments are only for treatment that requires Day 15 dosing of chemotherapy. 
 
6.2.7.1 Dose Delays / Modification for Non-Hematologic Toxicities: Platinum Therapies 
Dose modification should be made for drug-induced non-hematologic toxicities, with the 
exception of alopecia, according to the table below.  
Non-hematological toxicities must have improved to NCI-CTC Grade ≤ 2 prior to re-treatment.  
Treatment may be resumed according to the guidelines below.  
For Grade 4 toxicities the suggested dose reductions listed below and continuation of treatment 
should only be implemented if considered by the investigator to be in the best interest of the 
patient. 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 46 of 99 
Table 7: 
Platinum Therapies - Adverse Event Dose Modifications: Non-Hematological  
Adverse event (AE) 
Dose reduction / Modification 
> Grade 2 neurotoxicity, ototoxicity 
Reduce cisplatin by 25% 
or change to carboplatin 
> Grade 2 Serum creatinine  
(> 1.6 – 2.5 mg/dl) 
Reduce cisplatin by 25% 
or change to carboplatin 
Any other Grade 3 or 4 toxicities not 
previously mentioned. 
Reduce Chemotherapy 
(Both Chemotherapy in a platinum based doublet) by 25%. 
 
If the above AEs occur following previous dose reduction, then reduce agent by another 25% 
from the previously administered dosage.  If more than 2 dose reductions are needed, the patient 
will be taken off the study. This may exclude nausea/vomiting/diarrhea, without maximal 
symptomatic treatment and metabolic toxicities that are easily correctable within 24 hours such 
as glucose, hypokalemia, hypomagnesemia, hypophosphatemia and hyponatremia, and fatigue. 
In the case of nausea/vomiting/diarrhea without maximal symptomatic treatment, 
implementation of current practice guidelines for this toxicity will take place.  
If despite maximal symptomatic treatments the toxicities do not improve to ≤ Grade 2 then all 
protocol defined therapies will be held until toxicity improves to ≤ Grade 1 or pre-treatment 
baseline.  
6.2.7.2 Nab-Paclitaxel (Abraxane) Dose Modifications 
Table 8: 
Dose Modifications for Hepatic Impairment: Nab-Paclitaxel (Abraxane) 
 
SGOT (AST) Levels 
 
Bilirubin Levels 
Abraxane Dose 
Mild 
< 10 x ULN 
AND 
> ULN to ≤ 1. 5 x ULN 
100 mg/m2 
Moderate 
< 10 x ULN 
AND 
> 1.5 to ≤ 3 x ULN 
80 mg/m2 * 
Severe 
< 10 x ULN 
AND 
> 3 to ≤ 5 x ULN 
80 mg/m2 * 
 
> 10 x ULN 
OR 
> 5 x ULN 
Not recommended 
* If the patient tolerates the reduced dose for two cycles, a dose increase to 100 mg/m2 in subsequent courses should 
be considered  
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 47 of 99 
Table 9: 
Dose Modifications for neurologic and hematologic adverse drug reactions: 
Nab-Paclitaxel (Abraxane) 
Do not administer nab-paclitaxel on Day 1 of a cycle until absolute neutrophil count (ANC) is at least 
1500 cells/mm3 and platelet count is at least 100,000 cells/mm3  
In patients who develop severe neutropenia or thrombocytopenia withhold treatment until counts 
recover to an absolute neutrophil count of at least 1500 cells/mm3 and platelet count of at least 
100,000 cells/mm3 on Day 1 or to an absolute neutrophil count of at least 500 cells/mm3 and platelet 
count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle. Upon resumption of dosing, 
permanently reduce nab-paclitaxel and carboplatin doses as outlined in the table excerpted from the 
nab-paclitaxel package insert 
Withhold nab-paclitaxel for Grade 3-4 peripheral neuropathy. Resume nab-paclitaxel and carboplatin at 
reduced doses (see excerpted table below) when peripheral neuropathy improves to Grade 1 or 
completely resolves 
From: http://www.abraxane.com/downloads/Abraxane_PrescribingInformation.pdf 
Table 10: 
Permanent Dose Reductions for Hematologic and Neurologic Drug Reactions 
in NSCLC: Nab-Paclitaxel (Abraxane) 
 
 
6.2.7.3 Paclitaxel Dose Modifications 
• If baseline PMN <1500/m³, do not re-treat until PMN >1500/m³ and platelet count 
>100,000/m³.  
• If severe neutropenia occurs (PMN <500/m³ for 7 days), reduce subsequent doses by 
20%.  
• If Grade 2 peripheral neuropathy occurs reduce dose to 70 mg/m2. If > Grade 3 
discontinue. 
• Renal impairment: No dosage adjustment required 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 48 of 99 
• For hepatic impairment: 
o AST/ALT <10 x ULN and bilirubin up to 2 x ULN: 135 mg/m² over 3 hr 
o AST/ALT <10 x ULN and bilirubin 5 x ULN: 90 mg/m² over 3 hr 
o AST/ALT ≥10 x ULN OR bilirubin >5 x ULN: Do not administer 
• For other > Grade 2 toxicity (except alopecia) defer therapy for 1 week until resolved to 
< Grade 1 and then resume at 70 mg/m2. 
 
6.2.7.4 Etoposide Dose Modifications 
The following table describes etoposide dose modifications based on renal function.  
Table 11: 
Etoposide Dose Modifications for Renal Function 
Measured Creatinine Clearance 
>50 mL/min 
15-50 mL/min 
Etoposide 
100% 
75% 
(From: http://packageinserts.bms.com/pi/pi_etophos.pdf) 
Data are not available in patients with creatinine clearances <15 mL/min and further dose 
reduction should be considered in these patients. 
Etoposide is associated with: 
a) 
Dose-limiting bone marrow suppression. The occurrence of a platelet count below 
50,000/mm3 or an absolute neutrophil count below 500/mm3 is an indication to withhold 
further therapy until the blood counts have sufficiently recovered 
b) The possible occurrence of an anaphylactic reaction manifested by chills, fever, 
tachycardia, bronchospasm, dyspnea, and hypotension. In case of anaphylactic reaction, 
the infusion should be terminated immediately, and may be followed by the 
administration of pressor agents, corticosteroids, antihistamines, or volume expanders at 
the discretion of the physician 
c) 
Injection site reactions. Closely monitor the infusion site for possible infiltration during 
drug administration. No specific treatment for extravasation reactions is known. 
 
6.2.7.5 Pemetrexed Dose Modifications 
Hepatic impairment: no dose adjustments 
Hematological toxicity: neutrophils <1.5 x 109/L or platelets <100 x 109/L. Delay for one week. 
Repeat complete blood count. If within normal parameters resume treatment with 100% doses. 
If 2 or more delays, consider a 25% dose reduction. 
Renal impairment: CrCl (mL/min) >45 give 100% dose. If CrCl <45 not recommended. 
Other toxicities: Grade 3 or 4 mucositis, give 50% of previous dose. Any other Grade 3 or 4 
toxicities or any diarrhea requiring hospitalization give 75% of previous dose. 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 49 of 99 
6.3 Concomitant and Excluded Therapies 
All concomitant medications and blood products, as well as interventions, received by patients 
from the first dose of study drug until the end of study visit must be recorded. 
6.3.1 Supportive Care guidelines 
Palliative and supportive care for disease-related symptoms, including palliative radiotherapy, 
blood transfusions, pain medications, anti-inflammatories, radiation and antiemetics, 
bisphosphonates and RANK ligand inhibitors, is permitted. Hematopoietic growth factors such 
as erythropoietin or G-CSF are allowed if clinically indicated (see Section 6.2.4 for additional 
detail).   
6.3.2 Anti-neoplastics 
Use of anti-neoplastic or anti-tumor agents not part of the study therapy, including 
chemotherapy, immunotherapy, and hormonal anticancer therapy, is not permitted while 
participating in this study.  
6.3.3 Investigational Agents 
Use of concurrent investigational agents is not permitted. 
6.3.4 Warfarin/Coumarin Anticoagulants 
Avoid if possible with paclitaxel, as use often causes an elevation or fluctuation in the INR –  
consider switching patient to a low molecular weight heparin during treatment or if the patient 
continues taking an oral anticoagulant monitor the INR at least once a week and adjust dose 
accordingly.  
6.4 Study Assessments 
A flowchart of scheduled study assessments is provided in Appendix G. 
All patients will be closely monitored for safety and tolerability during all cycles of therapy, at 
study treatment completion/early study treatment discontinuation, and during the survival 
follow-up period. 
6.4.1 Definitions of Study Assessments 
a. Medical History 
Medical/Oncology history should include history of malignancy (date of first diagnosis, 
disease course, and prior therapies), surgeries, current ECOG performance status, current 
symptom inventory, past medical history, all medications taken during the 30 days prior to 
start of study treatment (including prescriptions, over-the-counter, and herbal/homeopathic 
remedies), social history (including smoking history and alcohol history), family history and 
allergies. 
b. Demographics 
Demographics consist of age, gender, race, and ethnicity. 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 50 of 99 
c. Vital Signs 
Vital signs will include measurement of height (at Screening only), weight, pulse rate, blood 
pressure and temperature. 
d. Physical Examination 
Changes from baseline abnormalities should be recorded at each subsequent physical 
examination. New or worsened abnormalities should be recorded as adverse events if 
appropriate. During the screening visit, a full, comprehensive history and physical exam will 
be conducted. Thereafter the history and physical exam may be problem focused in 
accordance with the protocol Schedule of Assessments (Appendix G).  
e. Performance Status 
Performance status will be evaluated according the ECOG criteria listed in Appendix B. 
f. Laboratory Assessments 
Clinical laboratory assessments as described in the Schedule of Assessments will be 
performed by local institutional lab.  
In addition, results of tumor markers as drawn per standard of care/ institutional practice are 
to be provided to sponsor as available. 
g. Central Laboratory Samples 
Tumor markers from CTCs, CEPs, CECs as well as immune subsets, and protein 
hyperacetylation will be studied (see Section 4.4.3). For further description see the latest 
study lab manual. 
h. Tumor Biopsy and/or collection of archival tissue 
New tumor biopsy, if feasible, will performed on an optional basis prior to infusion of 
RRx-001 (baseline) and prior to initial platinum rechallange Day 1 (up to 7 Days prior but 
following discontinuation of RRx-001).  Archival tissue, if available, will be collected at 
baseline. For details regarding the processing of samples please refer to the latest study lab 
manual. 
i. Tumor Assessment 
CT (diagnostic with contrast) will be used as the primary imaging tool for response 
assessment. Anatomical areas should be imaged per institutional standard of care per disease 
cohort.  Imaging will be performed at the time points outlined in the Schedule of 
Assessments (Appendix G).  
Assessment of radiographic response will occur according to RECIST v1.1 (Appendix A). 
In case partial response (PR), CR, or progressive disease (PD) is observed according to 
RECIST v.1.1, confirmatory tumor assessments may be repeated at least 4 weeks after initial 
documentation. Study treatments will continue until disease progression is confirmed by the 
Investigator, patients’ refusal, or unacceptable toxicity, whichever occurs first. 
6.4.2 Screening and Pretreatment Assessments 
Diagnostic or laboratory studies performed exclusively to determine eligibility for this trial will 
be done only after obtaining written informed consent.  Documentation of the informed consent 
for screening will be maintained in the patient’s research chart and medical record. Studies or 
procedures that were performed for clinical indications (not exclusively to determine study 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 51 of 99 
eligibility) may be used for baseline values even if the studies were done before informed 
consent was obtained, so long as they fall within the protocol Screening window. 
The study population for this trial will consist of patients with pathologically confirmed 
advanced resistant/refractory SCC, EGFR positive NSCLC, resistant/refractory EOC or HGNEC. 
All patients must have measurable disease. CT imaging will confirm measurable lesions within 
the schedule defined in the Schedule of Assessments. All patients who meet the inclusion and 
exclusion criteria will be offered enrollment into this study.  To confirm patient eligibility for 
study participation, the following assessments and procedures will be completed during the 
screening period.  
All screening procedures must be performed within the schedule defined in the Schedule of 
Assessments. The screening procedures include: 
a. Written informed consent. 
b. Review of inclusion and exclusion criteria. 
c. Complete medical/oncology history. 
d. Documentation of concomitant medications. 
e. Demographics. 
f. Complete physical examination, including vital signs and physical measurements (body 
weight and height). 
g. Optional tumor biopsy, if feasible, and/or collection of archival tissue 
h. ECOG performance status assessment. 
i. Documentation of tumor status (radiologic tumor assessment) 
j. Local Laboratory Assessments: CBC and CMP.  
 
Note: if blood samples are taken within 5 days of the first dose of study treatment, Day 1 
samples do not need to be re-collected. 
k. Central Laboratory Samples: CTC, Immune Subsets, Lysine Acetylation, CEC/CEP, 
Serum miRNA analysis 
l. Single-item Visual Analogue Fatigue Scale to be completed by the patient  
m. Pregnancy test, if female of childbearing potential. 
6.4.3 Treatment Discontinuation Assessments 
Patients should be seen in the clinic or contacted by telephone to determine if any serious or non-
serious adverse events have occurred within 30 days of termination of protocol defined 
treatment. 
Patients may withdraw from the study at any time. Any patient who stops study treatment will be 
encouraged to return to the study center for a follow-up visit within 4-6 weeks of 
discontinuation. The primary reason for discontinuation should be documented. 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 52 of 99 
6.4.4 Follow-Up Assessments 
Patients will be followed until death, or withdrawal of informed consent. Follow-up will consist 
of phone calls approximately every 8 weeks (± 7 days) to document survival.  If a patient, family 
member or healthcare proxy cannot be reached, medical records or the Social Security Death 
Index (SSDI) may be used to document survival.  For patients continuing to be imaged at the 
study site, a copy of the imaging and local radiology report will be made available upon request.  
Patients may choose to withdraw from making their imaging available during the follow-up 
period. 
6.5 Patient Discontinuation 
Patients may discontinue study treatment at any time.  Any patient who discontinues treatment 
will be encouraged to return to the study center to undergo treatment discontinuation 
assessments. The primary reason for discontinuation should be recorded.  Reasons for 
discontinuation of a patient by the investigator include, but are not limited to, the following:   
• Voluntary withdrawal from treatment (follow-up permitted); patients that withdraw from 
radiology follow-up should still be followed for overall survival 
• Voluntary withdrawal of consent (termination of treatment and follow-up), 
• Documented disease progression by RECIST v1.1 criteria after start of platinum doublets 
• Clinically significant deterioration of the patient’s condition prior to treatment 
discontinuation,  
• Patient noncompliance, 
• Experience of serious and unexpected toxicity, as defined in Section 5.1.1, 
• Investigator determination that it is not in the patient’s best interest to continue 
participation, 
• Pregnancy, 
• Development of second malignancy (except for basal cell carcinoma, squamous cell 
carcinoma of the skin, localized prostate, or cervical cancer) that requires treatment which 
would interfere with the study, 
• Lost to follow-up. 
6.6 Study Discontinuation 
Reasons for terminating the study may include, but are not limited to, the following: 
• Completion of the study. 
• The incidence or severity of adverse events in this study indicates a potential health hazard. 
• Withdrawal of EpicentRx Inc. approval. 
• Inaccurate or incomplete data recording. 
• Suggested by early stopping guidelines for futility of second or third line chemotherapy.   
• Suggested by early stopping guideline for risk of clinical deterioration during RRx-001 
treatment period. 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 53 of 99 
7 STATISTICAL METHODS OF DATA ANALYSIS 
7.1 Study Design 
This study is designed to explore the potential of the epigenetic agent RRx-001 to sensitize 
patients who previously received a platinum based doublet regimen. RRx-001 is administered 
with autologous blood once weekly followed by or in combination with a protocol defined 
therapy.  
The primary endpoint is Overall Survival (OS) and Overall Response Rate (ORR). 
The four cohorts under consideration are patients with NSCLC, SCC, High Grade 
Neuroendocrine Tumors, or refractory resistant epithelial ovarian tumors (or MMMT of ovary or 
uterus) and who meet eligibility criteria defined in the inclusion / exclusion criteria.  
Stopping guidelines for safety in platinum therapy period of treatment - Stage 2 
If the limiting toxicity events convincingly exceed 30%, we will temporarily halt the study 
pending safety consultation. Specifically, we will apply a Bayesian toxicity monitoring rule that 
suspends the enrollment if the posterior probability of risk being larger than 0.30 is 70% or 
higher. The prior distribution was chosen to be beta (1, 5), representing our prior guess that 
limiting toxicities occur in 1 out of 6 patients and there is 90% chance that this toxicity rate is 
between 1.0% and 45%. The stopping boundaries along with corresponding operating 
characteristics are presented in the following tables based on 5000 simulations. 
Stop if #  
Serious & Unexpected 
Toxicity  
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Out of N 
3-4 
5-7 
8-10 
11-13 
14-16 
17-19 
20-22 
23-25 
26-28 
29-30 
 
Underlying risk of  
adverse events 
Probability of early 
stopping 
Average sample 
size 
0.10 
0.8% 
29.8 
0.20 
9.2% 
28.1 
0.30 
36.5% 
23.4 
0.40 
74.7% 
16.2 
0.50 
94.9% 
10.4 
 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 54 of 99 
Amendment 10 Statistical updates:  
General design considerations, effective as of Amendment 10:  
1. Small Cell Carcinoma: Newly enrolled patients (post Amendment 10) will be allocated to 
one of two treatment arms using a 2-to-1 randomization ratio, (approximately 26 to 
Arm 1 and 13 to Arm 2). 
The two treatment arms are as follows: 
Arm 1: RRx-001 weekly for 3 weeks followed by up to 4 cycles of platinum plus etoposide 
chemotherapy ‘rechallenge’ and then RRx-001 & platinum maintenance (for patients 
with stable disease (SD) or better at discontinuation of platinum rechallenge) 
Arm 2: Standard of Care Investigator’s Choice Control Arm, treatment options of 
platinum plus etoposide, irinotecan or vinorelbine until progression or intolerable 
toxicity 
2. Ovarian: Newly enrolled patients (post Amendment 10) will be allocated to one of two 
treatment arms using a 2-to-1 randomization ratio, (approximately 26 to Arm 1 and 13 to 
Arm 2). 
The two treatment arms are as follows: 
Arm 1: RRx-001 weekly for 2 weeks followed by 2 cycles of carboplatin ‘rechallenge’ 
and then ‘maintenance’, cycling between 1 dose of RRx-001 followed by 2 cycles of 
carboplatin, which repeats until progression or intolerable toxicity 
Arm 2: Standard of Care Investigator’s Choice Control Arm, treatment options of one of 
the following: carboplatin, etoposide, doxil, gemcitabine, vinorelbine or taxane 
treatments until progression or intolerable toxicity 
3. Neuroendocrine: The only modification with amendment 09 forward to the existing 
treatment schedule is the addition of a RRx-001 maintenance for patients with > SD 
following discontinuation of platinum based chemotherapy (for up to 6 cycles).  
4. NSCLC: Patients enrolled post Amendment 09 will receive 3 consecutive doses of 
RRx-001, after which, RRx-001 is discontinued and platinum based chemotherapy is 
started for up to 6 cycles. In addition, a RRx-001 maintenance for patients with > SD 
following discontinuation of platinum based chemotherapy (for up to 6 cycles) was 
added.  
Sample size determination and power considerations: 
The extension stage of the study will approximately enroll 39 patients to the small cell carcinoma 
cohort and also 39 patients to the ovarian cohort. In each cohort, a 2-to-1 randomization 
allocation ratio will be employed (approximately 26 in Arm 1 and 13 in Arm 2, in each chort). 
The proposed sample size modification is motivated by recent clinical obersvations arising from 
current study data results. This upward sample size adjustment should provide sufficient 
precision to derive estimates of responses and time-to-event endpoints. Inferential statistics are 
not the main focus of this newly proposed focus study extension. 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 55 of 99 
7.2 Efficacy Variables 
7.2.1 Primary Efficacy Variables 
The primary efficacy endpoint is OS defined as the time from the date of enrollment to disease 
progression or death from any cause.  Patients will be followed until their date of death, loss to 
follow-up, withdrawal of consent for further follow-up for survival or final database closure.   
Patients who are lost to follow-up or are not known to have disease progression at the time of 
data cut-off for analysis will be censored at last date shown to be alive.  Patients who do not have 
any follow up since enrollment will be censored at the date of enrollment. 
The primary efficacy analysis of OS will be based on the modified ITT population. Kaplan-
Meier estimates of the survival curves and the median survival times and their corresponding 
95% CI will be presented.  
Subgroup analyses of OS will be performed to assess whether the treatment effect is concordant 
among subgroups. The planned subgroup analyses are based on age category (<40 years, 40 to 
<65 years, and ≥65 years), race (Caucasian vs. other). Other subgroup analyses may be 
performed and specified in the statistical analysis plan. 
ORR is the other primary endpoint, which will be assessed at each radiographic assessment using 
RECIST v1.1 criterion. ORR will be defined as the proportion of patients with a CR or a PR per 
RECIST v1.1 based upon the best response as assessed; confirmation of response is not required. 
ORR will be analyzed using the CMH test stratified by the randomization stratification factors to 
assess the significance of the treatment effect on ORR. The treatment effect on ORR will be 
quantified using the odds ratio relative to the historical control. Clopper-Pearson 2-sided 95% 
confidence limits will be calculated for the proportion of patients with ORR. 
ORR analyses will be performed for the Efficacy Evaluable population. Patients who do not have 
measurable disease at baseline will be excluded from the population. 
In addition to representing ORR, the best response using response categories CR, PR, SD, PD 
and NE will be tabulated. The proportion of the response in each response category will be 
calculated. Patients who do not have any post-baseline tumor assessment will be counted under 
the category NE. 
ORR rate at best-confirmed response will also be assessed and analyzed using a similar approach 
as for Overall Response Rate. All patients meeting the eligibility criteria that have signed a 
consent form and have begun treatment will be evaluable for the primary endpoint.  Statistical 
analyses will be primarily descriptive in nature. Evidence of efficacy will consist of an ORR rate 
of 10% or higher in a particular treatment cohort. 
7.2.1.1 Transition Probability 
The transition probability between disease progression and disease amelioration attributable to 
resensitization will be estimated. A semi-Markov model will be used to capture the transition 
probability matrix between disease progression states (Jackson 2015, Sharples 2003). 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 56 of 99 
The average time each patient spends in a given disease state will be estimated and its 95% 
confidence interval derived. The expected time spent healthy (or diseased) before death will also 
be estimated.   
7.2.1.2 Disease Control Rates (DCR) 
The percentage of patients who have achieved complete response, partial response and stable 
disease (as per RECIST v1.1). 
7.2.1.3 Progression Free Survival 
PFS defined from the time from registration to the time of the first radiographic documentation 
of objective progression as defined by RECIST v1.1 for platinum therapy or death from any 
cause. The analysis of PFS will be similar to the analysis of OS. 
7.2.1.4 Toxicity  
Rate of Grade 3 and Grade 4 hematologic toxicities between reintroduced platinum based 
chemotherapy and historical data. The analysis of this toxicity rate will use the CMH test 
stratified by the randomization stratification factors. The proportion of patients experiencing the 
given toxicity (by grade) will be quantified using the odds ratio relative to the historical control. 
Clopper-Pearson 2-sided 95% confidence limits will be calculated for the toxicity proportion (by 
grade). 
7.2.1.5 Analysis of Activity Data 
Descriptive statistics arranged by treatment group (within each of the four cohorts) are planned. 
Graphical depiction of the statistical summaries (ORR, DCR, OS, PFS) will accompany the 
tabular formatted data results for a more complete presentation of the statistical findings. 
Specifically, Kaplan-Meier curves and estimation of time-to-event medians with their 
corresponding 95% confidence intervals will be produced. ORR and DCR responses will be 
derived and the Clopper-Pearson method will be used to derive the responses 95% confidence 
intervals. 
Small Cell Carcinoma and Ovarian Patients enrolled to Amendment 10 or later will be 
analyzed separately (from patients enrolled prior to Amendment 10), the corresponding activity 
data analyses will be separated accordingly. Safety data summaries will be provided separately 
and in aggregation (pre-and-post Amendment 10). As of the time of Amendment 10 (and its 
execution), only newly enrolled patients (to the extension of the study, as of Amendment 10) will 
be required to consent and follow all required eligibility/randomization requirements. 
There will be two databases with separate database locks: 
1. An original database for patients enrolled prior to Amendment 10. This database will 
have its own database procedures and lock timelines. 
2. An extension database for patients enrolled to Amendment 10 or later with its own 
database lock procedures and timelines. 
NSCLC and Neuroendocrine enrolled to the study (pre & post Amendment 10) will be analyzed 
as a single group for each cancer type.  
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 57 of 99 
7.3 Safety Variables 
Safety data summary will be presented by study stage. Adverse events with RRx-001 and 
cumulative adverse events with a protocol defined therapy (description, timing, grade severity, 
seriousness, and relatedness) will be summarized using sample size frequency of occurrence 
percentage. Adverse event data will be descriptively evaluated by cohort and for overall patients.  
Incidence of TEAEs by MedDRA SOC, preferred term and relationship (Related/Not Related) to 
study drug will be summarized based on the safety population. Changes in the level of serum 
biomarkers, clinical laboratory abnormalities, and changes in physical exam and vital signs will 
be compared to baseline samples using one-sample tests (e.g., paired t test or Wilcoxon signed 
rank test).   
Adverse events will be coded by SOC and preferred term using MedDRA, version 18.1.  
Adverse event severity will be based on NCI CTCAE Grade (version 5.0). A TEAE is defined as 
an AE that was not present prior to treatment with study drug, but appeared following treatment 
or was present at treatment initiation, but worsened during treatment. 
Percentage and Time to non-hematologic toxicity Grades 3-5 adverse events will also be 
summarized using time-to-event techniques such as Kaplan-Meier curves. The median time to a 
given toxicity event (by grade) will be estimated (along with its 95% confidence interval) and 
descriptively compared to historical toxicity information. The hematologic toxicity Grade 3-5 
under consideration comprises anemia, thrombocytopenia, neutropenia, febrile neutropenia and 
infections. 
Amendment 10 Section Updates (Small Cell Carcinoma & Ovarian): 
In addition to the safety summary described above, safety summaries will be presented by 
treatment arm within the small cell carcinoma and ovarian cohorts.  
7.4 Statistical and Analytical Methods 
Besides explicitly mentioned variables and their analyses, all collected variables will be 
presented at least descriptively.  Categorical data will be analyzed using frequency tables.  
Longitudinal data will also be presented as change from baseline, if appropriate. 
The statistical analysis plan, including a comprehensive list of planned output, will describe all 
analyses in more depth. 
7.4.1 Statistical Model 
A two-sided log-rank test will be used to compare each disease cohort to the historical control 
cohort. Kaplan-Meier estimates will be derived for the one-sample disease cohort and the median 
with its 95% confidence interval estimates will be derived.  
7.4.2 Hypothesis Testing 
OS, ORR and PFS endpoints will be compared between the disease cohorts and the 
corresponding historical control. 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 58 of 99 
7.4.3 Analysis Populations 
The following population definitions will be used to analyze selected endpoints using the 
appropriate subpopulation of the enrolled patients.  If the need arises, additional subpopulations 
will be defined in the statistical analysis plan.  
7.4.3.1 Safety Analysis Population 
The Safety Population will comprise all study patients who receive at least 1 dose of any study 
medication.  The safety population will be used for the analysis of all safety parameters.  For the 
purposes of this analysis, patients will be assigned to the treatment groups based on the 
treatments they actually received. 
7.4.3.2 Efficacy Analysis Population(s)  
• In NSCLC and neuroendocrine cohorts, all enrolled patients who receive study treatment 
will be included in the modified ITT population and analyzed according to the treatment 
schedule they were enrolled to.  
• For the small cell carcinoma and ovarian randomized patients, the modified intention-to-
treat will comprise all randomized patients who receive study drug, and will be analyzed 
as randomized.   
• The Per Protocol population is defined as the subset of modified ITT population who 
received at least one study treatment cycle and had no major violation of the protocol 
inclusion and exclusion criteria.  
All efficacy analyses will be based on the modified ITT population.  The primary and secondary 
efficacy analyses will be repeated using the Per Protocol population to confirm the overall study 
results.  Further efficacy analyses may be conducted as described in the statistical analysis plan. 
7.5 Power Considerations and Sample Size Determination 
The extension stage of the study will approximately enroll 39 patients to the small cell carcinoma 
cohort and also 39 patients to the ovarian cohort, both in a 2:1 randomization, respectively (26 in 
ARM 1 and 13 in ARM 2 for each). The sample size is based on clinical observations motivated 
by currently available study data results, and should provide sufficient precision to derive 
estimates of responses and time-to-event endpoints. Inferential statistics are not the main focus of 
this newly proposed focus study extension. 
7.6 Interim Analysis and Data Monitoring 
Safety data will be reviewed periodically to examine safety information, including TEAEs, 
SAEs, and deaths, and factors relating to quality of trial conduct will be reviewed. During Part 2, 
an IDMC will be established to review the safety data summaries and examine the findings of the 
interim futility analysis. 
All patients will be evaluable for toxicity from the time of their first treatment with protocol 
specified treatment until the end of protocol specified treatment.  However, cumulative adverse 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 59 of 99 
events during the period of treatment will be continuously monitored. If the limiting toxicity 
events exceed 30%, the trial will be temporarily halted pending safety consultation. 
Efficacy will be assessed on a periodic basis to determine the best course for future development. 
OS, PFS and ORR will be evaluated at each data review when appropriate data maturity is 
achieved. 
Data Monitoring: Safety data will be reviewed periodically to examine safety information, 
including TEAEs, SAEs, toxicity, deaths, and factors relating to quality of trial conduct will be 
reviewed.  An informal DMC will be established to review the safety data summaries and 
examine the findings of the interim data summaries, and will consist of two physicians not 
involved in the conduct of this trial and one biostatistician. Administrative staff will assist the 
informal DMC with operational details and coordinate the generation of DMC minutes. 
DMC members will review safety analyses in order to investigate potential safety risks to the 
patients participating in the study that would suggest a change in study conduct or in the ICF. 
The DMC charter describes details including the primary responsibilities of the DMC, its 
relationship with other trial components, its membership, the purpose and timing of its meetings, 
statistical monitoring guidelines to be implemented, and statistical analysis for the open and 
closed sessions (if appropriate). The informal DMC Charter and meeting minutes will be 
submitted as part of the final Clinical Study Report. 
7.7 Institutional Review Board 
The PI must obtain IRB approval for the investigation.  Initial IRB approval and all materials 
approved by the IRB for this study including the patient consent form and recruitment materials 
must be maintained by the Investigator and made available for inspection. 
7.8 Data Quality Assurance 
Data will be collected via notes in the electronic medical record, radiological imaging and 
outside reports and entered into the appropriate Electronic Data Capture (EDC) Case Report 
Forms (CRFs).  
 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 60 of 99 
8 ASSESSMENT OF SAFETY 
The safety of RRx-001 and other protocol defined therapy will be assessed through collection 
and analyses of adverse events (AEs) and laboratory tests. Patients will be assessed for safety 
through the duration of study while receiving protocol defined treatment. 
8.1 Specification of Safety Variables 
Safety assessments will consist of monitoring and reporting adverse events (AEs) and serious 
adverse events (SAEs) that are considered related to RRx-001 or protocol specified standard of 
care therapy (e.g., carboplatin, cisplatin, investigator’s choice treatment), all events of death, and 
any study specific issue of concern. 
8.1.1 Adverse Events 
An adverse event (AE) is defined as any new untoward medical occurrence or worsening of a 
pre-existing medical condition in a patient or clinical investigation patient administered an 
investigational (medicinal) product and that does not necessarily have a causal relationship with 
this treatment.  An AE can therefore be any unfavorable or unintended sign (including abnormal 
laboratory finding, for example), symptom or disease temporally associated with the use of 
investigational product, whether or not considered related to the investigational product. 
This includes the following: 
• AEs not previously observed in the patient that emerge during the protocol specified AE 
reporting period, including signs or symptoms associated with SCC, T790M- NSCLC, 
HGNEC, rEOC that were not present prior to the AE reporting period. 
• Complications that occur as a result of protocol-mandated interventions (e.g., invasive 
procedures such as biopsies). 
• Preexisting medical conditions (other than the condition being studied) judged by the 
investigator to have worsened in severity or frequency or changed in character during the 
protocol-specified AE reporting period. 
• Clinical progression of SCC, EGFR+ NSCLC, HGNEC or EOC should not be reported as 
an AE. 
 
8.1.2 Serious Adverse Events 
An AE should be classified as an SAE if: 
• It results in death (i.e., the AE actually causes or leads to death).  
• It is life threatening (i.e., the AE, in the view of the investigator, places the patient at 
immediate risk of death. It does not include an AE that, had it occurred in a more severe 
form, might have caused death.). 
• It requires or prolongs inpatient hospitalization. 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 61 of 99 
• It results in persistent or significant disability/incapacity (i.e., the AE results in 
substantial disruption of the patient’s ability to conduct normal life functions). 
• It results in a congenital anomaly/birth defect in a neonate/infant born to a mother 
exposed to the investigational product. 
• It is considered a significant medical event by the investigator based on medical 
judgment (e.g., may jeopardize the patient or may require medical/surgical intervention to 
prevent one of the outcomes listed above). 
 
All AEs that do not meet any of the criteria for serious should be regarded as non-serious AEs. 
The terms “severe” and “serious” are not synonymous.  Severity (or intensity) refers to the grade 
of a specific AE, e.g., mild (Grade 1), moderate (Grade 2), or severe (Grade 3) myocardial 
infarction. “Serious” is a regulatory definition (see previous definition) and is based on patient or 
event outcome or action criteria usually associated with events that pose a threat to a patient’s 
life or functioning.  Seriousness (not severity) serves as the guide for defining regulatory 
reporting obligations from the Sponsor to applicable regulatory authorities.  
Severity and seriousness should be independently assessed when recording AEs and SAEs on the 
CRF. 
8.2 Methods and Timing for Assessing and Recording Safety Variables 
The investigator is responsible for ensuring that all AEs and SAEs that are observed or reported 
during the study are collected and reported to the FDA, IRB, and EpicentRx, Inc. in accordance 
with CFR 312.32 (IND Safety reporting). 
8.2.1 Adverse Event Reporting Period 
The study period during which all AEs and SAEs must be reported begins after informed consent 
is obtained and ends 30 days following the last administration of protocol specified treatment 
(i.e., RRx-001, carboplatin, cisplatin, investigator’s choice treatment, etc.) or study 
discontinuation/termination, whichever is earlier.  After this period, investigators should only 
report SAEs that are attributed to prior study treatment. 
8.2.2 Assessment of Adverse Events 
Investigators will assess the occurrence of AEs and SAEs at all patient evaluation time points 
during the study. All AEs and SAEs whether volunteered by the patient, discovered by study 
personnel during questioning, or detected through physical examination, laboratory test, or other 
means will be recorded in the patient’s medical record and on the appropriate AE or SAE CRF 
page. 
Each recorded AE or SAE will be described by its duration (i.e., start and end dates), severity 
(see Table 12), regulatory seriousness criteria if applicable, suspected relationship to the 
investigational product (see following guidance), and actions taken. 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 62 of 99 
The AE grading (severity) scale found in the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI-CTCAE), Version 5.0, will be used for AE reporting. 
Table 12: 
Adverse Event Grading (Severity) Scale 
Grade 
Severity 
Alternate Description a 
1 
Mild (apply event-specific NCI-CTCAE 
grading criteria) 
Transient or mild discomfort (< 48 hours); no interference 
with the patient’s daily activities; no medical 
intervention/therapy required 
2 
Moderate (apply event-specific  
NCI-CTCAE grading criteria) 
Mild to moderate interference with the patient’s daily 
activities; no or minimal medical intervention/therapy 
required 
3 
Severe (apply event-specific  
NCI-CTCAE grading criteria) 
Considerable interference with the patient’s daily 
activities; medical intervention/therapy required; 
hospitalization possible 
4 
Very severe, life threatening,  
or disabling (apply event-specific NCI-
CTCAE grading criteria) 
Extreme limitation in activity; significant medical 
intervention/therapy required, hospitalization probable 
5 
Death related to AE 
 
Note:  Regardless of severity, some events may also meet regulatory serious criteria.  Refer to definitions of an 
SAE (see Section 8.1.2). 
aUse these alternative definitions for Grade 1, 2, 3, and 4 events when the observed or reported AE is not in the 
NCI-CTCAE listing. 
 
To ensure consistency of AE and SAE causality assessments, investigators should apply the 
following general guideline: 
• YES 
There is a plausible temporal relationship between the onset of the AE and administration of the 
investigational product, and the AE cannot be readily explained by the patient’s clinical state, 
intercurrent illness, or concomitant therapies; and/or the AE follows a known pattern of response 
to the investigational product; and/or the AE abates or resolves upon discontinuation of the 
investigational product or dose reduction and, if applicable, reappears upon re-challenge. 
• NO 
Evidence exists that the AE has an etiology other than the investigational product 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, or concomitant 
medication); and/or the AE has no plausible temporal relationship to administration of the 
investigational product (e.g., cancer diagnosed 2 days after first dose of study drug). 
Expected adverse events are those adverse events that are listed or characterized in the Product 
Label or current Investigator Brochure. 
Unexpected adverse events are those not listed in the Product Label or current Investigator 
Brochure or not identified. This includes adverse events for which the specific or severity is no 
consistent with the previous description. 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 63 of 99 
8.2.3 Specific Instructions for Recording Adverse Events 
Investigators are strongly encouraged to use correct medical terminology/concepts when 
reporting AEs or SAEs and to avoid colloquialisms and abbreviations. 
a. Diagnosis vs. Signs and Symptoms 
If known at the time of reporting, a diagnosis should be reported rather than individual signs and 
symptoms. However, if a constellation of signs and/or symptoms cannot be medically 
characterized as a single diagnosis or syndrome at the time of reporting, it is ok to report the 
information that is currently available. If a diagnosis is subsequently established, it should be 
reported as follow-up information. 
b. Deaths 
All deaths that occur during the protocol-specified AE reporting period (see Section 8.1.2), 
regardless of attribution, will be reported to the appropriate parties. When recording a death, the 
event or condition that caused or contributed to the fatal outcome should be reported as the single 
medical concept. If the cause of death is unknown and cannot be ascertained at the time of 
reporting, report “Unexplained Death”. 
c. Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the start of the study. Such conditions 
should be reported as medical and surgical history. A preexisting medical condition should be re-
assessed throughout the trial and reported as an AE or SAE only if the frequency, severity, or 
character of the condition worsens during the study. When reporting such events, it is important 
to convey the concept that the preexisting condition has changed by including applicable 
descriptors (e.g., “more frequent headaches”). 
d. Hospitalizations for Medical or Surgical Procedures 
Any AE that results in hospitalization or prolonged hospitalization should be documented and 
reported as an SAE. If a patient is hospitalized to undergo a medical or surgical procedure as a 
result of an AE, the event responsible for the procedure, not the procedure itself, should be 
reported as the SAE. For example, if a patient is hospitalized to undergo coronary bypass 
surgery, record the heart condition that necessitated the bypass as the SAE. 
Hospitalizations for the following reasons do not require reporting: 
• 
Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for preexisting conditions 
• 
Hospitalization or prolonged hospitalization required to allow efficacy measurement 
for the study or 
• 
Hospitalization or prolonged hospitalization for scheduled therapy of the target 
disease of the study. 
e. Pregnancy 
If a female patient becomes pregnant while receiving investigational therapy or within 90 days 
after the last dose of study drug, a report should be completed and expeditiously submitted to the 
EpicentRx, Inc. Follow-up to obtain the outcome of the pregnancy should also occur. Abortion, 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 64 of 99 
whether accidental, therapeutic, or spontaneous, should always be classified as serious, and 
expeditiously reported as an SAE. Similarly, any congenital anomaly/birth defect in a child born 
to a female patient exposed to the investigational product should be reported as an SAE. 
f. Post-Study Adverse Events 
The investigator should expeditiously report any SAE occurring after a patient has completed or 
discontinued study participation if attributed to prior investigational product exposure. If the 
investigator should become aware of the development of cancer or a congenital anomaly in a 
subsequently conceived offspring of a female patient who participated in the study, this should 
be reported as an SAE. 
8.3 Reporting Requirements for Adverse Events 
8.3.1 Expedited Reporting Requirements for Serious Adverse Events 
If an SAE occurs, the Sponsor and its designee are to be notified within 24 hours of awareness 
of the event by the Investigator. In particular, if the SAE is fatal or life-threatening, notification 
to the Sponsor or designee must be made immediately, irrespective of the extent of the available 
SAE information. This timeframe also applies to additional new information (follow up) on 
previously forwarded SAE reports as well as to the initial and follow up reporting of Exposure in 
Utero (Pregnancy) cases. 
In the rare event that the Investigator does not become aware of the occurrence of an SAE 
immediately (e.g., if an outpatient trial patient initially seeks treatment elsewhere), the 
Investigator is to report the event within 24 hours of first awareness of the SAE and to document 
the time of his/her first awareness of the SAE. 
For all SAEs, the Investigator is obligated to pursue and provide information to the Sponsor or 
designee in accordance with the timeframes for reporting specified above. In addition, an 
Investigator may be requested by the Sponsor or designee to obtain specific additional follow up 
information in an expedited fashion. This information may be more detailed than information 
captured on the AE CRF. In general, this will include a description of the AE in sufficient detail 
to allow for a complete medical assessment of the case and independent determination of 
possible causality. Information on other possible causes of the event, such as concomitant 
mediations and illnesses must be provided. In the case of a patient death, a summary of available 
autopsy findings must be submitted as soon as possible to Sponsor or designee.  
The completed SAE CRF page or MedWatch form should be emailed to EpicentRx’s Drug 
Safety Department at: 
 
SAEREPORTING@epicentrx.com 
 
The Medical Monitor, Dr. Bryan Oronsky can be reached at (408) 569-3202 (cell) or 
boronsky@epicentrx.com should any questions arise regarding an SAE or SAE reporting. 
Relevant follow-up information should be submitted to EpicentRx’s Drug Safety as soon as it 
becomes available and/or upon request. 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 65 of 99 
MedWatch 3500A Reporting Guidelines 
In addition to completing appropriate patient demographic and suspect medication information, 
the report should include the following information within the Event Description (Section 5) of 
the MedWatch 3500A form (http://www.fda.gov/medwatch/index.html): 
• Treatment regimen (dosing frequency, combination therapy) 
• Protocol description (and number, if assigned) 
• Description of event, severity, treatment, and outcome, if known 
• Supportive laboratory results and diagnostics 
• Investigator’s assessment of the relationship of the adverse event to each investigational 
product and suspect medication 
 
Follow-up information 
Additional information may be added to a previously submitted report by any of the following 
methods: 
• Adding to the original MedWatch 3500A report and submitting it as follow-up 
• Adding supplemental summary information and submitting it as follow-up with the 
original MedWatch 3500A form  
• Summarizing new information and faxing it with a cover letter including patient 
identifiers (i.e., D.O.B., initials, patient number), protocol description and number, if 
assigned, suspect drug, brief adverse event description, and notation that additional or 
follow-up information is being submitted (The patient identifiers are important so that the 
new information is added to the correct initial report.) 
Occasionally, EpicentRx may contact the reporter for additional information, clarification or 
current status of the patient for whom an adverse event was reported.  For questions regarding 
STEAE reporting, you may contact the EpicentRx Drug Safety representative (Bryan Oronsky, 
MD, (408) 569-3202). 
• The Human Research Protections Program (HRPP) must be notified within 10 business 
days of “any unanticipated problems involving risk to patients or others” (UPR).  
The following events meet the definition of UPR: 
1. 
Any serious event (injuries, side effects, deaths or other problems), which in the 
opinion of the Principal Investigator was unanticipated, involved risk to patients 
or others, and was possibly related to the research procedures. 
2. 
Any serious accidental or unintentional change to the IRB-approved protocol that 
alters the level of risk. 
3. 
Any deviation from the protocol taken without prior IRB review to eliminate 
apparent immediate hazard to a research patient. 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 66 of 99 
4. 
Any new information (e.g., publication, safety monitoring report, updated sponsor 
safety report), interim result or other finding that indicates an unexpected change 
to the risk/benefit ratio for the research. 
5. 
Any breach in confidentiality that may involve risk to the patient or others. 
6. 
Any complaint of a patient that indicates an unanticipated risk or that cannot be 
resolved by the Principal Investigator. 
8.3.2 Routine Reporting of Adverse Events 
• The HRPP will be notified of any adverse events that are not unanticipated problems 
involving risk to patients or other (non-UPRs) at the time of the annual Continuing 
Review. 
8.4 Type and Duration of Follow-Up of Patients After Adverse Events 
All AEs and SAEs that are encountered during the protocol-specified AE reporting period that 
are considered at least possibly related to the study drug should be followed to their resolutions, 
or until the investigator assesses them as stable, or the patient is lost to follow-up.  Resolution of 
AEs and SAEs (with dates) should be documented on the appropriate AE CRF page and in the 
patient’s medical record to facilitate source data verification. 
Recording of Adverse Events includes the study period during protocol specified treatment 
(i.e., RRx-001, carboplatin, cisplatin, investigator’s choice treatment, etc.) until the patient is off 
study.  
For some SAEs, the Sponsor or its designee may follow-up by telephone, fax, electronic mail, 
and/or a monitoring visit to obtain additional case details deemed necessary to appropriately 
evaluate the SAE report (e.g., hospital discharge summary, consultant report, or autopsy report). 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 67 of 99 
9 SPONSOR AND INVESTIGATOR REQUIREMENTS 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of Helsinki. 
The Principal Investigator is responsible for personally overseeing the treatment of all study 
patients. The Principal Investigator must assure that all study site personnel, including sub-
investigators and other study staff members, adhere to the study protocol and all FDA/GCP/NCI 
regulations and guidelines regarding clinical trials both during and after study completion. 
The Principal Investigator will be responsible for assuring that all the required data will be 
collected and entered onto the Case Report Forms. Periodically, monitoring visits will be 
conducted and the Principal Investigator will provide access to his/her original records to permit 
verification of proper entry of data. At the completion of the study, all case report forms will be 
reviewed by the Principal Investigator and will require his/her final signature to verify the 
accuracy of the data. 
9.1 Study Initiation 
Before the start of this study and the shipment of investigational agent to the study site, the 
following documents must be on file at EpicentRx, Inc. 
• U.S. Food and Drug Administration (FDA) Form 1572, signed by the Principal Investigator 
• The names of any sub-investigators must appear on this form.  Investigators must also 
complete all regulatory documentation as required by local regulations 
• Current curricula vitae and license of the Principal Investigator 
• Final Protocol and ICF 
• A signed and dated investigator brochure acceptance form 
• Written documentation of IRB approval of protocol and ICF (identified by title and date of 
approval) for each site 
• A signed Confidentiality Agreement  
• A signed Research Agreement  
9.2 Informed Consent 
The informed consent documents must be signed by the patient, or the patient’s legally 
authorized representative, before his or her participation in the study.  The case history for each 
patient shall document that informed consent was obtained prior to participation in the study.  A 
copy of the informed consent documents must be provided to the patient or the patient’s legally 
authorized representative.  If applicable, they will be provided in a certified translation of the 
local language. 
Original signed consent forms must be filed in the site study binder or in each patient’s study 
file. 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 68 of 99 
9.3 Institutional Review Board Approval 
This protocol, the informed consent document, and relevant supporting information must be 
submitted to the IRB for review and must be approved before the study is initiated.  In addition, 
any advertising materials must be approved by the IRB.  The study will be conducted in 
accordance with U.S. FDA, applicable national and local health authority, and IRB requirements. 
The Principal Investigator is responsible for keeping the IRB apprised of the progress of the 
study and of any changes made to the protocol as deemed appropriate, but in any case, the IRB 
must be updated at least once a year.  The Principal Investigator must also keep the IRB 
informed of any significant adverse events. 
Investigators are required to promptly notify their respective IRB of all adverse drug reactions 
that are both serious and unexpected.  This generally refers to serious adverse events that are not 
already identified in the Investigator Brochure and that are considered possibly or probably 
related to the study drug by the investigator.  Investigators must forward to their IRB any written 
safety report or update provided by EpicentRx (e.g., IND safety report, Investigator Brochure, 
safety amendments and updates, etc.). 
9.4 Study Monitoring Requirements 
The Sponsor will designate a Sponsor’s Study Monitor (i.e., clinical research associate (CRA)) 
who will be responsible for monitoring this clinical trial. The Sponsor’s Study Monitor will 
monitor the study conduct; insure the proper completion and retention of source documentation 
completion and retention, accurate study drug accountability records and prompt data entry to 
CRF. To this end, the Sponsor’s Study Monitor will visit the study site at suitable intervals and 
be in frequent contact through verbal and written communication.  Monitoring may also be 
carried out remotely.  It is essential that the Sponsor’s Study Monitor have access to all 
documents (related to the study and the individual participants) at any time these are requested. 
In turn, the Sponsor’s Study Monitor will adhere to all requirements for patient confidentiality as 
outlined in the Informed consent form (ICF). The Investigator(s) or their representative(s) will be 
expected to cooperate with the Sponsor’s Study Monitor, to be available during a portion of the 
monitoring visit to answer questions, and to provide any missing information. Investigator(s) or 
their representative(s) are required to respond in writing to any deficiencies or protocol 
deviations noted by the monitor in the site visit report. 
9.5 Data Collection 
Study documentation includes all Case Report Forms, data correction forms or queries, source 
documents, correspondence, monitoring logs/letters, and regulatory documents (e.g., protocol 
and amendments, IRB correspondence and approval, signed patient consent forms). 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research study.  
All source documents produced in this study will be maintained by the Investigator, and made 
available for inspection by the Sponsor, regulatory authorities, or both, and redacted copies may 
be requested by Sponsor.   
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 69 of 99 
9.6 Study Medication Accountability 
EpicentRx will provide all study drug (RRx-001) required for completion of this study. The 
recipient will acknowledge receipt of the drug by returning the drug receipt form indicating 
shipment content and condition.  Damaged supplies will be replaced. 
Study drug accountability records should be maintained by the site in accordance with the 
regulations. 
All drug supply requests of RRx-001 will be submitted directly to EpicentRx from the site per 
instructions in the study Pharmacy Manual. 
At the time of study closure, the unused, used and expired study drug will be destroyed at the site 
per Institutional SOPs and EpicentRx should be provided with documentation when this has 
occurred. 
9.7 Disclosure of Data 
Patient medical information obtained by this study is confidential, and disclosure to third parties 
other than those noted below is prohibited. 
In accordance with the Health Information Portability and Accountability Act (HIPAA), patients 
who have provided written informed consent must also sign a patient authorization to release 
medical information to his or her personal physician or other appropriate medical personnel 
responsible for his or her welfare, to EpicentRx and authorized representatives of EpicentRx, 
upon request, for source verification of study documentation.   
Data generated by this study must be available for inspection upon request by representatives of 
the U.S. FDA, local health authorities, EpicentRx, Inc., and their authorized representative(s), 
collaborators and licensees, and the HRPP. 
9.8 Retention of Records 
U.S. FDA regulations (21 CFR §312.62[c]) require that records and documents pertaining to the 
conduct of this study and the distribution of investigational drug, including CRFs, consent forms, 
laboratory test results, and medication inventory records, must be retained by the Principal 
Investigator for 2 years after marketing application approval.  If no application is filed, these 
records must be kept 2 years after the study is discontinued and the U.S. FDA and the applicable 
national and local health authorities are notified.   
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 70 of 99 
10 REFERENCES 
1. 
Abbasi S, Badheeb A, Prognostic Factors in Advanced Non-Small-Cell Lung Cancer 
Subjects: Subject Characteristics and Type of Chemotherapy, Lung Cancer International, 
2011, Article ID 152125, 4 pages 
2. 
Alberola V, Camps C, Provencio M, et al. Cisplatin Plus Gemcitabine Versus a Cisplatin-
Based Triplet Versus Nonplatinum Sequential Doublets in Advanced Non-Small-Cell 
Lung Cancer: A Spanish Lung Cancer Group Phase III Randomized Trial. J Clin Oncol 
2003;21:3207-13. 
3. 
Allen J., Jahanzeb M., Extensive-stage small-cell lung cancer: evolution of systemic 
therapy and future directions, Clin Lung Cancer, 2008, 9(5):262-270 
4. 
Ardizzoni A., Tiseo M, Boni L, Validation of standard definition of sensitive versus 
refractory relapsed small cell lung cancer: A pooled analysis of topotecan second-line 
trials, Eu J Cancer, 2014, 50(13): 2211-2218 
5. 
British Thoracic Society Bronchoscopy Guidelines Committee, a Subcommittee of 
Standards of Care Committee of British Thoracic Society. British thoracic society 
guidelines on diagnostic flexible bronchoscopy. Thorax 2001;56(suppl 1):i1–21. 
6. 
Brzezniak C, Schmitz BA, Peterson PG, Degesys A, Oronsky BT, Scicinski JJ, 
Caroen SZ, Carter CA, RRx-001-Induced Tumor Necrosis and Immune Cell Infiltration in 
an EGFR Mutation-Positive NSCLC with Resistance to EGFR Tyrosine Kinase Inhibitors: 
A Case Report. Case Rep Oncol 2016;9:45-50 
7. 
Burger RA, Brady MF, Bookman MA et al. Incorporation of bevacizumab in the primary 
treatment of ovarian cancer. N. Engl. J. Med.365,2473–2483 (2011). 
8. 
Carbone DP, Minna JD. Chemotherapy for non-small cell lung cancer. BMJ 
1995;311:889-90. 
9. 
Chan BA, Coward, JIG, Chemotherapy advances in small-cell lung cancer, J Thorac 
Disease Lung Cancer, 2013, 5(5): 565 578 
10. Chiou VL, Burotto M, Pseudoprogression and Immune-Related Response in Solid 
Tumors. J Clin Oncol. 2015 Nov 1;33(31):3541-3. 
11. Davies AM, Evans WK, Mackay JA, et al. Treatment of recurrent small cell lung cancer. 
Hematol Oncol Clin North Am, 2004, 18:387-416. 
12. Desai N, Trieu V, Yao Z, et al. (2006) Increased antitumor activity, intratumor paclitaxel 
concentrations, and endothelial cell transport of cremophor-free, albumin-bound 
paclitaxel, ABI-007, compared with cremophor-based paclitaxel. Clin Cancer Res 
12:1317–1324. 
13. DeVore RF, Johnson DH, Chemotherapy of small cell lung cancer. In: Pass HI, Mitchell 
JB, Johnson DH, Turrisi AT,editors. Lung Cancer: Principles and Practice. 1996, 
Philadelphia: Lippincott; p. 825-35. 
14. Douillard JY, Lerouge D, Monnier A, et al. Combined paclitaxel and gemcitabine as first-
line treatment in metastatic non-small cell lung cancer: a multicentre phase II study. Br J 
Cancer 2001;84:1179-84. 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 71 of 99 
15. Dowell J.E., Small cell lung cancer: Are we making progress? Am. J. Med. Sci., 2010, 
339:68–76 
16. Drivsholm, L., Paloheimo, L.I., and Osterlind, K. Chromogranin A, a significant 
prognostic factor in small cell lung cancer, Br. J. Cancer, 1999; 81: 667–671 
17. Eberhardt R, Anantham D, Ernst A, Feller-Kopman D, Herth F. Multimodality 
bronchoscopic diagnosis of peripheral lung lesions: a randomized controlled trial. Am J 
Respir Crit Care Med 2007;176:36–41. 
18. Fossella FV, DeVore R, Kerr RN, et al. Randomized phase III trial of docetaxel versus 
vinorelbine or ifosfamide in subjects with advanced non-small-cell lung cancer previously 
treated with platinum-containing chemotherapy regimens. The TAX 320 Non-Small Cell 
Lung Cancer Study Group. J Clin Oncol 2000;18:2354-62. 
19. Fukuoka M, Yano S, Giaccone G, et al. Multi-institutional randomized phase II trial of 
gefitinib for previously treated subjects with advanced non-small-cell lung cancer (The 
IDEAL 1 Trial) [corrected]. J Clin Oncol 2003;21:2237-46. 
20. Garassino MC, Torri V, Michetti G, Lo Dico M, La Verde N, Aglione S, Mancuso A, et 
al, Outcomes of small-cell lung cancer subjects treated with second-line chemotherapy: a 
multi-institutional retrospective analysis, Lung Cancer, 2011 72(3): 378-383 
21. Georgoulias V, Papadakis E, Alexopoulos A, et al. Platinum-based and non-platinum-
based chemotherapy in advanced non-small-cell lung cancer: a randomised multicentre 
trial. Lancet 2001;357:1478-84. 
22. Gordon AN, Tonda M, Sun S, Rackoff W, Doxil Study 30-49 Investigators. Long-term 
survival advantage for women treated with pegylated liposomal doxorubicin compared 
with topotecan in a phase 3 randomized study of recurrent and refractory epithelial ovarian 
cancer. Gynecol Oncol. 2004 Oct; 95(1):1-8. 
23. Govindan R, Page N, Morgensztern D et al. Changing epidemiology of small-cell lung 
cancer in the United States over the last 30 years: analysis of the Surveillance, 
Epidemiologic, and End Results database. Journal of Clinical Oncology, 2006, 24:4539-
44. 
24. Gridelli C, Gallo C, Shepherd FA, et al. Gemcitabine Plus Vinorelbine Compared With 
Cisplatin Plus Vinorelbine or Cisplatin Plus Gemcitabine for Advanced Non-Small-Cell 
Lung Cancer: A Phase III Trial of the Italian GEMVIN Investigators and the National 
Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2003;21:3025-34. 
25. Gubbels JA, Claussen N, Kapur AK, Connor JP, Patankar MS, The detection, treatment, 
and biology of epithelial ovarian cancer. J Ovarian Res, 2010, 29(3):8. 
26. Hann CL, Ettinger DS. The change in pattern and pathology of small cell lung cancer. In: 
Govindan R. eds. American Society of Clinical Oncology. 2009, Alexandria, VA. 
27. Hanna N, Shepherd FA, Fossella FV, et al. Randomized phase III trial of pemetrexed 
versus docetaxel in subjects with non-small-cell lung cancer previously treated with 
chemotherapy. J Clin Oncol 2004;22:1589-97. 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 72 of 99 
28. Harter P, Du Bois A, Hahmann M, Hasenburg A, Burges A, Loibl S, et al. Surgery in 
recurrent ovarian cancer: the Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) 
DESKTOP OVAR trial. Annals of Surgical Oncology. 2006 p. 1702– 10. 
29. Ingrid H. Olsen, et al. The Scientific World Journal, Volume 2012 (2012), Article ID 
170496, 4 pages 
30. Jackson C. Multi-State Markov and Hidden Markov Models in Continuous Time. R 
package License GPL. 18 November 2015. 
31. Jemal A, Murray T, Ward E, Samuels A, Tiwari RC, Ghafoor A, Feuer EJ, Thun MJ: 
Cancer statistics, CA Cancer J Clin, 2005, 55(1): 10-30. 
32. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J 
Clin 2009;59:225-49. 
33. Kazarian, M., Laird-Offringa, A., Small-cell lung cancer-associated autoantibodies: 
potential applications to cancer diagnosis, early detection, and therapy, Molecular Cancer, 
2011, 10:33 
34. Khan UK, Usmani MS (2011). Radionuclide Infection Imaging: Conventional to Hybrid, 
12 Chapters on Nuclear Medicine, Dr. Ali Gholamrezanezhad (Ed.), ISBN: 978-953-307-
802-1, InTech 
35. Klimstra, DS, et al. Pancreas: August 2010 - Volume 39 - Issue 6 - pp 707-712 
36. Kosmidis P, Mylonakis N, Nicolaides C, et al. Paclitaxel plus carboplatin versus 
gemcitabine plus paclitaxel in advanced non-small-cell lung cancer: a phase III 
randomiz'Aed trial. J Clin Oncol 2002;20:3578-85. 
37. Ledermann JA, Raja FA, Fotopoulou C, Gonzalez-Martin A, Colombo N, Sessa C; ESMO 
Guidelines Working Group. Newly diagnosed and relapsed epithelial ovarian carcinoma: 
ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 
2013 Oct;24 Suppl 6:vi24-32. 
38. Leighl, NB. Treatment paradigms for subjects with metastatic non-small-cell lung cancer: 
first second-, and third-line. Current Oncology, [S.l.], v. 19, p. S52-58, Jun. 2012. ISSN 
1718-7729. 
39. Markman M, Blessing J, Rubin SC, Connor J, Hanjani P, et al. Phase II trial of weekly 
paclitaxel (80 mg/m2) in platinum and paclitaxel-resistant ovarian and primary peritoneal 
cancers: a Gynecologic Oncology Group study. Gynecol Oncol. 2006;101:436–440. 
40. Massarelli E, Andre F, Liu DD, et al. A retrospective analysis of the outcome of subjects 
who have received two prior chemotherapy regimens including platinum and docetaxel for 
recurrent non-small-cell lung cancer. Lung Cancer 2003;39:55-61. 
41. Mirza MR, Monk BJ, Ledermann JA, Oza AM, Del Campo JM, Berek JS, Mahner S, 
Wenham RM, Vergote IB, Fabbro M, Marth C, Dørum A, Lorusso D, Katsaros D, 
Bruchim I, Malander S, Herrstedt J, Agarwal S, Martell RE, Matulonis U, 
941TiPENGOT-OV16/NOVA: a phase 3 randomized double-blind trial of maintenance 
with parp-inhibitor niraparib versus placebo in subjects with platinum-sensitive ovarian 
cancer, Ann Oncol (2014) 25 (suppl 4): iv325 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 73 of 99 
42. Mitry E, Baudin E, Ducreeux M, Sabourin JC, Rufie P, Aparicio T, Lasser P et al. 
Treatment of poorly differentiated neuroendocrine tumours with etoposide and cisplatin, 
Br J Cancer, 1999, 81(8): 1351-1355 
43. Moertel CG, Kvols LK, O'Connell MJ, Rubin J. Treatment of neuroendocrine carcinomas 
with combined etoposide and cisplatin. Evidence of major therapeutic activity in the 
anaplastic variants of these neoplasms. Cancer. 1991, 68(2): 227–232 
44. O’Brien ME, Ciuleanu TE, Tsekov H, et al. Phase III trial comparing supportive care 
alone with supportive care with oral topotecan in subjects with relapsed small-cell lung 
cancer. J Clin Oncol. 2006;24:5441–5447. 
45. Pelayo Alvarez M, Gallego Rubio O, Bonfill Cosp X, Agra Varela Y, Chemotherapy 
versus best supportive care for extensive small cell lung cancer. Cochrane Database Syst 
Rev, 2009 7(4) 
46. Perez-Soler R, Chachoua A, Hammond LA, et al. Determinants of tumor response and 
survival with erlotinib in subjects with non-small-cell lung cancer. J Clin Oncol 
2004;22:3238-47. 
47. Pisano C, Bruni GS, Facchini G, Marchetti C, Pignata S: Treatment of recurrent epithelial 
ovarian cancer. Ther Clin Risk Manag. 2009, 5: 421-426. 
48. Pujade-Lauraine E, Hilpert F, Weber B, Reuss A, Poveda A, Kristensen G, Sorio R, 
Vergote I, Witteveen P, Bamias A, Pereira D, Wimberger P, Oaknin A, Mirza MR, 
Follana P, Bollag D, Ray-Coquard I. Bevacizumab combined with chemotherapy for 
platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase 
III trial. J Clin Oncol. 2014 May 1;32(13):1302-8.  
49. Reid T, Dad S, Korn R, Oronsky B, Knox S, Scicinski J, Two Case Reports of 
Resensitization to Previous Chemotherapy with the Novel Hypoxia-Activated 
Hypomethylating Anticancer Agent RRx-001 in Metastatic Colorectal Cancer Subjects. 
Case Reports in Oncology, 2014. 7: p. 79–85. 
50. Reid T, Oronsky B, Scicinski J, Scribner CL, Knox SJ, Ning S, Peehl DM, Korn R, Stirn 
M, Carter CA, Oronsky A, Taylor MJ, Fitch WL, Cabrales P, Kim MM, Burris HA, Lao 
CD, Abrouk NED, Fanger GR, Infante JR: Safety and activity of RRx-001 in subjects with 
advanced cancer: a first-in-human, open-label, dose-escalation phase 1 study. The Lancet 
Oncology 2015, 16:1133–1142. 
51. Rien BJD, Gupta S, Dada R, Safi J, Michener C, Agarwal A: Potential markers for 
detection and monitoring of ovarian cancer. J Oncology 2011, 2011:475983. 
52. Rodriguez A J, Cortes J, Calvo E, et al. Paclitaxel, cisplatin, and gemcitabine combination 
chemotherapy within a multidisciplinary therapeutic approach in metastatic nonsmall cell 
lung carcinoma. Cancer 2000;89:2622-9. 
53. Scagliotti G, Hanna N, Fossella F, et al. The Differential Efficacy of Pemetrexed 
According to NSCLC Histology: A Review of Two Phase III Studies. Oncologist 2009. 
54. Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus 
gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive subjects with 
advanced-stage non-small-cell lung cancer. J Clin Oncol 2008;26:3543-51. 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 74 of 99 
55. Sharples LD, Sharples CH, Jackson J, Parameshwar J, Wallwork J, Large SR. Diagnostic 
accuracy of coronary angiography and risk factors for post heart-transplant cardiac 
allograft vasculopathy. Transplantation. 2003; 76(4):679-682.  
56. Shepherd FA, Crowley J, Van Houtte P, et al. The International Association for the Study 
of Lung Cancer lung cancer staging project: proposals regarding the clinical staging of 
small cell lung cancer in the forthcoming (seventh) edition of the tumor, node, metastasis 
classification for lung cancer. J Thorac Oncol, 2007, 2:1067-77 
57. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-
small-cell lung cancer. N Engl J Med 2005;353:123-32. 
58. Shia J, Tang LH, Weiser MR, Brenner B, Adsay NV, Stelow EB, Saltz LB et al. Is 
nonsmall cell type high-grade neuroendocrine carcinoma of the tubular gastrointestinal 
tract a distinct disease entity? Am J Surg Pathol, 2008, 32(5): 719-731 
59. Smit EF, van Meerbeeck JPAM, Lianes P, et al. Three-Arm Randomiz'Aed Study of Two 
Cisplatin-Based Regimens and Paclitaxel Plus Gemcitabine in Advanced Non-Small-Cell 
Lung Cancer: A Phase III Trial of the European Organiz'Aation for Research and 
Treatment of Cancer Lung Cancer Group--EORTC 08975. J Clin Oncol 2003;21:3909-17. 
60. Strosberg JR, Coppola D, Klimstra DS, Phan AT, Kulke MH, Wiseman GA, Kvols LK, 
for the North American Neuroendocrine Tumor Society The NANETS consensus 
guidelines for the diagnosis and management of poorly differentiated (high-grade) 
extrapulmonary neuroendocrine carcinomas. Pancreas. 2010;39:799–800. 
61. Wolchok JD, Hoos A, O'Day S, Weber JS, Hamid O, Lebbé C, Maio M, Binder M, 
Bohnsack O, Nichol G, Humphrey R, Hodi FS, Guidelines for the evaluation of immune 
therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res. 2009 
Dec 1; 15(23):7412-20. 
62. Yu H, Arcila ME, Rekhtman N, et al. Analysis of mechanisms of acquired resistance to 
EGFR TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res 
2013;19(8):2240-2247. 
63. Mano MS, Rosa DD, Azambuja E, Ismael G, et al. Current management of ovarian 
carcinosarcoma. Int J Gynecol Cancer. 2007 Mar;17(2):316-24. 
64. Seidman JD, Kurman RJ.Pathology of ovarian carcinoma. Hematol Oncol Clin North Am. 
2003 Aug;17(4):909-25, vii. 
65. Silasi DA, Illuzzi JL, Kelly MG, Rutherford TJ. Carcinosarcoma of the ovary. Int J 
Gynecol Cancer. 2008;18(1):22 
66. Vaidya AP1, Horowitz NS, Oliva E, Halpern EF, Duska LR., Uterine malignant mixed 
mullerian tumors should not be included in studies of endometrial carcinoma. Gynecol 
Oncol. 2006 Nov;103(2):684-7. Epub 2006 Jun 23 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 75 of 99 
11 APPENDICES 
Appendix A. Response evaluation criteria in solid tumors  
Tumor assessments will be made according to the schedule of assessments. Response and 
progression will be evaluated using RECIST v1.1 [Eisenhauer et al. 2009]. 
A1 
MEASURABILITY OF TUMOR AT BASELINE 
A1.1 Definitions 
At baseline, tumor lesions will be categorized as follows: 
A1.1.1 
Measurable 
Tumor lesions: must be accurately measured in at least one dimension (longest diameter in the 
plane of measurements is to be recorded) with a minimum size of: 
• 10 mm by CT scan (CT scan slice thickness no greater than 5 mm). 
• 10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measureable). 
• 20 mm by chest X-ray. 
 
Malignant lymph nodes: to be considered pathologically enlarged and measurable, a lymph node 
must be >= 15 mm in short axis when assessed by CT scan. At baseline and in follow-up, only 
the short axis will be measured and followed. 
A1.1.2 
Non-measurable 
All other lesions, including small lesions (longest diameter < 10 mm or pathological lymph 
nodes with >= 10 to < 15 mm short axis) as well as truly non-measurable lesions. Lesions 
considered truly non-measurable include: leptomeningeal disease, ascites, pleural or pericardial 
effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques. 
A1.1.3 
Special considerations regarding lesion measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment: 
Bone lesions: 
• Bone scan, PET scan or plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 
• Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that 
can be evaluated by cross sectional imaging techniques such as CT or MRI can be considered 
as measurable lesions if the soft tissue component meets the definition of measurability 
described above. 
• Blastic bone lesions are non-measurable.  
 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 76 of 99 
Cystic lesions: 
• Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
• ‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if noncystic 
lesions are present in the same subject, these are preferred for selection as target lesions. 
 
Lesions with prior local treatment: 
• Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-
regional therapy, are usually not considered measurable unless there has been demonstrated 
progression in the lesion. Study protocols should detail the conditions under which such 
lesions would be considered measurable. 
 
A1.2 Specifications by methods of measurements 
 
A1.2.1 
Measurement of lesions 
All measurements should be recorded in metric notation, using calipers if clinically assessed. All 
baseline evaluations should be performed as close as possible to the treatment start and never 
more than 4 weeks before the beginning of the treatment. 
A1.2.2 
Method of assessment 
A diagnostic CT with contrast imaging will be permitted as the baseline evaluation at the 
screening assessment and for lesion assessment. Imaging based evaluation should always be 
done rather than clinical examination unless the lesion(s) being followed cannot be imaged but 
are assessable by clinical exam. 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
and P10mm diameter as assessed using calipers (e.g. skin nodules). For the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesion is 
suggested. As noted above, when lesions can be evaluated by both clinical exam and imaging, 
imaging evaluation should be undertaken since it is more objective and may also be reviewed at 
the end of the study. 
Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions. However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung. 
CT: For the purposes of this study a diagnostic CT with contrast will be used for lesion 
assessment.  
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next. If new lesions are identified by ultrasound in the course of the study, confirmation by MRI 
is advised. 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 77 of 99 
Endoscopy, laparoscopy: The utilization of these techniques for objective tumor evaluation is 
not advised. However, they can be useful to confirm complete pathological response when 
biopsies are obtained or to determine relapse in trials where recurrence following complete 
response or surgical resection is an endpoint. 
Tumor markers: Tumor markers alone cannot be used to assess objective tumor response. If 
markers are initially above the upper normal limit, however, they must normalize for a patient to 
be considered in complete response. Because tumor markers are disease specific, instructions for 
their measurement should be incorporated into protocols on a disease specific basis.  
Cytology, histology: These techniques can be used to differentiate between PR and CR in rare 
cases if required by protocol (for example, residual lesions in tumor types such as germ cell 
tumors, where known residual benign tumors can remain). When effusions are known to be a 
potential adverse effect of treatment (e.g. with certain taxane compounds or angiogenesis 
inhibitors), the cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment can be considered if the measurable tumor has met criteria for response 
or stable disease in order to differentiate between response (or stable disease) and progressive 
disease. 
B2 
TUMOR RESPONSE EVALUATION 
 
B2.1 
Baseline documentation of ‘target’ and ‘non-target’ lesions 
When more than one measurable lesion is present at baseline all lesions up to a maximum of five 
lesions total (and a maximum of two lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline (this means 
in instances where patients have only one or two organ sites involved a maximum of two and 
four lesions respectively will be recorded).  
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion which 
can be measured reproducibly should be selected.  
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
P15mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. The 
short axis of the node is the diameter normally used by radiologists to judge if a node is involved 
by solid tumor. Nodal size is normally reported as two dimensions in the plane in which the 
image is obtained (for CT scan this is almost always the axial plane; for MRI the plane of 
acquisition may be axial, sagittal or coronal). The smaller of these measures is the short axis. 
For example, an abdominal node which is reported as being 20mm· 30mm has a short axis of 
20mm and qualifies as a malignant, measurable node. In this example, 20mm should be recorded 
as the node measurement. All other pathological nodes (those with short axis P10mm but 
<15 mm) should be considered non-target lesions. Nodes that have a short axis <10mm are 
considered non-pathological and should not be recorded or followed. 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 78 of 99 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease. 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’ 
(more details to follow). In addition, it is possible to record multiple non-target lesions involving 
the same organ as a single item on the case record form (e.g. ‘multiple enlarged pelvic lymph 
nodes’ or ‘multiple liver metastases’). 
B2.3 
Response criteria 
This section provides the definitions of the criteria used to determine objective tumor response 
for target lesions. 
B2.3.1 
Evaluation of target lesions 
Complete Response (CR):  
Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to 
<10 mm. 
Partial Response (PR):  
At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters. 
Progressive Disease (PD):  
At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study). In addition to the 
relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. (Note: the appearance of one or 
more new lesions is also considered progression). 
Stable Disease (SD):  
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum 
diameters while on study.  
 
B2.3.2 
Special notes on the assessment of target lesions 
Lymph nodes. Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline examination), 
even if the nodes regress to below 10mm on study. This means that when lymph nodes are 
included as target lesions, the ‘sum’ of lesions may not be zero even if complete response criteria 
are met, since a normal lymph node is defined as having a short axis of <10mm. Case report 
forms or other data collection methods may therefore be designed to have target nodal lesions 
recorded in a separate section where, in order to qualify for CR, each node must achieve a short 
axis <10mm. For PR, SD and PD, the actual short axis measurement of the nodes is to be 
included in the sum of target lesions. 
Target lesions that become ‘too small to measure’. While on study, all lesions (nodal and non-
nodal) recorded at baseline should have their actual measurements recorded at each subsequent 
evaluation, even when very small (e.g. 2 mm). However, sometimes lesions or lymph nodes 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 79 of 99 
which are recorded as target lesions at baseline become so faint on MRI scan that the radiologist 
may not feel comfortable assigning an exact measure and may report them as being ‘too small to 
measure’. When this occurs it is important that a value be recorded on the case report form. If it 
is the opinion of the radiologist that the lesion has likely disappeared, the measurement should be 
recorded as 0mm. If the lesion is believed to be present and is faintly seen but too small to 
measure, a default value of 5 mm should be assigned (Note: It is less likely that this rule will be 
used for lymph nodes since they usually have a definable size when normal and are frequently 
surrounded by fat such as in the retroperitoneum; however, if a lymph node is believed to be 
present and is faintly seen but too small to measure, a default value of 5mm should be assigned 
in this circumstance as well).  The measurement of these lesions is potentially non-reproducible; 
therefore providing this default value will prevent false responses or progressions based upon 
measurement error. To reiterate, however, if the radiologist is able to provide an actual measure, 
that should be recorded, even if it is below 5 mm. 
Lesions that split or coalesce on treatment. When non-nodal lesions ‘fragment’, the longest 
diameters of the fragmented portions should be added together to calculate the target lesion sum. 
Similarly, as lesions coalesce, a plane between them may be maintained that would aid in 
obtaining maximal diameter measurements of each individual lesion. If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in this 
instance should be the maximal longest diameter for the ‘coalesced lesion’. 
B2.3.3 
Evaluation of non-target lesions 
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions. While some non-target lesions may actually be measurable, they 
need not be measured and instead should be assessed only qualitatively at the time points 
specified in the protocol. 
Complete Response (CR):  
Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size 
(<10 mm short axis). 
Non-CR/Non-PD:  
Persistence of one or more non-target lesion(s) and/or maintenance 
of tumor marker level above the normal limits. 
Progressive Disease (PD):  
Unequivocal progression (see comments below) of existing non-
target lesions. (Note: the appearance of one or more new lesions is 
also considered progression).  
 
B2.3.4 
Special notes on assessment of progression of non-target disease 
The concept of progression of non-target disease requires additional explanation as follows: 
When the patient also has measurable disease. In this setting, to achieve ‘unequivocal 
progression’ on the basis of the non-target disease, there must be an overall level of substantial 
worsening in non-target disease such that, even in presence of SD or PR in target disease, the 
overall tumor burden has increased sufficiently to merit discontinuation of therapy. A modest 
‘increase’ in the size of one or more non-target lesions is usually not sufficient to quality for 
unequivocal progression status. The designation of overall progression solely on the basis of 
change in non-target disease in the face of SD or PR of target disease will therefore be extremely 
rare. 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 80 of 99 
When the patient has only non-measurable disease. This circumstance arises in some phase III 
trials when it is not a criterion of study entry to have measurable disease. The same general 
concepts apply here as noted above, however, in this instance there is no measurable disease 
assessment to factor into the interpretation of an increase in non-measurable disease burden. 
Because worsening in non-target disease cannot be easily quantified (by definition: if all lesions 
are truly non-measurable) a useful test that can be applied when assessing patients for 
unequivocal progression is to consider if the increase in overall disease burden based on the 
change in non-measurable disease is comparable in magnitude to the increase that would be 
required to declare PD for measurable disease: i.e.an increase in tumor burden representing an 
additional 73% increase in ‘volume’ (which is equivalent to a 20% increase diameter in a 
measurable lesion). Examples include an increase in a pleural effusion from ‘trace’ to ‘large’, an 
increase in lymphangitic disease from localized to widespread, or may be described in protocols 
as ‘sufficient to require a change in therapy’. If ‘unequivocal progression’ is seen, the patient 
should be considered to have had overall PD at that point. While it would be ideal to have 
objective criteria to apply to non-measurable disease, the very nature of that disease makes it 
impossible to do so, therefore the increase must be substantial.  
B2.4.5 
New lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal: i.e. not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumor (for example, some ‘new’ 
bone lesions may be simply healing or flare of pre-existing lesions). This is particularly 
important when the patient’s baseline lesions show partial or complete response.  
A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. An example of this is 
the patient who has visceral disease at baseline and while on study has a CT or MRI brain 
ordered which reveals metastases. The patient’s brain metastases are considered to be evidence 
of PD even if he/she did not have brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy and follow-
up evaluation will clarify if it represents truly new disease. If repeat scans confirm there is 
definitely a new lesion, then progression should be declared using the date of the initial scan. 
While FDG-PET response assessments need additional study, it is sometimes reasonable to 
incorporate the use of FDG-PET scanning to complement CT scanning in assessment of 
progression (particularly possible ‘new’ disease). New lesions on the basis of FDG-PET imaging 
can be identified according to the following algorithm: 
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow- up: 
If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by 
CT, this is PD. If the positive FDG-PET at follow-up is not confirmed as a new site of 
disease on CT, additional follow-up CT scans are needed to determine if there is truly 
progression occurring at that site (if so, the date of PD will be the date of the initial 
abnormal FDG-PET scan). If the positive FDG-PET at follow-up corresponds to a pre-
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 81 of 99 
existing site of disease on CT that is not progressing on the basis of the anatomic images, 
this is not PD. 
B2.4 
Evaluation of best overall response  
The best overall response is the best response recorded from the start of the study treatment until 
the end of treatment taking into account any requirement for confirmation. On occasion a 
response may not be documented until after the end of therapy so protocols should be clear if 
post-treatment assessments are to be considered in determination of best overall response. 
Protocols must specify how any new therapy introduced before progression will affect best 
response designation. The patient’s best overall response assignment will depend on the findings 
of both target and non-target disease and will also take into consideration the appearance of new 
lesions. Furthermore, depending on the nature of the study and the protocol requirements, it may 
also require confirmatory measurement. Specifically, in non-randomized trials where response is 
the primary endpoint, confirmation of PR or CR is needed to deem either one the ‘best overall 
response’. This is described further below. 
B2.4.1 
Time point response 
It is assumed that at each protocol specified time point, a response assessment occurs. Table 1 
provides a summary of the overall response status calculation at each time point for patients who 
have measurable disease at baseline. 
When patients have non-measurable (therefore non-target) disease only, Table 2 is to be used. 
Table 1. Time point response: patients with target (+ non-target) disease. 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
Inevaluable 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
Table 2. Time point response: patients with non-target disease only. 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD 
Not all evaluated 
No 
Inevaluable 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
B2.4.2 
Missing assessments and unevaluable designation 
When no imaging/measurement is done at all at a particular time point, the patient is not 
evaluable (NE) at that time point. If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered NE at that time point, unless a convincing 
argument can be made that the contribution of the individual missing lesion(s) would not change 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 82 of 99 
the assigned time point response. This would be most likely to happen in the case of PD. For 
example, if a patient had a baseline sum of 50 mm with three measured lesions and at follow-up 
only two lesions were assessed, but those gave a sum of 80 mm, the patient will have achieved 
PD status, regardless of the contribution of the missing lesion. 
B2.4.3 
Best overall response: all time points 
The best overall response is determined once all the data for the patient is known. 
Best response determination in trials where confirmation of complete or partial response IS NOT 
required: Best response in these trials is defined as the best response across all time points (for 
example, a patient who has SD at first assessment, PR at second assessment, and PD on last 
assessment has a best overall response of PR). When SD is believed to be best response, it must 
also meet the protocol specified minimum time from baseline. If the minimum time is not met 
when SD is otherwise the best time point response, the patient’s best response depends on the 
subsequent assessments. For example, a patient who has SD at first assessment, PD at second 
and does not meet minimum duration for SD, will have a best response of PD. The same patient 
lost to follow-up after the first SD assessment would be considered unevaluable. 
Best response determination in trials where confirmation of complete or partial response IS 
required: Complete or partial responses may be claimed only if the criteria for each are met at a 
subsequent time point as specified in the protocol (generally 4 weeks later). In this circumstance, 
the best overall response can be interpreted as in Table 3. 
Table 3. Best overall response when confirmation of CR and PR required. 
Overall response 
First time point 
Overall response 
Subsequent time point 
BEST overall response 
CR 
CR 
CR 
CR 
PR 
SD, PD OR PR 
CR 
SD 
SD provided minimum criteria for SD duration met, 
otherwise PD 
CR 
PD 
SD provided minimum criteria for SD duration met, 
otherwise PD 
CR 
Inevaluable 
SD provided minimum criteria for SD duration met, 
otherwise inevaluable 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration met, 
otherwise PD 
PR 
Inevaluable 
SD provided minimum criteria for SD duration met, 
otherwise inevaluable 
Inevaluable 
Inevaluable 
Inevaluable 
 
B2.4.4 
Special notes on response assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to ‘normal’ 
size (<10 mm), they may still have a measurement reported on scans. This measurement should 
be recorded even though the nodes are normal in order not to overstate progression should it be 
based on increase in size of the nodes. As noted earlier, this means that patients with CR may not 
have a total sum of ‘zero’ on the case report form (CRF). 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 83 of 99 
In trials where confirmation of response is required, repeated ‘NE’ time point assessments may 
complicate best response determination. The analysis plan for the trial must address how missing 
data/assessments will be addressed in determination of response and progression. For example, 
in most trials it is reasonable to consider a patient with time point responses of PR-NE-PR as a 
confirmed response. 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
‘symptomatic deterioration’. Every effort should be made to document objective progression 
even after discontinuation of treatment. Symptomatic deterioration is not a descriptor of an 
objective response: it is a reason for stopping study therapy. The objective response status of 
such patients is to be determined by evaluation of target and non-target disease as shown in 
Tables 1–3. 
Conditions that define ‘early progression, early death and inevaluability’ are study specific and 
should be clearly described in each protocol (depending on treatment duration, treatment 
periodicity). 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends upon this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) before assigning a status of 
complete response. FDG-PET may be used to upgrade a response to a CR in a manner similar to 
a biopsy in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring. The use of FDG-PET in this circumstance should be prospectively described in the 
protocol and supported by disease specific medical literature for the indication. However, it must 
be acknowledged that both approaches may lead to false positive CR due to limitations of FDG-
PET and biopsy resolution/sensitivity. 
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic changes 
or necrosis in existing lesions), treatment may continue until the next scheduled assessment. If at 
the next scheduled assessment, progression is confirmed, the date of progression should be the 
earlier date when progression was suspected. 
B2.5 
Confirmatory measurement/duration of response 
B2.5.1 
Confirmation 
In non-randomized trials where response is the primary endpoint, confirmation of PR and CR is 
required to ensure responses identified are not the result of measurement error. This will also 
permit appropriate interpretation of results in the context of historical data where response has 
traditionally required confirmation in such trials. However, in all other circumstances, i.e. in 
randomized trials (Phase II or III) or studies where stable disease or progression are the primary 
endpoints, confirmation of response is not required since it will not add value to the 
interpretation of trial results. However, elimination of the requirement for response confirmation 
may increase the importance of central review to protect against bias, in particular in studies that 
are not blinded. 
In the case of SD, measurements must have met the SD criteria at least once after study entry at a 
minimum interval that is defined in the study protocol. 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 84 of 99 
B2.5.2 
Duration of overall response 
The duration of overall response is measured from the time measurement criteria are first met for 
CR/PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest measurements 
recorded on study). 
The duration of overall complete response is measured from the time measurement criteria are 
first met for CR until the first date that recurrent disease is objectively documented. 
B2.5.3 
Duration of stable disease 
Stable disease is measured from the start of the treatment (in randomized trials, from date of 
randomization) until the criteria for progression are met, taking as reference the smallest sum on 
study (if the baseline sum is the smallest, this is the reference for calculation of PD). 
The clinical relevance of the duration of stable disease varies in different studies and diseases. If 
the proportion of patients achieving stable disease for a minimum period of time is an endpoint 
of importance in a particular trial, the protocol should specify the minimal time interval required 
between two measurements for determination of stable disease. 
Note: The duration of response and stable disease as well as the progression-free survival are 
influenced by the frequency of follow-up after baseline evaluation. It is not in the scope of this 
guideline to define a standard follow-up frequency. The frequency should take into account 
many parameters including disease types and stages, treatment periodicity and standard practice. 
However, these limitations of the precision of the measured endpoint should be taken into 
account if comparisons between trials are to be made. 
Reference: 
Eisenhauer EA, Therasse P, Bogaerts J et al. New response evaluation criteria in solid tumours: 
Revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45:228-247. 
 
 
 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 85 of 99 
Appendix B. ECOG performance status scale 
 
 
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance 
without restriction 
1 
Restricted in physically strenuous activity but ambulatory 
and able to carry out work of a light or sedentary nature, 
e.g., light housework or office work 
2 
Ambulatory and capable of all self-care but unable to 
carry out any work activities.  Up and about >50% of 
waking hours 
3 
Capable of only limited self-care, confined to a bed or 
chair >50% of waking hours 
4 
Completely disabled.  Cannot carry on any self-care.   
Totally confined to bed or chair 
5 
Dead 
 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 86 of 99 
Appendix D. Visual Analogue Fatigue Scale  
 
Please mark an “X” on the number scale to indicate your overall fatigue level with 0 being not at 
all tired and 10 being extremely tired  
 
 
 
 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 87 of 99 
Appendix F. Imaging Collection for Independent Review: 
Upon request, all imaging performed while patient is on-study, including imaging performed 
during screening, is to be sent to EpicentRx or uploaded to an imaging assessor web based 
platform within six (6) weeks of procedure visit for independent radiology assessment.  
 
Imaging should be redacted to exclude patient identifiers in accordance with HIPPA regulations 
and, when provided outside of a web based platform, prepared in electronic format (e.g., CD, 
USB flash drive, etc.) to include: 
a. Site and patient number (XXX-XXX) 
b. Imaging procedure date (MM/DD/YYYY) 
c. Copy of local radiology report 
 
 
Attn: Scott Caroen 
EpicentRx 
11099 North Torrey Pines Rd, Suite 160 
La Jolla, CA 92037 
Phone: 415-715-7786 
 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 88 of 99 
Appendix G. Schedules of Assessments 
SCC (Arm 1, table 1 of 2) RRx-001 Priming, Platinum Rechallenge (3-week cycles)  
– RRx-001 / Platinum ‘Maintenance’ for patients that complete the Platinum Rechallenge with > SD is shown on the subsequent table 
 
 
 
Assessment / Procedure 
 
Screening 
< 14 days 
of C0 D1 
RRx-001 Priming* 
Platinum Rechallenge 
 
±3 day window unless otherwise stated in footnotes 
Imaging 
Assessment 
q2 platinum 
cycles 
(± 7 days) 
End of 
Study 
(EOS)10 
Follow-
up 
Period11 
(± 7 days) 
C 0 
D 1 
C 0 
D 8 
C 0 
D 15 
C 1 
D 1 
C 1  
D 8 
C 2-4 
D 1 
Informed Consent 
X 
  
  
  
  
  
  
  
  
  
Med/Onc History 
X 
  
  
  
  
  
  
  
  
  
Demographics 
X 
  
  
  
  
  
  
  
  
  
Physical Exam1 
X 
X 
X 
X 
X 
X 
X 
  
X 
  
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
  
X 
  
ECOG Status 
X 
X 
X 
X 
X 
X 
X 
  
X 
  
Lesion Assessment by diagnostic CT with contrast2 
X 
  
  
X 
  
  
  
X 
  
  
Brain Imaging (CT or MRI) 
X 
  
  
  
  
  
  
  
  
  
Administer RRx-0013 
  
X 
X 
X 
  
 
  
  
  
  
Administer Platinum-Based Chemotherapy4 
  
  
  
  
X 
 
X 
  
  
  
CBC and CMP (incl Magnesium, LDH) 5 
X 
X5 
X5 
X5 
X 
X 
X 
  
X 
  
Beta Natriuretic Peptide (BNP)6 
X 
  
  
  
  
  
X  
(C4 only) 
  
  
  
Hemoglobin A1C (HbA1C) 
X 
  
  
  
  
  
X 
(C4 only) 
  
  
  
25-OH vitamin D (25-OHD) 
X 
  
  
  
  
  
X 
(C4 only) 
  
  
  
Tumor Tissue7 
X 
  
  
  
X 
  
  
  
  
  
Pregnancy Test8 
X 
  
  
  
  
  
  
  
  
  
Record adverse events 
X 
X 
X 
X 
X 
X 
X 
  
X 
  
Record concomitant therapies, medications and/or 
procedures 
X 
X 
X 
X 
X 
X 
X 
  
X 
  
Visual Analogue Fatigue Scale (Appendix D) 
X 
X 
  
  
X 
  
X 
  
  
  
Central Lab Collection: Circulating Tumor Cells (CTCs)9 
  
X 
  
  
X 
  
  
  
  
  
Central Lab Collection: Immune Subsets9 
  
X 
  
  
X 
  
  
  
  
  
Central Lab Collection: Lysine Acetylation9 
  
X 
  
  
X 
  
  
  
  
  
Central Lab Collection: CEC/CEP9 
  
X 
  
  
X 
  
  
  
  
  
Central Lab Collection: Serum miRNA Analysis9 
  
X 
  
  
X 
  
  
  
  
  
Survival Contact 
  
  
  
  
  
  
  
  
  
X 
* If patient experiences disease progression during the RRx-001 Priming (initial 3 weeks), subject may discontinue RRx-001 and proceed to Platinum Rechallenge  
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 89 of 99 
1. 
Full physical exam is required at Screening. Subsequent physical exams may be symptom-directed. Each PE must include vital signs and weight. 
2. 
Screening imaging must be obtained within 14 days prior to C0D1. A diagnostic CT with contrast must be performed at the end of Cycle 0, prior to initiation of platinum 
treatment, then every 2 cycles from start of platinum treatment (every 2 cycles ±7 Days) during the Platinum Rechallenge. SCC patients also require a Brain MRI within 8 
weeks prior to C0D1 (does not need to be repeated if SOC imaging performed within window; head CT is allowed if MRI is contraindicated). Lesion assessment will be by 
RECIST v1.1.  In addition to local assessment, upon request, all imaging performed while patient is ‘on-study’ is to be sent to EpicentRx within six (6) weeks of procedure visit 
for independent radiology review. Reference Appendix F for format and shipping instructions.  During the ‘follow-up period’, for subjects continuing to be imaged at the study 
site, a copy of the imaging and local radiology report will be made available upon request.  Subjects may choose to withdraw from making their imaging available during the 
follow-up period (once they are ‘off-study’). 
3. 
Premedication with 10 mg of dexamethasone, or a similar corticosteroid, and a low-dose aspirin (81 mg) or Acetaminophen (500 mg) is required within 2 hours prior to the 
infusion of RRx-001 blood mix. If patient is already receiving dexamethasone or equivalent corticosteroid, premedication with dexamethasone should not be given. 
4. 
During the ‘Platinum Rechallenege’, Administer carboplatin AUC 5-6 IV on day 1 or cisplatin 60-80 mg/m2 IV on day 1 plus etoposide per protocol and approved package 
insert every 21 days for up to 4 cycles. 
5. 
During the RRx-001 Priming period for RRx-001 dosing visits on Day 1 and Day 8, the LDH lab value should be processed and sent to EpicentRx (entered into EDC or emailed 
to study manager) within 48 hours of test blood collection. If LDH value increases by > 25% from Day 1 to Day 8, RRx-001 is to be discontinued and Platinum Rechallenge 
will begin 1 week sooner than scheduled (skipping the RRx-001 Priming Period Day 15 visit).  
6. 
Only to be performed if subject is a smoker. During screening and Day 1 of Cycle 4 only.  
7. 
New tumor biopsy, if feasible, will performed on an optional basis prior to infusion of RRx-001 (baseline) and prior to initial platinum rechallange Day 1 (up to 7 Days prior but 
following discontinuation of RRx-001).  Archival tissue, if available, will be collected at baseline.  For details regarding the processing of samples please refer to the latest study 
lab manual. 
8. 
For women of childbearing potential (WOCBP), a negative serum or urine pregnancy test is required prior to entering this study WOCBP and men whose partners are able to 
become pregnant will be asked to use non-hormonal methods of contraception for the entire duration of the study and for up to 90 days after their last dose with RRx-001 and 
through platinum phase. 
9. 
To be collected and sent to sponsor-designated central lab and may be collected up to 3 days prior to treatment administration. Blood samples will be drawn from all subjects by 
venipuncture or central venous catheter. For detailed collection, processing, and shipment requirements reference the Collection Flow Chart in the latest study lab manual. 
10. If subject demonstrates progressive disease (PD) during platinum treatment, treatment will be discontinued and subject will complete End of Study (EOS) visit within 30 days of 
termination of platinum dosing and move into follow-up period. If subject has > SD at discontinuation of Platinum Rechallenge period, subject continues onto 
maintenance portion of ARM 1 (see section below). 
11. Follow-up Period begins when patient has PD during Platinum Rechallenge or RRx-001/Platinum Maintenance treatment, or discontinues treatment for any other reason. 
Subjects with stable disease or better (SD, PR or CR) at discontinuation of Platinum Rechallenge continue into the RRx-001/Platinum Maintenance until progression. Survival 
contact will occur via medical record review, telephone call or Social Security Death Index every 8 weeks (± 7 days) until death. For subjects continuing to be imaged at the 
study site, a copy of the imaging and local radiology report will be made available upon request.  Subjects may choose to withdraw from making their imaging available during 
the follow-up period (once they are ‘off-study’). 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 90 of 99 
SCC (Arm 1, table 2 of 2) RRx-001 & Platinum (single agent) ‘Maintenance’  
2 Weeks RRx-001 followed by 2 Cycles Platinum (Carboplatin or Cisplatin, single agent), repeating until PD 
(For Subjects with > SD at Discontinuation of ‘Platinum Rechallenge’) 
 
 
 
Assessment / Procedure 
RRx-001 
Maintenance 
Platinum  
Maintenance 
±3 day window unless  
otherwise stated in footnotes 
Imaging 
Assessment 
q2 platinum 
cycles 
(± 7 days) 
End of 
Study 
(EOS)5 
Follow-up 
Period6 
(± 7 days) 
Each 
Cycle 
D 1 
Each 
Cycle 
D 8 
Each 
Cycle  
D 1 
Physical Exam1 
X 
X 
X 
  
X 
  
Vital Signs 
X 
X 
X 
  
X 
  
ECOG Status 
X 
X 
X 
  
X 
  
Lesion Assessment by diagnostic CT with contrast2 
  
  
  
X 
  
  
Brain Imaging (CT or MRI) 
  
  
  
  
  
  
Administer RRx-0013 
X 
X 
  
  
  
  
Administer Single Agent Platinum Chemotherapy4 
  
  
X 
  
  
  
CBC and CMP (incl Magnesium, LDH) 
X 
X 
X 
  
X 
  
Record adverse events 
X 
X 
X 
  
X 
  
Record concomitant therapies, medications and/or 
procedures 
X 
X 
X 
  
X 
  
Visual Analogue Fatigue Scale (Appendix D) 
X 
  
X 
  
  
  
Survival Contact 
  
  
  
  
  
X 
 
1. 
Maintenance RRx-001 and Platinum physical exams may be symptom-directed. Each PE must include vital signs and weight. 
2. 
During the Maintenance RRx-001 and Platinum period, a diagnostic CT with contrast must be performed every 2 platinum cycles (approximately every 8 weeks ±7 Days). 
Lesion assessment will be by RECIST v1.1.  In addition to local assessment, upon request, all imaging performed while patient is ‘on-study’ is to be sent to EpicentRx within 
six (6) weeks of procedure visit for independent radiology review. Reference Appendix F for format and shipping instructions.  During the ‘follow-up period’, for subjects 
continuing to be imaged at the study site, a copy of the imaging and local radiology report will be made available upon request.  Subjects may choose to withdraw from making 
their imaging available during the follow-up period (once they are ‘off-study’). 
3. 
Premedication with 10 mg of dexamethasone, or a similar corticosteroid, and a low-dose aspirin (81 mg) or Acetaminophen (500mg) is required within 2 hours prior to the 
infusion of RRx-001 blood mix. If patient is already receiving dexamethasone or equivalent corticosteroid, premedication with dexamethasone should not be given. 
4. 
During ‘Platinum Maintenance’, Administer carboplatin AUC 5-6 IV on day 1 or cisplatin 60-80 mg/m2 IV on day 1 as a single agent per protocol and approved package 
insert every 21 days for 2 cycles. 
5. 
RRx-001 Maintenance and Platinum Maintenance repeat until progression or intolerable toxicity. If subject demonstrates progressive disease (PD) during RRx-001/Platinum 
Maintenance, treatment will be discontinued and subject will complete End of Study (EOS) visit within 30 days of termination of treatment and move into follow-up period. 
6. 
Follow-up Period begins when patient has PD during Platinum Rechallenge or RRx-001/ Platinum Maintenance treatment, or discontinues treatment for any other reason. 
Survival contact will occur via medical record review, telephone call or Social Security Death Index every 8 weeks (± 7 days) until death. For subjects continuing to be imaged 
at the study site, a copy of the imaging and local radiology report will be made available upon request.  Subjects may choose to withdraw from making their imaging available 
during the follow-up period (once they are ‘off-study’). 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 91 of 99 
Ovarian (Arm 1, table 1 of 2) RRx-001 Priming, Platinum Rechallenge  
– RRx-001 / Platinum ‘Maintenance’ for patients that complete the Platinum Rechallenge with > SD is shown on the subsequent table 
 
 
 
Assessment / Procedure 
 
Screening 
< 14 days 
of C0 D1 
RRx-001 Priming* 
Platinum Rechallenge 
 
±3 day window unless otherwise 
stated in footnotes 
Imaging Assessment 
q2 platinum cycles 
(± 7 days) 
End of 
Study 
(EOS)8 
Follow-up 
Period9 
(± 7 days) 
C 0 
D 1 
C 0 
D 8 
C 1 
D 1 
C 1  
D 8 
C 2 
D 1 
Informed Consent 
X 
  
  
  
  
  
  
  
  
Med/Onc History 
X 
  
  
  
  
  
  
  
  
Demographics 
X 
  
  
  
  
  
  
  
  
Physical Exam1 
X 
X 
X 
X 
X 
X 
  
X 
  
Vital Signs 
X 
X 
X 
X 
X 
X 
  
X 
  
ECOG Status 
X 
X 
X 
X 
X 
X 
  
X 
  
Lesion Assessment by diagnostic CT with contrast2 
X 
  
  
  
  
  
X 
  
  
Administer RRx-0013 
  
X 
X 
  
 
  
  
  
  
Administer Platinum (Carboplatin) Chemotherapy4 
  
  
  
X 
 
X 
  
  
  
CBC and CMP (incl Magnesium, LDH) 
X 
X 
X 
X 
X 
X 
  
X 
  
Tumor Tissue5 
X 
  
  
X 
  
  
  
  
  
Pregnancy Test6 
X 
  
  
  
  
  
  
  
  
Record adverse events 
X 
X 
X 
X 
X 
X 
  
X 
  
Record concomitant therapies, medications and/or 
procedures 
X 
X 
X 
X 
X 
X 
  
X 
  
Visual Analogue Fatigue Scale (Appendix D) 
X 
X 
  
X 
  
X 
  
  
  
Central Lab Collection: Circulating Tumor Cells (CTCs)7 
  
X 
  
X 
  
  
  
  
  
Central Lab Collection: Immune Subsets7 
  
X 
  
X 
  
  
  
  
  
Central Lab Collection: Lysine Acetylation7 
  
X 
  
X 
  
  
  
  
  
Central Lab Collection: CEC/CEP7 
  
X 
  
X 
  
  
  
  
  
Central Lab Collection: Serum miRNA Analysis7 
  
X 
  
X 
  
  
  
  
  
Survival Contact 
  
  
  
  
  
  
  
  
X 
 
* If patient experiences disease progression during the RRx-001 Priming (initial 2 weeks), subject may discontinue RRx-001 and proceed to Platinum Rechallenge 
1. 
Full physical exam is required at Screening. Subsequent physical exams may be symptom-directed. Each PE must include vital signs and weight. 
2. 
Screening imaging must be obtained within 14 days prior to C0D1. A diagnostic CT with contrast must be performed at the end of Cycle 0, prior to initiation of platinum 
treatment, then every 2 cycles from start of platinum treatment (every 2 cycles ±7 Days) during the Platinum Rechallenge. Lesion assessment will be by RECIST v1.1.  In 
addition to local assessment, upon request, all imaging performed while patient is ‘on-study’ is to be sent to EpicentRx within six (6) weeks of procedure visit for independent 
radiology review. Reference Appendix F for format and shipping instructions.  During the ‘follow-up period’, for subjects continuing to be imaged at the study site, a copy of 
the imaging and local radiology report will be made available upon request.  Subjects may choose to withdraw from making their imaging available during the follow-up period 
(once they are ‘off-study’). 
3. 
Premedication with 10 mg of dexamethasone, or a similar corticosteroid, and a low-dose aspirin (81 mg) or Acetaminophen (500 mg) is required within 2 hours prior to the 
infusion of RRx-001 blood mix. If patient is already receiving dexamethasone or equivalent corticosteroid, premedication with dexamethasone should not be given. 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 92 of 99 
4. 
During the ‘Platinum Rechallenege’, Administer carboplatin AUC 5-6 IV on day 1 per protocol and approved package insert every 21 days for 2 cycles. 
5. 
New tumor biopsy, if feasible, will performed on an optional basis prior to infusion of RRx-001 (baseline) and prior to initial platinum rechallange Day 1 (up to 7 Days prior but 
following discontinuation of RRx-001).  Archival tissue, if available, will be collected at baseline.  For details regarding the processing of samples please refer to the latest study 
lab manual. 
6. 
For women of childbearing potential (WOCBP), a negative serum or urine pregnancy test is required prior to entering this study. WOCBP and men whose partners are able to 
become pregnant will be asked to use non-hormonal methods of contraception for the entire duration of the study and for up to 90 days after their last dose with RRx-001 and 
through platinum phase. 
7. 
To be collected and sent to sponsor-designated central lab and may be collected up to 3 days prior to treatment administration. Blood samples will be drawn from all subjects by 
venipuncture or central venous catheter. For detailed collection, processing, and shipment requirements reference the Collection Flow Chart in the latest study lab manual. 
8. 
If subject demonstrates progressive disease (PD) during platinum treatment, treatment will be discontinued and subject will complete End of Study (EOS) visit within 30 days of 
termination of platinum dosing and move into follow-up period. If subject has > SD at discontinuation of Platinum Rechallenge period, subject continues onto 
maintenance portion of ARM 1 (see section below). 
9. 
Follow-up Period begins when patient has PD during Platinum Rechallenge or RRx-001/Platinum Maintenance treatment, or discontinues treatment for any other reason. 
Survival contact will occur via medical record review, telephone call or Social Security Death Index every 8 weeks (± 7 days) until death. For subjects continuing to be imaged 
at the study site, a copy of the imaging and local radiology report will be made available upon request.  Subjects may choose to withdraw from making their imaging available 
during the follow-up period (once they are ‘off-study’). 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 93 of 99 
Ovarian (Arm 1, table 2 of 2) RRx-001 & Platinum (single agent) ‘Maintenance’  
1 Week RRx-001 followed by 2 Cycles Platinum (Carboplatin), repeating until PD 
(For Subjects with > SD at Discontinuation of ‘Platinum Rechallenge’) 
 
 
 
Assessment / Procedure 
RRx-001 
Maintenance 
Platinum  
Maintenance 
±3 day window unless  
otherwise stated in 
footnotes 
Imaging 
Assessment 
q2 platinum 
cycles 
(± 7 days) 
End of 
Study 
(EOS)5 
Follow-up 
Period6 
(± 7 days) 
Each 
Cycle 
D 1 
Each 
Cycle 
D 1 
Physical Exam1 
X 
X 
  
X 
  
Vital Signs 
X 
X 
  
X 
  
ECOG Status 
X 
X 
  
X 
  
Lesion Assessment by diagnostic CT with contrast2 
  
  
X 
  
  
Administer RRx-0013 
X 
  
  
  
  
Administer Platinum (Carboplatin) Chemotherapy4 
  
X 
  
  
  
CBC and CMP (incl Magnesium, LDH) 
X 
X 
  
X 
  
Record adverse events 
X 
X 
  
X 
  
Record concomitant therapies, medications and/or 
procedures 
X 
X 
  
X 
  
Visual Analogue Fatigue Scale (Appendix D) 
X 
X 
  
  
  
Survival Contact 
  
  
  
  
X 
 
1. 
Maintenance RRx-001 and Platinum physical exams may be symptom-directed. Each PE must include vital signs and weight. 
2. 
During the Maintenance RRx-001 and Platinum period, a diagnostic CT with contrast must be performed every 2 platinum cycles (approximately every 7 weeks ±7 Days). Lesion 
assessment will be by RECIST v1.1.  In addition to local assessment, upon request, all imaging performed while patient is ‘on-study’ is to be sent to EpicentRx within six (6) weeks of 
procedure visit for independent radiology review. Reference Appendix F for format and shipping instructions.  During the ‘follow-up period’, for subjects continuing to be imaged at the 
study site, a copy of the imaging and local radiology report will be made available upon request.  Subjects may choose to withdraw from making their imaging available during the 
follow-up period (once they are ‘off-study’). 
3. 
Premedication with 10 mg of dexamethasone, or a similar corticosteroid, and a low-dose aspirin (81 mg) or Acetaminophen (500 mg) is required within 2 hours prior to the infusion of 
RRx-001 blood mix. If patient is already receiving dexamethasone or equivalent corticosteroid, premedication with dexamethasone should not be given. 
4. 
During ‘Platinum Maintenance’, Administer carboplatin AUC 5-6 IV on day 1 as a single agent per protocol and approved package insert every 21 days for 2 cycles. 
5. 
If subject demonstrates progressive disease (PD) during RRx-001/Platinum Maintenance, treatment will be discontinued and subject will complete End of Study (EOS) visit within 30 
days of termination of treatment and move into follow-up period. 
6. 
Follow-up Period begins when patient has PD during Platinum Rechallenge or RRx-001/ Platinum Maintenance treatment, or discontinues treatment for any other reason. Survival 
contact will occur via medical record review, telephone call or Social Security Death Index every 8 weeks (± 7 days) until death. For subjects continuing to be imaged at the study site, a 
copy of the imaging and local radiology report will be made available upon request.  Subjects may choose to withdraw from making their imaging available during the follow-up period 
(once they are ‘off-study’). 
 
 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 94 of 99 
SCC & Ovarian (Arm 2): “Investigator’s Choice”  
 
 
 
Assessment / Procedure 
 
Screening 
< 14 days 
of C1 D1 
Investigator’s Choice 
±3 day window unless 
otherwise stated in 
footnotes 
Imaging Assessment 
Per SOC Intervals 
approximately every 
6-8 wks ± 7 days 
End of 
Study 
(EOS)5 
Follow-up 
Period6 
(± 7 days) 
C 1 
D 1 
C 1  
D 8 
C 2+ 
D 1 
Informed Consent 
X 
  
  
  
  
  
  
Med/Onc History 
X 
  
  
  
  
  
  
Demographics 
X 
  
  
  
  
  
  
Physical Exam1 
X 
X 
X 
X 
  
X 
  
Vital Signs 
X 
X 
X 
X 
  
X 
  
ECOG Status 
X 
X 
X 
X 
  
X 
  
Lesion Assessment by diagnostic CT with contrast2 
X 
  
  
  
X 
  
  
Administer Investigator’s Choice Chemotherapy3 
  
X 
 
X 
  
  
  
CBC and CMP (incl Magnesium, LDH) 
X 
X 
X 
X 
  
X 
  
Pregnancy Test4 
X 
  
  
  
  
  
  
Record adverse events 
X 
X 
X 
X 
  
X 
  
Record concomitant therapies, medications and/or 
procedures 
X 
X 
X 
X 
  
X 
  
Visual Analogue Fatigue Scale (Appendix D) 
X 
X 
  
X 
  
  
  
Survival Contact 
  
  
  
  
  
  
X 
 
1. 
Full physical exam is required at Screening. Subsequent physical exams may be symptom-directed. Each PE must include vital signs and weight. 
2. 
Screening imaging must be obtained within 14 days prior to C1D1. A diagnostic CT with contrast must be performed every 6-8 weeks ±7 Days per standard of care until progression or 
intolerable toxicity. SCC patients also require a Brain MRI within 8 weeks prior to C1D1 (does not need to be repeated if SOC imaging performed within window; head CT is allowed if 
MRI is contraindicated). Lesion assessment will be by RECIST v1.1.  In addition to local assessment, upon request, all imaging performed while patient is ‘on-study’ is to be sent to 
EpicentRx within six (6) weeks of procedure visit for independent radiology review. Reference Appendix F for format and shipping instructions.  During the ‘follow-up period’, for 
subjects continuing to be imaged at the study site, a copy of the imaging and local radiology report will be made available upon request.  Subjects may choose to withdraw from making 
their imaging available during the follow-up period (once they are ‘off-study’). 
3. 
Administer Investigator’s Choice Treatment per protocol and approved package insert until progression or intolerable toxicity.  
4. 
For women of childbearing potential (WOCBP), a negative serum or urine pregnancy test is required prior to entering this study. WOCBP and men whose partners are able to become 
pregnant will be asked to use non-hormonal methods of contraception for the entire duration of the study and for up to 90 days after their last dose with RRx-001 and through platinum 
phase. 
5. 
If subject demonstrates progressive disease (PD) during investigator’s choice treatment, treatment will be discontinued and subject will complete End of Study (EOS) visit within 30 days 
of termination of treatment dosing and move into follow-up period.  
6. Follow-up Period begins when patient has PD during investigator’s choice treatment, or discontinues treatment for any other reason. Survival contact will occur via medical record review, 
telephone call or Social Security Death Index every 8 weeks (± 7 days) until death. For subjects continuing to be imaged at the study site, a copy of the imaging and local radiology report 
will be made available upon request.  Subjects may choose to withdraw from making their imaging available during the follow-up period (once they are ‘off-study’). 
 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 95 of 99 
Neuroendocrine Sequential Treatment: Weekly RRx-001 Therapy (21-day cycle) until progression followed by Cisplatin/Carboplatin 
+ Etoposide Therapy (21-day cycles) x 4-6 Cycles 
Assessment / Procedure 
Screening 
< 28 days 
of C1 D1 
RRx-001 Therapy until progression 
Platinum Therapy  
4-6 cycles 
Imaging 
Assessment 
q2 cycles 
(± 7 days) 
End of 
Study 
(EOS)9 
Follow-
up 
Period10 
(± 7 days) 
C 1 
D 1 
±3 day window unless otherwise stated in footnotes 
C 1 
D 8 
C 1 
D 15 
 C 2+ 
D 1 
 C 2+ 
D 8 
C 2+  
D 15  
C 1  
D 1 
C 1  
D 8 
C 2-6  
D 1 
Informed Consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
Med/Onc History 
X 
  
  
  
  
  
  
  
  
  
  
  
  
Demographics 
X 
  
  
  
  
  
  
  
  
  
  
  
  
Physical Exam1 
X 
X 
X 
X 
X 
  
  
X 
X 
X 
  
X 
  
Vital Signs 
X 
X 
X 
X 
  
  
  
X 
X 
X 
  
X 
  
ECOG Status 
X 
X 
X 
X 
X 
  
  
X 
X 
X 
  
X 
  
Lesion Assessment by diagnostic CT with 
contrast2 
X 
  
  
  
  
  
  
X 
  
  
X 
  
  
Administer RRx-0013 
  
X 
X 
X 
X 
X 
X 
  
 
  
  
  
  
Administer Platinum-Based Chemotherapy4 
  
  
  
  
  
  
  
X 
 
X 
  
  
  
CBC and CMP (incl Magnesium, LDH) 
X 
X 
X 
X 
X 
  
  
X 
X 
X 
  
X 
  
Beta Natriuretic Peptide (BNP)5 
X 
  
  
  
  
  
  
  
  
X  
(C6 only) 
  
  
  
Hemoglobin A1C (HbA1C) 
X 
  
  
  
  
  
  
  
  
X 
(C6 only) 
  
  
  
25-OH vitamin D (25-OHD) 
X 
  
  
  
  
  
  
  
  
X 
(C6 only) 
  
  
  
Tumor Tissue6 
X 
  
  
  
 
  
  
X  
  
  
  
  
  
Pregnancy Test7 
X 
  
  
  
  
  
  
  
  
  
  
  
  
Record adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
X 
  
Record concomitant therapies, medications 
and/or procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
X 
  
Visual Analogue Fatigue Scale (Appendix D) 
X 
X 
  
  
X 
  
  
X 
  
X 
  
  
  
Central Lab Collection: Circulating Tumor 
Cells (CTCs)8 
  
X 
  
  
  
  
  
X 
  
  
  
  
  
Central Lab Collection: Immune Subsets8 
  
X 
  
  
  
  
  
X 
  
  
  
  
  
Central Lab Collection: Lysine Acetylation8 
  
X 
  
  
  
  
  
X 
  
  
  
  
  
Central Lab Collection: CEC/CEP8 
  
X 
  
  
  
  
  
X 
  
  
  
  
  
Central Lab Collection: Serum miRNA 
Analysis8 
  
X 
  
  
  
  
  
X 
  
  
  
  
  
Survival Contact 
  
  
  
  
  
  
  
  
  
  
  
  
X 
 
 
 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 96 of 99 
1. 
Full physical exam is required at Screening. Subsequent physical exams may be symptom-directed. Each PE must include vital signs and weight. 
2. 
Screening imaging must be obtained within 28 days prior to C1D1. A diagnostic CT with contrast must be performed every 2 cycles from start of RRx-001 treatment (every 
2 cycles ±7 Days), prior to initiation of platinum treatment, then every 2 cycles from start of platinum treatment (every 2 cycles ±7 Days). Lesion assessment will be by 
RECIST v1.1.  In addition to local assessment, upon request, all imaging performed while patient is ‘on-study’ is to be sent to EpicentRx within six (6) weeks of procedure 
visit for independent radiology review. Reference Appendix F for format and shipping instructions.  During the ‘follow-up period’, for subjects continuing to be imaged at the 
study site, a copy of the imaging and local radiology report will be made available upon request.  Subjects may choose to withdraw from making their imaging available during 
the follow-up period (once they are ‘off-study’). 
3. 
Premedication with 10 mg of dexamethasone, or a similar corticosteroid, and a low-dose aspirin (81 mg) or Acetaminophen (500 mg) is required within 2 hours prior to the 
infusion of RRx-001 blood mix. If patient is already receiving dexamethasone or equivalent corticosteroid, premedication with dexamethasone should not be given. 
4. 
Administer carboplatin AUC 5-6 IV on day 1 or cisplatin 60-80 mg/m2 IV on day 1 plus second agent per protocol and approved package insert every 21 days for 4-6 cycles.  
5. 
Only to be performed if subject is a smoker. 
6. 
New tumor biopsy, if feasible, will performed on an optional basis prior to infusion of RRx-001 (baseline) and prior to initial platinum rechallange Day 1 (up to 7 Days prior 
but following discontinuation of RRx-001).  Archival tissue, if available, will be collected at baseline.  For details regarding the processing of samples please refer to the latest 
study lab manual. 
7. 
For women of childbearing potential (WOCBP), a negative serum or urine pregnancy test is required prior to entering this study. WOCBP and men whose partners are able to 
become pregnant will be asked to use non-hormonal methods of contraception for the entire duration of the study and for up to 90 days after their last dose with RRx-001 and 
through platinum phase. 
8. 
To be collected and sent to sponsor-designated central lab and may be collected up to 3 days prior to or after visits. Blood samples will be drawn from all subjects by 
venipuncture or central venous catheter. For detailed collection, processing, and shipment requirements reference the Collection Flow Chart in the latest study lab manual. 
9. 
If subject demonstrates progressive disease (PD) during platinum treatment, treatment will be discontinued and subject will complete End of Study (EOS) visit within 30 days 
of termination of platinum dosing and move into long-term follow-up (LTFU). 
10. Follow-up Period begins when patient has PD during platinum treatment or RRx-001 Maintenance treatment, or discontinues treatment for any other reason. Subjects with 
stable disease or better (SD, PR or CR) at discontinuation of platinum treatment continue into the RRx-001 Maintenance Phase until progression (see RRx-001 Maintenance 
Phase, End of Study Visit, and Follow-up). Survival contact will occur via medical record review, telephone call or Social Security Death Index every 8 weeks (± 7 days) until 
death. For subjects continuing to be imaged at the study site, a copy of the imaging and local radiology report will be made available upon request.  Subjects may choose to 
withdraw from making their imaging available during the follow-up period (once they are ‘off-study’). 
 
 
 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 97 of 99 
NSCLC Sequential Treatment: Weekly RRx-001 Therapy (21-day cycle) x 1 Cycle followed by Cisplatin/Carboplatin + Second Agent 
Therapy (21-day cycles) x 4-6 Cycles 
Assessment / Procedure 
Screening 
< 28 days 
of C0 D1 
C 0  
D 1 
 
±3 day window unless otherwise stated in footnotes 
Imaging 
Assessment 
End of 
Study 
(EOS)9 
Follow-
up 
Period10 
(± 7 days) 
C 0  
D 8 
C 0  
D 15 
C 1  
D 1 
C 1  
D 8 
C1 
D 15 
C 2-6  
D 1 
C 2-6 
D 8 
C 2-6 
D 15 
q2 cycles  
(± 7 days) 
Informed Consent 
X 
  
  
  
  
  
 
  
  
 
  
  
  
Med/Onc History 
X 
  
  
  
  
  
 
  
  
 
  
  
  
Demographics 
X 
  
  
  
  
  
 
  
  
 
  
  
  
Physical Exam1 
X 
X 
X 
X 
X 
X 
 
X 
 
 
  
X 
  
Vital Signs 
X 
X 
X 
X 
X 
X 
 
X 
 
 
  
X 
  
ECOG Status 
X 
X 
X 
X 
X 
X 
 
X 
 
 
  
X 
  
Lesion Assessment by diagnostic CT with 
contrast2 
X 
  
  
X 
  
  
 
  
  
 
X 
  
  
Administer RRx-0013 
  
X 
X 
X 
  
 
 
  
 
 
  
  
  
Administer Platinum-Based Chemotherapy4 
  
  
  
  
X4 
  
  
  
CBC and CMP (incl Magnesium, LDH) 
X 
X 
X 
X 
X 
X 
 
X 
 
 
  
X 
  
Beta Natriuretic Peptide (BNP)5 
X 
  
  
  
  
  
 
X 
(C6 only) 
  
 
  
  
  
Hemoglobin A1C (HbA1C) 
X 
  
  
  
  
  
 
X 
(C6 only) 
  
 
  
  
  
25-OH vitamin D (25-OHD) 
X 
  
  
  
  
  
 
X 
(C6 only) 
  
 
  
  
  
Tumor Tissue6 
X 
  
  
  
X 
  
 
  
  
 
  
  
  
Pregnancy Test7 
X 
  
  
  
  
  
 
  
  
 
  
  
  
Record adverse events 
X 
X 
X 
X 
X 
X 
 
X 
 
 
  
X 
  
Record concomitant therapies, medications 
and/or procedures 
X 
X 
X 
X 
X 
X 
 
X 
 
 
  
X 
  
Visual Analogue Fatigue Scale (Appendix D) 
X 
X 
  
  
X 
  
 
X 
  
 
  
  
  
Central Lab Collection: Circulating Tumor 
Cells (CTCs)8 
  
X 
  
  
X 
  
 
  
  
 
  
  
  
Central Lab Collection: Immune Subsets8 
  
X 
  
  
X 
  
 
  
  
 
  
  
  
Central Lab Collection: Lysine Acetylation8 
  
X 
  
  
X 
  
 
  
  
 
  
  
  
Central Lab Collection: CEC/CEP8 
  
X 
  
  
X 
  
 
  
  
 
  
  
  
Central Lab Collection: Serum miRNA 
Analysis8 
  
X 
  
  
X 
  
 
  
  
 
  
  
  
Survival Contact 
  
  
  
  
  
  
 
  
  
 
  
  
X 
* If patient experiences disease progression during Cycle 0 before 3 doses have been administered, subject may discontinue RRx-001 and proceed to Cisplatin/Carboplatin + Partner 
Agent Treatment 
 
 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 98 of 99 
1. 
Full physical exam is required at Screening. Subsequent physical exams may be symptom-directed. Each PE must include vital signs and weight. 
2. 
Screening imaging must be obtained within 28 days prior to C0D1. A diagnostic CT with contrast must be performed at the end of Cycle 0, prior to initiation of platinum 
treatment, then every 2 cycles from start of platinum treatment (every 2 cycles ±7 Days). Lesion assessment will be by RECIST v1.1.  In addition to local assessment, upon 
request, all imaging performed while patient is ‘on-study’ is to be sent to EpicentRx within six (6) weeks of procedure visit for independent radiology review. Reference 
Appendix F for format and shipping instructions.  During the ‘follow-up period’, for subjects continuing to be imaged at the study site, a copy of the imaging and local 
radiology report will be made available upon request.  Subjects may choose to withdraw from making their imaging available during the follow-up period (once they are ‘off-
study’). 
3. 
Premedication with 10 mg of dexamethasone, or a similar corticosteroid, and a low-dose aspirin (81 mg) or Acetaminophen (500 mg) is required within 2 hours prior to the 
infusion of RRx-001 blood mix. If patient is already receiving dexamethasone or equivalent corticosteroid, premedication with dexamethasone should not be given. 
4. 
Administer carboplatin AUC 5-6 IV on day 1 or cisplatin 60-80 mg/m2 IV on day 1 plus second agent per protocol and approved package insert every 21 days for 4-6 cycles. 
For subjects receiving pegylated liposomal doxorubicin, cycles will be 4 weeks (28-days) in length. 
5. 
Only to be performed if subject is a smoker. 
6. 
New tumor biopsy, if feasible, will performed on an optional basis prior to infusion of RRx-001 (baseline) and prior to initial platinum rechallange Day 1 (up to 7 Days prior 
but following discontinuation of RRx-001).  Archival tissue, if available, will be collected at baseline.  For details regarding the processing of samples please refer to the latest 
study lab manual. 
7. 
For women of childbearing potential (WOCBP), a negative serum or urine pregnancy test is required prior to entering this study. WOCBP and men whose partners are able to 
become pregnant will be asked to use non-hormonal methods of contraception for the entire duration of the study and for up to 90 days after their last dose with RRx-001 and 
through platinum phase. 
8. 
To be collected and sent to sponsor-designated central lab and may be collected up to 3 days prior to or after visits. Blood samples will be drawn from all subjects by 
venipuncture or central venous catheter. For detailed collection, processing, and shipment requirements reference the Collection Flow Chart in the latest study lab manual. 
9. 
If subject demonstrates progressive disease (PD) during platinum treatment, treatment will be discontinued and subject will complete End of Study (EOS) visit within 30 days 
of termination of platinum dosing and move into long-term follow-up (LTFU). 
10. Follow-up Period begins when patient has PD during platinum treatment or RRx-001 Maintenance treatment, or discontinues treatment for any other reason. Subjects with 
stable disease or better (SD, PR or CR) at discontinuation of platinum treatment continue into the RRx-001 Maintenance Phase until progression (see RRx-001 Maintenance 
Phase, End of Study Visit, and Follow-up). Survival contact will occur via medical record review, telephone call or Social Security Death Index every 8 weeks (± 7 days) until 
death. For subjects continuing to be imaged at the study site, a copy of the imaging and local radiology report will be made available upon request.  Subjects may choose to 
withdraw from making their imaging available during the follow-up period (once they are ‘off-study’). 
 
 
 
 
 
IND 107,674/Serial No. 0149

QUADRUPLE THREAT 
 
RRx-001 For Injection 
RRx001-211-01 
 
 
Amendment 10 
 
Confidential Information 
20 JUL 2018 FINAL 
 
Page 99 of 99 
RRx-001 Maintenance Treatment Schedule: For Neuroendocrine & NSCLC; 21-Day Cycle (until PD) 
Assessment / Procedure 
±3 day window unless otherwise 
stated in footnotes 
Imaging 
Assessment 
q2 cycles  
(± 7 days) 
End of 
Study 
(EOS)4 
Follow-up 
Period5 
(± 7 days) 
Each 
Cycle  
D 1 
Each 
Cycle  
D 8 
Each 
Cycle  
D 15 
Physical Exam1 
 X 
  
  
  
X 
  
Vital Signs 
  
  
  
  
X 
  
ECOG Status 
  
  
  
  
X 
  
Administer RRx-0012 
X 
X 
X 
  
  
  
Lesion Assessment by diagnostic CT with contrast3 
  
  
  
X 
 
 
CBC and CMP (incl Magnesium, LDH) 
X 
  
X 
  
X 
  
Record adverse events 
X 
X 
X 
 
X 
 
Record concomitant therapies, medications and/or procedures 
X 
X 
X 
 
X 
 
Visual Analogue Fatigue Scale (Appendix D) 
X 
  
  
  
  
  
Central Lab Collection: Circulating Tumor Cells (CTCs)6 
X 
  
  
  
  
  
Survival Contact 
  
  
  
  
  
X 
 
1. 
Physical exams may be symptom-directed.  
2. 
Premedication with 10 mg of dexamethasone, or a similar corticosteroid, and a low-dose aspirin (81 mg) or Acetaminophen (500mg) is required within 2 hours prior to the 
infusion of RRx-001 blood mix. If patient is already receiving dexamethasone or equivalent corticosteroid, premedication with dexamethasone should not be given. 
3. 
A diagnostic CT with contrast must be performed every 2 cycles from start of RRx001 maintenance treatment (every 2 cycles ±7 Days). Assessment will be by RECIST v1.1.  
In addition to local assessment, upon request, all imaging performed while patient is ‘on-study’, including screening, is to be sent to EpicentRx within six (6) weeks of 
procedure visit for independent radiology review.  Reference Appendix F for format and shipping instructions. 
4. 
End of Study (EOS) visit is to be performed at the time of progression on RRx-001 Maintenance treatment. Patients will then move into long-term follow-up (LTFU). 
5. 
Follow-up Period begins when patient has PD during platinum + RRx-001 treatment or RRx-001 Maintenance treatment, or discontinues treatment for any other reason. 
Survival contact will occur via medical record review, telephone call or Social Security Death Index every 8 weeks (± 7 days) until death. For patients continuing to be imaged 
at the study site, a copy of the imaging and local radiology report will be made available upon request.  Patients may choose to withdraw from making their imaging available 
during the follow-up period (once they are ‘off-study’). 
6. 
To be collected and sent to sponsor-designated central lab and may be collected up to 3 days prior to or after visits. Blood samples will be drawn from all patients by 
venipuncture or central venous catheter. For detailed collection, processing, and shipment requirements reference the latest study lab manual. 
IND 107,674/Serial No. 0149