A Phase 2a Randomized, Parallel Group, Open Label, Multicenter Study to Assess the Safety and Efficacy of RRx-001 in the Attenuation of Oral Mucositis in Patients Receiving Chemoradiation for the Treatment of Locally Advanced Squamous Cell Carcinoma of the Oral Cavity or Oropharynx
Phase: PHASE2
Conditions: Oral Mucositis
Sponsor: EpicentRx, Inc.

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CLINICAL STUDY PROTOCOL 
 
Protocol No. 
PR-001 
Product 
RRx-001 
Title: 
PREVLAR: A Phase 2a Randomized, Parallel Group, Open-
Label, Multicenter Study to Assess the Safety and Efficacy of 
Different Schedules of RRx-001 in the Attenuation of Oral 
Mucositis in Patients Receiving Concomitant Chemoradiation 
for the Treatment of Locally Advanced Squamous Cell 
Carcinomas of the Oral Cavity or Oropharynx 
Development Phase 
 
IND #: 
Phase 2a 
 
107674 
Version Date: 
 
June 04, 2018 
Amendment No.  
 
Amendment 01 
 
Sponsor: 
EpicentRx, Inc. 
11099 North Torrey Pines Road, Suite 160 
La Jolla, CA 
92037 
 
Sponsor’s Medical Contact: 
 
Bryan Oronsky, MD 
Chief Medical Officer 
Email: boronsky@epicentrx.com 
Phone: 408-569-3202 
 
 
 
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recipient that no previously unpublished information contained herein will be published or disclosed without the prior written approval of 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. 
 
 
 
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INVESTIGATOR AGREEMENT PAGE 
 
EpicentRx, Inc. 
 
Protocol No. PR-001,  
PREVLAR: A Phase 2a Randomized, Parallel Group, Open-Label, Multicenter Study to Assess 
the Safety and Efficacy of Different Schedules of RRx-001 in the Attenuation of Oral Mucositis 
in Patients Receiving Concomitant Chemoradiation for the Treatment of Locally Advanced 
Squamous Cell Carcinomas of the Oral Cavity or Oropharynx 
 
June 04, 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: 
 
 
 
 
 
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PROTOCOL APPROVAL PAGE 
TITLE: 
PREVLAR: A Phase 2a Randomized, Parallel Group, Open-Label, Multicenter 
Study to Assess the Safety and Efficacy of Different Schedules of RRx-001 in the 
Attenuation of Oral Mucositis in Patients Receiving Concomitant Chemoradiation 
for the Treatment of Locally Advanced Squamous Cell Carcinomas of the Oral 
Cavity or Oropharynx 
SPONSOR: 
EpicentRx, Inc. 
11099 North Torrey Pines Road, Suite 160 
La Jolla, CA 92037 
Bryan Oronsky, M.D.   
  Date  04 June 2018 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ...................................................................................................6 
1 
STUDY SCHEMA AND ASSESSMENTS .....................................................................7 
1.1 
Treatment Schemas .................................................................................................... 7 
1.2 
Schedule of Assessments Table.................................................................................. 8 
2 
STUDY SUMMARY ..................................................................................................... 10 
3 
INTRODUCTION AND RATIONALE ....................................................................... 14 
3.1 
Mucositis in Head and Neck Cancer Patients Treated with Radiotherapy and 
Systemic Chemotherapy .......................................................................................... 14 
3.2 
Nonclinical Studies .................................................................................................. 16 
3.3 
Clinical Experience with RRx-001 ........................................................................... 18 
3.4 
Dose and Dose Schedule of RRx-001 ....................................................................... 21 
4 
PROPOSED MECHANISMS OF RADIOPROTECTION ......................................... 21 
5 
STUDY OBJECTIVES ................................................................................................. 22 
6 
STUDY DESIGN ........................................................................................................... 22 
6.1 
Description of the Study .......................................................................................... 22 
7 
STUDY POPULATION ................................................................................................ 23 
7.1 
Eligibility Criteria .................................................................................................... 23 
8 
DRUG TREATMENT .................................................................................................. 23 
8.1 
RRx-001 Drug Treatment ........................................................................................ 23 
8.2 
Cisplatin Drug Treatment ......................................................................................... 26 
8.3 
Dose Modifications .................................................................................................. 26 
8.4 
Missed or Omitted Doses and Alternative Treatment Schedules ............................... 28 
9 
RADIATION THERAPY ............................................................................................. 28 
10 
OTHER THERAPY ...................................................................................................... 28 
10.1 
Permitted Concomitant Supportive Therapy ............................................................. 28 
10.2 
Non-permitted Concomitant Supportive Therapy ..................................................... 28 
11 
EFFICACY ASSESSMENTS ....................................................................................... 29 
11.1 
Oral Mucositis (OM) Assessments ........................................................................... 29 
11.2 
Pain Assessments ..................................................................................................... 30 
11.3 
Analgesic Use .......................................................................................................... 30 
11.4 
Other Assessments ................................................................................................... 30 
11.5 
Tumor Assessments ................................................................................................. 31 
12 
ASSESSMENT OF SAFETY........................................................................................ 31 
12.1 
Specification of Safety Variables ............................................................................. 31 
12.2 
Methods and Timing for Assessing and Recording Safety Variables ........................ 32 
12.3 
Reporting Requirements for Adverse Events ............................................................ 35 
12.4 
Type and Duration of Follow-Up of Patients After Adverse Events.......................... 35 
13 
STATISTICAL METHODS ......................................................................................... 36 
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13.1 
Sample Size ............................................................................................................. 36 
13.2 
Efficacy Analysis ..................................................................................................... 36 
13.3 
Safety Analysis ........................................................................................................ 37 
14 
SPONSOR AND INVESTIGATOR REQUIREMENTS ............................................ 38 
14.1 
Institutional Review Board Approval ....................................................................... 38 
14.2 
Study Monitoring Requirements .............................................................................. 39 
14.3 
Data Collection ........................................................................................................ 39 
14.4 
Disclosure of Data ................................................................................................... 39 
14.5 
Retention of Records ............................................................................................... 40 
15 
REFERENCES.............................................................................................................. 41 
16 
APPENDICES ............................................................................................................... 43 
Appendix A. 
ECOG Performance Status Scale ................................................................ 43 
Appendix B. 
RECIST 1.1 ................................................................................................ 44 
Appendix C. 
Oral Mucositis WHO Grading System ........................................................ 45 
Appendix D. 
Oral Mucositis Daily Questionnaire (OMDQ) ............................................ 46 
Appendix E. 
Anatomy of the Mouth ............................................................................... 49 
Appendix F. 
Standard Oral Health Maintenance Regimen .............................................. 50 
Appendix G. 
Patient Oral Care Instructions ..................................................................... 51 
 
 
 
List of Tables 
Table 1: 
Carboplatin vs. Cisplatin Incidence of > Grade 3 Cytopenias from a Meta-
Analysis in SCLC .................................................................................................... 19 
Table 2: 
RRx-001 Regimen Premedication Description ......................................................... 25 
Table 3: 
Dose Modifications for RRx-001 Administration ..................................................... 26 
Table 4: 
Adverse Event Grading (Severity) Scale .................................................................. 33 
 
List of Figures 
Figure 1: Incidence of Diarrhea During Irinotecan Treatment After Exposure to RRx-001 ...... 19 
Figure 2: Bar Graph Showing Comparative Incidences of Myelotoxicity from Platinum on 
an Ovarian Cancer NCIC Study (Source FDA Package Insert) vs. Platinum 
Administered After RRx-001 ................................................................................... 20 
 
 
 
 
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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 
CMP 
Comprehensive Metabolic Panel 
CRT 
Chemo-Radiation Therapy 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DDP 
Cis-diamminedichloridoplatinum (cisplatin) 
DLT 
Dose Limiting Toxicity 
DMA 
N, N-Dimethylacetamide 
ECOG 
Eastern Cooperative Oncology Group 
HNC 
Head and Neck Cancer 
HRPP 
Human Research Protections Program 
IMRT 
Intensity-Modulated Radiation Therapy 
IRB 
Institutional Review Board 
NCCN 
National Comprehensive Cancer Network 
NYHA 
New York Heart Association 
OM 
Oral Mucositis 
OS 
Overall Survival 
PET 
Positron Emission Tomography 
POC 
Proof-of-Concept 
q.d. 
quaque die/every day 
RBC 
Red Blood Cell 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SOM 
Severe Oral Mucositis 
TEAE 
Treatment Emergent Adverse Events 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cells 
WHO 
World Health Organization 
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1 STUDY SCHEMA AND ASSESSMENTS 
1.1 
Treatment Schemas 
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1.2 
Schedule of Assessments Table 
Procedures 
Screening 
Pre-
Treatment  
Combination Treatment 
Mucositis 
Observation 
Follow-up 
28 Day Post 
IMRT Safety 
Visit17 
Long-Term Follow-Up18 
Wk 
-2 
Wk 
-1 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
716 
weekly 
(until OM grade ≤ 1) 
 
3 mo 
post RT 
6 mo 
post RT 
9 mo 
post RT 
12 mo 
post RT 
< 28 Days 
of  
Tx Start 
D1 
±2d  
D8 
±2d 
D15 
±2d 
D22 
±2d 
D29 
±2d 
D36 
±2d 
D43 
±2d 
D50 
±2d 
D57 
±2d 
following end of 
IMRT 
28 days post 
end of IMRT 
 +5 days 
± 7 
days 
± 14 
days 
± 14 
days 
± 14 
days 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical & Onc History1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dental Assessment2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laryngopharyngoscopy3 
X 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
Audiogram4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Oral Mucositis Assessment 
(WHO, CTCAE)6 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Oral Mucositis Daily 
Questionnaire (OMDQ)7 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Oral Routine Assessment8 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
ECOG Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Lab Assessments9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
 
Pregnancy Test10 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Concomitant Medications 
& Procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
X  
X  
X  
Chest CT or PET/CT11 
X 
 
 
 
 
 
 
 
 
 
X11 
CT, MRI, or PET/CT of 
tumor site & neck nodes12 
X 
 
 
 
 
 
 
 
 
 
X12 
RRx-001 Administration13 
 
X13 
 
 
 
 
 
 
 
Cisplatin Administration14 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Radiation Therapy 
(IMRT)15 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
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Schedule of Assessments Table Footnotes 
1. 
Record patient cancer and medical history as well as previous oral history (i.e. previous occurrences of oral mucositis, history of smoking, alcohol consumption, dry mouth 
(xerostomia), chewing tobacco usage, and dental history). 
2. 
Dental Assessment: ENT examination recommended during screening to perform dental assessment. 
3. 
Laryngopharyngoscopy: mirror (indirect laryngopharyngoscopy) and/or fiberoptic (direct laryngopharyngoscopy) procedure is recommended at these time points but is not 
required (at discretion of treating physician). 
4. 
Audiogram: Recommended within 84 days of starting treatment but is not required. 
5. 
Physical Exams:  
• 
A full physical exam must be performed during screening (including: ECOG status, swallowing assessment and assessment for PEG Tube), and during Combination 
Treatment week 1 and at the 28 Day Safety Visit (post treatment).  
• 
A brief physical exam, to include ECOG status, by a Radiation Oncologist and/or Medical Oncologist and/or ENT or Head & Neck Surgeon must be done weekly during 
Pre-Treatment, Combination Treatment, and during the Mucositis Observation Follow-up until OM grade < 1 is achieved. 
6. 
Oral Mucositis Assessment will be performed by a trained on-site assessor at screening, day 1 prior to start of RRx-001 pretreatment, day 15 prior to the start of Combination 
Treatment (chemoradiation), twice a week (no less than 48 hours apart) during Combination Treatment (weeks 1 - 7), and once each week on the same day (±1 day) during the 
Mucositis Observation Follow-up until an OM grade < 1 is achieved. Lesions will be scored by a central assessor according to WHO (Appendix C) and WHO grade 
assessment will be communicated back to site study team by the central assessor.  
7. 
Oral Mucositis Daily Questionnaire (OMDQ) to be completed in clinic at screening and then daily in the provided OMQD Booklet starting Week 1 (protocol Day 15) of  
combination treatment, continuing through the Mucositis Observation Follow-up until an OM grade < 1 is achieved.  See Appendix D. 
8. 
Record current oral routines (i.e. smoking and chewing tobacco) at screening. If oral routines change, please update oral assessment accordingly. Review patient oral care 
instructions (Appendix G) and dispense oral hygiene kit following enrollment and prior to start of chemoradiation. 
9. 
Lab Assessments include a Complete Blood Count (CBC) with differential, a Complete Metabolic Panel (CMP), magnesium and phosphate: to be performed at screening, 
weekly during Pre-Treatment, Combination Treatment, 28 Day Safety Visit, and as clinically indicated per institutional guidelines. CMP to include: sodium, potassium, 
glucose, calcium, albumin, bilirubin, ALT, AST, and Alk Phos.  
10. Negative serum or urine pregnancy test required within 14 calendar days prior to start of treatment for women of childbearing potential. 
11. Chest CT scan, or PET/CT scan, must be done within 42 calendar days prior to starting treatment to rule out metastatic disease. Chest CT scan, or PET/CT scan, imaging 
during Long-Term Follow-Up to be performed per institutional standards and assessed via RECIST v1.1 until progression (PD) or start of next cancer directed therapy or 12 
month post RT visit, whichever occurs first. When measurable disease is not present (e.g. post-operative patients), RECIST v1.1 assessment is not performed until measurable 
disease presents (considered PD) or start of next cancer directed therapy. 
12. CT scan, MRI, or PET/CT scan of the tumor site and neck nodes must be done within 42 calendar days prior to starting treatment. Note: The CT scan of the neck and/or 
PET/CT performed for radiation planning may serve as both staging and planning tools. Imaging evaluations of the primary tumor and neck should be performed via 
institutional standards and assessed via RECIST v1.1 until progression or start of next therapy. When measurable disease is not present (e.g. post-operative patients), RECIST 
v1.1 assessment is not performed until measurable disease presents (considered PD) or start of next cancer directed therapy. The post-radiation imaging can be contrast 
enhanced CT, MRI, or PET/CT of the head and neck, or whole body PET/CT (minimum neck and chest), based on the preference of the treating clinician.  
13. Administration of RRx-001 to be performed according to the schema Section 1.1 and Section 8.1.2, with pre-medications as described in the pre-medications Section 8.1.5.   
14. For Cisplatin dosage, refer to Section 8.2. 
15. Radiation Therapy (IMRT) will consist of single daily fractions of 2.0 to 2.2 Gy with a cumulative radiation dose between 60 Gy and 72 Gy, lasting 6 to 7 weeks in duration. 
16. Combination Treatment will be a duration of 6 to 7 weeks depending on IMRT fractionated scheduling. The Mucositis Observation Follow-up day 1 is the day following the 
last dose of IMRT.  
17. A 28 Day Safety Visit will occur 4 weeks (28 days) post last dose of radiation treatment (+5 day window). If the patient has an OM grade ≥ 2, patient will continue with the 
Mucositis Observation Follow-up weekly visits until an OM grade of < 1 is achieved. If the patient finished Combination Treatment with an OM grade < 1, the patient will 
return to clinic 28 days post IMRT (+ 5 days) for this 28 Day Safety Visit. Once the patient is assigned an OM grade < 1 and has completed the 28 Day Safety Visit, the 
patient will proceed into Long Term Follow Up.  
18. Long-Term Follow-Up may be performed via chart review. All procedures performed during the follow-up period should be recorded as Concomitant Procedures. Patients 
should continue to be followed monthly if experiencing an adverse event related to the investigational agent of RRx-001 until resolution, or event is assessed as a grade ≤ 2. 
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2 STUDY SUMMARY 
Title 
PREVLAR: A Phase 2a Randomized, Parallel Group, Open-Label, Multicenter Study to 
Assess the Safety and Efficacy of Different Schedules of RRx-001 in the Attenuation of 
Oral Mucositis in Patients Receiving Concomitant Chemoradiation for the Treatment of 
Locally Advanced Squamous Cell Carcinomas of the Oral Cavity or Oropharynx 
Phase 
Phase 2a 
Patient Population 
Pathologically-confirmed diagnosis of squamous cell carcinoma (SCC) of the oral cavity or 
oropharynx planned to be treated with cisplatin plus concurrent IMRT  
Note: Patients with unknown HPV positive primary tumors (SCC) whose treatment plan 
matches the requirements specified in Inclusion Criteria #2 below are eligible for the trial 
Objectives 
Safety: 
To assess the safety and tolerability of varying dosing schedules of RRx-001 during 
treatment and for 28 days following end of IMRT. 
To assess the long-term effect of RRx-001 on tumor response to standard concomitant 
chemoradiation. 
Efficacy: 
To assess the efficacy of RRx-001 in the attenuation of severe oral mucositis (SOM) in 
patients receiving cisplatin and radiation therapy for the treatment cancers of the oral cavity 
or oropharynx.  
Number of Patients 
Approximately 40 evaluable patients 
Study Design 
This is a Phase 2a, randomized, open-label, parallel group trial to assess the safety and 
efficacy of three schedules of RRx-001 compared to standard of care in patients receiving a 
standard regimen of tri-weekly cisplatin plus concomitant IMRT in patients being treated for 
cancers of the oral cavity or oropharynx. 
Patients meeting the eligibility criteria and consenting to participate will be randomized 
1:1:1:1 to one of the three regimens of RRx-001 or a control (~10 patients per arm) with 1 
stratification factor (two levels: oral cavity or oropharynx): 
Arm 1: “RRx-001 Pre-Treatment + SOC Chemoradiation” 
Two infusions of RRx-001 will be given each week during the two weeks prior to the 
start of chemoradiation (four doses total). No additional RRx-001 will be given during 
chemoradiation. 
Arm 2: “RRx-001 Pre-Treatment + 2 Concurrent Doses + SOC Chemoradiation” 
Two infusions of RRx-001 will be given each week during the two weeks prior to the 
start of chemoradiation. In addition, one dose of RRx-001 will be given on the last 
radiation day in each of weeks 2 and 5 during chemoradiation 
Arm 3: “RRx-001 Pre-Treatment + 6 Concurrent Doses + SOC Chemoradiation” 
Two infusions of RRx-001 will be given each week during the two weeks prior to the 
start of chemoradiation. In addition, one dose of RRx-001 will be given on the last 
radiation day of each of the first 6 weeks during chemoradiation 
Arm 4: “SOC Chemoradiation Only (Control)”  
No doses of RRx-001 will be administered. Patients assigned to this arm will receive 
only standard of care chemoradiation 
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All patients will receive standard of care (SOC) chemoradiation in the form of a 7-week 
course of fractionated radiation therapy concurrent with a QW or Q3W cisplatin regimen. 
Cisplatin should not be given within 24 hours of RRx-001 administrations.   
All doses of RRx-001 will be given at 4 mg per infusion. Administration of RRx-001 will 
not be blinded, so patient and study staff may be aware of the treatment assignment. 
The study will be performed in four stages: 
1. 
Screening phase (≤ 4 weeks before randomization).  Patients assessed for eligibility. 
2. 
Pre-Treatment and Combination Treatment dosing periods.  This will consist of the 
time beginning two weeks prior to the start of chemoradiation (Pre-Treatment) and 
ending on the last day of radiation therapy (LDRT). A baseline assessment will be 
performed on the first day of RRx-001 administration. 
3. 
Post Treatment “Mucositis Observation Follow-up”.  This will consist of the time 
from the end of IMRT until ulcerative oral mucositis grade is < 1 (WHO scale) 
4. 
Long-term follow-up will consist of the 12 months from the LDRT.  
Patients will be followed for safety endpoints throughout the study. Patients will be 
evaluated for the presence and severity of oral mucositis during the course of 
chemoradiation and following end of treatment until oral mucositis grade is < 1.   
During the combination treatment period (until end of radiotherapy), mucositis severity will 
be assessed twice weekly by trained evaluators. Following the end of radiotherapy (known 
as the “Mucositis Observation Follow-up”), mucositis will be assessed once weekly until 
resolution (WHO grade 0 or 1) of ulcerative mucositis.  
Patients in the study will be followed for one year following radiotherapy (IMRT), in order 
to evaluate long-term safety and tumor outcomes. 
Eligibility Criteria 
(Inclusion and 
Exclusion) 
Inclusion Criteria 
1. Pathologically confirmed diagnosis of squamous cell carcinoma (SCC) of the oral 
cavity and oropharynx 
Note: Patients with unknown primary tumors whose treatment plan matches the 
requirements specified in Inclusion Criterion #2 below are eligible for the trial 
2. Treatment planned to include standard cisplatin monotherapy administered either every 
three weeks (100 mg/m2 for 3 doses) or weekly (40 mg/m2 for 7 doses) with 
concomitant radiation delivered as a continuous course of IMRT with single daily 
fractions of 2.0 to 2.2 Gy with a cumulative radiation dose between 60 Gy and 72 Gy. 
Planned radiation treatment fields must include at least two oral sites (buccal mucosa, 
floor of mouth, tongue, soft palate) that are each planned to receive a total of > 55 Gy. 
Patients who have had prior surgery are eligible, provided they have fully recovered 
from surgery, and patients who may have surgery in the future are eligible. 
3. ECOG performance status ≤ 2. 
4. Participants must have adequate organ and marrow function as defined below:   
A. Absolute neutrophil count (ANC) ≥ 1,500 / mm3 
B. Platelets ≥ 100,000 / mm3 
C. Hemoglobin ≥ 9.0 g/dL  
5. Adequate renal and liver function as indicated by: 
A. Serum creatinine acceptable for treatment with cisplatin per institutional 
guidelines) 
B. Total bilirubin ≤ 1.5 x upper-normal limit (ULN) 
C. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x 
ULN 
D. Alkaline phosphatase ≤ 2.5 x ULN 
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6. Human papilloma virus (HPV) status in tumor has been documented using tumor 
immunohistochemistry for HPV-p16 or other accepted test for patients with cancers of 
the oropharynx, base of tongue, or unknown primary. 
7. Age 18 years or older 
8. Patient must consent to the access, review and analysis of previous medical and cancer 
history, including imaging data by the sponsor or a third party nominated by the 
sponsor. 
9. Ability to understand and sign a written informed consent document. 
10. 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.   
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 
11. Adequate visual access to permit examination of the following oral cavity sites: lips, 
buccal mucosa, floor of mouth, ventral and lateral tongue and soft palate. 
Exclusion Criteria 
1. Prior radiation to the head and neck 
2. Prior induction chemotherapy 
3. Tumor of the lips, nasopharynx, hypopharynx, larynx, or salivary glands 
4. Patients with simultaneous primaries 
5. Stage IV, M1 (distant metastasis) 
6. Malignant tumors other than HNC within the last 5 years, unless treated definitively and 
with low risk of recurrence in the judgment of the treating investigator 
7. Presence of oral mucositis (WHO Score ≥ Grade 1) or other oral mucosal ulceration at 
study entry  
8. Grade 3 or 4 dysphagia or odynophagia (National Cancer Institute Common Toxicity 
Criteria, version 5.0) or inability to eat a normal diet 
9. Requirement at baseline for parenteral or gastrointestinal tube-delivered nutrition for 
any reason. Prophylactic placement is allowed. 
10. Known history of HIV or active hepatitis B/C (patients who have been vaccinated for 
hepatitis B and do not have a history of infection are eligible) 
11. 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). 
12. Pregnant or nursing 
13. Untreated active oral or dental infection 
14. Known allergies or intolerance to cisplatin and similar platinum-containing compounds 
15. Evidence of immediate life-threatening disease or a life expectancy of less than 3 
months 
16. Receipt of unapproved or off-label medication within 30 days prior to start of study 
treatment, including use of an investigational agent 
17. Sjogren syndrome 
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Statistical Methods 
Safety Endpoints: 
• 
Incidence of adverse events, including serious adverse events (SAEs) and clinically 
significant laboratory abnormalities.  
• 
Overall tumor response to treatment using RECIST or site preference criteria. 
Efficacy Endpoints: 
• 
Duration (in days) of severe oral mucositis (SOM, WHO grades 3 or 4) 
• 
Time (in days) to onset of SOM 
• 
Incidence of SOM 
• 
Incidence and duration of ulcerative mucositis (WHO grades 2, 3, 4) 
• 
Patient-reported mucositis pain as measured by question 2 of the Oral Mucositis 
Daily Questionnaire 
Design:   
This is a randomized, open-label, parallel group, Phase 2 study to assess the safety and 
radioprotective potential of RRx-001 in patients undergoing chemoradiation therapy for 
locally advanced head and neck cancer.  
A total of approximately 40 patients will participate in this study.  All patients will receive 
standard chemoradiation therapy consisting of cisplatin either every three weeks (100 mg/m2 
for 3 doses) or weekly (40 mg/m2 for 7 doses)  + radiotherapy (IMRT) administered daily 
(except weekends) for 7 weeks.  In conjunction with this “standard of care” (SOC), patients 
will be randomly assigned to receive one of 3 regimens of RRx-001 or a control (no 
treatment). 
Sample Size:   
A sample size of approximately 40 patients (~10 per group) is considered adequate for this 
proof-of-concept (POC) study to explore the radioprotective potential of RRx-001 and 
identify a safe regimen for further development.    
Statistical Methods: 
Efficacy and safety data will be summarized using descriptive statistics, including the mean, 
standard deviations, median, minimum and maximum for continuous endpoints and 
frequency tables for categorical data.   
Efficacy Analysis:   
Hypothesis testing of efficacy endpoints will be performed for exploratory purposes only. 
For continuous efficacy endpoints, non-parametric methods will be used to compare each 
RRx-001 group to the untreated control group (Wilcoxon rank-sum tests).  Fisher’s exact 
test will be used to evaluate treatment differences for binary outcomes. Two-sided 95% 
confidence intervals will be calculated for proportions using the Clopper-Pearson method. 
Safety Analysis: 
Safety data, including adverse events (AEs), serious adverse events (SAEs), ECOG 
performance status, clinical laboratory tests, vital signs and physical examination results will 
be listed and summarized descriptively by treatment group. 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).   
Descriptive statistics (sample size, mean, median, standard deviation, quartiles and range) 
and graphical methods (longitudinal plots) will be used to present change from pre-treatment 
values in laboratory parameters during the treatment period.  The incidence of febrile 
neutropenia, bacterial infections, grade 3 or 4 cervicofacial dermatitis, and other toxicities of 
clinical interest (xerostomia, trismus, fatigue, weight loss, radiation dermatitis, and 
dysgeusia) will be tabulated by treatment arm.  
 
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3 INTRODUCTION AND RATIONALE 
3.1 
Mucositis in Head and Neck Cancer Patients Treated with Radiotherapy and 
Systemic Chemotherapy 
Worldwide, head and neck cancer is the sixth most common form of the disease with over 
500,000 new cases this year.  In the United States, head and cancers account for approximately 
3% of all cancers with over 60,000 new cases anticipated this year.  Of those, the overwhelming 
majority will be tumors of the mouth and oropharynx.  Historically, tobacco and alcohol use is 
the major risk factor for the most common histologic subtype (90%), squamous cell carcinoma 
(HNSCC).  However, over recent decades the predominant pathoetiology of HNC has shifted 
from carcinogen-induced mucosal transformation to HPV-mediated cancer.  This shift has 
impacted the clinical presentation, epidemiology, management and prognosis of the disease.  
Firstly, unlike tobacco-related HNSCC, which presents in the oral cavity (tongue/floor of 
mouth), HPV-related cancers mainly develop from the oropharynx.  Secondly, HPV-driven 
tumors tend to affect a significantly younger patient population with less extensive tobacco 
exposure and a better performance status compared to HPV-negative tumors, thereby 
incentivizing more aggressive “curative” treatment.  Thirdly, HPV-related cancers are 
significantly more treatment-responsive than tobacco-associated squamous cell cancers of the 
head and neck, which may tip the balance in favor of non-surgical management. And, finally, 
HPV imparts a better prognosis in terms of tumor control and survival.   
Regardless of the etiology, the vast majority of patients with locally invasive cancers of the 
mouth or oropharynx are treated with concomitant chemoradiation, a combination that is 
superior to radiation alone since chemotherapy increases the susceptibility of the tumor cell to 
radiation-induced lysis.  For locally advanced disease (Stages II-IVB), the standard of care is 
concurrent chemoradiation therapy in lieu of or in addition to surgery. Conventional 
fractionation for concurrent chemoradiation is up to 70 Gy (2.0 Gy/fraction; daily Monday-
Friday in 7wk).  Cisplatin, given as a radiosensitizer, is typically administered in one of two 
regimens: either every three weeks during radiation (100 mg/m2) or weekly as a lower dose 
(40 mg/m2).  Recent data suggests that the higher dose regimen has better survival benefit. 
Oral mucositis is among the most common and devastating acute toxicities associated with 
radiation therapy to the head and neck.  The characteristic ulcerative lesions, which occur on the 
oropharyngeal mucosa included in the radiation fields are associated with progressive, 
unrelenting pain that profoundly impacts quality of life in multiple dimensions.  As a case in 
point, the poem below, written by a patient with mucositis, vividly and graphically 
communicates the extreme suffering due to mucositis, forcing the reader to vicariously 
experience the horribly sadistic details through the writer’s pain-distorted perceptions of teeth, 
touch and taste: 
A fish hook lodges in my throat. 
Spittle, kindergarten paste, thickens everything – even vision. 
Mouth, pocked with sores & blisters, swollen ulcerated tongue. 
Topside, sandpapered with number 7 coarsest grade. 
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Taste buds, saliva glands, seared. 
Cool water, corrosive acid now. 
The tongue rests; teeth become enemies. 
Coiled steel razored wire atop dentate prison walls. 
Only moans escape my lips. I cannot eat or speak. 
Inside a howl festers. 
Pain lengthens time. 
 
Anita Hart Balter (NEJM 1990) 
Due to the severe oral morbidity, mucositis may impact the ability to eat normally.  
Consequently, changes to liquid-based diets are common and, in about a quarter of cases, 
percutaneous feeding via a gastrostomy feeding tube and/or parenteral nutrition is required.  
Ulcerative mucositis is a significant cause of unscheduled chemoradiation treatment breaks, 
typically lasting a week, which may improve palliation at the expense of survival.  In 
granulocytopenic patients, oral mucositis is a potential site of secondary infection and portal of 
entry for the indigenous oral flora, often leading to bacteremia and sepsis.  Finally, mucositis 
drives healthcare resource use and costs through emergency room visits, surgical insertion of 
feeding tubes and hospitalizations.  It is not surprising that the incremental cost of mucositis 
exceeds $17,000 per patient.  Despite its high clinical and economic burden, an approved 
interventional agent for radiation-induced mucositis is not yet available. 
Patients with radiation-induced mucositis generally show highly consistent clinical courses. 
Concomitant chemotherapy increases both the risk and severity of mucositis.  Signs and 
symptoms typically begin by the completion of the first week of treatment (cumulative radiation 
dose of 10 Gy) and consist primarily of mucosal erythema and symptoms akin to a burned mouth 
from hot food or drink that are easily controlled with standard OTC pain medications. At 
cumulative radiation doses of 20 Gy to 30 Gy, the integrity of the mucosa breaks down and 
mucosal ulcerations that are usually limited to the movable mucosa (the more keratinized 
epithelium of the hard palate, dorsal tongue and gingiva are unaffected), occur.  Unlike common 
oral ulcers like aphthous stomatitis, the ulcers associated with mucositis are irregular, deep and 
disproportionately painful, requiring more aggressive symptom management such as the use of 
narcotic analgesia.  Ulceration severity usually peaks at radiation doses of around 50 Gy (end of 
week 5).  The lesions expand and become confluent.  Breakthrough pain, even with morphine or 
fentanyl is not uncommon.  Lesions typically heal spontaneously after 2-4 weeks following the 
cessation of radiation therapy. 
A variety of scales are used to assess mucositis severity, of these, the WHO scale is the most 
consistent and widely used. This scale, which has been effectively used in clinical trials, is based 
on a combination of functional (ability to eat) and objective (presence of ulceration or erythema) 
criteria. WHO scores correlate with patient-reported outcomes, analgesic use and resource use.  
Other available scales include RTOG and NCI-CTCv5, which have evolved to contain elements 
that are similar to WHO criteria. 
Concepts of the pathogenesis of mucositis have undergone dramatic revisions from Sonis’ 
original hypothesis in 1998 of epithelial injury due to direct clonogenic cell death of epithelial 
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stem cells to a complex biologic process involving oxidative stress and immune activation that 
culminates in epithelial apoptosis, atrophy, ulceration and healing [Sonis 1998]. 
To date, palifermin (KGF1), a pleiotropic growth factor, is the only agent approved for mucositis 
and its use is limited to patients receiving stomatotoxic conditioning regimens prior to 
hematologic stem cell transplant.  Despite an active developmental pipeline of compounds to 
prevent and/or treat OM, which includes dusquetide, an immunomodulatory peptide, GC4419, a 
dismutase mimetic, brilacidin, a defensin mimetic, current treatment options are mainly limited 
to topical barrier devices for symptom management, opioid and NSAID analgesics, ice chips 
(cryotherapy) and oral rinses such as “magic mouthwashes” that vary in composition depending 
on institutional folklore.   None of these approaches has adequately mitigated the clinical 
development of mucositis or its symptoms. Thus, the degree of the unmet need in mucositis is 
related to the severity of symptoms and the lack of an approved treatment regimen, which, if 
addressed, would substantially improve quality of life and treatment outcomes for head & neck 
cancer patients.  
The rationale for this trial is that RRx-001, as a systemically non-toxic putative dual 
radiochemoprotector/sensitizer with activity in multiple tumors types including small cell 
carcinoma of the oral cavity, will protect the normal mucosa but not the tumor and delay the 
duration of oral toxicity. 
3.2 
Nonclinical Studies 
3.2.1 
RRx-001 Antitumor Activity 
RRx-001 is a novel anticancer agent of the dinitroazetidine class that has demonstrated 
selectivity of action in tumor cells versus normal tissues, and inhibition of tumor growth in vivo 
with minimal toxicity [Das 2016; Ning 2012]. The activity of RRx-001 is thought to be 
associated with a nucleophilic substitution by circulating thiol compounds and covalent binding 
of RRx-001 to cysteinyl residues in red blood cell hemoglobin. This binding event is responsible 
for the autooxidation of hemoglobin and the generation of reactive oxygen and nitrogen species 
(RONS) inside red blood cells (RBCs) [Reid 2015]. Nitro-oxidative stress leads to plasma 
membrane translocation of phosphatidylserine (PS), which in turn is involved in PS-mediated 
erythrocyte adhesion to the hypoxic tumor vasculature. Allosteric modification of hemoglobin by 
the RRx-001 adduct catalyzes the reduction of nitrite to nitric oxide under these hypoxic 
conditions and normalizes the tumor vasculature, resulting in improved tumor oxygenation and 
response to radiation treatment [Brouse 2015].  Endocytosis of RRx-001-adducted red blood 
cells by tumor associated macrophages induces polarization to the M1 phenotype and 
immunosensitization via release of inflammatory chemokines and cytokines [Oronsky 2017a]. 
3.2.2 
RRx-001 Combination with Cisplatin 
The effects of combined treatment of RRx-001 and cisplatin were evaluated.  Mice received 
vehicle or RRx-001 via intravenous injection at 5 mg/kg for 3 times, once every 48 hours prior to 
receiving intraperitoneal injection of cisplatin 2 mg/kg for 5 times, once every other day.  
Pretreatment with RRx-001 significantly attenuated the cisplatin-induced reduction in 
hematological parameters (hemoglobin concentration, leukocyte count and platelet count) 
indicative of protection against these toxic effects in bone marrow.  In addition, there was a trend 
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toward reduction in cisplatin-induced renal toxicity with apparent attenuation of increases in 
serum creatinine and blood urea nitrogen levels.  When the combination was tested in mice 
bearing sarcoma 180 tumors, RRx-001 treatment appeared to attenuate the body weight loss 
caused by cisplatin but did not diminish antitumor efficacy [Oronsky 2017b].  
3.2.3 
RRx-001 Radiosensitization of Tumor Cells 
When combined in vitro with radiation, RRx-001 (1 μM) shifted the radiation survival curves of 
tumor cell lines downward.  The radiation survival at 2Gy was decreased from 72% to 12% in 
HT29 cells and from 89% to 1.4% in SCC VII cells.  At 10Gy, RRx-001 further decreased the 
radiation survival from 1.3% to 0.07% for HT29 cells and from 3.3% to 0.03% in SCC VII cells.  
The radiation dose modifying factors (DMFs) of RRx-001 were 1.7 and 1.6 at 10% survival for 
HT29 and SCC VII cells, respectively.  The in vivo radiosensitizing properties of RRx-001 were 
demonstrated in mice bearing SCC VII tumor xenografts.  Tumor-bearing mice were treated with 
either 5 mg/kg RRx-001 i.p. daily for 5 days or local tumor irradiation of 250 cGy for 5 days or 
both.  Either radiation alone or RRx-001 alone inhibited tumor growth and produced tumor 
growth delay (TGD) times of 3.2 ± 1.8 days and 1.8 ± 0.6 days, respectively.  The combination 
of radiation and RRx-001 resulted in a statistically significant lengthening TGD time of 7.0 ± 2.1 
days.  Higher daily doses of radiation (400 cGy) and RRx-001 (6 mg/kg) enhanced the 
therapeutic efficacy of radiotherapy and prolonged the TGD time from 7.9 ± 2.4 days for 
radiation alone to 13.9 ± 1.9 days for combination therapy.  Each combination regimen did not 
cause a significant decrease in animal body weight compared with untreated control mice or 
radiation-treated mice [Ning 2012]. 
3.2.4 
RRx-001 Radioprotection of Normal Cells 
Mice were treated with vehicle or RRx-001 10 mg/kg i.p. 24 hours prior to irradiation (9.35 Gy 
delivered at 0.6 Gy/min).  Survival was evaluated over 30 days post-exposure and was 
significantly increased in the RRx-001-treated mice, 67% compared to 33% in vehicle-treated 
mice (p<0.005). In addition, RRx-001-treated mice showed accelerated recovery of bone marrow 
cellularity and Colony Forming Units compared to vehicle-treated mice after a sublethal total 
body radiation exposure (7 Gy delivered at 0.6 Gy/min) (Jurgensen et al., 2017 Radiation 
Research Society).  In another study, RRx-001 treatment enhanced intestinal stem cell (crypt 
cell) survival and regeneration in mice that were exposed to total body irradiation of 10-15 Gy in 
combination with RRx-001 (10 mg/kg i.p.) as compared to mice treated with radiation alone 
[Scicinski 2015].  
3.2.5 
RRx-001 Toxicology 
Repeated-dose toxicity studies of RRx-001 (3 times/week up to 4 weeks in duration) were 
conducted in rats at dose levels of 12, 20.1 and 30 mg/kg per day and in dogs at dose levels of 4, 
8 and 12 mg/kg per day (due to clinical signs the 8 and 12 mg/kg doses were reduced to 3 and 
5 mg/kg on Day 4).  The no observed adverse effect level (NOAEL) was < 12 mg/kg in rats and 
5 mg/kg in dogs.  Target organs of RRx-001 in rats were spleen and lungs.  Effects on lungs 
were observed in dogs.  RRx-001 was genotoxic in the in vitro bacterial reverse mutation assay. 
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3.3 
Clinical Experience with RRx-001 
3.3.1 
Safety 
To date, based on the sum of the data from 9 total Phase 1 and Phase 2 trials, RRx-001 is well 
tolerated over time with a consistently favorable safety profile in which the majority of serious 
adverse events are cancer-related.  The two main (and arguably the only) RRx-001 related 
adverse events are: 1) non-dangerous infusion site reactions and 2) immune-mediated 
pseudoprogression or tumor flare, which is generally a favorable sign despite the potential for 
transient tumor enlargement.  A total of approximately 220 patients with cancer have been 
treated with RRx-001 either alone or in combination with chemotherapy, radiotherapy or 
chemoradiotherapy over a timespan of approximately 6 years. 
As a single agent, the majority of treatment-emergent adverse events, besides local infusion pain, 
which has since largely resolved with co-infusion of autologous blood, have resulted from 
disease progression or intercurrent illness.  No evidence of drug-related organ damage 
(hepatotoxicity, cardiotoxicity, renal toxicity, pulmonary toxicity or bone marrow suppression) 
or clinically relevant changes in physical examination, vital signs, EKG, and hematology or 
clinical chemistry parameters have been observed over time. 
In concurrent combination with radiation, chemotherapy (temozolomide and irinotecan) and 
immunotherapy (nivolumab), the serious adverse events that have been observed are consistent 
with the known toxicity profiles of these other agents. 
When dosed as a single agent until progression followed sequentially with chemotherapy, 
RRx-001 may partially protect normal tissues from the cytotoxicities of chemotherapy, resulting 
in an increased relative dose intensity (RDI) of chemotherapy. 
Overall RRx-001 has been well tolerated (especially when co-infused with autologous blood) 
both alone and in combination with minimal to no evidence of systemic toxicity.  Two serious 
adverse events (SAEs) have been attributed by Principal Investigators to single agent RRx-001: 
1. Rectal bleeding in a colorectal patient with an elevated INR and daily aspirin use 
2. Ischemic stroke in a patient with brain metastases and multiple vascular risk factors 
including morbid obesity, untreated hypercholesterolemia and a previous history of 
hypercoagulability 
 
No SAEs have been attributed to RRx-001 in combination with radiation or chemoradiation. 
3.3.2 
Activity 
3.3.2.1 Clinical Chemoprotection Data  
Data from two trials, ROCKET and QUADRUPLE THREAT in colorectal cancer and lung and 
ovarian cancer, respectively, suggest attenuation of the bone marrow and GI toxicities of 
sequentially administered chemotherapy, in which irinotecan and cisplatin/etoposide, 
respectively, were administered after discontinuation of RRx-001 treatment.  The topoisomerase 
I inhibitor, irinotecan, is associated with significant toxicity, particularly diarrhea and 
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neutropenia with Grade 3 or 4 diarrhea reported in up to 34% of patients even with anti-diarrheal 
treatment and Grade 3 or 4 neutropenia reported in 23–44% of patients [Vanhoefer 2001].  In the 
ROCKET colorectal trial, of the 19 patients that were rechallenged with irinotecan after 
RRx-001 treatment, Grades 3-4 diarrhea and neutropenia were not observed in any patients. 
Figure 1: Incidence of Diarrhea During Irinotecan Treatment After Exposure to RRx-001 
 
 
For the platinum agents, cisplatin and carboplatin, the incidence of Grade 3-4 bone marrow 
toxicities are as follows according to the Carboplatin package insert: 
Table 1: 
Carboplatin vs. Cisplatin Incidence of > Grade 3 Cytopenias from a Meta-
Analysis in SCLC 
 
Carboplatin  
Cisplatin 
Thrombocytopenia 
41 
6 
Neutropenia 
81 
79 
Leukopenia 
68 
52 
Anemia 
18 
12 
 
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By contrast, in an analysis of 50 patients with safety data from the QUADRUPLE THREAT 
trial, 30 of whom to date have received platinum (either cisplatin or carboplatin) after RRx-001, 
the incidence of bone marrow toxicities is dramatically less as shown below: 
• thrombocytopenia 3.3% 
• neutropenia 30% 
• leukopenia 3.3% 
• anemia 16.7% 
 
Figure 2: Bar Graph Showing Comparative Incidences of Myelotoxicity from Platinum 
on an Ovarian Cancer NCIC Study (Source FDA Package Insert) vs. Platinum 
Administered After RRx-001 
 
 
3.3.2.2 Clinical Radioprotection Data  
Evidence of clinical radioprotection is also potentially present in the Phase 1 BRAINSTORM 
trial in which 31 patients (22 evaluable) with brain metastases received concurrent whole brain 
radiotherapy (WBRT) and RRx-001 up to a dose of 33 mg.  In this trial the intracranial response 
rate was 50% and the intracranial disease control rate in evaluable patients (stable disease or 
better) was 100%.  No grade 3 or 4 neurotoxicities were reported, potentially indicative of 
neuroprotection.  
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3.3.3 
Metabolism 
In blood, RRx-001 reacts non-enzymatically and covalently with reduced glutathione (GSH), and 
with the beta93Cys residue of hemoglobin (Hb), forming RRx-001-GSH and RRx-001-Hb 
metabolites, respectively.  Pharmacokinetics given the rapid conversion of the RRx-001 parent 
molecule to its glutathione (GSH) and hemoglobin conjugates, RRx-001-GSH, as the 
predominant measurable metabolite in the plasma, was chosen as a surrogate for drug exposure. 
Terminal half-life of RRx-001-GSH was calculated as approximately 30 minutes.  AUC and Cmax 
were mostly dose proportional for doses up to 55 mg/m2 in Phase 1.  Unfortunately, since the red 
blood cell is the main intermediary of RRx-001 activity (and local toxicity), the absorption, 
distribution, metabolism and excretion profile of the GSH conjugate is not a useful or relevant 
measure of the pharmacology and safety of RRx-001. 
3.4 
Dose and Dose Schedule of RRx-001 
The 4 mg dose has been chosen on the basis of previous experience in two chemoradiation trials 
for brain metastases and primary GBM, as well as a lower incidence of infusion reactions and a 
hypothesized lower incidence of pseudoprogression. 
Based on clinically observed blood flow changes in the tumor, which last for at least 7 days, the 
optimal frequency of dosing was determined to be once weekly, although twice weekly has also 
been tried in clinical studies.  
 
4 PROPOSED MECHANISMS OF RADIOPROTECTION 
RRx-001 bound to hemoglobin in red blood cells produces reactive oxygen and nitrogen species, 
which leads to compensatory anti-inflammatory gene expression in tissues from upregulation of 
Nrf2 (nuclear factor erythroid 2-related factor 2), a regulatory transcription factor with a critical 
role in the antioxidant response pathway.  The protective role of Nrf2 was evaluated in mice 
bearing SSC VII tumor xenografts that received a single intravenous dose of RRx-001 
(10 mg/kg). Histological examination of the tumors demonstrated that the intensity of Nrf2 
(nuclear factor erythroid 2-related factor 2) cytoplasmic and nuclear proteins was dramatically 
higher in RRx-001-treated tumors compared to that in control tumors.  This higher nuclear 
expression of Nrf2 suggests that after RRx-001 treatment Nrf2 translocates to the nucleus and 
induces antioxidant gene expression. The downstream expression of Nrf2-activated antioxidant 
enzymes, heme oxygenase 1 and NAD(P)H dehydrogenase quinone, was assessed both in vitro 
and in vivo in SCC VII tumor cells following RRx-001 treatment and showed a time-dependent 
increase of expression [Ning 2015].  Hence, it is hypothesized that RRx-001 protects tissues 
from radiation injury via Nrf2 nuclear translocation and upregulation of multiple antioxidant 
pathways, which minimizes oxidative stress and maintains the redox status. 
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5 STUDY OBJECTIVES 
This is an exploratory, open-label study, which is intended to examine varying dosing schedules 
of RRx-001 in combination with standard of care for cancers of the oral cavity and oropharynx. 
The study seeks to assess the safety and tolerability of varying dosing schedules of RRx-001 
during treatment and for 28 days following end of treatment and to assess the long-term effect of 
RRx-001 on tumor response to standard concomitant chemoradiation. 
It is also the objective of the study to assess the efficacy of RRx-001 in the attenuation of severe 
oral mucositis (SOM) in patients receiving cisplatin and radiation therapy for the treatment 
cancers of the oral cavity or oropharynx.  
 
6 STUDY DESIGN 
6.1 
Description of the Study 
The purpose of this proof-of-concept study is to determine whether RRx-001 has the potential to 
reduce the severity and duration of oral mucositis, an acute inflammatory condition, which 
generally peaks within 3 weeks after the start of chemoradiation therapy and, in the majority of 
cases, subsides shortly after the cessation of therapy. 
This is a 4‐arm Phase 2 exploratory proof-of-concept trial in which patients requiring standard 
chemoradiation therapy (concomitant cisplatin and radiation therapy) are randomized to receive 
one of three different regimens of RRx-001 (experimental groups) or standard care alone (control 
group). Approximately 40 patients will be randomized to 1 of the following 4 arms with 1 
stratification factor (two levels: oral cavity or oropharynx): 
Arm 1: “RRx-001 Pre-Treatment + SOC Chemoradiation (IMRT + Cisplatin)” 
Two infusions of RRx-001 4 mg with 10 mg dexamethasone as a premedication will be given 
each week during the two weeks prior to the start of chemoradiation SOC followed by cisplatin 
either every three weeks (100 mg/m2 for 3 doses) or weekly (40 mg/m2 for 7 doses) and IMRT 
administered daily (excepting weekends) for 7 weeks.  No additional RRx-001 will be given 
during the course of chemoradiation. 
Arm 2: “RRx-001 Pre-Treatment + 2 Concurrent Doses + SOC Chemoradiation (IMRT + 
Cisplatin)” 
Two infusions of RRx-001 4 mg with 10 mg dexamethasone as a premedication will be given 
each week during the two weeks prior to the start of chemoradiation SOC, followed by cisplatin 
either every three weeks (100 mg/m2 for 3 doses) or weekly (40 mg/m2 for 7 doses) and IMRT 
administered daily (excepting weekends) for 7 weeks. In addition, one dose of RRx-001 4 mg 
with 10 mg dexamethasone as a premedication will be given in each of weeks 2 and 5 of the 
course of chemoradiation. 
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Arm 3: “RRx-001 Pre-Treatment + 6 Concurrent Doses + SOC Chemoradiation (IMRT + 
Cisplatin)” 
Two infusions of RRx-001 4 mg with 10 mg dexamethasone as a premedication will be given 
each week during the two weeks prior to the start of SOC chemoradiation, followed by cisplatin 
either every three weeks (100 mg/m2 for 3 doses) or weekly (40 mg/m2 for 7 doses) and IMRT 
administered daily (excepting weekends) for 7 weeks. In addition, one dose of RRx-001 4 mg 
with 10 mg dexamethasone as a premedication will be given in each of the first 6 weeks of the 
course of chemoradiation. 
Arm 4: “SOC Chemoradiation Only (Control)”  
No doses of RRx-001 will be administered.  Patients assigned to this arm will receive only 
standard of care (SOC) chemoradiation in the form of cisplatin either every three weeks 
(100 mg/m2 for 3 doses) or weekly (40 mg/m2 for 7 doses) and IMRT administered daily 
(excepting weekends) for 7 weeks. 
Administration of RRx-001 will not be blinded, so patient and study staff may be aware of the 
treatment assignment. 
Patients will be followed for safety endpoints throughout the study.  Patients will be evaluated 
for the presence and severity of oral mucositis during the course of chemoradiation and for up to 
6 weeks following the cessation of RT. 
Oral mucositis (OM) will be evaluated according to Section 11.1.  
Patients in the study will be followed up to one year following the end of radiotherapy, in order 
to evaluate safety and tumor outcomes. 
 
7 STUDY POPULATION 
7.1 
Eligibility Criteria 
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. 
 
8 DRUG TREATMENT 
8.1 
RRx-001 Drug Treatment 
See Section 1.1 Treatment Schemas for treatment schedule. 
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8.1.1 
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, 
using aseptic techniques, to yield a solution containing 66% PEG-400 and 33% DMA. This 
solution will then be diluted, using aseptic techniques, to 2.0 mg/mL with Water for injection 
(WFI). Please refer to pharmacy manual for drug storage conditions and drug preparation 
instructions.  
8.1.2 
RRx-001 Administration 
RRx-001 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, per the schedule outlined in the 
study schema (Section 1.1).  
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. 
RRx-001 Therapy Handling: 
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. 
The methodology for administering the RRx-001 dose by premixing with the patient’s blood that 
has been anticoagulated with Acid-Citrate-Dextrose Formula A (ACD-A) is based on procedures 
used in blood product transfusions.  Standard procedures for avoiding 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.  
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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.  
RRx-001 Therapy Administration Procedure in the Clinic: 
The RRx-001 and ACD-A anticoagulant doses should be properly labeled per institutional 
standards and in accordance with the latest pharmacy manual guidelines.   
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.  
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. 
8.1.3 
Storage and Stability 
RRx-001 is not light sensitive.  The product should be used within 30 minutes 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 to be stored in a secured site with restricted access. 
8.1.4 
Supply 
RRx-001 will be supplied by the Sponsor. 
8.1.5 
Pre-Medications 
Corticosteroids are required as a premedication: Dexamethasone (10 mg, IV or PO) or an 
equivalent dosage of another steroid.  
Table 2: 
RRx-001 Regimen Premedication Description 
Premedication RRx-001 
Route 
Schedule 
10 mg Dexamethasone 
(or equivalent dose of another corticosteroid) 
IV or PO 
Same day prior to dosing 
 
8.1.6 
Prohibited Medications / Supplements 
Contraindications  
Due to their antioxidant properties (and in the case of alpha lipoic acid iron chelating properties), 
which are presumed to counteract the free radical generation of radiation therapy, the following 
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are contraindicated: alpha lipoic acid, Vitamin E, N-acetylcysteine and omega 3 fatty acid 
supplements. 
8.2 
Cisplatin Drug Treatment 
Combination Treatment: Patients will receive cisplatin per Investigators Discretion: 
• 
Option 1: 3 doses at 100 mg/m2 on Day 1 (± 2 Days) of Weeks 1, 4, and 7 
• 
Option 2: 7 doses at 40 mg/m2 on Day 1 (± 2 Days) of Weeks 1, 2, 3, 4, 5, 6, and 7 
• 
Note: Cisplatin should not be given within 24 hours of RRx-001 
 
Patients will receive cisplatin in accordance with applicable guidelines such as NCCN and/or the 
package insert; however, these guidelines are not intended to supersede or replace institutional 
guidelines with respect to appropriate and necessary care for individual patients [Ang 2010]. 
8.2.1 
Supply 
Cisplatin is commercially available. 
8.2.2 
Pre-Medications 
Cisplatin premedication should be provided via institutional guidelines.  
8.3 
Dose Modifications 
8.3.1 
Dosing Delays/Dosing Modifications: RRx-001 Therapy  
The starting 4 mg dose has been chosen on the basis of previous experience in two 
chemoradiation trials for brain metastases and primary GBM, as well as a lower incidence of 
infusion reactions and hypothesized lower incidence of pseudoprogression. The most common 
toxicity of RRx-001 is mild or moderate infusion-related reactions.  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.  
Table 3: 
Dose Modifications for RRx-001 Administration 
Sequential Dose 
Modifications 
RRx-001 Dose 
(mg) 
RRx-001 Dose 
(mg/m2) 
mL 
Infusion Time 
Frequency 
Initial 
4 
2.3 
2.0 
Not to exceed 4 hours 
from extraction of blood  
Per SOA 
Dose reduction 
2 
1.15 
1.0 
Not to exceed 4 hours 
from extraction of blood 
Per SOA 
Dose reduction 
0.5 
0.29 
0.25 
Not to exceed 4 hours 
from extraction of blood 
Per SOA 
 
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8.3.2 
Dosing Delays/Dosing Modifications: Cisplatin 
• 
Neutropenia: If on the day of scheduled treatment with cisplatin the absolute neutrophil 
count (ANC) is < 1200, hold treatment until ANC ≥ 1200, then treat at 100% dose. 
Neutropenic fever will require permanent 25% dose reduction.  Per CTCAE, v. 5.0, 
febrile neutropenia is described as ANC < 1000/mm3 with a single temperature of 
> 38.3 degrees C (101 degrees F) or a sustained temperature of ≥ 38 degrees C 
(100.4 degrees F) for more than 1 hour. 
• 
Thrombocytopenia: If on the day of scheduled treatment with cisplatin the platelet count 
is < 75,000, hold treatment until platelets are > 75,000, then treat at 100% dose. 
Thrombocytopenia that results in bleeding will require a 25% dose reduction 
• 
Neurotoxicity: If any signs of grade 3 or greater neurotoxicity occur, discontinue 
cisplatin. Continue radiation therapy (RT). 
• 
Renal Adverse Events: Cisplatin should be administered on the scheduled day of 
treatment using the following guidelines. Note: If creatinine is > 1.2 mg/dL, clearance 
must be calculated (Cockcroft-Gault) in order to make dose adjustment. If the calculated 
nomogram is 50 mL/min or above, a 24-hour urine collection is not needed, but if the 
calculation is less than 50 mL/min, a 24-hour urine collection is mandated. 
Creatinine Clearance 
Cisplatin Dose 
100 mg/m2 
Cisplatin Dose 
40 mg/m2 
> 50 mL/min 
100 mg/m2 
40 mg/m2 
40-50 mL/min 
50 mg/m2 
20 mg/m2 
< 40 mL/min 
Hold drug* 
Hold drug* 
 
*Cisplatin should be held (but RT continued), and the creatinine measured weekly. If creatinine 
clearance is > 50 mL/min, then the second dose of cisplatin can be given at the reduced dose of 
50 mg/m2or 20 mg/m2. Also see Section 8.4.2 below. 
• 
Other Adverse Events  
o Mucositis: Significant mucositis from radiation and cisplatin is expected and will 
not be an indication for cisplatin dose modification. No cisplatin dose reductions 
will be made.  
o Ototoxicity: For new clinical hearing loss not requiring a hearing aid or for 
tinnitus that interferes with activities of daily living, treat at 50% dose reduction. 
For hearing loss requiring a hearing aid, discontinue cisplatin. Continue RT and 
RRx-001. If the physician is unsure about the severity of the hearing loss, an 
audiogram is encouraged.  
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8.4 
Missed or Omitted Doses and Alternative Treatment Schedules 
8.4.1 
Missed Doses: RRx-001  
If doses of RRx-001 doses are missed those doses will be skipped.  If all the doses of RRx-001 
are missed that patient may be considered non-evaluable.  The missed or omitted dose(s) and the 
reason for omission should be recorded. 
8.4.2 
Missed or Omitted Doses: Cisplatin 
In the event of any grade 3 or 4 event, treatment will be delayed.  If the delay is more than 
21 days because of hematologic or renal adverse events, that dose will be omitted.  If a dose of 
cisplatin is missed or omitted, it will not be made up or added to the end of treatment. 
If radiotherapy is held, cisplatin should similarly be held and resumed when radiation resumes. 
In this case, the cisplatin dose is not considered skipped or omitted, but delayed. 
9 RADIATION THERAPY 
Intensity Modulated Radiation Therapy (IMRT) in accordance with the American College of 
Radiology (ACR) and American Society for Radiation Oncology (ASTRO) Practice Guideline 
for IMRT) is mandatory for this study [Hartford 2012]. 
 
10 OTHER THERAPY 
10.1 
Permitted Concomitant Supportive Therapy 
Patients should receive full supportive care while on this study.  This includes blood product 
support, antibiotic treatment, antifungal treatment, and treatment of other newly diagnosed or 
concurrent medical conditions.  All supportive care should be listed as a concomitant medication.  
Patients will conform to a standard oral care regimen consistent with national/international 
guidelines and will be provided instructions and supplies to assure adherence (Appendix F & 
Appendix G). 
10.2 
Non-permitted Concomitant Supportive Therapy 
• Amifostine 
• Topical antibiotic rinses, creams or troches 
• Benzydamine hydrochloride 
• Caphosol 
• Glutamine (topically applied) 
• GM-CSF (Leukine) 
• IL-11 
• Magic mouthwash or Miracle mouthwashes are allowed as long they do not contain any 
of the following: 
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o Chlorhexidine 
o Diphenhydramine 
o Tetracycline or other antibiotic 
o Hydrogen peroxide 
• Other disallowed medications: 
o Herbal, alternative remedies, other natural product (i.e. honey) and alcohol-
containing mouthrinses. 
o MuGard 
o GelClair 
o Episil 
o Prothelial 
o Palifermin or other growth factors 
o Povidone-iodine rinses 
o Prevention mouth rinse 
o ReBalance 
o Steroid rinses or gels 
o Sucralfate suspension for topical use (oral formulations, i.e., tablets are allowed). 
o Other biologic modifiers.  Hematopoietic growth factors such as GCSF are 
allowed. 
o Other investigational agents. 
 
If non-permitted concomitant supportive therapies are used (Section 10.2) the data may be 
censored and the patient may be replaced. 
 
11 EFFICACY ASSESSMENTS 
11.1 
Oral Mucositis (OM) Assessments 
Mucositis assessments will be completed at the screening visit, day 1 of pretreatment prior to 
administration of RRx-001, twice weekly (no less than 48 hours apart) within each 5-day 
radiation week during the combination treatment phase, at the end of the combination treatment 
phase (last day of radiation) and the same day each week (± 1 day) during the Mucositis 
Observation Follow-up until resolution of ulcerative mucositis occurs (WHO grade 0 or 1). 
Oral mucositis will be assessed by a trained evaluator using a standard oral mucositis assessment 
instrument.  If a patient withdraws prior to the end of the combination treatment phase, an oral 
assessment must be completed on the day of withdrawal, and it is suggested that patients be 
assessed weekly until resolution of ulcerative mucositis occurs (WHO grade 0 or 1).  Patients 
will be instructed not to discuss their treatment regimens with the assessor.  Additionally, the 
assessor will be provided training to assure uniform interactions with patients to limit bias in the 
assessment. 
Specific training and instructions are required for all individuals who perform mucositis 
assessments.  Such training will be provided by the sponsor or its designee.  Site study staff 
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designated as oral evaluators must be licensed professionals and properly delegated such tasks 
(on DOA log).  Oral evaluators will conduct all assessments using a standardized and consistent 
method.  To reduce inter-observer variability, as few oral evaluators as possible should be 
involved in the assessments of an individual patient.  Ideally, the same assessor will evaluate a 
single patient throughout the combination treatment and mucositis observation follow-up.  All 
efforts to maintain uniformity should be used. 
The study’s efficacy endpoints will be based on WHO mucositis criteria.  Since patients’ ability 
to eat is a component of the WHO scale, standardization of the assessment of food intake and, 
particularly, the definition of solids, liquids and “nothing by mouth” is critical. 
• 
A normal solid diet is defined as firm, shaped food that does not flow or conform to the 
shape of its container and requires chewing. Examples include rice, meat including fish, 
poultry, bread, rolls, toast, salad, cereal. 
• 
A modified soft solid diet consists of foods that do not conform to the shape of its 
container, still require minimal chewing, but are less dense than standard solids. 
Examples include eggs, pasta, fruit or soup. 
• 
For the purposes of the clinical trial mucositis assessment, liquids are defined as foods 
that take the shape of their container and which don’t require chewing.   In addition to 
things we typically think of as pure liquids like juice, milk shakes, smoothies or frappes, 
also heavily pureed foods, yogurt, oatmeal and jello fall into this category. 
• 
The “nothing by mouth” category is appropriate for patients who can’t eat or swallow 
EXCEPT for medication. Please note that sips of water used to help aid in swallowing 
medication still constitute a “nothing by mouth” selection. This would also be the best 
option for patients who require the assistance of a feeding tube. 
 
11.2 
Pain Assessments 
Pain will be assessed with the OMDQ Question 2 (mouth and throat soreness or MTS), which 
will be completed daily from baseline until oral mucositis assessment grade 0 or 1.  The OMDQ 
is provided in Appendix D.  The OMDQ will be provided in booklets for patient distribution 
during Combination Treatment and Mucositis Observation Follow-up. 
11.3 
Analgesic Use 
Patients often require analgesics, including opioids for pain control. Patients will record any 
analgesic use, including name, dose, and frequency of dose, in the OMDQ Booklet.  Information 
from the source documents and the diary will be recorded into the EDC system as a concomitant 
medication. Analgesics will be converted to morphine equivalents at the time of data analysis. 
11.4 
Other Assessments 
Frequency and duration of interruptions in radiation therapy will be recorded.   
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11.5 
Tumor Assessments 
Tumor assessments will be performed according to the schedule of assessments. The patient’s 
tumor response will be assessed using RECIST v1.1 [Eisenhauer et al. 2009] until progression, 
start of next therapy or until end of Long Term Follow-up, whichever comes first [Appendix B]. 
When measurable disease is not present (e.g. post-operative patients), RECIST v1.1 assessment 
is not performed until measurable disease presents (this is considered progression and no further 
assessments will be done) or start of next therapy.  Tumor status information will be collected 
and will include disease progression, and survival. During the follow up period, data will be 
collected at standard of care intervals, i.e., month 3 (± 7 days) and also at months 6, 9 and 12 
(each ± 14 days) following the last day of combination therapy to document start date of 
subsequent therapies. 
 
12 ASSESSMENT OF SAFETY 
The safety of RRx-001 will be assessed through collection and analyses of adverse events (AEs) 
and laboratory tests.   
12.1 
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, cisplatin or radiation therapy, all 
events of death, and any study specific issue of concern. 
12.1.1 
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 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 should not be reported as an AE. 
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12.1.2 
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. 
• 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 into 
the EDC system. 
12.2 
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). 
12.2.1 
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 study treatment (RRx-001, 
cisplatin and radiation therapy) or study discontinuation/termination, whichever is earlier.  After 
this period, investigators should only report SAEs that are attributed to prior study treatment. 
12.2.2 
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 
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personnel during questioning, or detected through physical examination, laboratory test, or other 
means will be recorded in the patient’s medical record and into the EDC system. 
Each recorded AE or SAE will be described by its duration (i.e., start and end dates), severity, 
regulatory seriousness criteria if applicable, suspected relationship to the investigational product 
(see following guidance), and actions taken. 
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 4: 
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  
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 (RRx-001), 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 (RRx-001); and/or the AE abates or resolves 
upon discontinuation of the investigational product (RRx-001) or dose reduction and, if 
applicable, reappears upon re-challenge. 
• NO 
Evidence exists that the AE has an etiology other than the investigational product (RRx-001) 
(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 (RRx-001) (e.g., cancer diagnosed 2 days after first dose of study drug). 
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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. 
12.2.3 
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. Deaths 
All deaths that occur during the protocol-specified AE reporting period, 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”. 
b. 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”). 
c. 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. 
d. 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, 
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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. 
e. 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. 
12.3 
Reporting Requirements for Adverse Events 
12.3.1 
Expedited Reporting Requirements for Serious Adverse Events 
All SAEs are required to be reported to the Sponsor on the SAE CRF within 24 hours of a site’s 
knowledge of the SAE.  Please send all SAE reports to:  
Fax Number: (650) 396-4450 or 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. 
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 
SAE reporting, you may contact the EpicentRx Medical Contact (re: page 1). 
12.3.2 
Routine Reporting of Adverse Events 
• The Institutional Review Board (IRB) should be notified per local guidelines.  
12.4 
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. 
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). 
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13 STATISTICAL METHODS 
13.1 
Sample Size 
A sample size of 40 patients is considered adequate for this POC study to explore the 
radioprotective potential of RRx-001 and identify a safe regimen for further development.    
With 10 patients per group, the study will have approximately 80% power to detect a 75% 
reduction in the average number of days with severe OM (from 24 to 6 days) at the two-sided 5% 
significance level; this calculation is based on Student’s t-test and assumes the standard deviation 
for duration of severe OM is 13 days.  While not powered for more modest treatment effects, the 
study will yield important safety information and trends in efficacy data to inform decisions 
about future study designs. 
13.2 
Efficacy Analysis 
Statistical methods for the calculation and analysis of efficacy endpoints are provided below.  
Limited hypothesis-testing will be performed, as this is a small POC study. All statistical 
analyses are exploratory. 
Duration of Severe Oral Mucositis (SOM):  The duration of SOM (WHO grade 3 or 4) will be 
calculated as the number of days from the onset of SOM (first time a WHO grade 3 or 4 is 
observed) to the day when severe OM has resolved (first time WHO grade 2 or less is observed 
after last WHO grade 3 or 4). Durations of 0 will be assigned to patients who do not experience 
severe OM. Any patient who dies or withdraws prior to resolution of severe OM will be assumed 
to have severe OM for the remainder of the observation period.  All available OM assessments 
will be used to derive efficacy endpoints, including WHO grades recorded during the treatment 
and follow-up period in order to capture resolution of OM. 
The duration of SOM will be compared for each of the 3 RRx-001 regimens versus the untreated 
control group using the Wilcoxon rank-sum test.  This rank-based test does not depend on 
normality assumptions for these small sample sizes.  All patients randomized (the intent-to-treat 
population) will be used for this analysis. 
Time to onset of SOM: The number of days from the start of chemotherapy until the date of 
first OM assessment grade 3 or 4 will be listed and summarized descriptively for each treatment 
group.   
Incidence of SOM: The incidence of SOM (WHO grade 3 or 4) will be calculated as the number 
of patients with at least one OM WHO grade 3 or 4, divided by the number patients in the 
treatment group.  Patients with no OM assessments will be assumed to have severe scores. 
Patients who die or withdraw without experiencing OM grade 3 or 4 will also be assumed to 
have severe scores.  The incidence of SOM will be compared between each RRx-001 group and 
the control arm using Fisher’s Exact test.  Clopper-Pearson two-sided 95% confidence limits will 
be calculated for the proportion of patients with SOM in each treatment arm.    
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Duration and incidence of ulcerative OM: The duration of ulcerative OM (WHO grade 2, 3, 
and 4) will be calculated in a manner similar to duration of severe OM.  That is, the duration of 
ulcerative OM will be calculated as the number of days from the onset of ulcerative OM (first 
time a WHO grade 2, 3, or 4 is observed) to the day when ulcerative OM has resolved (first time 
WHO grade 0 or 1 is observed after last WHO grade 2, 3 or 4).  A similar imputation scheme 
will be used in the event that patients die or withdraw prior to resolution of OM to grade 0 or 1. 
The Wilcoxon rank-sum tests will be used to compare treatment groups. Incidence of ulcerative 
OM will be calculated and analyzed as described above for severe OM.  
Patient-reported pain:  The average of patient-reported mouth and throat soreness (MTS) 
scores, graded on a scale from 0 (no soreness) to 4 (extreme soreness), will be summarized by 
treatment group during each study week and displayed graphically.  The number of patients with 
scores of 0 or 1 will be enumerated by time and treatment group. 
13.3 
Safety Analysis 
Safety will be evaluated on the basis of treatment-emergent AEs (TEAEs), vital signs, weight, 
physical examinations, tumor assessments, and clinical laboratory assessments. 
All adverse events will be coded by Preferred Term and System Organ Class using the most 
recent version of MedDRA.  The National Cancer Institute Common Terminology Criteria for 
Adverse Events (CTCAE) (Version 5.0) will be used to grade both clinical and laboratory AEs. 
By-patient listings of deaths, SAEs, and AEs leading to discontinuation will be provided.  The 
by-patient AE data listings will include onset and resolution dates, verbatim term, Preferred 
Term, treatment, severity (grade), relationship to treatment, action taken for the event, and 
outcome. 
The incidence of treatment-emergent AEs (TEAEs) will be summarized by treatment group and 
tabulated by System Organ Class (SOC) and Preferred Term (PT).  A TEAE is defined as an AE 
that first occurs or worsens in severity on or after the first dose of the study medication.  
Vital signs (systolic and diastolic blood pressure, pulse, and temperature) and body weight will 
be summarized for each treatment group using descriptive statistics.  Summary statistics (n, 
mean, median, standard deviation, minimum, and maximum) will be calculated for both the 
actual value and the change from baseline value at each scheduled visit. 
Clinical laboratory data will be presented for each treatment group using descriptive statistics 
based on the observed values and change from baseline values at each scheduled visit.  Summary 
statistics (n, mean, median, SD, minimum, and maximum) will be calculated for quantitative 
safety data and frequency counts will be compiled for classification of qualitative safety data.   
Shift tables from baseline to the worst post-baseline values during the treatment period will be 
provided for chemistry parameters and hematology parameters that have NCI-CTCAE v5.0 
toxicity grades.  Both scheduled and unscheduled post baseline values during the treatment 
period will be considered.  Additionally, the number and percentage of patients with Grade ≥ 3 
will be presented for each CTCAE gradable laboratory test. 
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All clinical laboratory data will be listed by patient. Values outside the normal ranges will be 
flagged and toxicity grades will be displayed for relevant parameters. 
Pre-study abnormalities and reported abnormalities at the end of study will be tabulated by body 
system.  Changes in physical examinations will be described in the text of the final study report. 
Tumor response assessments at each follow-up visit will be tabulated by treatment group. 
Prior and concomitant medications will be tabulated for each treatment group; details regarding 
dose regimens and start/stop dates will be presented in by-patient data listings. 
Progression Free Survival (PFS) defined from the time of registration to the time of the first 
radiographic documentation of objective progression (per RECIST v1.1) or the date of death, 
whichever is earlier, will be evaluated using Kaplan-Meier methods. Subjects still alive without 
progressive disease at the time of analysis will be censored on the date of the last objective 
progression-free observation prior to the start of subsequent anti-cancer therapy. 
 
14 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 into the EDC system.  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, data entered into the EDC system will be 
reviewed by the Principal Investigator and will require his/her final signature to verify the 
accuracy of the data. 
14.1 
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. 
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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.). 
14.2 
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 will also be 
carried out remotely using redacted source documents.  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. 
14.3 
Data Collection 
Study documentation includes all data entered into the EDC system, 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.   
14.4 
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.   
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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. 
14.5 
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 electronic data, 
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.   
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15 REFERENCES 
1. 
Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI, Nguyen-Tân PF, et al. Human 
papillomavirus and survival of patients with oropharyngeal cancer. New England Journal 
of Medicine. 2010 Jul 1;363(1):24-35. 
2. 
Brouse C, Ortiz D, Su Y, Oronsky B, Scicinski J, Cabrales P. Impact of hemoglobin nitrite 
to nitric oxide reductase on blood transfusion for resuscitation from hemorrhagic shock. 
Asian journal of transfusion science. 2015 Jan;9(1):55. 
3. 
Das DS, Ray A, Das A, Song Y, Tian Z, Oronsky B, et al. A novel hypoxia-selective 
epigenetic agent RRx-001 triggers apoptosis and overcomes drug resistance in multiple 
myeloma cells. Leukemia. 2016 Nov;30(11):2187. 
4. 
Dose, AM. The symptom experience of mucositis, stomatitis, and xerostomia. Semin Oncol 
Nurs, 1995;11(4):248–255. 
5. 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, 
Arbuck S, Gwyther S, Mooney M, Rubinstein L. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). European journal of cancer. 2009 Jan 
1;45(2):228-47. 
6. 
Hartford AC, Galvin JM, Beyer DC, Eichler TJ, Ibbott GS, Kavanagh B, et al. American 
College of Radiology (ACR) and American Society for Radiation Oncology (ASTRO) 
practice guideline for intensity-modulated radiation therapy (IMRT). American journal of 
clinical oncology. 2012 Dec 1;35(6):612-7. 
7. 
Koukourakis  MI.  Amifostine: is there evidence of tumour protection? Semin Oncol 
2003;30(Suppl): S18-30. 
8. 
McCullough RW. Actual duration of patient-reported mucositis: far longer than 2 to 4 
weeks and may be avoidable altogether. Korean J Clin Oncol. 2016;12(1):1-6. 5. 
9. 
Ning S, Bednarski M, Oronsky B, Scicinski J, Saul G, Knox SJ. Dinitroazetidines are a 
novel class of anticancer agents and hypoxia-activated radiation sensitizers developed from 
highly energetic materials. Cancer research. 2012 May 15;72(10):2600-8. 
10. Ning S, Sekar TV, Scicinski J, Oronsky B, Peehl DM, Knox SJ, Paulmurugan R. Nrf2 
activity as a potential biomarker for the pan-epigenetic anticancer agent, RRx-001. 
Oncotarget. 2015 Aug 28;6(25):21547. 
11. Oronsky B, Paulmurugan R, Foygel K, Scicinski J, Knox SJ, Peehl D, et al. RRx-001: a 
systemically non-toxic M2-to-M1 macrophage stimulating and prosensitizing agent in 
Phase II clinical trials. Expert opinion on investigational drugs. 2017a Jan 2;26(1):109-19. 
12. Oronsky B, Reid TR, Larson C, Carter CA, Brzezniak CE, Oronsky A, Cabrales P. RRx-
001 protects against cisplatin-induced toxicities. Journal of cancer research and clinical 
oncology. 2017b Sep 1;143(9):1671-7. 
13. Reid T, Oronsky B, Scicinski J, Scribner CL, Knox SJ, Ning S, et al. Safety and activity of 
RRx-001 in patients with advanced cancer: a first-in-human, open-label, dose-escalation 
phase 1 study. The Lancet Oncology. 2015 Sep 30;16(9):1133-42. 
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14. Scicinski J, Oronsky B, Ning S, Knox S, Peehl D, Kim MM, Langecker P, Fanger G. NO to 
cancer: The complex and multifaceted role of nitric oxide and the epigenetic nitric oxide 
donor, RRx-001. Redox biology. 2015 Dec 1;6:1-8. 
15. Sonis ST, Elting LS, Keefe D, Peterson DE, Schubert M, Hauer‐Jensen M, et al. 
Perspectives on cancer therapy‐induced mucosal injury. Cancer. 2004 May 
1;100(S9):1995-2025. 
16. Sonis ST. Mucositis as a biological process: a new hypothesis for the development of 
chemotherapy-induced stomatotoxicity. Oral oncology. 1998 Jan 1;34(1):39-43. 
17. Sonis ST. Oral mucositis. Anti-Cancer Drugs. 2011;22:607-612. 
18. Stiff PJ, Erder H, Bensinger WI, Emmanouilides C, Gentile T, Isitt J, Lu ZJ, Spielberger R. 
Reliability and validity of a patient self-administered daily questionnaire to assess impact 
of oral mucositis (OM) on pain and daily functioning in patients undergoing autologous 
hematopoietic stem cell transplantation (HSCT). Bone marrow transplantation. 2006 
Feb;37(4):393. 
19. Vanhoefer U, Harstrick A, Achterrath W, Cao S, Seeber S, Rustum YM. Irinotecan in the 
treatment of colorectal cancer: clinical overview. J Clin Oncol. 2001;19:1501–1518. 
20. Vokes EE, Weichselbaum RR, Lippman SM, Hong WK. Head and neck cancer. N Engl J 
Med 1993; 328(3):184–194. 
 
 
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16 APPENDICES 
Appendix A. 
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 
 
 
 
 
 
 
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Appendix B. 
RECIST 1.1 
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]. 
 
 
 
 
 
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Appendix C. 
Oral Mucositis WHO Grading System  
 
 
 
 
 
 
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Appendix D. 
Oral Mucositis Daily Questionnaire (OMDQ) 
This questionnaire (see next page) has been used as a tool to assess oral mucositis in patients 
undergoing hematopoietic stem cell transplantation [Stiff et al., 2006]. 
Patients should be instructed to complete the OMDQ in its entirety in a comfortable area at about 
the same time each day. The OMDQ should be completed prior to the oral mucositis assessment 
on a given study day. For days the patient does not visit the clinic, the patient is to complete it at 
home.  
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Study Day ____              Date: ___________ 
 
Instructions: Please list all medications you have used or taken today. 
 
Time 
Medication Name 
Dose per 
Unit 
Number of Units 
Reason for 
Using/Taking 
Medication 
08 : 10 
AM/PM 
Tylenol Extra 
Strength Gel Capsules 
500 mg 
2 pills 
Jaw Pain 
03 : 15 
AM/PM 
Oral Anesthetic Paste 
Maximum Strength 
Thin Layer 
1 application 
Inner Cheek irritation 
____:____ 
AM/PM 
 
 
 
 
____:____ 
AM/PM 
 
 
 
 
____:____ 
AM/PM 
 
 
 
 
____:____ 
AM/PM 
 
 
 
 
____:____ 
AM/PM 
 
 
 
 
____:____ 
AM/PM 
 
 
 
 
____:____ 
AM/PM 
 
 
 
 
____:____ 
AM/PM 
 
 
 
 
____:____ 
AM/PM 
 
 
 
 
____:____ 
AM/PM 
 
 
 
 
 
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Appendix E. 
Anatomy of the Mouth 
 
 
 
 
 
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Appendix F. 
Standard Oral Health Maintenance Regimen 
The following protocol is strongly recommended to standardize the maintenance regimen for all 
dentulous or partially dentulous study participants to optimize oral health during radiation 
therapy and minimize the risk of post-radiation dental sequelae.  As per standard practice, all 
patients should be instructed on the risks to oral health of concomitant chemoradiation including 
dental caries, periodontal disease and osteoradionecrosis.  The following should be discussed 
with each patient and written materials (provided in next appendix) should be reviewed.  A 
study-supplied Oral Hygiene Kit should be dispensed to each patient at study start and renewed 
as needed. 
1. Diet – Minimize foods that contain refined sugars such as cookies, cakes, candy, sugar-
containing drinks, etc.  Favor fruits and vegetables. 
2. Avoid alcohol and tobacco products. 
3. Practice scrupulous oral hygiene: 
a. Use the soft toothbrush provided in the oral hygiene kit or an electric toothbrush 
at least twice daily. 
b. Use the toothpaste provided in the oral hygiene kit or a similar product. 
c. Clean spaces between the teeth using dental floss or similar device. 
4. Chew sugarless chewing gum after meals (Xylitol-containing gum is supplied in the oral 
hygiene kit).  Avoid other forms of chewing gum. 
5. Brush at bedtime with a 0.4% stannous fluoride gel  
6. Rinse twice daily with a fluoride-containing mouthrinse such as CloSYS or similar rinse. 
 
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Appendix G. Patient Oral Care Instructions 
(to be reviewed with patient during screening) 
 
Dear Patient, 
 
Thank you for participating in this trial.  To help minimize your risk of developing oral health-
related issues during and after radiation therapy, you’ll receive an oral hygiene kit containing a 
soft toothbrush (AIM), a standard fluoride-containing toothpaste gel (PRO-SYS Flouride 
Toothgel), xylitol-containing chewing gum (Epic), 0.4% stannous fluoride gel (ESPE OMNI 
Gel), flossers (DenTek) and a fluoride mouthrinse (CloSYS). Here are some instructions on how 
best to use them and some strategies to keep your mouth comfortable and healthy. 
1. Keep your mouth moist 
a. Drink plenty of water. 
b. Suck ice chips. 
c. Use a saliva substitute to help moisten your mouth. 
 
2. Clean your mouth, tongue, and gums 
a. Use the soft toothbrush provided in the oral hygiene kit or an electric toothbrush. Brush 
your teeth and tongue after every meal using the fluoride toothpaste. 
b. Chew the sugarless gum after meals. 
c. At bedtime brush your teeth with the 0.4% stannous fluoride gel (ESPE OMNI Gel).  
d. Rinse twice daily with the fluoride-containing mouthwash such (CloSYS). 
e. Floss your teeth gently every day. If your gums bleed and hurt, avoid the areas that are 
bleeding or sore, but keep flossing your other teeth. 
 
3. If your mouth is sore, watch what you eat and drink 
a. Choose foods that are good for you and easy to chew and swallow. 
b. Take small bites of food, chew slowly, and sip liquids with your meals. 
c. Eat moist, soft foods such as cooked cereals, mashed potatoes, and scrambled eggs. 
d. If you have trouble swallowing, soften your food with gravy, sauces, broth, yogurt, or 
other liquids. 
 
4. Remember to stay away from 
a. Sharp, crunchy foods, like taco chips, that could scrape or cut your mouth. 
b. Spicy or acidic foods, like citrus fruits and juices, which may irritate your mouth. 
c. Sugary foods and drinks, like candy or soda, that could cause cavities. 
d. Toothpicks, because they may cut your mouth. 
e. Tobacco and alcohol products. 
 
 
 
If you have any questions, please don’t hesitate to ask your study nurse. 
 
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