RRx-001 for Reducing Oral Mucositis in Patients Receiving Chemotherapy and Radiation for Head and Neck Cancer

Inclusion Criteria:

1. Pathologically confirmed diagnosis of squamous cell carcinoma (SCC) of the oralcavity or oropharynx Note: Patients with primary cancers that are presumed to be oforopharyngeal origin may be included if they meet radiation field dosing criteria asspecified in Inclusion Criterion #2 below. Unknown primaries which are HPV+ areacceptable. HPV determination must be made for all patients.

2. Radiation Treatment planned to receive standard IMRT with daily fractions of 2.0 to 2.2 Gy for a total cumulative dose of 60-72 Gy in conjunction with definitive oradjuvant chemotherapy. Planned radiation treatment fields must include at least twooral sites (soft palate, floor of mouth, buccal mucosa, tongue) that are eachplanned to receive a total of > 55 Gy. Patients who have had prior surgery areeligible, provided they have fully recovered from surgery, and patients who may havesurgery in the future are eligible.

3. ECOG performance status ≤ 2.

4. Participants must have adequate organ and marrow function as defined below:

• Absolute neutrophil count (ANC) ≥ 1,500 / mm3 2. Platelets ≥ 75,000 / mm3 3.Hemoglobin ≥ 9.0 g/dL

5. Adequate renal and liver function as indicated by:

• Serum creatinine acceptable for treatment with cisplatin per institutionalguidelines) 2. Total bilirubin ≤ 1.5 x upper-normal limit (ULN) 3. Aspartateaminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 x ULN 4. Alkalinephosphatase ≤ 2.5 x ULN

6. Human papilloma virus (HPV) status in tumor must be documented using tumorimmunohistochemistry for HPV-p16 or other accepted test (such as such as in situhybridization) for patients with cancers of the oropharynx (Rooper et al, 2016,Martens 2017). HPV status at baseline optional for oral cavity tumors.

7. Age 18 years or older

8. Patient must consent to the access, review, and analysis of previous medical andcancer history, including imaging data, by the sponsor or a third party nominated bythe sponsor.

9. Ability and willingness to understand and sign a written informed consent document.

10. Women of childbearing potential and men with partners of child-bearing potentialmust agree to use adequate contraception (hormonal or barrier method of birthcontrol) prior to study entry, for the duration of study participation, and for 90days following completion of therapy. Note: A woman of child-bearing potential is any female (regardless of sexualorientation, having undergone a tubal ligation, or remaining celibate by choice) whomeets 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 radiotherapy to the head and neck region.

2. Prior induction chemotherapy.

3. Tumors of the lips, salivary gland, nasopharynx, hypopharynx, or larynx.

4. Patients with simultaneous primaries

5. Stage IV, M1 (distant metastasis)

6. Prior or current use of approved or investigational anticancer agent other thanthose provided in this study.

7. Grade 3 or 4 dysphagia or odynophagia (National Cancer Institute Common ToxicityCriteria, version 5.0) or inability to eat a normal (solid) diet

8. Requirement at baseline for parenteral or gastrointestinal tube-delivered nutritionfor any reason or prophylactic insertion of gastrostomy tube with dependency on tubefeeding at baseline.

9. Malignant tumors other than squamous cell carcinoma of the head and neck within last 5 years, unless treated definitively and with low risk of recurrence in the judgmentof the treating investigator.

10. Active infectious disease excluding oral candidiasis.

11. Presence of oral mucositis (WHO Score ≥ Grade 1) or other oral mucosal ulceration atbaseline.

12. Untreated active oral or dental infection

13. Known history of human immunodeficiency virus or active hepatitis B or C.

14. Any significant medical diseases or conditions, as assessed by the investigators andsponsor that would substantially increase the medical risks of participating in thisstudy (e.g, immunosuppression, uncontrolled diabetes, NYHA II-IV congestive heartfailure, myocardial infarction within 6 months of study, severe chronic pulmonarydisease or active uncontrolled infection, uncontrolled or clinically relevantpulmonary edema)

15. Use of the following within 48 hours of enrollment and duration of Oral Mucositisfollow up: vitamin B12 (cobalamin) or synthetic vitamin B12, cyanocobalamin, or thevitamin B12 precursor, cobinamide, or any supplement or multivitamin with vitaminB12 or vitamin E in it since both vitamin B12 and vitamin E interact negatively withRRx-001.

16. Use of prebiotics and probiotics

17. Pregnant or nursing.

18. Known allergies or intolerance to cisplatin or other platinum-containing compounds.

19. Sjogren syndrome