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

Study Overview
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Brief Summary
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The purpose of this study is to determine if RRx-001, which is added on to the cisplatin and radiation treatment, reduces the incidence of severe oral mucositis in patients with head and neck cancers. All patients in this study will receive 7 weeks of standard of care radiation therapy given with the chemotherapy agent, cisplatin. Patients will receive RRx-001 or placebo before start of standard of care treatment.

Detailed Description
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The standard treatment for head and neck cancer currently includes a chemotherapy drug called cisplatin that is given by intravenous (IV) infusion and radiation, which is delivered from a machine that precisely targets the tumor. One common and unfortunate side effect of treatment with cisplatin and radiation is oral mucositis, which refers to irritation of the lining of the mouth. Oral mucositis is a serious problem 1) because the open mouth sores from oral mucositis may lead to severe pain, nutritional problems and dehydration from an inability to eat and drink, an increased risk of infection from bacteria and fungus and delay or discontinuation of treatment and 2) because there is only one approved therapy to treat or prevent it.

Official Title
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A Randomized Placebo-Controlled Trial of Two Schedules of RRx-001 for the Attenuation of Severe Oral Mucositis in Patients Receiving Concomitant Chemoradiation for the Treatment of Locally Advanced Squamous Cell Carcinoma of the Oral Cavity or Oropharynx

Conditions
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Oral Mucositis

Intervention / Treatment
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* Drug: RRx-001
* Radiation: Intensity Modulated Radiation Therapy (IMRT)
* Drug: Cisplatin for injection 100 mg/m2


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathologically confirmed diagnosis of squamous cell carcinoma (SCC) of the oral cavity or oropharynx Note: Patients with primary cancers that are presumed to be of oropharyngeal origin may be included if they meet radiation field dosing criteria as specified in Inclusion Criterion #2 below. Unknown primaries which are HPV+ are acceptable. HPV determination must be made for all patients. 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 or adjuvant chemotherapy. Planned radiation treatment fields must include at least two oral sites (soft palate, floor of mouth, buccal mucosa, tongue) 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. ECOG performance status ≤ 2. 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 institutional guidelines) 2. Total bilirubin ≤ 1.5 x upper-normal limit (ULN) 3. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 x ULN 4. Alkaline phosphatase ≤ 2.5 x ULN 6. Human papilloma virus (HPV) status in tumor must be documented using tumor immunohistochemistry for HPV-p16 or other accepted test (such as such as in situ hybridization) for patients with cancers of the oropharynx or base of tongue (Rooper et al, 2016, Martens 2017). Age 18 years or older 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 and willingness to understand and sign a written informed consent document. Women of childbearing potential and men with partners of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control) 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: Prior radiotherapy to the head and neck region. Prior induction chemotherapy. Tumors of the lips, salivary gland, nasopharynx, hypopharynx, or larynx. Patients with simultaneous primaries Stage IV, M1 (distant metastasis) Prior or current use of approved or investigational anticancer agent other than those provided in this study. Grade 3 or 4 dysphagia or odynophagia (National Cancer Institute Common Toxicity Criteria, version 5.0) or inability to eat a normal (solid) diet Requirement at baseline for parenteral or gastrointestinal tube-delivered nutrition for any reason or prophylactic insertion of gastrostomy tube with dependency on tube feeding at baseline. Current use of analgesics (prescription and over the counter such as pregabalin, gabapentin, skeletal muscle relaxants, benzodiazepines, sedative/hypnotics, anxiolytics, oral analgesics, NSAIDs and opioids) are prohibited 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 judgment of the treating investigator. Active infectious disease excluding oral candidiasis. Presence of oral mucositis (WHO Score ≥ Grade 1) or other oral mucosal ulceration at baseline. Untreated active oral or dental infection Known history of human immunodeficiency virus or active hepatitis B or C. 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) Pregnant or nursing. Known allergies or intolerance to cisplatin or other platinum-containing compounds. Sjogren syndrome

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RRx-001 Pre-Treatment (8mg RRx-001) + Chemoradiation Therapy (CRT)<br>Pretreatment consists of 8 mg RRx-001 given twice weekly during the 2 weeks prior to the start of CRT (4 doses total) followed by the CRT treatment period | Drug: RRx-001<br>* RRx-001 for injection (4 mg or 8 mg)<br>Radiation: Intensity Modulated Radiation Therapy (IMRT)<br>* Intensity Modulated Radiation Therapy of up to 72 Gy<br>Drug: Cisplatin for injection 100 mg/m2<br>* Cisplatin for injection 100 mg/m2<br>|
| Experimental: RRx-001 Pre-Treatment (4mg RRx-001) + Chemoradiation Therapy (CRT)<br>Pretreatment consists of 4 mg RRx-001 given twice weekly during the 2 weeks prior to the start of CRT (4 doses total) followed by the CRT treatment period. | Drug: RRx-001<br>* RRx-001 for injection (4 mg or 8 mg)<br>Radiation: Intensity Modulated Radiation Therapy (IMRT)<br>* Intensity Modulated Radiation Therapy of up to 72 Gy<br>Drug: Cisplatin for injection 100 mg/m2<br>* Cisplatin for injection 100 mg/m2<br>|
| Placebo Comparator: Placebo Pre-Treatment + Chemoradiation Therapy (CRT)<br>No doses of RRx-001 will be administered. Patients assigned to this arm will receive placebo twice weekly during the 2 weeks prior to the start of CRT followed by the CRT treatment period. | Radiation: Intensity Modulated Radiation Therapy (IMRT)<br>* Intensity Modulated Radiation Therapy of up to 72 Gy<br>Drug: Cisplatin for injection 100 mg/m2<br>* Cisplatin for injection 100 mg/m2<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Severe Oral Mucositis (SOM) through Intensity-modulated radiation therapy (IMRT) | The incidence of SOM defined as the proportion of patients with any WHO Grade >= 3 (severe to life threatening) oral mucositis during the observation period from the start of CRT through IMRT | Estimated up to 18 Months | 
| Incidence of Severe Oral Mucositis through 60 Gy of the Radiation Treatment Plan | incidence of SOM defined as the proportion of patients with any WHO Grade >= 3 (severe to life threatening) oral mucositis during the observation period from the start of CRT through 60 Gy | Estimated up to 18 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Severe Oral Mucositis (SOM) through Intensity-modulated radiation therapy (IMRT) | Duration of SOM (through the last day of radiation therapy, DoSOM). Its principal analysis employs the probability of being in response (PBIR), an intuitive concept based on the realization that the duration of response which is quantified as the area under the curve delimited by the duration of exposure (x axis) and the response probability (y axis). | Estimated up to 18 Months | 
| Duration of Severe Oral Mucositis (SOM) through 60 Gy | Duration of SOM (through 60 Gy, DoSOM) is compared between RRx-001 arms and Placebo using a two-sided log-rank test. | Estimated up to 18 Months | 
| Time to onset of Sever Oral Mucositis (ttSOM) | Time onset to SOM (ttSOM) is defined as the time interval measured from the start of the observation period to the first time SOM is observed. | Estimated up to 18 Months | 
| Incidence and severity of dysphagia | Incidence and severity of dysphagia will be analyzed similarly to the primary efficacy endpoint. | Estimated up to 18 Months | 
| Cumulative radiation dose to onset of SOM | Cumulative radiation dose to onset of SOM is compared between RRx-001 arms and placebo | Estimated up to 18 Months | 
| Incidence of grade 4 oral mucositis | Incidence of grade 4 oral mucositis through 60 Gy | Estimated up to 18 Months | 
| Narcotic use through resolution of SOM | Narcotic use through resolution of SOM will be analyzed similarly to the cumulative radiation dose | Estimated up to 18 Months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Oropharynx, Oral cavity, Oral cancer, Mucositis, Squamous cell carcinoma (SCC), Head and Neck Cancer, Neck cancer, HPV, IMRT