Safety and Efficacy of RRx-001 in the Attenuation of Oral Mucositis in Patients Receiving Chemoradiation for the Treatment of Oral Cancers

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 duration or length 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 in arms 1, 2 and 3 will also receive RRx-001 on different schedules.

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 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

Conditions
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Oral Mucositis

Intervention / Treatment
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* Drug: RRx-001
* Drug: Cisplatin for injection
* Radiation: Radiation Therapy


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 and oropharynx Note: Patients with unknown primary tumors whose treatment plan matches the requirements specified in Inclusion Criterion #3 below are eligible for the trial Treatment planned to include standard cisplatin monotherapy administered either every three weeks (100 mg/m2 for 3 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. ECOG performance status ≤ 2. 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 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 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. 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. Ability to understand and sign a written informed consent document. 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 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 radiation to the head and neck Tumor of the lips, nasopharynx, hypopharynx, larynx, or salivary glands Patients with simultaneous primaries or bilateral tumors Metastatic disease (M1) Stage IV 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 Presence of oral mucositis (WHO Score ≥ Grade 1) or other oral mucosal ulceration at study entry Grade 3 or 4 dysphagia or odynophagia (National Cancer Institute Common Toxicity Criteria, version 5.0) or inability to eat a normal diet Requirement at baseline for parenteral or gastrointestinal tube-delivered nutrition for any reason 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) 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 Untreated active oral or dental infection, including severe tooth decay (caries) Known allergies or intolerance to cisplatin and similar platinum-containing compounds Evidence of immediate life-threatening disease or a life expectancy of less than 3 months Receipt of unapproved or off-label medication within 30 days prior to start of study treatment 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: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RRx-001 Pre-Treatment plus SOC<br>Two infusions of RRx-001 will be given each week during the two weeks prior to the start of RT/cisplatin SOC (four doses total). No additional RRx-001 will be given during the course of RT/cisplatin | Drug: RRx-001<br>* RRx-001 for injection<br>Drug: Cisplatin for injection<br>* Patients will receive 3 doses of cisplatin at 100 mg/m2 in accordance with applicable guidelines such as NCCN; however, these guidelines are not intended to supersede or replace institutional guidelines with respect to appropriate and necessary care for individual patients<br>Radiation: Radiation Therapy<br>* 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<br>|
| Experimental: RRx-001 Pre-Treatment, 2 Concurrent Doses plus SOC<br>Two infusions of RRx-001 will be given each week during the two weeks prior to the start of RT/cisplatin SOC. In addition, one dose of RRx-001 will be given on the last radiation day in each of weeks 2 and 5 during RT/cisplatin administration | Drug: RRx-001<br>* RRx-001 for injection<br>Drug: Cisplatin for injection<br>* Patients will receive 3 doses of cisplatin at 100 mg/m2 in accordance with applicable guidelines such as NCCN; however, these guidelines are not intended to supersede or replace institutional guidelines with respect to appropriate and necessary care for individual patients<br>Radiation: Radiation Therapy<br>* 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<br>|
| Experimental: RRx-001 Pre-Treatment, 6 Concurrent Doses plus SOC<br>Two infusions of RRx-001 will be given each week during the two weeks prior to the start of RT/cisplatin SOC. In addition, one dose of RRx-001 will be given on the last radiation day of each of the first 6 weeks during RT/cisplatin administration | Drug: RRx-001<br>* RRx-001 for injection<br>Drug: Cisplatin for injection<br>* Patients will receive 3 doses of cisplatin at 100 mg/m2 in accordance with applicable guidelines such as NCCN; however, these guidelines are not intended to supersede or replace institutional guidelines with respect to appropriate and necessary care for individual patients<br>Radiation: Radiation Therapy<br>* 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<br>|
| Active Comparator: Standard of Care<br>No doses of RRx-001 will be administered. Patients assigned to this arm will receive only standard of care in the form of a 7-week course of fractionated radiation therapy concurrent with a high-dose cisplatin regimen (100 mg/m2 dose in each of RT weeks 1, 4, and 7). | Drug: Cisplatin for injection<br>* Patients will receive 3 doses of cisplatin at 100 mg/m2 in accordance with applicable guidelines such as NCCN; however, these guidelines are not intended to supersede or replace institutional guidelines with respect to appropriate and necessary care for individual patients<br>Radiation: Radiation Therapy<br>* 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Severe Oral Mucositis (SOM) | Duration in days of severe oral mucositis (SOM). Defined as oral mucositis grade 3 or 4 on the WHO Mucositis Grading Scale which comprises 5 grades: 0 = none, 1=oral soreness, erythema, 2=oral erythema, ulcers, solid diet tolerated, 3=oral ulcers, liquid diet only, and 5=oral alimentation impossible. Sever Oral Mucositis duration is obtained by totaling the number of days a given patient experiences oral mucositis grade 3 or 4 during the randomized treatment period. Higher Sever Oral Mucositis duration numbers are indicative of worst outcomes. The total Sever Oral Mucositis duration for a given patient will range between 0 days and the maximum number of days the patient participated in the randomized treatment period. | up to one year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to onset of Sever Oral Mucositis | Time to onset of Sever Oral Mucositis defined as time (in days) from randomization to the first observed Sever Oral Mucositis. Longer Sever Oral Mucositis onset times are indicative of a better outcome. The time to onset of Sever Oral Mucositis for a given patient will range between 0 days and the maximum number of days the patient participated in the randomized treatment period. | up to one year | 
| Incidence of Sever Oral Mucositis | Incidence of Sever Oral Mucositis defined as the proportion of patients experiencing Sever Oral Mucositis during the randomized treatment period. Sever Oral Mucositis incidence range is 0 to 100%, and higher percentages are indicative of worse outcomes. | up to one year | 
| Duration of ulcerative Oral Mucositis | Duration (in days) of ulcerative oral mucositis defined as the proportion of patients experiencing oral mucositis during the randomized treatment period. Defined as oral mucositis grade 0 or 1 on the WHO Mucositis Grading Scale (described above). Longer duration of ulcerative oral mucositis is indicative of a worse outcome. The total ulcerative oral mucositis duration for a given patient will range between 0 days and the maximum number of days the patient participated in the randomized treatment period. | up to one year | 
| Incidence of ulcerative Oral Mucositis | Incidence of ulcerative oral mucositis defined as the proportion of patients experiencing ulcerative oral mucositis during the randomized treatment period. Ulcerative oral mucositis is defined as oral mucositis grade 0 or 1 on the WHO Mucositis Grading Scale (described above) and ranges from 0 to 100% with higher percentages being indicative of worse outcomes. | up to one year | 
| Patient-reported pain | Patient-reported mouth and throat soreness score obtained from Question #2 from the Oral Mucositis Daily Questionnaire (OMDQ) filled out by the patient. OMDQ Question #2 asked During the last 24 hours, how much mouth and throat soreness did you have?. OMDQ Question # 2 uses the following five-point categorical scale to quantity mouth and throat soreness: 0=no soreness, 1=a little soreness, 2=moderate soreness, 3=quite a lot of soreness and 4=extreme soreness. Higher mouth and throat soreness values are indicative of worse outcomes. The range of the month and throat values is 0, 1, 2, 3, 4. | up to one year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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head and neck cancer, squamous, neck cancer, oral cancer, mucositis, sores, mouth