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

• ClinicalTrials.gov Identifier: NCT03515538
• Recruitment Status: Completed
• First Posted: May 3, 2018
• Last Update Posted: January 11, 2021
• Sponsor: EpicentRx, Inc.
• Collaborator: Prothex Pharma, Inc.
• Information provided by (Responsible Party): EpicentRx, Inc.

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Oral Mucositis	Drug: RRx-001; Drug: Cisplatin for injection; Radiation: Radiation Therapy	Phase 2

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 48 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Supportive Care
• Official Title: 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
• Actual Study Start Date: July 12, 2018
• Actual Primary Completion Date: October 22, 2019
• Actual Study Completion Date: October 8, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: RRx-001 Pre-Treatment plus SOC; 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; RRx-001 for injection; Drug: Cisplatin for injection; 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; Radiation: 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
Experimental: RRx-001 Pre-Treatment, 2 Concurrent Doses plus SOC; 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; RRx-001 for injection; Drug: Cisplatin for injection; 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; Radiation: 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
Experimental: RRx-001 Pre-Treatment, 6 Concurrent Doses plus SOC; 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; RRx-001 for injection; Drug: Cisplatin for injection; 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; Radiation: 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
Active Comparator: Standard of Care; 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; 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; Radiation: 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

Outcome Measures

Primary Outcome Measures :

1. Duration of Severe Oral Mucositis (SOM) [ Time Frame: up to one year ]
   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.

Secondary Outcome Measures :

1. Time to onset of Sever Oral Mucositis [ Time Frame: up to one year ]
   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.
2. Incidence of Sever Oral Mucositis [ Time Frame: up to one year ]
   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.
3. Duration of ulcerative Oral Mucositis [ Time Frame: up to one year ]
   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.
4. Incidence of ulcerative Oral Mucositis [ Time Frame: up to one year ]
   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.
5. Patient-reported pain [ Time Frame: up to one year ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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 #3 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) 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

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. Tumor of the lips, nasopharynx, hypopharynx, larynx, or salivary glands
3. Patients with simultaneous primaries or bilateral tumors
4. Metastatic disease (M1) Stage IV
5. 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
6. Presence of oral mucositis (WHO Score ≥ Grade 1) or other oral mucosal ulceration at study entry
7. Grade 3 or 4 dysphagia or odynophagia (National Cancer Institute Common Toxicity Criteria, version 5.0) or inability to eat a normal diet
8. Requirement at baseline for parenteral or gastrointestinal tube-delivered nutrition for any reason
9. 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)
10. 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).
11. Pregnant or nursing
12. Untreated active oral or dental infection, including severe tooth decay (caries)
13. Known allergies or intolerance to cisplatin and similar platinum-containing compounds
14. Evidence of immediate life-threatening disease or a life expectancy of less than 3 months
15. Receipt of unapproved or off-label medication within 30 days prior to start of study treatment
16. Sjogren syndrome

Contacts and Locations

Locations

United States, California

John Wayne Cancer Institute @ Providence St. John's Health Center

Santa Monica, California, United States, 90401

United States, Colorado

Centura Health Research Center

Denver, Colorado, United States, 80210

United States, District of Columbia

George Washington University

Washington, District of Columbia, United States, 20037

United States, Florida

Florida Hospital

Orlando, Florida, United States, 32804

United States, New York

Montefiore Medical Center

Bronx, New York, United States, 10467

United States, North Carolina

East Carolina University

Greenville, North Carolina, United States, 27834

United States, Ohio

University of Cincinnati Medical Center

Cincinnati, Ohio, United States, 45267

Ohio State University

Columbus, Ohio, United States, 43210

United States, Pennsylvania

Thomas Jefferson University

Philadelphia, Pennsylvania, United States, 19107

United States, Tennessee

Ballad Health

Johnson City, Tennessee, United States, 37604

Vanderbilt-Ingram Cancer Center

Nashville, Tennessee, United States, 37232

United States, Texas

UT Southwestern

Dallas, Texas, United States, 75390

Sponsors and Collaborators

EpicentRx, Inc.

Prothex Pharma, Inc.

Investigators

• Study Director: Bryan Oronsky, MD, PhD; EpicentRx, Inc.

More Information

• Responsible Party: EpicentRx, Inc.
• ClinicalTrials.gov Identifier: NCT03515538
• Other Study ID Numbers: PR-001
• First Posted: May 3, 2018
• Last Update Posted: January 11, 2021
• Last Verified: January 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by EpicentRx, Inc.:

head and neck cancer; squamous; neck cancer; oral cancer; mucositis; sores; mouth

Additional relevant MeSH terms:

Mucositis; Stomatitis; Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Mouth Diseases; Stomatognathic Diseases; Cisplatin; Antineoplastic Agents