Oral Mucositis
Conditions
Keywords
head and neck cancer, squamous, neck cancer, oral cancer, mucositis, sores, mouth
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.
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.
Interventions
DRUGRRx-001
RRx-001 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
RADIATIONRadiation 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
Sponsors
Prothex, Inc.
EpicentRx, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Severe Oral Mucositis (SOM) | From start of treatment through 28 days post treatment for up to 11 weeks from Start of Treatment | 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 4 = oral alimentation impossible. Severe 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 Severe Oral Mucositis duration numbers are indicative of worst outcomes. The total Severe 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
| Measure | Time frame | Description |
|---|---|---|
| Time to Onset of Severe Oral Mucositis | Time from Day 1 to Oral Mucositis Onset (up to 8 weeks) | Time to onset of Severe Oral Mucositis defined as time (in days) from randomization to the first observed Severe Oral Mucositis. Longer Severe Oral Mucositis onset times are indicative of a better outcome. The time to onset of Severe 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. |
| Incidence of Severe Oral Mucositis | Baseline through end of treatment (up to 11 weeks). Data collected every week. | Incidence of Severe Oral Mucositis defined as the number of patients who experienced a Severe Oral Mucositis grade 4 during the randomized treatment period. |
| Opioid Use | Baseline through end of radiation treatment (through 8 weeks). Data collected every week. | Opioid use from the time to onset (TTO) and duration of opioid use among patients who were not taking opioids at radiation start or who required a second opioid during active treatment. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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
RRx-001: RRx-001 for injection
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 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 | 12 |
| 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
RRx-001: RRx-001 for injection
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 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 | 11 |
| 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
RRx-001: RRx-001 for injection
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 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 | 13 |
| 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).
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 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 | 10 |
| Total | 46 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Death | 0 | 0 | 1 | 0 |
| Overall Study | Lack of Efficacy | 2 | 0 | 2 | 0 |
| Overall Study | Physician Decision | 1 | 0 | 0 | 1 |
| Overall Study | Protocol Violation | 0 | 0 | 0 | 1 |
| Overall Study | Screen failure (baseline dropout) | 0 | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 2 | 1 | 3 |
Baseline characteristics
| Characteristic | RRx-001 Pre-Treatment Plus SOC | RRx-001 Pre-Treatment, 2 Concurrent Doses Plus SOC | RRx-001 Pre-Treatment, 6 Concurrent Doses Plus SOC | Standard of Care | Total |
|---|---|---|---|---|---|
| Age, Continuous | 57.7 years STANDARD_DEVIATION 11.17 | 56.7 years STANDARD_DEVIATION 7.64 | 59 years STANDARD_DEVIATION 11.94 | 59.5 years STANDARD_DEVIATION 6 | 58.2 years STANDARD_DEVIATION 9.48 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants | 10 Participants | 13 Participants | 9 Participants | 43 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized White | 11 Participants | 10 Participants | 12 Participants | 8 Participants | 41 Participants |
| Region of Enrollment United States | 12 participants | 11 participants | 13 participants | 10 participants | 46 participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 1 Participants | 1 Participants | 6 Participants |
| Sex: Female, Male Male | 10 Participants | 9 Participants | 12 Participants | 9 Participants | 40 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 11 | 1 / 13 | 0 / 10 |
| other Total, other adverse events | 9 / 12 | 10 / 11 | 12 / 13 | 6 / 10 |
| serious Total, serious adverse events | 4 / 12 | 4 / 11 | 6 / 13 | 5 / 10 |
Outcome results
Primary
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 4 = oral alimentation impossible. Severe 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 Severe Oral Mucositis duration numbers are indicative of worst outcomes. The total Severe 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.
Time frame: From start of treatment through 28 days post treatment for up to 11 weeks from Start of Treatment
Population: All participants: number of days from the start of oral mucositis greater than a grade zero until resolution.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| RRx-001 Pre-Treatment Plus SOC | Duration of Severe Oral Mucositis (SOM) | 22.9 Days | Standard Deviation 19.08 |
| RRx-001 Pre-Treatment, 2 Concurrent Doses Plus SOC | Duration of Severe Oral Mucositis (SOM) | 27.7 Days | Standard Deviation 23.72 |
| RRx-001 Pre-Treatment, 6 Concurrent Doses Plus SOC | Duration of Severe Oral Mucositis (SOM) | 35.2 Days | Standard Deviation 28.83 |
| Standard of Care | Duration of Severe Oral Mucositis (SOM) | 37.8 Days | Standard Deviation 29.33 |
Secondary
Incidence of Severe Oral Mucositis
Incidence of Severe Oral Mucositis defined as the number of patients who experienced a Severe Oral Mucositis grade 4 during the randomized treatment period.
Time frame: Baseline through end of treatment (up to 11 weeks). Data collected every week.
Population: All participants who received study treatment and who experienced Oral Mucositis score greater than zero.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RRx-001 Pre-Treatment Plus SOC | Incidence of Severe Oral Mucositis | 0 Participants |
| RRx-001 Pre-Treatment, 2 Concurrent Doses Plus SOC | Incidence of Severe Oral Mucositis | 4 Participants |
| RRx-001 Pre-Treatment, 6 Concurrent Doses Plus SOC | Incidence of Severe Oral Mucositis | 6 Participants |
| Standard of Care | Incidence of Severe Oral Mucositis | 3 Participants |
Secondary
Opioid Use
Opioid use from the time to onset (TTO) and duration of opioid use among patients who were not taking opioids at radiation start or who required a second opioid during active treatment.
Time frame: Baseline through end of radiation treatment (through 8 weeks). Data collected every week.
Population: Participants who required opioid use during treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| RRx-001 Pre-Treatment Plus SOC | Opioid Use | Week 5 | 4 Participants |
| RRx-001 Pre-Treatment Plus SOC | Opioid Use | Week 8 | 4 Participants |
| RRx-001 Pre-Treatment Plus SOC | Opioid Use | Week 4 | 4 Participants |
| RRx-001 Pre-Treatment Plus SOC | Opioid Use | Week 6 | 4 Participants |
| RRx-001 Pre-Treatment Plus SOC | Opioid Use | Week 2 | 2 Participants |
| RRx-001 Pre-Treatment Plus SOC | Opioid Use | Week 7 | 4 Participants |
| RRx-001 Pre-Treatment Plus SOC | Opioid Use | Week 3 | 4 Participants |
| RRx-001 Pre-Treatment Plus SOC | Opioid Use | Week 1 | 1 Participants |
| RRx-001 Pre-Treatment, 2 Concurrent Doses Plus SOC | Opioid Use | Week 3 | 2 Participants |
| RRx-001 Pre-Treatment, 2 Concurrent Doses Plus SOC | Opioid Use | Week 6 | 2 Participants |
| RRx-001 Pre-Treatment, 2 Concurrent Doses Plus SOC | Opioid Use | Week 5 | 2 Participants |
| RRx-001 Pre-Treatment, 2 Concurrent Doses Plus SOC | Opioid Use | Week 2 | 0 Participants |
| RRx-001 Pre-Treatment, 2 Concurrent Doses Plus SOC | Opioid Use | Week 4 | 2 Participants |
| RRx-001 Pre-Treatment, 2 Concurrent Doses Plus SOC | Opioid Use | Week 1 | 0 Participants |
| RRx-001 Pre-Treatment, 2 Concurrent Doses Plus SOC | Opioid Use | Week 8 | 2 Participants |
| RRx-001 Pre-Treatment, 2 Concurrent Doses Plus SOC | Opioid Use | Week 7 | 2 Participants |
| RRx-001 Pre-Treatment, 6 Concurrent Doses Plus SOC | Opioid Use | Week 3 | 2 Participants |
| RRx-001 Pre-Treatment, 6 Concurrent Doses Plus SOC | Opioid Use | Week 1 | 0 Participants |
| RRx-001 Pre-Treatment, 6 Concurrent Doses Plus SOC | Opioid Use | Week 4 | 2 Participants |
| RRx-001 Pre-Treatment, 6 Concurrent Doses Plus SOC | Opioid Use | Week 5 | 3 Participants |
| RRx-001 Pre-Treatment, 6 Concurrent Doses Plus SOC | Opioid Use | Week 2 | 1 Participants |
| RRx-001 Pre-Treatment, 6 Concurrent Doses Plus SOC | Opioid Use | Week 6 | 3 Participants |
| RRx-001 Pre-Treatment, 6 Concurrent Doses Plus SOC | Opioid Use | Week 7 | 3 Participants |
| RRx-001 Pre-Treatment, 6 Concurrent Doses Plus SOC | Opioid Use | Week 8 | 4 Participants |
| Standard of Care | Opioid Use | Week 2 | 2 Participants |
| Standard of Care | Opioid Use | Week 5 | 4 Participants |
| Standard of Care | Opioid Use | Week 8 | 5 Participants |
| Standard of Care | Opioid Use | Week 7 | 4 Participants |
| Standard of Care | Opioid Use | Week 4 | 4 Participants |
| Standard of Care | Opioid Use | Week 3 | 4 Participants |
| Standard of Care | Opioid Use | Week 1 | 1 Participants |
| Standard of Care | Opioid Use | Week 6 | 4 Participants |
Secondary
Time to Onset of Severe Oral Mucositis
Time to onset of Severe Oral Mucositis defined as time (in days) from randomization to the first observed Severe Oral Mucositis. Longer Severe Oral Mucositis onset times are indicative of a better outcome. The time to onset of Severe 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.
Time frame: Time from Day 1 to Oral Mucositis Onset (up to 8 weeks)
Population: All participants: number of days from start of treatment until participant experiences a OM grade of greater than zero.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| RRx-001 Pre-Treatment Plus SOC | Time to Onset of Severe Oral Mucositis | 38 Days to Onset |
| RRx-001 Pre-Treatment, 2 Concurrent Doses Plus SOC | Time to Onset of Severe Oral Mucositis | 33 Days to Onset |
| RRx-001 Pre-Treatment, 6 Concurrent Doses Plus SOC | Time to Onset of Severe Oral Mucositis | 37 Days to Onset |
| Standard of Care | Time to Onset of Severe Oral Mucositis | 26 Days to Onset |