Topical MTS-01 for Dermatitis During Radiation and Chemotherapy for Anal Cancer

Study Overview
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Brief Summary
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Background: - Radiation and chemotherapy treatments for anal cancer can cause irritation of the skin that can lead to redness and tenderness, and in some cases can be so severe that it results in blistering or peeling of the skin during treatment. These conditions cause discomfort and may require breaks from radiation treatment. Researchers are interested in determining whether MTS-01, a drug that protects cells and tissues from the effects of radiation, can be given before radiation treatment to prevent these side effects and reduce the irritation of the skin during chemotherapy and radiation for anal cancer. Objectives: - To determine the safety and effectiveness of topical MTS-01 given before radiation in the groin and gluteal cleft of patients receiving combined radiation and chemotherapy for anal cancer. Eligibility: - Individuals at least 18 years of age who have been diagnosed with cancer of the anal canal and are eligible to receive radiation and chemotherapy treatments. Design: Participants will be screened with a physical examination, medical history, blood tests, imaging studies and physical examination of the anal canal, and biopsies as needed to evaluate eligibility for treatment. Participants will be scheduled for radiation and chemotherapy treatments on the following schedule: Radiation given 5 days per week for 6 weeks, with topical MTS-01 treatment on the skin in the groin areas and between the buttocks before each treatment Mitomycin C given intravenously on days 1 and 29 of treatment 5-Fluorouracil given intravenously over 4 days (first week and fifth week) during radiation treatment Participants will be monitored throughout the treatment for side effects, with photographs of the treatment area and frequent blood tests. Following the end of radiation, participants will have followup visits for 1 year with blood tests and imaging studies to evaluate the response to treatment.

Detailed Description
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Background: Patients with non-metastatic carcinoma of the anal canal are treated with concurrent mitomycin C (MMC), 5-fluorouracil (5-FU), and radiotherapy (RT) in the curative setting in an attempt to preserve the anal sphincter. Radiation dermatitis is a uniform complication of this therapy which frequently results in treatment delay due to pain and discomfort. High grade dermatitis may also become superinfected in the setting of decreased blood counts from chemotherapy and diarrhea from radiation proctitis, further delaying therapy. Approaches that decrease toxicity may be particularly important in patients infected with human immunodeficiency virus (HIV). MTS-01 (tempol, 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl) is a piperidine nitroxide known to act as a chemical radioprotector with selective protection of normal versus tumor tissue. Tempol gel (tempol 70 mg/mL plus water, ethanol, and hydroxypropyl cellulose) has been evaluated as a topical radioprotector in pilot trials that included a variety of sites. Objectives: Primary Objective: To determine the safety and tolerability of topical MTS-01 on a daily basis prior to irradiation in the groin and gluteal cleft of patients receiving combined therapy with MMC, 5-FU, and RT for carcinoma of the anal canal. Secondary Objectives will include evaluation of the following endpoints in a preliminary fashion: To describe the rates and severity of skin toxicity in patients treated with this regimen To describe the need for toxicity related treatment breaks with this regimen To describe the opiate requirements in patients treated with this regimen To describe 12-month progression-free survival, disease-free survival, and overall survival in patients treated with concurrent chemotherapy, radiation therapy, and MTS-01 Evaluate the effects of antiretroviral therapy, 5-fluorouracil, mitomycin C, and radiation on low level persistent HIV viremia and HIV genetic diversity during therapy and recovery To evaluate the feasibility of collecting HIV ribonucleic acid (RNA) and mononuclear cells from rectal associated lymphoid tissue for correlative studies Collect and store anal cytology and core needle biopsies of tumor for future human papillomavirus infection (HPV) and tumor based analyses Eligibility: Age greater than or equal to 18 years. Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2. Histologically confirmed carcinoma of the anal canal without evidence of distant metastases No contraindications to definitive chemoradiotherapy for carcinoma of the anal canal Design: This is a pilot trial of topical MTS-01 in patients receiving MMC, 5-FU, and intensity-modulated radiation therapy (IMRT) for definitive management of carcinoma of the anal canal. Fifteen patients will be enrolled. MMC will be delivered at a dose of 10mg/m(2) on days 1 and 29. 5-FU will be delivered as 1000mg/m(2)/day as 96 hour continuous infusion beginning on day 1 and 29. RT will be delivered to a total dose of 50-54 Gy based on tumor characteristics. Tempol gel will be applied to the bilateral groins and the gluteal cleft, avoiding a 3 cm radius from the anal verge, immediately prior to each fraction of RT. Radiation Therapy Oncology Group (RTOG) grading will be used to evaluate skin toxicity in both the groin and gluteal cleft weekly during treatment and at 4 weeks, 3 months and 6 months after completion of treatment. The duration of treatment, number of treatment breaks, opiate requirements, and level of pain will be evaluated weekly during treatment and at 4 weeks and 3 months after the completion of treatment. Disease control will be assessed at 4 weeks, 3 months, 6 months, 9 months, and 12 months of follow-up.

Official Title
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A Pilot Trial Assessing the Feasibility of Delivering Topical MTS-01 to Reduce Dermatitis in Patients Receiving Intensity Modulated Radiation With Concurrent 5-Fluorouracil and Mitomycin-C for Stage I-III Carcinoma of the Anal Canal

Conditions
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Anal Cancer

Intervention / Treatment
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* Drug: Tempol
* Drug: 5-Fluorouracil
* Drug: Mitomycin-C
* Procedure: Radiation Therapy


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Histologically proven, invasive primary squamous, basaloid, or cloacogenic carcinoma of the anal canal, stage T1-4, N0-3 No previous therapy for anal cancer. Age greater than or equal to 18 years Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2 Adequate bone marrow, renal, and hepatic function defined as Absolute neutrophil count greater than or equal to 1,000 cells/mm(3) Platelet count greater than or equal to 100,000/mm(3) Hemoglobin greater than or equal to 8mg/dL Creatinine clearance > 60 mL/min using Cockcroft-Gault formula Bilirubin less than or equal to 1.5 times upper limit of normal (ULN) unless, during screening, the patient is receiving protease inhibitor therapy (i.e. indinavir, ritonavir, nelfinavir, and atazanavir) known to be associated with increased bilirubin: in this case total bilirubin less than or equal to 7.5 mg/dl and the direct fraction is less than or equal to 0.7 mg/dl. White blood cell (WBC) greater than or equal to 3,000/microL Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) less than or equal to 3 times the upper limit of normal International normalized ratio (INR) less than or equal to 1.5 Patients of childbearing potential must be willing to use a medically effective means of birth control for the duration of treatment and six weeks after treatment. Patients must be willing and able to provide informed consent EXCLUSION CRITERIA: Contraindications to radiotherapy such as a history of prior radiotherapy to the pelvis or a history of inflammatory bowel disease Prior malignancy except: non-melanoma skin cancer controlled Kaposi's Sarcoma (no chemotherapy for KS for 3 months, and no expected need for chemotherapy for the 12-month period of the study) other malignancies with disease free period of at least 3 years Presence of metastatic disease (M1) Co-morbidity that in the estimation of the principal investigator would make the patient unable to tolerate treatment Pregnant or lactating females Human immunodeficiency virus (HIV) positive patients with cluster of differentiation 4 (CD4) < 100 cells/mL AND ECOG performance status (PS) greater than 2. Dermatitis in the anticipated radiation treatment portal.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1/Chemo + Radiation<br>Chemo + Radiation | Drug: Tempol<br>* Tempol gel will be applied to the bilateral groins and the gluteal cleft, avoiding a 3 cm radius from the anal verge, immediately prior to each fraction of radiation therapy (RT).<br>* Other names: MBM-02;Drug: 5-Fluorouracil<br>* 5-FU will be delivered as 1000mg/m(2)/day as 96 hour continuous infusion beginning on day 1 and 29.<br>* Other names: 5-FU;Drug: Mitomycin-C<br>* Mitomycin-C (MMC) will be delivered at a dose of 10mg/m(2) on days 1 and 29<br>* Other names: MMC;Procedure: Radiation Therapy<br>* Radiation therapy (RT) will be delivered to a total dose of 50-54 Gray (Gy) based on tumor characteristics.<br>* Other names: RT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Grade 1 and Higher Adverse Events Possibly, Probably, or Definitely Related to Topical MTS-01 and 5-Fluoruracil (5-FU)/Mitomycin C (MMC)/Intensity-modulated Radiotherapy (IMRT) | Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life threatening, and Grade 5 is death related to adverse event. | Date treatment consent signed to date off study, approximately, 36 months and 10 days. | 
| Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) | Here is the number of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. | Date treatment consent signed to date off study, approximately, 36 months and 10 days. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Grade of Toxicity at Each Timepoint and Location for All Participants Who Underwent Treatment | RTOG grade 1-5 were used to assess skin toxicity in the groin (right and left inguinal area) and gluteal cleft, as well as two control sites. Grade 0 is no skin toxicity, Grade 1 is follicular, faint or dull erythema, Grade 3 is tender or bright erythema, Grade 3 is confluent, moist desquamation, Grade 4 is ulceration, hemorrhage, or necrosis, and Grade 5 is death due to radiation toxicity. | baseline, weeks 1-6, follow up at 1 week, follow up at 2 weeks, and follow up at 4 weeks | 
| Number of Participants That Required a Treatment Break Relative to Hematologic Toxicity (Non-dermatologic) | Number of participants that required a treatment break relative to hematologic (e.g. thrombocytopenia, leukopenia) toxicity (non-dermatologic). | From beginning until completion of radiation treatment up to 46 days | 
| Number of Participants Treated With Topical MTS-01 and 5-Fluoruracil (5-FU)/Mitomycin C (MMC)/Intensity-modulated Radiotherapy (IMRT) That Required Opiates | Opiates are strong drugs prescribed by prescription used for maximum pain relief. | Completion of study, approximately 14 months after start of treatment | 
| Number of Participants With 12-month Progression-free Survival Treated With 5-Fluoruracil (5-FU)/Mitomycin C (MMC)/Intensity-modulated Radiotherapy (IMRT) | PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. Progression was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST0 version 1.1. Progression is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. And the appearance of one or more new lesions. | 12 months | 
| Change in the Levels of Number of Human Immunodeficiency Virus (HIV) in the Circulation Pre and Post Treatment | Change in the levels of number of Human Immunodeficiency Virus (HIV) in the circulation pre and post treatment | Completion of study, approximately 14 months | 
| Ratio of the Number of Cluster of Differentiation 4 (CD4): Cluster of Differentiation 8 (CD8) Cells in the Circulation and Tissue Pre and Post Treatment | Ratio of the number Cluster of Differentiation 4 (CD4): Cluster of Differentiation 8 (CD8) cells in the circulation and tissue pre and post treatment. The number of cells of CD4 are divided by the number of cells of CD8. | Pre-treatment and post treatment tissue (CD4), and pre-treatment and post treatment circulation (CD8) | 
| Number of Participants With 12 Month Disease Free Survival (DFS) Treated With 5-Fluoruracil (5-FU)/Mitomycin C (MMC)/Intensity-modulated Radiotherapy (IMRT) | DFS is defined as the duration of time from start of treatment to time of progression. Progression was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST0 version 1.1. Progression is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. And the appearance of one or more new lesions. | 12 months | 
| Overall Survival | OS is defined as the duration of time from start of treatment to time of death. | start of treatment to time of death, approximately 14 months | 
| Peripheral Blood Mononuclear Cells (Vascular Endothelial Growth Factor (VEGF), Tumor Necrosis Factor Alpha (TNF-alpha), Interleukin-7 (IL-7), and Transforming Growth Factor Beta-1 (TGF-beta1) Cell Counts at Baseline and Course 1 Day 28 | Peripheral blood mononuclear cells (Vascular Endothelial Growth Factor (VEGF), Tumor Necrosis Factor alpha (TNF-alpha), Interleukin-7 (IL-7), and Transforming Growth Factor beta-1 (TGF-beta1) were sampled from peripheral blood from rectal associated lymphoid tissue to evaluate immune cell subsets at baseline and after treatment with MTS-0 and 15-Fluoruracil (5-FU)/Mitomycin C (MMC)/Intensity-modulated Radiotherapy (IMRT). It is unknown if a lower or higher numbers has prognostic significance. | Baseline and Course 1 Day 28 | 
| Number of Participants With Tumor Tissue Negative for Human Papilloma Virus (HPV) | HPV is a sexually transmitted infection that can cause warts and cervical cancer. HPV test detects deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) of HPV in a cell sample (i.e. cervical). | Pretreatment | 
| Brief Pain Inventory Score | The Brief Pain Inventory Scale is a questionnaire that asks the participant to rate their pain on a scale of 0 (no pain) to 10 (worst pain). | Baseline, Week 3, Week 6, 1 month follow up, and 3 months follow up | 
| Pain Interference | The Brief Pain Inventory Scale questionnaire were used to assess pain interference. Participants rated pain interference on a scale of 0 (does not interfere) to 10 (completely interferes). | Baseline, Week 3, Week 6, 1 month follow up, and 3 months follow up | 
| Mean Percentage Pain Relief After Medication | The Brief Pain Inventory Scale questionnaire were used to assess pain relief after medication. Participants rated pain relief on a scale of 0% (no relief) to 100% (complete relief) and a mean and full range were reported. | Baseline, Week 3, Week 6, 1 month follow up, and 3 months follow up | 
| Duration of Overall Response (DOR) | Duration of overall response is measured from the time measurement criteria are met for Complete Response until the first date that recurrent or progressive disease is objectively document. Complete Response was measured by the Response Evaluation Criteria in Solid Tumors (RECIST0 version 1.1. Complete Response is disappearance of all target lesions. | 12 months of follow up, approximately 14 months | 
| Percentage of Total Viable Cells That Were Cluster of Differentiation 3+ (CD3+) Cells in Biopsied Tissue | Percentage of total viable cells that were Cluster of differentiation 3+ (CD3+) cells in biopsied tissue. | Baseline and 1 year | 
| Absolute Number of Cluster of Differentiation 3+ (CD3) Cells Per Gram of Biopsied Intestinal Tissue | Absolute number of Cluster of differentiation 3+ (CD3) cells per gram of biopsied intestinal tissue. The number of CD3 positive cells were analyzed with flow cytometry of cellular suspensions from biopsy tissue. | Baseline and 1 year follow up | 
| Number of Cluster of Differentiation 8+ (CD8) Cells Per Gram of Biopsied Intestinal Tissue | Number of Cluster of differentiation 8+ (CD8) cells per gram of biopsied intestinal tissue. The number of CD8 positive cells were analyzed with flow cytometry of cellular suspensions from biopsy tissue. | Baseline and 1 year follow up | 
| Number of Cluster of Differentiation 4+ (CD4) Cells Per Gram of Biopsied Intestinal Tissue | Number of Cluster of Differentiation 4+ (CD4) cells per gram of biopsied intestinal tissue. The number of CD4 positive cells were analyzed with flow cytometry of cellular suspensions from biopsy tissue. | Baseline and 1 year follow up | 
| Number of Participants With Human Immunodeficiency Virus (HIV) in Biopsy Tissue From Rectal Mucosa | Optional snag biopsies pre and post were collected from participants rectal mucosa to enumerate cell counts. | Baseline and Course 1 Day 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Anal Cancer, Radioprotector, Topical, Radiation, Dermatitis