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

Overview

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.

Full Title of Study: “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”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Non-Randomized
    • Intervention Model: Single Group Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: April 15, 2015

Detailed Description

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 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 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 HPV and tumor based analyses

Eligibility:

- Age greater than or equal to 18 years.

- 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 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. 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.

Interventions

  • Drug: Tempol
    • 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.
  • Drug: 5-Fluorouracil
    • 5-FU will be delivered as 1000mg/m2/day as 96 hour continuous infusion beginning on day 1 and 29.
  • Drug: Mitomycin-C
    • MMC will be delivered at a dose of 10mg/m2 on days 1 and 29
  • Procedure: Radiation Therapy
    • RT will be delivered to a total dose of 50-54 Gy based on tumor characteristics.

Arms, Groups and Cohorts

  • Experimental: 1
    • Chemo + Radiation

Clinical Trial Outcome Measures

Primary Measures

  • 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.
    • Time Frame: Completion of study

Secondary Measures

  • To describe the rates and severity of skin toxicity in patients treated with this regimen
    • Time Frame: Completion of study
  • To describe the need for toxicity related treatment breaks with this regimen
    • Time Frame: Completion of study
  • To describe the opiate requirements in patients treated with this regimen
    • Time Frame: Completion of study
  • To describe 12-month progression-free survival, disease-free survival, and overall survival in patients treated with concurrent chemotherapy, radiation therapy, MTS-01
    • Time Frame: Completion of study
  • Evaluate the effects of antiretroviral therapy, 5-fluorouracil, mitomycin C, and radiation on low level persistent HIV viremia and HIV genetic diversity
    • Time Frame: Completion of study
  • To evaluate the feasibility of collecting HIV RNA and mononuclear cells from rectal associated lymphoid tissue for correlative studies
    • Time Frame: Completion of study
  • Collect and store anal cytology and core needle biopsies of tumor for future HPV and tumor based analyses
    • Time Frame: Completion of study

Participating in This Clinical Trial

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
  • 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 Cockroft-Gault formula
  • Bilirubin less than or equal to 1.5 times 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.
  • WBC greater than or equal to 3,000/microL
  • ALT/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
  • HIV positive patients with CD4 < 100 cells/mL AND ECOG PS greater than 2.
  • Dermatitis in the anticipated radiation treatment portal.

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 90 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • National Cancer Institute (NCI)
  • Overall Official(s)
    • Deborah E Citrin, M.D., Principal Investigator, National Cancer Institute (NCI)

References

Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J Clin. 2009 Jul-Aug;59(4):225-49. doi: 10.3322/caac.20006. Epub 2009 May 27.

Bower M, Powles T, Newsom-Davis T, Thirlwell C, Stebbing J, Mandalia S, Nelson M, Gazzard B. HIV-associated anal cancer: has highly active antiretroviral therapy reduced the incidence or improved the outcome? J Acquir Immune Defic Syndr. 2004 Dec 15;37(5):1563-5.

Crum-Cianflone NF, Hullsiek KH, Marconi VC, Ganesan A, Weintrob A, Barthel RV, Agan BK; Infectious Disease Clinical Research Program HIV Working Group. Anal cancers among HIV-infected persons: HAART is not slowing rising incidence. AIDS. 2010 Feb 20;24(4):535-43. doi: 10.1097/QAD.0b013e328331f6e2.

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