Combined Modality Therapy for Patients With With HIV and Stage I, Stage II, or Stage III Anal Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as cisplatin and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as cetuximab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving cisplatin, fluorouracil, and cetuximab together with radiation therapy may kill more tumor cells. PURPOSE: This phase II trial is studying how well giving cisplatin, fluorouracil, and cetuximab together with radiation therapy works in treating patients with HIV and stage I, stage II, or stage III anal cancer.

Detailed Description
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OBJECTIVES: Primary Determine the 2-year local failure rate in patients with HIV-associated stage I-IIIB anal carcinoma treated with cisplatin, fluorouracil, cetuximab, and radiotherapy. Determine the objective response rate (complete and partial), progression-free survival, relapse-free survival, colostomy-free survival, overall survival, quality of life, and overall toxicity in patients treated with this regimen. Secondary Characterize the effect of this regimen on the underlying HIV condition by describing changes in viral load, CD4 counts, and the incidence of opportunistic illnesses, including the development of AIDS during and in the first year after treatment. Evaluate the effect of this regimen on anogenital human papilloma virus (HPV) infection and anal cytology. OUTLINE: This is an open-label, multicenter study. Patients receive cetuximab IV over 1-2 hours on days 1, 8, 15, 22, 29, and 35*, fluorouracil IV continuously on days 1-4 and 29-32, and cisplatin IV over 1 hour on days 1 and 29. Beginning on day 1, patients undergo concurrent radiotherapy to the primary tumor 5 days a week for 5-7 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity. NOTE: *Patients receiving 7 weeks of radiotherapy also receive cetuximab on days 42 and 49. Quality of life is assessed at baseline, at the completion of study treatment, and then at months 3, 6, 12, 24, and 36. After completion of study treatment, patients are followed periodically for 5 years. PROJECTED ACCRUAL: A total of 47 patients will be accrued for this study.

Official Title
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Phase II Trial of Combined Modality Therapy Plus Cetuximab in HIV-Associated Anal Carcinoma

Conditions
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Anal Cancer

Intervention / Treatment
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* Biological: cetuximab
* Drug: cisplatin
* Drug: fluorouracil
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed stage I-IIIB invasive anal canal or perianal (anal margin) squamous cell carcinoma, including tumors with any of the following nonkeratinizing histologies: Basaloid Transitional cell Cloacogenic Documented HIV infection by 1 of the following: Antibody detection Culture Quantitative assay of plasma HIV RNA PATIENT CHARACTERISTICS: Karnofsky performance status 60-100% Absolute neutrophil count ≥ 1,500/mm³ Platelet count ≥ 100,000/mm³ Hemoglobin ≥ 10 g/dL (transfusions, epoetin alfa, or myeloid growth factor support allowed provided blood counts are stable for ≥ 2 weeks prior to study entry) Creatinine ≤ 1.5 times upper limit of normal (ULN) OR creatinine clearance > 60 mL/min AST and ALT ≤ 3 times ULN Bilirubin ≤ 2 times ULN Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No acute active, serious, uncontrolled opportunistic infection No other prior invasive malignancy diagnosed within the past 24 months, excluding in situ cervical cancer, anal dysplasia or carcinoma in situ, nonmelanoma skin carcinoma, or Kaposi's sarcoma that has not required systemic chemotherapy within the past 24 months No peripheral neuropathy > grade 1 No severe or poorly controlled diarrhea No medical or psychiatric illness that would preclude study requirements PRIOR CONCURRENT THERAPY: No prior chemotherapy or radiotherapy for this malignancy Prior radiotherapy for another condition (e.g., Kaposi's sarcoma) allowed

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 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: CMT with Radiation Therapy<br>All patients will receive combined modality therapy (CMT) with 2 cycles of cisplatin and 5-FU chemotherapy, given concurrently with radiation therapy. CMT consists of: Cetuximab 400 mg/m2 IV Day -7 (1 week before the cycle 1, Day 1 cisplatin/5-FU and RT), then 250 mg/m2 IV Days 1, 8, 15, 22, 29, 36 and 43 (a minimum of 6 and a maximum of 8 doses of cetuximab will be administered, including the loading dose). Cisplatin 75 mg/m2 IV on Day 1 (cycle 1) and Day 29 (cycle 2) 5-FU 1000 mg/m2/day by continuous intravenous infusion on Days 1-4 (cycle 1) and Days 29-32 (cycle 2) | Biological: cetuximab<br>* 400 mg/m2 IV Day -7 (1 week before the cycle 1, Day 1 cisplatin/5-FU and RT), then 250 mg/m2 IV Days 1, 8, 15, 22, 29, 36 and 43 (a minimum of 6 and a maximum of 8 doses of cetuximab will be administered, including the loading dose)<br>* Other names: Erbitux;Drug: cisplatin<br>* 75 mg/m2 IV on Day 1 (cycle 1) and Day 29 (cycle 2)<br>* Other names: Platinol;Drug: fluorouracil<br>* 1000 mg/m2/day by continuous intravenous infusion on Days 1-4 (cycle 1) and Days 29-32 (cycle 2)<br>* Other names: Fluoroplex;Radiation: radiation therapy<br>* Irradiation to tumor site and inguinal nodes beginning on cycle 1, Day 1 cisplatin/5-FU (minimum 45.0 Gy [5 weeks if given on schedule and without interruption], maximum 54.0 Gy [6 weeks if given on schedule and without interruption). IMRT may be used at the discretion of the treating physician.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Local Failure Rate at 3 Years | Patients will be classified into two groups for purposes of primary endpoint analysis: failure or no failure at 3 years (in the primary analysis, patients lost to follow-up prior to 3 years will be considered failures). For the secondary endpoint of objective response, patients will be classified as responders | 3 years following treatment discontinuation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | Progression-free survival at 1 year is the percentage of patients who are alive and have not experienced progressive disease, defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started, or the appearance of one or more new lesions. | 1 year | 
| Relapse-free Survival | Percentage of participants who are alive and have not experienced progressive disease and have not relapsed | 1 year | 
| Colostomy-free Survival at 1 Year | Percentage of participants who are alive and have not had a colostomy | 1 year | 
| Overall Survival | Percentage of participants who are alive at one year | 1 year | 
| Quality of Life | EORTC QLQ-C30 Global Score at 1 year. The EORTC QLQ-C30 is a validated questionnaire that evaluates quality of life. The global score is an overall score for quality of life that ranges from 0 to 100. Higher scores indicate between quality of life | 1 year | 
| Toxicity | Delayed toxicities are defined as toxicities that occur over 90 days following treatment completion | 90 days following treatment discontinuation | 
| Changes in CD4 Counts During and for 1 Year After Completion of Study Treatment | Change in absolute CD4 counts from start of treatment to 1 year after completion of study treatment | 1 year following treatment discontinuation | 
| Incidence of Opportunistic Illnesses | Incidence of opportunistic illnesses, including the development of AIDS during and for 1 year after completion of study treatment | 1 year following treatment discontinuation | 
| Anogenital Human Papilloma Virus (HPV) Infection and Anal Cytology |  | 6 months following treatment discontinuation | 
| Objective Response Rate (Complete and Partial) | Number of participants with complete and partial responses based on the RECIST criteria | 3 years following treatment discontinuation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage I anal cancer, stage II anal cancer, stage IIIA anal cancer, stage IIIB anal cancer, squamous cell carcinoma of the anus, basaloid carcinoma of the anus, cloacogenic carcinoma of the anus