Cetuximab, Cisplatin, Fluorouracil, and Radiation Therapy in Treating Patients With Anal Cancer

Study Overview
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Brief Summary
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RATIONALE: Monoclonal antibodies, such as cetuximab, can block tumor growth in different ways. Some find tumor cells and kill them or carry tumor-killing substances to them. Others interfere with the ability of tumor cells to grow and spread. 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. Radiation therapy uses high-energy x-rays to kill tumor cells. Cetuximab may help cisplatin and fluorouracil work better by making tumor cells more sensitive to the drugs. It may also make tumor cells more sensitive to radiation therapy. Giving cetuximab together with chemotherapy and radiation therapy may kill more tumor cells. PURPOSE: This phase II trial is studying how well giving cetuximab together with cisplatin, fluorouracil, and radiation therapy works in treating immunocompetent patients with stage I (closed to accrual as of 11/3/2008), stage II, (some stage II closed to accrual as of 11/3/2008) or stage III anal cancer.

Detailed Description
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OBJECTIVES: Primary Objective: Determine whether the addition of cetuximab to combined modality therapy (CMT) comprising cisplatin, fluorouracil, and radiotherapy reduces the local failure rate by ≥ 50% at 3 years (compared with historical data) in immunocompetent patients with stage I-III invasive anal carcinoma. Secondary Objectives: Determine objective response rate (complete and partial), progression-free survival, colostomy-free survival, and overall survival. Determine the overall toxicity of concurrent cisplatin, fluorouracil, and radiation therapy combined with cetuximab. Exploratory Objectives: Evaluate the effect of cetuximab and CMT on anogenital herpes papilloma virus (HPV) infection and anal cytology. Evaluate whether moderate to strong expression of epidermal growth factor receptor, Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), and P-Akt (as determined by immunohistochemistry) is associated with an increased risk of local failure. OUTLINE: This is a multicenter study with two sequential arms. Arm I was closed to accrual as of 11/3/2008, and arm II opened to accrual on 8/18/2009. Patients are assigned to 1 of the 2 treatment arms. Arm I (closed to accrual as of 11/3/2008): Patients receive cisplatin intravenously (IV) over 60 minutes on days 1, 29, 57, and 85 and fluorouracil IV continuously over 96 hours on days 1-4, 29-32, 57-60, and 85-88. Patients also receive cetuximab IV over 120 minutes on day 50 and then IV over 60 minutes on days 57, 64, 71, 78, 85, 92, and 99 and undergo radiotherapy once daily 5 days a week for 5 weeks, beginning on day 57. Arm II (open to accrual on 8/18/2009): Patients receive cetuximab IV over 120 minutes on day 1 and then IV over 60 minutes on days 8, 15, 22, 29, 36, 43, and 50. Patients also receive cisplatin IV over 60 minutes on days 8 and 36, fluorouracil IV continuously over 96 hours on days 8-11 and 36-39, and undergo radiotherapy once daily 5 days a week for 5 weeks beginning on day 8. After completion of study treatment, patients are followed periodically for up to 10 years. PROJECTED ACCRUAL: A total of 62 patients will be accrued for this study.

Official Title
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Phase II Trial of Cetuximab Plus Cisplatin, 5- Fluorouracil and Radiation in Immunocompetent Patients With Anal Carcinoma

Conditions
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Anal Cancer

Intervention / Treatment
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* Biological: cetuximab
* Drug: cisplatin
* Drug: fluorouracil
* Radiation: radiotherapy


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Histologically confirmed anal canal or perianal (anal margin) squamous cell carcinoma Stage I-IIIB (closed to accrual as of 11/3/2008) Stage II (T3, N0 only), IIIA, or IIIB Tumors of nonkeratinizing histology, such as basaloid, transitional cell, or cloacogenic histology, allowed No well-differentiated stage I anal margin cancer Eastern Cooperative Oncology Group (ECOG) performance status 0-2 Hemoglobin ≥ 10 g/dL Platelet count ≥ 100,000/mm^3 Absolute neutrophil count > 1,500/mm^3 Creatinine ≤ 1.5 times upper limit of normal (ULN) OR creatinine clearance > 60 mL/min Bilirubin ≤ 2 times ULN Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 times ULN Negative pregnancy test Fertile patients must use effective contraception during and for ≥ 3 months after completion of study treatment No other malignancies except nonmelanomatous skin cancer Prior malignancies must be in remission for ≥ 5 years Patients with a known risk factor for human immunodeficiency virus (HIV) infection must undergo HIV testing within 90 days before study entry AND must be HIV negative by antibody detection, culture, or quantitative assay of plasma HIV ribonucleic acid (RNA) EXCLUSION CRITERIA: Presence of the following conditions within the past 6 months: Active infection Uncontrolled diabetes New York Heart Association class II-IV congestive heart failure Cerebrovascular accident Transient ischemic attack Uncontrolled hypertension Unstable angina Myocardial infarction History of rheumatic disorders, irritable bowel syndrome, or inflammatory bowel disease Known HIV positivity Known risk factors for HIV infection Prior radiotherapy or chemotherapy for this malignancy Prior pelvic radiotherapy Prior potentially curative surgery (i.e., abdominal or peritoneal resection) for anal cancer Pregnant or nursing

Ages Eligible for Study
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Minimum Age: 18 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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (closed to accrual as of 11/3/2008)<br>Patients receive cisplatin IV over 60 minutes on days 1, 29, 57, and 85 and fluorouracil IV continuously over 96 hours on days 1-4, 29-32, 57-60, and 85-88. Patients also receive cetuximab IV over 120 minutes on day 50 and then IV over 60 minutes on days 57, 64, 71, 78, 85, 92, and 99 and undergo radiotherapy once daily 5 days a week for 5 weeks, beginning on day 57. Treatment continues in the absence of disease progression or unacceptable toxicity. | Biological: cetuximab<br>* Given IV<br>* Other names: Erbitux;Drug: cisplatin<br>* Given IV<br>* Other names: DDP;Drug: fluorouracil<br>* Given IV<br>* Other names: Efudex;Radiation: radiotherapy<br>* Given once daily 5 days a week for 5 weeks<br>* Other names: radiation therapy;|
| Experimental: Arm II (open to accrual on 8/18/2009)<br>Patients receive cetuximab IV over 120 minutes on day 1 and then IV over 60 minutes on days 8, 15, 22, 29, 36, 43, and 50. Patients also receive cisplatin IV over 60 minutes on days 1 and 36, fluorouracil IV continuously over 96 hours on days 8-11 and 36-39, and undergo radiotherapy once daily 5 days a week for 5 weeks beginning on day 8. Treatment continues in the absence of disease progression or unacceptable toxicity. | Biological: cetuximab<br>* Given IV<br>* Other names: Erbitux;Drug: cisplatin<br>* Given IV<br>* Other names: DDP;Drug: fluorouracil<br>* Given IV<br>* Other names: Efudex;Radiation: radiotherapy<br>* Given once daily 5 days a week for 5 weeks<br>* Other names: radiation therapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Local Failure Rate at 3 Years | Local failure was defined as progression/relapse of disease in the anal canal and/or regional organs and/or regional lymph nodes after completion of protocol therapy, or progression during protocol therapy. Lost to follow-up and death (regardless of cause of death) prior to 3 years were also considered as local failures. For the calculation of local failure rate at 3 years, patients were classified into two groups (ie, coded as binary variable): failure (patients with local failure events prior to 3 years) vs. no failure (patients who still alive and had no local failure at 3 years). The binomial proportion and its exact two-sided 80% confidence interval (CI) were used to estimate it. | assessed every 3 months for patients within 2 years of registration, then every 6 months for patients in year 3 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 3-year Overall Survival Rate | Overall survival (OS) is defined as time from registration to death from any cause. Patients alive are censored at the last contact date. Kaplan-Meier method was used to estimate the 3-year OS rate. | assessed every 3 months for patients within 2 years of registration, then every 6 months for patients in year 3 | 
| 3-year Progression-free Survival Rate | Progression-free survival (PFS) was defined as time from registration to disease progression, relapse or death (whichever occurred first), censoring cases without PFS events at the date of last disease assessment documenting the patient was free of progression/relapse. Progression was defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Kaplan-Meier method was used to estimate the 3-year PFS rate. | assessed every 3 months for patients within 2 years of registration, then every 6 months for patients in year 3 | 
| Objective Response Rate | Objective response rate is defined as number of patients with complete response (CR) or partial response (PR) divided by all eligible and treated patients. Responses are evaluated using the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline. CR is defined as disappearance of all target and non-target lesions. PR is defined as at least a 30% decrease in the sum of the diameters of target lesions (taking as reference the baseline sum diameters), and/or persistence of one or more non-target lesion(s). | Tumor assessments were made at baseline, within 4 weeks of the completion of protocol treatment, then every 6 months if patient was 1-4 years from registration, yearly if patient was 5-10 years from registration until progression/relapse using the RECIST | 
| 3-year Colostomy-free Survival Rate | Colostomy-free survival was defined as time from registration until time of colostomy or death without colostomy, censoring cases without colostomy at the data of last disease assessment documenting the patient was free of colostomy. Kaplan-Meier method was used to estimate the 3-year colostomy-free survival rate. | assessed every 3 months for patients within 2 years of registration, then every 6 months for patients in year 3 | 

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