Capecitabine, Oxaliplatin, and Radiation Therapy in Treating Patients With 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 capecitabine and oxaliplatin, work in different ways to stop tumor cells from dividing so they stop growing or die. Capecitabine may stop the growth of tumor cells by stopping blood flow to the tumor. Radiation therapy uses high-energy x-rays to damage tumor cells. Capecitabine and oxaliplatin may make tumor cells more sensitive to radiation therapy. Combining capecitabine and oxaliplatin with radiation therapy may kill more tumor cells. PURPOSE: This phase II trial is studying how well giving capecitabine and oxaliplatin together with radiation therapy works in treating patients with stage II or stage III anal cancer.

Detailed Description
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OBJECTIVES: Primary Determine time to treatment failure in patients with stage II-IIIB squamous cell carcinoma of the anal canal treated with capecitabine, oxaliplatin, and radiotherapy (i.e. Capecitabine (Xeloda)/Oxaliplatin (Eloxatin) With Concomitant Radiotherapy (XRT) shortened to XELOX/XRT). Determine the toxic effects of this regimen in these patients. Secondary Determine the complete response rate in patients treated with this regimen. Determine 2-year local regional control in patients treated with this regimen. Determine 2-year colostomy-free survival in patients treated with this regimen. Determine 2-year median overall survival in patients treated with this regimen. Determine 2-year progression-free survival in patients treated with this regimen. OUTLINE: Patients receive oral capecitabine* twice daily on days 1-2, 6-10, 20-24, 27-31, and 41-42, and undergo radiotherapy* once daily on days 1-3, 6-10, 13-17, 20-24, 27-31, 34-38, and 41-42. Patients also receive oxaliplatin intravenous (IV) over 2 hours on days 1, 8, 22, and 29. Treatment continues in the absence of disease progression or unacceptable toxicity. NOTE: *Patients with T3-4 lesions also receive oral capecitabine twice daily and undergo radiotherapy once daily on days 43 and 44. Patients are followed at 4-6 and 12 weeks and then periodically thereafter. PROJECTED ACCRUAL: A total of 71 patients will be accrued for this study.

Official Title
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A Phase II Study of Capecitabine (Xeloda)/Oxaliplatin (Eloxatin) With Concomitant Radiotherapy (XRT), XELOX/RT in Squamous Cell Carcinoma of the Anal Canal

Conditions
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Anal Cancer

Intervention / Treatment
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* Drug: Capecitabine
* Drug: Oxaliplatin
* Radiation: Radiation Therapy (XRT)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Previously untreated patients with histologically proven squamous cell carcinoma of the anal canal. American Joint Committee on Cancer (AJCC) stage II-IIIB (TX 1-4, NX, MO). Age >/= 16 yrs old. Eastern Cooperative Oncology Group (ECOG) Performance Scale (PS) 0-1. Adequate organ function including: Absolute neutrophil Count (ANC) >/= 1,500/uL, Platelets >/= 100,000/uL, Total bilirubin </= 1.5 * upper limit of normal (ULN), aspartate aminotransferase (AST or SGOT)/alanine aminotransferase (ALT or SGPT) </= 3 * ULN, Creatinine </= 1.5mg/dL or Creatinine Clearance (CrCL) >/= 50 cc/min. Patients may have measurable or non-measurable disease. Patients with measurable disease, as defined by the modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria, have at least one lesion that can be accurately measured in at least one dimension with longest diameter to be recorded >/= 20 mm using conventional techniques or >/= 10 mm with spiral CT scan (with minimum lesion size no less than double the slice thickness). Lesions seen on colonoscopy or barium studies are not considered measurable lesions. A negative pregnancy test in all women of child-bearing potential, within two weeks of initiating treatment. The effects of oxaliplatin and capecitabine on the developing human fetus at the recommended therapeutic dose are unknown. For this reason and because cytotoxic agents are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. Ability to understand and the willingness to sign the written informed consent/authorization document. Exclusion Criteria: Prior chemotherapy with oxaliplatin, capecitabine, or 5-fluorouracil. Prior radiation to the pelvis. Prior surgery for anal cancer excluding prior biopsy. Known history of dihydropyrimidine (DPD) deficiency. Known history of hypersensitivity to platinum-containing compounds. Peripheral neuropathy of >/= grade 2 by Common Terminology Criteria for Adverse Events (CTCAE) 3.0. Calculated creatinine clearance (CrCl) < 50 cc/min. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit adherence with study requirements. Gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for intravenous (IV) alimentation. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with oxaliplatin or capecitabine, breast feeding should be discontinued. Because of the known interaction of capecitabine and coumadin, patients taking coumadin will be ineligible. Patients will be requested to discontinue coumadin and utilize Lovenox if agreeable. Patients must have discontinued coumadin for 7 days before initiating therapy. No prior malignancies (excluding non-melanomatous skin neoplasms) over the past 5 years. HIV-positive patients receiving combination anti-retroviral therapy are excluded from this study because of possible pharmacokinetic interactions with capecitabine or oxaliplatin. This exclusion is for patient safety since patients with immune deficiency are at increased risk of lethal infections when treated with marrow-suppressive therapy, and because very few HIV-positive anal canal cancer patients are seen at this institution. This hinders us from accruing enough patients to adequately test the safety of this regimen in this population. Patients with symptomatic pulmonary fibrosis.

Ages Eligible for Study
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Minimum Age: 16 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: Capecitabine + Oxaliplatin + XRT<br>Capecitabine (825 mg/m^2 twice a day, Monday-Friday during weeks 1, 2, 4, and 5) and Oxaliplatin (50 mg/m^2, Days 1, 8, 22, 29) during the duration of radiation therapy only. Radiotherapy once daily on days 1-3, 6-10, 13-17, 20-24, 27-31, 34-38, and 41-42. Participants with T3-4 lesions undergo radiotherapy once daily on days 43 and 44. The final dose of radiation therapy determined by the T stage of the primary tumor. Radiotherapy = XRT. | Drug: Capecitabine<br>* 825 mg/m^2 orally twice a day (BID), Mon-Fri during weeks 1, 2, 4, and 5.<br>* Other names: Xeloda;Drug: Oxaliplatin<br>* 50 mg/m^2 by vein (IV) over 2 hours on days 1, 8, 22, and 29.<br>* Other names: Eloxatin;Radiation: Radiation Therapy (XRT)<br>* Undergo radiotherapy* once daily on days 1-3, 6-10, 13-17, 20-24, 27-31, 34-38, and 41-42. *Patients with T3-4 lesions undergo radiotherapy once daily on days 43 and 44.<br>* Other names: Radiotherapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 2 Year Failure Free Survival | Treatment failure defined as: Biopsy proven residual disease identified 12 -14 weeks after the conclusion of chemoradiation therapy, Treatment-related mortality or Disease recurrence. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Complete Response at 2 Years | Response determined by computed tomography (CT)/magnetic resonance imaging (MRI), digital rectal examination, and proctoscopy, and a biopsy performed for clinical suspicion of residual or progressive disease. Response Evaluation Criteria in Solid Tumors (RECIST) where evaluation of target lesions Complete Response (CR): Disappearance of all target lesions; Partial Response (PR): At least a 30% decrease in sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD; Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions; Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started. | 2 Years | 
| Number of Participants With 2-year Colostomy-Free Survival | Colostomy-free survival reported as number of participants who did not develop local recurrence or require salvage resection with colostomy. | 2 Years with median study follow up of 19 months | 
| 2-year Local Regional Control |  | 2 Years | 
| 2-Year Median Overall Survival |  | 2 Years | 
| Number of Participants With Progression-Free Survival at 2-Year |  | 2 Years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Capecitabine, stage II anal cancer, stage IIIA anal cancer, stage IIIB anal cancer, squamous cell carcinoma of the anus, Xeloda, Oxaliplatin, Eloxatin, Radiotherapy, XRT