Capecitabine + Irinotecan Followed by Combined Modality Capecitabine and Radiation in Locally Advanced Rectal Cancer

Study Overview
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Brief Summary
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Preoperative induction chemotherapy has been successfully used in a variety of malignancies and provides several advantages over postoperative therapy. Combination of 5-FU/Leucovorin/CPT-11 has demonstrated significantly better response rate than 5-FU/Leucovorin alone. Replacing 5-FU with oral capecitabine in combination with CPT-11 has emerged as a potentially more effective, safe and convenient treatment option for metastatic colorectal cancer. Capecitabine is also well tolerated in concurrent treatment with radiation. Recent data has shown that preoperative radiation appears to be significantly more effective in increasing resectability rates. This trial will investigate the activity of capecitabine and CPT-11 combination in the preoperative setting followed by chemoradiation with capecitabine in locally advanced rectal cancer to improve response and decrease local recurrence. We will also study whether TS, TP, DPD and carboxyesterase expressions correlate with the objective response rate with this chemotherapy and chemoradiation regimen.

Detailed Description
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OUTLINE: This is a multi-center study. Biopsy per EUS Irinotecan 200 mg/m2 IV, day 1 Capecitabine 1000* mg/m2 PO BID day 1-14 Repeat every three weeks for two cycles* For calculated creatinine clearance of 30-50 mL/min or patients > 70years old, capecitabine starting dose is 825 mg/m2 PO BID Beginning at week 7 or following recovery from chemotherapy: Pelvic XRT 45 Gy/1.8 Gy/fx/qd+5.4 Gy/1.8 Gy/fx/qd for T3+9 Gy/1.8 Gy/fx/qd for T4 Capecitabine 825* mg/m2 PO BID, 5 days/week, throughout XRT* For calculated creatinine clearance of 30-50 mL/min or patients > 70years old, capecitabine starting dose is 650 mg/m2 PO BID Surgery within 8weeks following chemoradiotherapy Adjuvant Chemotherapy at investigator's discretion ECOG performance status 0 or 1 Hematopoietic:· ANC count >1,500 mm3· Platelets > 100,000/mm3· Hemoglobin > 9g/dL Prothrombin time (PT)/INR or PTT < 1.25 times upper limit of normal; Hepatic:· Bilirubin <1.5 times upper limit of normal Alanine Transaminase (ALT) or Aspartate Transaminase (AST) <2.5 times the upper limit of normal Renal:· Adequate renal function by calculated creatinine clearance > 30 mL/min (by Cockroft and Gault) Cardiovascular:· No congestive heart failure requiring therapy or NYHA class II or greater or active angina or known myocardial infarction within 12 months prior to study

Official Title
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A Phase II Trial of Preoperative Capecitabine Plus Irinotecan Followed by Combined Modality Capecitabine and Radiation for Locally Advanced Rectal Cancer: Hoosier Oncology Group GI03-53

Conditions
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Rectal Cancer

Intervention / Treatment
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* Drug: Capecitabine
* Drug: Irinotecan
* Procedure: EUS
* Drug: Neoadjuvant Chemotherapy
* Procedure: Preoperative Radiation
* Procedure: Surgery
* Procedure: Adjuvant Chemotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed adenocarcinoma of the rectum < 15 cm from the anal verge without evidence of distant metastasis· Measurable disease. · Either mobile cancers (with clinical stage T3 or T4 by endorectal ultrasound) or fixed cancer (defined as clinical T4 for this study) on palpation. · Malignant disease may not extend to the anal canal (across the dentate line) Exclusion Criteria: No prior chemotherapy or radiation therapy to the pelvis. Patients with clinical stage T 1-2, N0 rectal cancer who are candidates for primary resection are not eligible· No synchronous colonic cancer unless the synchronous tumor is Tis or T1 and has been completely resected· Patients must not be taking warfarin· No prior unanticipated severe reaction to fluoropyrimidine therapy, or known sensitivity to 5-Fluorouracil or known DPD deficiency.· No known existing uncontrolled coagulopathy· Negative pregnancy test· No current breastfeeding· No serious concomitant systemic disorders incompatible with the study· No prior malignancies with the exception of curatively treated basal or squamous carcinoma of the skin, carcinoma in-situ of the cervix, or any other cancer for which the patient has been disease-free for < 5 years.· Patients must not be treated with any of the following while on protocol therapy or within 28 days prior to beginning protocol therapy: sorivudine, brivudine, cimetidine, allopurinol. Patients on dilantin must have regular monitoring of dilantin levels.

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Investigational Treatment<br>Irinotecan 200 mg/m2 IV, day 1 Capecitabine 1000* mg/m2 po bid day 1-14; repeat every three weeks for two cycles For calculated creatinine clearance of 30-50 mL/min or patients > 70 years old, capecitabine starting dose is 825 mg/m2 po bid EUS Neoadjuvant Chemotherapy Preoperative Radiation Surgery Adjuvant Chemotherapy (at discretion of treating physician) | Drug: Capecitabine<br>* Capecitabine 1000* mg/m2 po bid day 1-14; repeat every three weeks for two cycles *For calculated creatinine clearance of 30-50 mL/min or patients > 70 years old, capecitabine starting dose is 825 mg/m2 po bid<br>* Other names: Xeloda;Drug: Irinotecan<br>* Irinotecan 200 mg/m2 IV, day 1<br>* Other names: Camptosar;Procedure: EUS<br>* biopsy per EUS<br>Drug: Neoadjuvant Chemotherapy<br>* Irinotecan 200 mg/m2 IV, day 1 Capecitabine 1000 mg/m2 po bid day 1-14; repeat every three weeks for two cycles<br>* Other names: Xeloda;Procedure: Preoperative Radiation<br>* Pelvic XRT 45 Gy/1.8 GY/fx/qd+5/4 Gy/1.8 Gy/fx/qd for T3+9 Gy/1.8/Gy/fx/qd for T4<br>Procedure: Surgery<br>* Surgery within 8 weeks following chemoradiotherapy<br>Procedure: Adjuvant Chemotherapy<br>* Adjuvant chemotherapy at investigator's discretion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathological Complete Response (pCR) Rate | · To determine the pathological response rate of preoperative chemotherapy with capecitabine and irinotecan followed by combined modality chemoradiation with capecitabine in patients with locally advanced rectal cancer. Pathological response was defined in the protocol as the proportion of complete (pCR) and non-complete pathological response (pNCR) among all evaluable patients. | 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Local and Distant Disease Recurrence Rates | To determine the rates of local and distant disease recurrence after treatment. | 36 months | 
| Rate of Clinical Response | To determine the rate of clinical response following induction chemotherapy with capecitabine and irinotecan, and also the overall clinical response after the completion of chemoradiation with capecitabine. | 36 months | 
| Disease-Free Survival | The three year rate of Disease-Free Survival | 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rectal Cancer