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

Phase 2

Terminated

• Conditions: Rectal Cancer
• Interventions: Drug: Capecitabine; Drug: Irinotecan; Procedure: EUS; Drug: Neoadjuvant Chemotherapy; Procedure: Preoperative Radiation; Procedure: Surgery; Procedure: Adjuvant Chemotherapy

• Registration Number: NCT00216086
• Lead Sponsor: Gabi Chiorean, MD

Brief Summary

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

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

Study Timeline

• Study Start: 2005-05
• Study First Submitted: 2005-09-09
• Study First Submitted QC: 2005-09-14
• Study First Posted: 2005-09-22
• Primary Completion: 2008-05
• Study Completion: 2008-05
• Results First Submitted: 2016-01-05
• Status Verified: 2016-04
• Results First Submitted QC: 2016-04-27
• Last Update Submitted: 2016-04-27
• Results First Posted: 2016-06-06
• Last Update Posted: 2016-06-06

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 22

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Investigational Treatment	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 \> 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)
Investigational Treatment	Adjuvant Chemotherapy	* 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)
Investigational Treatment	Neoadjuvant Chemotherapy	* 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)
Investigational Treatment	Preoperative Radiation	* 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)
Investigational Treatment	Surgery	* 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)
Investigational Treatment	Capecitabine	* 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)
Investigational Treatment	Irinotecan	* 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)

Primary Outcome Measures

Name	Time	Method
Pathological Complete Response (pCR) Rate	36 months	· 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.

Secondary Outcome Measures

Name	Time	Method
Local and Distant Disease Recurrence Rates	36 months	To determine the rates of local and distant disease recurrence after treatment.
Rate of Clinical Response	36 months	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.
Disease-Free Survival	36 months	The three year rate of Disease-Free Survival

Trial Locations

Locations (9)

AP&S Clinic; 🇺🇸 Terre Haute, Indiana, United States

Elkhart Clinic; 🇺🇸 Elkhart, Indiana, United States

Fort Wayne Oncology & Hematology, Inc; 🇺🇸 Fort Wayne, Indiana, United States

Indiana University Cancer Center; 🇺🇸 Indianapolis, Indiana, United States

Quality Cancer Center (MCGOP); 🇺🇸 Indianapolis, Indiana, United States

Northern Indiana Cancer Research Consortium; 🇺🇸 South Bend, Indiana, United States

Center for Cancer Care at Goshen Health System; 🇺🇸 Goshen, Indiana, United States

Medical Consultants, P.C.; 🇺🇸 Muncie, Indiana, United States

Center for Cancer Care, Inc., P.C.; 🇺🇸 New Albany, Indiana, United States