Irinotecan Compared With Combination Chemotherapy in Treating Patients With Advanced Colorectal Cancer

A Randomized Phase III Equivalence Trial of Irinotecan (CPT-11) Versus Oxaliplatin (OXAL)/5-Fluorouracil (5-FU)/Leucovorin (CF) in Patients With Advanced Colorectal Carcinoma Previously Treated With 5-FU

Randomized phase III trial to compare the effectiveness of irinotecan with that of combination chemotherapy in treating patients who have advanced colorectal cancer that has not responded to previous treatment. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells. It is not yet known which chemotherapy regimen is more effective for colorectal cancer.

Study Overview

• Status: Completed
• Conditions: Mucinous Adenocarcinoma of the Rectum; Signet Ring Adenocarcinoma of the Rectum; Stage IIIA Rectal Cancer; Stage IIIB Rectal Cancer; Stage IIIC Rectal Cancer; Mucinous Adenocarcinoma of the Colon; Signet Ring Adenocarcinoma of the Colon; Stage IIIA Colon Cancer; Stage IIIB Colon Cancer; Stage IIIC Colon Cancer; Recurrent Colon Cancer; Recurrent Rectal Cancer; Stage IVA Colon Cancer; Stage IVA Rectal Cancer; Stage IVB Colon Cancer; Stage IVB Rectal Cancer
• Intervention / Treatment: Drug: oxaliplatin; Drug: leucovorin calcium; Drug: fluorouracil; Procedure: quality-of-life assessment; Drug: irinotecan hydrochloride

Detailed Description

PRIMARY OBJECTIVES:

I. Determine whether in advanced colorectal carcinoma patients who have been previously treated with 5-FU, the overall survival of patients treated with OXAL + 5-FU + CF followed by CPT-11 is equivalent to the survival of patients treated with CPT-11 followed by OXAL + 5-FU + CF.

SECONDARY OBJECTIVES:

I. Evaluation of time to tumor progression, time to treatment failure, toxicity of treatment, and overall response rate in patients treated with these two regimens.

II. To compare quality-of-life measurements patients treated with these two regimens.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to performance status (ECOG 0-1 vs 2), primary indicator lesion (hepatic vs pulmonary vs other), age (less than 65 vs at least 65 years), alkaline phosphatase (less than 2 vs at least 2 times ULN), fluorouracil failure (adjuvant vs metastatic), and membership (intergroup vs expanded participation project). Patients are randomized to one of two treatment arms.

ARM I: Patients receive irinotecan IV over 90 minutes on day 1. Treatment repeats every 3 weeks in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive oxaliplatin IV over 2 hours on day 1, leucovorin calcium IV over 2 hours on days 1 and 2, and fluorouracil IV bolus followed by IV infusion over 22 hours on days 1 and 2. Treatment repeats every 2 weeks in the absence of disease progression or unacceptable toxicity.

Patients who experience progression or toxicity on the initial regimen may crossover to the other regimen. At least 3 weeks must elapse between regimens.

Quality of life is assessed at baseline, prior to each chemotherapy course, at crossover, and at the end of the study.

Patients are followed every 6 months for 3 years or until death.

• Study Type: Interventional
• Enrollment (Actual): 560
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • North Central Cancer Treatment Group

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histologically or cytologically confirmed locally advanced, locally recurrent,or metastatic colorectal adenocarcinoma not curable by surgery or radiotherapy

• Progressive disease following:

  • One prior fluorouracil based chemotherapy regimen for metastatic disease
  • Failure during or within 6 months after fluorouracil based adjuvant therapy
• Measurable or evaluable disease
• No CNS metastases or carcinomatous meningitis
• Performance status - ECOG 0-2
• At least 12 weeks
• Absolute neutrophil count at least 1,500/mm^3
• Platelet count at least 100,000/mm^3
• Hemoglobin at least 9 g/dL (transfusion allowed)
• Bilirubin no greater than 1.5 mg/dL
• AST no greater than 5 times upper limit of normal (ULN)
• Alkaline phosphatase no greater than 5 times ULN
• Creatinine no greater than 1.5 times ULN
• No uncontrolled high blood pressure
• No unstable angina
• No symptomatic congestive heart failure
• No myocardial infarction with the past 6 months
• No serious uncontrolled cardiac arrhythmias
• No New York Heart Association class III or IV heart disease
• No pleural effusion or ascites that cause respiratory compromise (e.g., dyspnea grade 2 or greater)
• No interstitial pneumonia or extensive and symptomatic interstitial fibrosis of the lung
• Not pregnant or nursing
• Fertile patients must use effective contraception
• Fluent in English
• No active or uncontrolled infection
• No other prior malignancy within the past 5 years, except:
• Adequately treated basal or squamous cell skin cancer
• Adequately treated noninvasive carcinomas
• No sensory neuropathy grade 2 or greater
• No uncontrolled colonic or small bowel disorders (greater than 3 loose stools daily)
• No concurrent sargramostim (GM-CSF)
• At least 4 weeks since prior chemotherapy and recovered
• No more than 1 prior chemotherapy regimen for advanced colorectal cancer
• No prior irinotecan or other camptothecin derivative (e.g., topotecan)
• No prior oxaliplatin
• No other concurrent investigational chemotherapy agents
• At least 4 weeks since prior major radiotherapy
• No prior radiotherapy to greater than 25% of bone marrow
• At least 4 weeks since prior major surgery and recovered
• At least 2 weeks since prior minor surgery and recovered

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I (irinotecan); Patients receive irinotecan IV over 90 minutes on day 1. Treatment repeats every 3 weeks in the absence of disease progression or unacceptable toxicity.	Procedure: quality-of-life assessment; Ancillary studies; Other Names: quality of life assessment; Drug: irinotecan hydrochloride; Given IV; Other Names: irinotecan; Campto; Camptosar; U-101440E; CPT-11
Experimental: Arm II (oxalipatin, fluorouracil, leucovorin calcium); Patients receive oxaliplatin IV over 2 hours on day 1, leucovorin calcium IV over 2 hours on days 1 and 2, and fluorouracil IV bolus followed by IV infusion over 22 hours on days 1 and 2. Treatment repeats every 2 weeks in the absence of disease progression or unacceptable toxicity.	Drug: oxaliplatin; Given IV; Other Names: 1-OHP; Dacotin; Dacplat; Eloxatin; L-OHP; Drug: leucovorin calcium; Given IV; Other Names: CF; CFR; LV; Drug: fluorouracil; Given IV; Other Names: 5-FU; 5-fluorouracil; 5-Fluracil; Procedure: quality-of-life assessment; Ancillary studies; Other Names: quality of life assessment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival	The primary analysis for this trial will be based on a one-sided Generalized Wilcoxon test.	At least 6 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Quality of life	Up to 3 years
Time-to-tumor progression	Time from start of therapy to documentation of disease progression, assessed up to 3 years
Time-to-treatment failure	Time from the date of randomization to the date at which the patient is removed from treatment due to progression, toxicity, refusal, or death, assessed up to 3 years
Objective tumor response rate (CR or PR) in patients with measureable disease	At least 4 weeks
Toxicity and dose intensity	Up to 3 years

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Collaborators: Eastern Cooperative Oncology Group; Southwest Oncology Group
• Investigators: Principal Investigator: Henry Pitot, North Central Cancer Treatment Group

Study record dates

Study Major Dates

• Study Start: November 1, 1999
• Primary Completion (Actual): December 1, 2006

Study Registration Dates

• First Submitted: April 6, 2000
• First Submitted That Met QC Criteria: January 26, 2003
• First Posted (Estimate): January 27, 2003

Study Record Updates

• Last Update Posted (Estimate): May 3, 2013
• Last Update Submitted That Met QC Criteria: May 1, 2013
• Last Verified: May 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Disease Attributes; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Neoplasms, Cystic, Mucinous, and Serous; Recurrence; Adenocarcinoma; Rectal Neoplasms; Cystadenocarcinoma; Colonic Neoplasms; Adenocarcinoma, Mucinous; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Topoisomerase Inhibitors; Micronutrients; Vitamins; Calcium-Regulating Hormones and Agents; Topoisomerase I Inhibitors; Antidotes; Vitamin B Complex; Fluorouracil; Oxaliplatin; Leucovorin; Irinotecan; Calcium; Levoleucovorin
• Other Study ID Numbers: NCI-2012-01847; U10CA025224 (U.S. NIH Grant/Contract); N9841; SWOG-N9841; NCCTG-N9841; CDR0000067623; ECOG-N9841