Combination Chemotherapy in Treating Patients With Colorectal Cancer

Time Finding Study of Chronomodulated Irinotecan, 5 Fluorouracil, Leucovorin and Oxaliplatin as First or Second Chemotherapy Line Against Metastatic Colorectal Cancer

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Giving drugs at the time of day that allows for the best drug response may allow the doctor to give higher doses of chemotherapy drugs and kill more tumor cells.

PURPOSE: Randomized phase II trial to determine the best time to give irinotecan combined with fluorouracil, leucovorin, and oxaliplatin in treating patients who have colorectal cancer.

Study Overview

• Status: Completed
• Conditions: Colorectal Cancer
• Intervention / Treatment: Drug: fluorouracil; Drug: leucovorin calcium; Drug: irinotecan hydrochloride; Drug: oxaliplatin

Detailed Description

OBJECTIVES:

• Determine the role of peak delivery time on the tolerability of irinotecan when administered with chronomodulated fluorouracil, leucovorin calcium, and oxaliplatin as first- or second-line therapy in patients with locoregional or metastatic colorectal cancer.
• Determine the antitumor activity of this regimen.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to participating center, WHO performance status (0-1 vs 2), and line of treatment (first vs second). Patients are randomized to receive irinotecan at 1 of 6 different times of the day.

Patients receive irinotecan IV over 6 hours on day 1 and fluorouracil IV and leucovorin calcium IV over 11 hours followed by oxaliplatin IV over 11 hours on days 2-5. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Patients are followed every 4 weeks until disease progression and then every 8 weeks thereafter.

PROJECTED ACCRUAL: A maximum of 186 patients (31 per irinotecan administration time) will be accrued for this study within 2 years.

• Study Type: Interventional
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Charleroi, Belgium, 6000
    • Centre Hospitalier Notre Dame - Reine Fabiola
  • Liege, Belgium, B-4000
    • CHU Liege - Domaine Universitaire du Sart Tilman
  • Liege, Belgium, B 4000
    • Clinique Saint-Joseph
  • Namur, Belgium, 5000
    • Clinique Sainte Elisabeth
  • Verviers, Belgium, B-4800
    • Centre Hospitalier Peltzer-La Tourelle
• France
  • Clermont-Ferrand, France, 63011
    • Centre Jean Perrin
  • Dijon, France, 21079
    • Centre de Lutte Contre le Cancer Georges-Francois Leclerc
  • Limoges, France, 87042
    • Centre Hospital Regional Universitaire de Limoges
  • Paris, France, 75475
    • Hôpital Saint-Louis
  • Saint Cloud, France, 92211
    • Centre René Huguenin
  • Villejuif, France, 94804
    • Hopital Paul Brousse
• Italy
  • Bolzano, Italy, 39100
    • Azienda Sanitaria di Bolzano
  • Chieti, Italy, 66100
    • Universita G.D'Annunzio Di Chieti
  • Milano (Milan), Italy, 20153
    • Ospedale San Carlo Borromeo
  • Orbassano, (Torino), Italy, 10043
    • Azienda Ospedale S. Luigi at University of Torino
  • Pavia, Italy, I-27100
    • Fondazione Salvatore Maugeri
  • RIONERO in VULTURE, Italy, I-58028
    • Ospedale Oncologico Regionale
  • Rome, Italy, 00161
    • Istituto Regina Elena
  • Vigevano, Italy, 27029
    • Istituto Clinico Beato Matteo
• Portugal
  • Amadora, Portugal, P-2700
    • Hospital Fernando Fonseca

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

DISEASE CHARACTERISTICS:

• Histologically confirmed colorectal cancer
• Unresectable metastatic or locoregional disease
• At least 1 measurable lesion outside a previously irradiated area or an area treated with physical devices (e.g., cryotherapy, laser, or thermoablation)
• No prior enrollment in EORTC-05963
• No symptomatic brain metastases

PATIENT CHARACTERISTICS:

Age:

• Over 18

Performance status:

• WHO 0-2

Life expectancy:

• Not specified

Hematopoietic:

• Neutrophil count greater than 2,000/mm^3
• Platelet count at least 90,000/mm^3

Hepatic:

• Bilirubin no greater than 2 times upper limit of normal (ULN)

Renal:

• Creatinine no greater than 1.5 times ULN
• No uncontrolled hypercalcemia

Cardiovascular:

• No overt cardiac disease

Pulmonary:

• No severe respiratory illness

Other:

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• Male patients must use effective barrier contraception during and for up to 6 months after study
• No baseline diarrhea greater than grade I (must have less than 4 stools per 24 hours)
• No prior grade III or IV toxicity related to irinotecan
• No sensory or motor neuropathy with functional impairment
• No prior hypersensitivity to any study drug
• No other primary tumor except basal cell skin cancer or carcinoma in situ of the cervix
• No uncontrolled infectious or chronic disease
• No psychological, familial, sociological, or geographical condition that would preclude study

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• No concurrent prophylactic growth factor therapy

Chemotherapy:

• At least 1 month since prior chemotherapy
• No prior irinotecan, fluorouracil, leucovorin calcium, and oxaliplatin as combination therapy
• Other prior therapy containing irinotecan and/or oxaliplatin allowed
• No more than 1 prior chemotherapy regimen for metastatic or locoregional disease
• Adjuvant chemotherapy considered first-line therapy if tumor relapsed within 6 months of completion of therapy

Endocrine therapy:

• No concurrent corticosteroids except for emergencies

Radiotherapy:

• See Disease Characteristics
• Palliative radiotherapy for bone lesion allowed except for disease progression

Surgery:

• See Disease Characteristics

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Peak delivery time for CPT11 tolerability over the first 3 courses of treatment in patients who started therapy

Secondary Outcome Measures

Outcome Measure
Progression-free survival
Overall survival
Peak delivery time for CPT11 tolerability over the first 3 courses of treatment in patients who started therapy, excluding those who stopped prior to course 3 for reasons other than toxicity
Peak delivery time for CPT11 activity over the first 3 courses
Peak delivery time for CPT11 tolerability and efficacy over the first 6 courses
Severe toxic events assessed by CTC v2.0 after each course of chemotherapy

Collaborators and Investigators

• Sponsor: European Organisation for Research and Treatment of Cancer - EORTC
• Investigators: Study Chair: Carlo Garufi, MD, Istituti Fisioterapici Ospitalieri - Roma

Publications and helpful links

General Publications

• Garufi C, Focan C, Tumolo S, et al.: Time finding study of chronomodulated irinotecan (I), fluorouracil (F), leucovorin (L) and oxaliplatin (O) (chronoIFLO) against metastatic colorectal cancer: results from randomized EORTC 05011 trial. [Abstract] J Clin Oncol 25 (Suppl 18): A-2566, 2007.

Study record dates

Study Major Dates

• Study Start: February 1, 2002
• Primary Completion (Actual): August 1, 2005

Study Registration Dates

• First Submitted: June 6, 2002
• First Submitted That Met QC Criteria: January 26, 2003
• First Posted (Estimate): January 27, 2003

Study Record Updates

• Last Update Posted (Estimate): July 13, 2012
• Last Update Submitted That Met QC Criteria: July 12, 2012
• Last Verified: July 1, 2012

More Information

Terms related to this study

• Keywords: stage IV rectal cancer; stage IV colon cancer; recurrent colon cancer; recurrent rectal cancer; stage III colon cancer; stage III rectal cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; 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: EORTC-05011