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Combination Chemotherapy in Treating Patients With Advanced Colorectal Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00003594
Recruitment Status : Completed
First Posted : September 25, 2003
Last Update Posted : April 29, 2020
Sponsor:
Collaborators:
National Cancer Institute (NCI)
NCIC Clinical Trials Group
Information provided by (Responsible Party):
Alliance for Clinical Trials in Oncology

Study Description
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Brief Summary:

RATIONALE: 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 regimen of combination chemotherapy is most effective in treating advanced colorectal cancer.

PURPOSE: Randomized phase III trial to compare the effectiveness of various combination chemotherapy regimens in treating patients who have advanced, recurrent, or metastatic colorectal cancer that cannot be treated with surgery or radiation therapy.


Condition or disease Intervention/treatment Phase
Colorectal Cancer Drug: irinotecan Drug: fluorouracil Drug: leucovorin calcium Drug: oxaliplatin Phase 3

Detailed Description:

OBJECTIVES:

  • Compare the time to progression in patients with locally advanced, locally recurrent, or metastatic colorectal adenocarcinoma treated with combinations of oxaliplatin, fluorouracil, leucovorin calcium, and irinotecan.
  • Compare the quality of life, response rate, time to treatment failure, and overall survival in patients treated with these regimens.
  • Compare the toxicity of these regimens in these patients.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to ECOG performance status (0-1 vs 2), prior adjuvant chemotherapy (yes vs no), prior immunotherapy (yes vs no), and age (under 65 vs 65 and over). Patients are randomized to one of three treatment arms.

Only arm II remains open to accrual.

  • Arm I (Saltz regimen): Patients receive irinotecan IV over 90 minutes followed by leucovorin calcium IV over 15 minutes and fluorouracil IV once a week for 4 weeks followed by 2 weeks of rest. Courses repeat every 6 weeks. (Arm I closed to accrual as of March 15, 2002.)
  • Arm II (FOLFOX4 regimen): Patients receive oxaliplatin IV over 2 hours on day 1 and leucovorin calcium IV over 2 hours plus fluorouracil IV over 22 hours on days 1 and 2. Courses repeat every 2 weeks.
  • Arm III (oxaliplatin plus irinotecan): Patients receive oxaliplatin IV over 2 hours and irinotecan IV over 30 minutes on day 1. Courses repeat every 3 weeks. (Arm III closed to accrual as of March 15, 2002.) Treatment continues in the absence of disease progression or unacceptable toxicity.

Quality of life is assessed before treatment, during treatment (arm specific), and after completion of treatment.

Patients are followed every 3 months for 1 year, every 6 months for 2 years, and then annually thereafter.

PROJECTED ACCRUAL: A total of 825 patients (275 per arm) have been accrued for this study thus far. Additional patients are being accrued on arm II. (Arms I and III closed to accrual as of March 15, 2002.)

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 1691 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized Phase III Trial of Three Different Regimens of CPT-11 Plus 5-Fluorouracil and Leucovorin Compared to 5-Fluorouracil and Leucovorin in Patients With Advanced Adenocarcinoma of the Colon and Rectum
Study Start Date : October 1998
Actual Primary Completion Date : October 2004
Actual Study Completion Date : October 2004

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: irinotecan + leucovorin + fluorouracil

Patients receive irinotecan IV over 90 minutes followed by leucovorin calcium IV over 15 minutes and fluorouracil IV once a week for 4 weeks followed by 2 weeks of rest. Courses repeat every 6 weeks.

Treatment continues in the absence of disease progression or unacceptable toxicity.

Quality of life is assessed before treatment, during treatment (arm specific), and after completion of treatment.

Patients are followed every 3 months for 1 year, every 6 months for 2 years, and then annually thereafter.

 Drug: irinotecan
Drug: fluorouracil
Drug: leucovorin calcium
Experimental: oxaliplatin + leucovorin + fluorouracil

Patients receive oxaliplatin IV over 2 hours on day 1 and leucovorin calcium IV over 2 hours plus fluorouracil IV over 22 hours on days 1 and 2. Courses repeat every 2 weeks.

Treatment continues in the absence of disease progression or unacceptable toxicity.

Quality of life is assessed before treatment, during treatment (arm specific), and after completion of treatment.

Patients are followed every 3 months for 1 year, every 6 months for 2 years, and then annually thereafter.

 Drug: fluorouracil
Drug: leucovorin calcium
Drug: oxaliplatin
Experimental: oxaliplatin + irinotecan

Patients receive oxaliplatin IV over 2 hours and irinotecan IV over 30 minutes on day 1. Courses repeat every 3 weeks.

Treatment continues in the absence of disease progression or unacceptable toxicity.

Quality of life is assessed before treatment, during treatment (arm specific), and after completion of treatment.

Patients are followed every 3 months for 1 year, every 6 months for 2 years, and then annually thereafter.

 Drug: irinotecan
Drug: oxaliplatin


Outcome Measures
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Primary Outcome Measures :
  1. time to progression [ Time Frame: Up to 5 years ]

Secondary Outcome Measures :
  1. overall survival [ Time Frame: Up to 5 years ]
  2. time to treatment failure [ Time Frame: Up to 5 years ]
  3. response rate [ Time Frame: Up to 5 years ]
  4. quality of life [ Time Frame: Up to 5 years ]

Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

DISEASE CHARACTERISTICS:

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

    • Histological or cytological requirement waived in patients who developed radiological or clinical evidence of metastatic cancer after a prior surgical resection unless:

      • More than 5 years has elapsed since primary surgery OR
      • Primary cancer was stage I or II
  • Site of primary lesion must be or have been confirmed endoscopically, radiologically, or surgically to be or have been in the large bowel
  • Measurable or evaluable disease
  • No CNS metastases or carcinomatous meningitis

PATIENT CHARACTERISTICS:

Age:

  • 18 and over

Performance status:

  • ECOG 0-2

Life expectancy:

  • At least 12 weeks

Hematopoietic:

  • Absolute granulocyte count at least 1,500/mm^3
  • Platelet count at least 100,000/mm^3
  • Hemoglobin at least 9.0 g/dL (transfusion allowed)

Hepatic:

  • 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

Renal:

  • Creatinine no greater than 1.5 times ULN

Cardiovascular:

  • No uncontrolled hypertension
  • No unstable angina
  • No symptomatic congestive heart failure
  • No myocardial infarction within the past 6 months
  • No serious uncontrolled arrhythmia
  • No New York Heart Association class III or IV cardiac disease

Pulmonary:

  • No interstitial pneumonia or extensive and symptomatic interstitial fibrosis of the lung
  • No pleural effusion or ascites that cause respiratory compromise (grade 2 or worse dyspnea)

Other:

  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception
  • No active or uncontrolled infection
  • No symptomatic sensory peripheral neuropathy
  • No known allergy to platinum compounds
  • No history of gastrointestinal bleeding unless it is determined to be acceptable by the enrolling physician
  • No other prior or concurrent malignancy within the past 3 years except nonmelanoma skin cancer, carcinoma in situ of the uterine cervix, or other resected malignant tumor with less than a 10% probability of tumor relapse within 3 years of diagnosis
  • No medical or psychiatric conditions that would preclude study
  • No colonic or small bowel disorders with uncontrolled symptoms of more than 3 loose stools per day
  • Colostomy or ileostomy allowed at investigator's discretion

PRIOR CONCURRENT THERAPY:

Biologic therapy:

  • Prior adjuvant immunotherapy for resected stage II-IV disease allowed if adjuvant therapy concluded at least 1 year before documentation of recurrent disease
  • No concurrent sargramostim (GM-CSF)

Chemotherapy:

  • No prior chemotherapy for advanced colorectal cancer
  • No prior standard adjuvant chemotherapy for rectal cancer
  • Prior adjuvant fluorouracil for resected stage II-IV disease allowed if adjuvant therapy concluded at least 1 year before documentation of recurrent disease

Radiotherapy:

  • See Disease Characteristics
  • At least 4 weeks since prior major radiotherapy (e.g., chest or bone palliative radiotherapy)
  • No prior radiotherapy to more than 15% of bone marrow
  • No prior standard adjuvant radiotherapy for rectal cancer

Surgery:

  • See Disease Characteristics
  • At least 4 weeks since prior major surgery (e.g., laparotomy) (2 weeks for minor surgery) and recovered
  • Insertion of a vascular access device not considered major or minor surgery

Other:

  • No other concurrent investigational agents
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00003594


Locations
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Sponsors and Collaborators
Alliance for Clinical Trials in Oncology
National Cancer Institute (NCI)
NCIC Clinical Trials Group
Investigators
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Study Chair: Henry C. Pitot, MD Mayo Clinic
More Information
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Additional Information:

Publications of Results:
Sargent DJ, Campbell M, Grothey A, et al.: Overall and 12 week tumor response versus actual tumor measurements as predictors of overall survival (OS) in advanced colorectal cancer (ACRC): findings from NCCTG N9741. [Abstract] American Society of Clinical Oncology 2008 Gastrointestinal Cancers Symposium, 25-27 January 2008, Orlando, FL. A-446, 2008.
Grothey A, Sargent DJ, Campbell ME, et al.: Waterfall plots provide detailed information on magnitude of response to conventional chemotherapy in colorectal cancer: lessons learned from N9741. [Abstract] American Society of Clinical Oncology 2007 Gastrointestinal Cancers Symposium, 19 -21 January 2007, Orlando, Florida A-337, 2007.
Goldberg RM, McLeod HL, Sargent DJ, et al.: Genetic polymorphisms, toxicity, and response rate in African Americans (AA) with metastatic colorectal cancer (MCRC) compared to Caucasians (C) when treated with IFL, FOLFOX or IROX in Intergroup N9741. [Abstract] J Clin Oncol 24 (Suppl 18): A-3503, 2006.
McLeod HL, Parodi L, Sargent DJ, et al.: UGT1A1*28, toxicity and outcome in advanced colorectal cancer: results from trial N9741. [Abstract] J Clin Oncol 24 (Suppl 18): A-3520, 2006.
Goldberg RM, Morton RF, Sargent DJ, et al.: N9741: oxaliplatin (Oxal) or CPT-11 + 5-fluorouracil (5FU)/leucovorin (LV) or oxal + CPT-11 in advanced colorectal cancer (CRC). Updated efficacy and quality of life (QOL) data from an intergroup study. [Abstract] Proceedings of the American Society of Clinical Oncology 22: A-1009, 252, 2003.
Goldberg RM, Morton RF, Sargent D, et al.: N9741: oxaliplatin (oxal) or CPT-11 + 5-fluorouracil (5FU)/leucovorin (LV) or oxal + CPT-11 in advanced colorectal cancer (CRC). Initial toxicity and response data from a GI Intergroup study. [Abstract] Proceedings of the American Society of Clinical Oncology 21: A-511, 2002.
Morton RF, Goldberg RM, Sargent DJ, et al.: Oxaliplatin (OXAL) or CPT-11 Combined with 5FU/Leucovorin (LV) in Advanced Colorectal Cancer (CRC): an NCCTG/CALGB Study. [Abstract] Proceedings of the American Society of Clinical Oncology 20: A-495, 2001.

Other Publications:
Campbell ME, Mandrekar SJ, Hillman SL, et al.: What is the added value of actual tumor measurements (TM) in predicting overall survival (OS)? The North Central Cancer Treatment Group (NCCTG) findings. [Abstract] J Clin Oncol 26 (Suppl 15): A-6520, 2008.
Grothey A, Hedrick EE, Mass RD, et al.: Response rate using conventional criteria is a poor surrogate for clinical benefit on progression-free (PFS) and overall survival (OS) in metastatic colorectal cancer (mCRC): a comparative analysis of N9741 and AVF2107. [Abstract] J Clin Oncol 24 (Suppl 18): A-3516, 2006.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Alliance for Clinical Trials in Oncology
ClinicalTrials.gov Identifier: NCT00003594    
Other Study ID Numbers: NCCTG-N9741
CDR0000066665 ( Registry Identifier: PDQ (Physician Data Query) )
CAN-NCIC-CO13
First Posted: September 25, 2003    Key Record Dates
Last Update Posted: April 29, 2020
Last Verified: April 2020
Keywords provided by Alliance for Clinical Trials in Oncology:
stage III colon cancer
stage IV colon cancer
stage III rectal cancer
stage IV rectal cancer
 recurrent colon cancer
recurrent rectal cancer
adenocarcinoma of the colon
adenocarcinoma of the rectum
Additional relevant MeSH terms:
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Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Leucovorin
Fluorouracil
Oxaliplatin
Irinotecan
 Calcium
Levoleucovorin
Calcium-Regulating Hormones and Agents
Physiological Effects of Drugs
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Antidotes
Protective Agents