Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Published Results
Related Publications
Trial Contact Information
Registry Information

Alternate Title

Combination Chemotherapy in Treating Patients With Advanced Colorectal Cancer

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase III	Treatment	Completed	18 and over	NCI	NCCTG-N9741 CAN-NCIC-CO13, CLB-89804, E-N9741, SWOG-N9741, N9741, NCT00003594, CO13

Objectives

1. 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.
2. Compare the quality of life, response rate, time to treatment failure, and overall survival in patients treated with these regimens.
3. Compare the toxicity of these regimens in these patients.

Entry 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

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

Endocrine therapy:

• Not specified

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

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/mm³
• Platelet count at least 100,000/mm³
• 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

Expected Enrollment

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.)

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.

Goldberg RM, Sargent DJ, Morton RF, et al.: NCCTG Study N9741: Leveraging Learning from an NCI Cooperative Group Phase III Trial. Oncologist : , 2009.[PUBMED Abstract]

Sanoff HK, Sargent DJ, Green EM, et al.: Racial differences in advanced colorectal cancer outcomes and pharmacogenetics: a subgroup analysis of a large randomized clinical trial. J Clin Oncol 27 (25): 4109-15, 2009.[PUBMED Abstract]

Fuchs CS, Goldberg RM, Sargent DJ, et al.: Plasma insulin-like growth factors, insulin-like binding protein-3, and outcome in metastatic colorectal cancer: results from intergroup trial N9741. Clin Cancer Res 14 (24): 8263-9, 2008.[PUBMED Abstract]

Sanoff HK, Sargent DJ, Campbell ME, et al.: Five-year data and prognostic factor analysis of oxaliplatin and irinotecan combinations for advanced colorectal cancer: N9741. J Clin Oncol 26 (35): 5721-7, 2008.[PUBMED Abstract]

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.

Dy GK, Krook JE, Green EM, et al.: Impact of complete response to chemotherapy on overall survival in advanced colorectal cancer: results from Intergroup N9741. J Clin Oncol 25 (23): 3469-74, 2007.[PUBMED Abstract]

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.

Goldberg RM, Sargent DJ, Morton RF, et al.: Randomized controlled trial of reduced-dose bolus fluorouracil plus leucovorin and irinotecan or infused fluorouracil plus leucovorin and oxaliplatin in patients with previously untreated metastatic colorectal cancer: a North American Intergroup Trial. J Clin Oncol 24 (21): 3347-53, 2006.[PUBMED Abstract]

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.

Delaunoit T, Alberts SR, Sargent DJ, et al.: Chemotherapy permits resection of metastatic colorectal cancer: experience from Intergroup N9741. Ann Oncol 16 (3): 425-9, 2005.[PUBMED Abstract]

Dy GK, Krook J, Green E, et al.: Impact of complete response to chemotherapy on overall survival (OS) in advanced colorectal cancer (CRC): results from Intergroup N9741. [Abstract] American Society of Clinical Oncology 2005 Gastrointestinal Cancers Symposium, 27-29 January 2005, Miami, Florida. A-185, 2005.

Delaunoit T, Goldberg RM, Sargent DJ, et al.: Mortality associated with daily bolus 5-fluorouracil/leucovorin administered in combination with either irinotecan or oxaliplatin: results from Intergroup Trial N9741. Cancer 101 (10): 2170-6, 2004.[PUBMED Abstract]

Fuchs C, Pollak M, Sargent DJ, et al.: Insulin-like growth factor-I (IGF-1), IGF binding protein-3 (IGFBP-3), and outcome in metastatic colorectal cancer (CRC): results from intergroup trial N9741. [Abstract] J Clin Oncol 22 (Suppl 14): A-3521, 250s, 2004.

Goldberg RM, Sargent DJ, Morton RF, et al.: A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 22 (1): 23-30, 2004.[PUBMED Abstract]

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.

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-independent survival benefit in metastatic colorectal cancer: a comparative analysis of N9741 and AVF2107. J Clin Oncol 26 (2): 183-9, 2008.[PUBMED Abstract]

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.

Goldberg R: Oxaliplatin in colorectal cancer: current studies. Oncology (Huntingt) 14 (12 Suppl 11): 42-7, 2000.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

North Central Cancer Treatment Group

Henry Pitot, MD, Protocol chair		Ph: 507-284-2511 Email: pitot.henry@mayo.edu
Roscoe Morton, MD, FACP, Protocol co-chair		Ph: 515-241-4141

Cancer and Leukemia Group B

Charles Fuchs, MD, Protocol chair		Ph: 617-632-5840; 866-790-4500

NCIC-Clinical Trials Group

Brian Findlay, MD, Protocol chair		Ph: 905-682-6451

Eastern Cooperative Oncology Group

Ramesh Ramanathan, MD, Protocol chair		Ph: 412-648-6507

Southwest Oncology Group

Stephen Williamson, MD, Protocol chair		Ph: 913-588-6029 Email: swilliam@kumc.edu

Registry Information
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
Trial Start Date		1998-10-27
Registered in ClinicalTrials.gov		NCT00003594
Date Submitted to PDQ		1998-09-25
Information Last Verified		2009-10-19
NCI Grant/Contract Number		CA25224

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