Leucovorin and Fluorouracil With or Without Oxaliplatin Compared to Capecitabine With or Without Oxaliplatin in Treating Patients With Metastatic Colorectal Cancer

Sponsor

Medical Research Council (Other)

Overall Status

Completed

CT.gov ID

NCT00070213

Collaborator

University of Leeds (Other)

460

Enrollment

Locations

Arms

Duration (Months)

115

Patients Per Site

1.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy, such as leucovorin, fluorouracil, capecitabine, and oxaliplatin, 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 whether leucovorin and fluorouracil with or without oxaliplatin is more effective than capecitabine with or without oxaliplatin in treating patients who have metastatic colorectal cancer.

PURPOSE: This randomized phase III trial is studying four different chemotherapy regimens to compare how well they work in treating patients with metastatic colorectal cancer.

Condition or Disease	Intervention/Treatment	Phase
Colorectal Cancer	Drug: FOLFOX regimen Drug: capecitabine Drug: fluorouracil Drug: leucovorin calcium Drug: oxaliplatin Procedure: quality-of-life assessment	Phase 3

Detailed Description

OBJECTIVES:

Primary

Compare the progression-free survival of patients with metastatic colorectal adenocarcinoma treated with leucovorin calcium and fluorouracil with vs without oxaliplatin or capecitabine with vs without oxaliplatin.
Compare the quality of life of patients treated with these fluorouracil-based vs capecitabine-based regimens.

Secondary

Compare the failure-free and overall survival of patients treated with these regimens.
Compare the toxic effects and adverse events associated with these regimens in these patients.
Compare the limited health assessments of patients treated with these regimens.
Compare the health economics associated with these regimens.

OUTLINE: This is a randomized, multicenter study. Patients are randomized to 1 of 4 treatment arms and receive 12 weeks of therapy.

Arm I (MdG regimen): Patients receive leucovorin calcium IV over 2 hours on day 1 and fluorouracil IV over 46 hours beginning on day 1. Treatment repeats every 14 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Patients with disease progression during or within 8 weeks of the completion of this regimen may cross over and receive second-line therapy on arm II.

Arm II (OxMdG regimen): Patients receive leucovorin calcium IV over 2 hours and oxaliplatin IV over 2 hours on day 1 and fluorouracil IV over 46 hours beginning on day

Treatment repeats every 14 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Patients with disease progression during or within 8 weeks of the completion of this regimen may receive second-line therapy or supportive care off-study.

Arm III (Cap regimen): Patients receive oral capecitabine twice daily on days 1-15. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.

Patients with disease progression during or within 8 weeks of the completion of this regimen may cross over and receive second-line therapy on arm IV.

Arm IV (OxCap regimen): Patients receive oxaliplatin IV over 2 hours on day 1 and oral capecitabine twice daily on days 1-15. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.

Patients with disease progression during or within 8 weeks of the completion of this regimen may receive second-line therapy or supportive care off-study.

All patients are then re-evaluated at least every 6 weeks and begin another 12 weeks of therapy at any evidence (e.g., clinical, radiological, or tumor marker) of disease progression. Patients with chemo-sensitive disease may repeat alternating 12-week therapy sessions and evaluation periods indefinitely.

Quality of life is assessed at baseline, at 12-14 weeks, at 24 weeks, and then every 3 months thereafter.

Patients are followed every 3 months.

Peer Reviewed and Funded or Endorsed by Cancer Research UK

PROJECTED ACCRUAL: A total of 460 patients (115 per treatment arm) will be accrued for this study within 2 years.

Study Design

Study Type:

Interventional

Actual Enrollment :

460 participants

Allocation:

Randomized

Intervention Model:

Single Group Assignment

Primary Purpose:

Treatment

Official Title:

Drug Treatment for Bowel Cancer: Making the Best Choices When a Milder Treatment is Needed

Study Start Date :

Sep 1, 2003

Actual Primary Completion Date :

Jun 1, 2011

Actual Study Completion Date :

Jun 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: MdG (modified de Gramont) 2 weekly 5FU/FA schedule	Drug: FOLFOX regimen Drug: fluorouracil Drug: leucovorin calcium Procedure: quality-of-life assessment
Experimental: OxMdG (80%) for 12 weeks MdG + oxaliplatin	Drug: FOLFOX regimen Drug: fluorouracil Drug: leucovorin calcium Drug: oxaliplatin Procedure: quality-of-life assessment
Experimental: Capcitabine	Drug: capecitabine Procedure: quality-of-life assessment
Experimental: OxCap	Drug: capecitabine Drug: oxaliplatin Procedure: quality-of-life assessment

Outcome Measures

Primary Outcome Measures

Compare progression-free survival (PFS) in pts. treated w/ leucovorin calcium + fluorouracil (MdG) vs leucovorin calcium + fluorouracil + oxaliplatin (OxMdG) and in pts. treated w/ capecitabine (Cap) vs capecitabine + oxaliplatin (OxCap) at 1 yr [PFS]
Compare progression-free survival (PFS) in pts. treated w/ leucovorin calcium + fluorouracil (MdG) vs leucovorin calcium + fluorouracil + oxaliplatin (OxMdG) and in pts. treated w/ capecitabine (Cap) vs capecitabine + oxaliplatin (OxCap) at 1 yr
Compare health assessment in patients treated with MdG vs Cap and in patients treated with OxMdG vs OxCap at baseline and 14 weeks [Baseline and 14 weeks]
Compare health assessment in patients treated with MdG vs Cap and in patients treated with OxMdG vs OxCap at baseline and 14 weeks

Secondary Outcome Measures

Compare health assessment, including quality of life, in patients treated with MdG vs OxMdG and in patients treated with Cap vs OxCap at baseline and 14 and 24 weeks [Baseline, 14 and 24 weeks]
Compare health assessment, including quality of life, in patients treated with MdG vs OxMdG and in patients treated with Cap vs OxCap at baseline and 14 and 24 weeks
Compare toxicity/adverse events in patients treated with MdG vs OxMdG and in patients treated with Cap vs OxCap [post 24 weeks]
Compare toxicity/adverse events in patients treated with MdG vs OxMdG and in patients treated with Cap vs OxCap
Compare overall failure-free survival in patients treated with MdG vs OxMdG and in patients treated with Cap vs OxCap [post 24 weeks]
Compare overall failure-free survival in patients treated with MdG vs OxMdG and in patients treated with Cap vs OxCap
Compare overall survival in patients treated with MdG vs OxMdG and in patients treated with Cap vs OxCap [post 24 weeks]
Compare overall survival in patients treated with MdG vs OxMdG and in patients treated with Cap vs OxCap
Compare health economics in patients treated with MdG vs OxMdG and in patients treated with Cap vs OxCap [Baseline, 14 and 24 weeks]
Compare health economics in patients treated with MdG vs OxMdG and in patients treated with Cap vs OxCap
Compare health assessment in patients treated with MdG vs Cap and in patients treated with OxMdG vs OxCap [Baseline, 14 and 24 weeks]
Compare toxicity/adverse events in patients treated with MdG vs Cap and in patients treated with OxMdG vs OxCap at baseline and 24 weeks [Baseline and 24 weeks]
Compare toxicity/adverse events in patients treated with MdG vs Cap and in patients treated with OxMdG vs OxCap at baseline and 24 weeks
Compare patients acceptability in patients treated with MdG vs Cap and in patients treated with OxMdG vs OxCap [post 24 weeks]
Compare patients acceptability in patients treated with MdG vs Cap and in patients treated with OxMdG vs OxCap
Compare PFS in patients treated with MdG vs Cap and in patients treated with OxMdG vs OxCap [post 24 weeks]
Compare PFS in patients treated with MdG vs Cap and in patients treated with OxMdG vs OxCap
Compare health economics in patients treated with MdG vs Cap and in patients treated with OxMdG vs OxCap [Baseline, 14 and 24 weeks]
Compare health economics in patients treated with MdG vs Cap and in patients treated with OxMdG vs OxCap

Eligibility Criteria

Criteria

Ages Eligible for Study:

0 Years to 120 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

DISEASE CHARACTERISTICS:

Diagnosis of colorectal adenocarcinoma, defined by 1 of the following:
Prior or current histologically confirmed primary adenocarcinoma of the colon or rectum with clinical/radiological evidence of advanced/metastatic disease
Histologically or cytologically confirmed metastatic adenocarcinoma with clinical/radiological evidence of colorectal primary tumor
Unidimensionally measurable disease
Unfit and unsuitable for full-dose combination chemotherapy, which would include 1 of the following circumstances:
Unsuitable or unwilling to be entered into any full-dose chemotherapy protocol
Ineligible or unsuitable for first-line standard combination as per National Institute of Clinical Excellence guidance

PATIENT CHARACTERISTICS:

Age

Not specified

Performance status

WHO 0-2

Life expectancy

Not specified

Hematopoietic

WBC greater than 3,000/mm^3
Platelet count greater than 100,000/mm^3

Hepatic

Bilirubin no greater than 3 times upper limit of normal (ULN)
AST or ALT no greater than 2.5 times ULN

Renal

Creatinine clearance greater than 50 mL/min OR
Glomerular filtration rate greater than 30 mL/min

Cardiovascular

No uncontrolled angina
No recent myocardial infarction

Other

Not pregnant
Negative pregnancy test
Fertile patients must use effective contraception
No partial or complete bowel obstruction
No concurrent severe uncontrolled medical illness that would preclude study treatment
No psychiatric or neurological condition that would preclude giving informed consent or complying with oral study medication
No other prior or concurrent malignant disease that would preclude study treatment or assessment of response
No prior neuropathy greater than grade 1

PRIOR CONCURRENT THERAPY:

Biologic therapy

Not specified

Chemotherapy

More than 4 months since prior adjuvant chemotherapy with fluorouracil with or without leucovorin calcium
More than 1 month since prior rectal chemoradiotherapy with fluorouracil with or without leucovorin calcium
No prior systemic palliative chemotherapy for metastatic disease

Endocrine therapy

Not specified

Radiotherapy

See Chemotherapy

Surgery

Not specified

Other

No concurrent brivudine or sorivudine

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cookridge Hospital	Leeds	England	United Kingdom	LS16 6QB
2	Clinical Trials and Research Unit of the University of Leeds	Leeds	England	United Kingdom	LS2 9JT
3	Medical Research Council Clinical Trials Unit	London	England	United Kingdom	NW1 2DA
4	Velindre Cancer Center at Velindre Hospital	Cardiff	Wales	United Kingdom	CF14 2TL