Clinical trial NCT00070213: Leucovorin and Fluorouracil With or Without Oxaliplatin Compared to Capecitabine With or Without Oxaliplatin in Treating Patients With Metastatic Colorectal Cancer
Official title: Drug Treatment for Bowel Cancer: Making the Best Choices When a Milder Treatment is Needed
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Colorectal Cancer
Keywords: adenocarcinoma of the colon
adenocarcinoma of the rectum
stage IV rectal cancer
stage IV colon cancer
recurrent rectal cancer
recurrent colon cancer
Lead sponsor: Medical Research Council
Sponsor class: OTHER_GOV
Collaborators: name: University of Leeds
First posted: 2003-10-07
Enrollment: 460
Sex: ALL
Minimum age (years): 0
Maximum age (years): 120
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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 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 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.

Eligibility criteria: 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

Primary outcomes:
measure: 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
timeFrame: PFS
measure: Compare health assessment in patients treated with MdG vs Cap and in patients treated with OxMdG vs OxCap at baseline and 14 weeks
timeFrame: Baseline and 14 weeks
Secondary outcomes:
measure: 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
timeFrame: Baseline, 14 and 24 weeks
measure: Compare toxicity/adverse events in patients treated with MdG vs OxMdG and in patients treated with Cap vs OxCap
timeFrame: post 24 weeks
measure: Compare overall failure-free survival in patients treated with MdG vs OxMdG and in patients treated with Cap vs OxCap
timeFrame: post 24 weeks
measure: Compare overall survival in patients treated with MdG vs OxMdG and in patients treated with Cap vs OxCap
timeFrame: post 24 weeks
measure: Compare health economics in patients treated with MdG vs OxMdG and in patients treated with Cap vs OxCap
timeFrame: Baseline, 14 and 24 weeks
measure: Compare health assessment in patients treated with MdG vs Cap and in patients treated with OxMdG vs OxCap
timeFrame: Baseline, 14 and 24 weeks
measure: Compare toxicity/adverse events in patients treated with MdG vs Cap and in patients treated with OxMdG vs OxCap at baseline and 24 weeks
timeFrame: Baseline and 24 weeks
measure: Compare patients acceptability in patients treated with MdG vs Cap and in patients treated with OxMdG vs OxCap
timeFrame: post 24 weeks
measure: Compare PFS in patients treated with MdG vs Cap and in patients treated with OxMdG vs OxCap
timeFrame: post 24 weeks
measure: Compare health economics in patients treated with MdG vs Cap and in patients treated with OxMdG vs OxCap
timeFrame: Baseline, 14 and 24 weeks
Other outcomes:
Locations:
city: Leeds
country: United Kingdom
facility: Cookridge Hospital
state: England
city: Leeds
country: United Kingdom
facility: Clinical Trials and Research Unit of the University of Leeds
state: England
city: London
country: United Kingdom
facility: Medical Research Council Clinical Trials Unit
state: England
city: Cardiff
country: United Kingdom
facility: Velindre Cancer Center at Velindre Hospital
state: Wales
Study officials:
affiliation: Cookridge Hospital
name: Matthew T. Seymour, MA, MD, FRCP
role: PRINCIPAL_INVESTIGATOR
affiliation: Medical Research Council
name: Gareth Griffiths
role: STUDY_CHAIR
References:
citation: Seymour MT, Thompson LC, Wasan HS, Middleton G, Brewster AE, Shepherd SF, O'Mahony MS, Maughan TS, Parmar M, Langley RE; FOCUS2 Investigators; National Cancer Research Institute Colorectal Cancer Clinical Studies Group. Chemotherapy options in elderly and frail patients with metastatic colorectal cancer (MRC FOCUS2): an open-label, randomised factorial trial. Lancet. 2011 May 21;377(9779):1749-59. doi: 10.1016/S0140-6736(11)60399-1. Epub 2011 May 11.
citation: Seymour MT, Maughan TS, Wasan HS, et al.: Capecitabine (Cap) and oxaliplatin (Ox) in elderly and/or frail patients with metastatic colorectal cancer: the FOCUS2 trial. [Abstract] J Clin Oncol 25 (Suppl 18): A-9030, 500s, 2007.