A Study of Capecitabine (Xeloda) as a First-line Therapy in Patients With Metastatic Colorectal Cancer

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT00069095
First received: September 15, 2003
Last updated: January 30, 2013
Last verified: January 2013
  Purpose

This 4 arm study assessed the efficacy and safety of oral capecitabine (Xeloda) or intravenous (iv) fluorouracil/leucovorin, in combination with iv oxaliplatin (Eloxatin) with or without iv bevacizumab (Avastin), as a first-line treatment in patients with metastatic colorectal cancer. Patients were randomized to receive 1) XELOX (Xeloda 1000 mg/m^2 orally [po] twice a day [bid] on Days 1-15 + oxaliplatin in 3 week cycles), 2) FOLFOX-4 (oxaliplatin + leucovorin + fluorouracil [5-FU] in 2 week cycles), 3) XELOX + bevacizumab (7.5 mg iv on Day 1 in 3 week cycles), or 4) FOLFOX-4 + bevacizumab (5 mg iv on Day 1 in 2 week cycles).


Condition Intervention Phase
Colorectal Cancer
Drug: Oxaliplatin 130 mg/m^2
Drug: Capecitabine 1000 mg/m^2
Drug: Bevacizumab 7.5 mg/kg
Drug: Placebo for bevacizumab 7.5 mg/kg
Drug: Oxaliplatin 85 mg/m^2
Drug: Leucovorin 200 mg/m^2
Drug: Fluorouracil 400 mg/m^2
Drug: Bevacizumab 5 mg/kg
Drug: Placebo for bevacizumab 5 mg/kg
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Factorial Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: A 2x2 Factorial Randomized Phase III Study of Intermittent Oral Capecitabine in Combination With Intravenous Oxaliplatin (Q3W) ("XELOX") With/Without Intravenous Bevacizumab (Q3W) Versus Bolus and Continuous Infusion Fluorouracil/Intravenous Leucovorin With Intravenous Oxaliplatin (Q2W) ("FOLFOX-4") With/Without Intravenous Bevacizumab (Q2W) as First-line Treatment for Patients With Metastatic Colorectal Cancer

Resource links provided by NLM:


Further study details as provided by Hoffmann-La Roche:

Primary Outcome Measures:
  • Progression-free survival (PFS) as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) [ Time Frame: Baseline to the 10 Feb 2005 data cut-off (up to 1 year 7 months) ] [ Designated as safety issue: No ]
    PFS was defined as the time from randomization to disease progression (PD) or death. All measurable lesions (maximum of 5 per organ and 10 in total, those with the longest diameter and suitability for accurate repeated measurements) were identified as target lesions (TL). A sum of the longest diameter for all TLs was calculated and reported as the baseline sum longest diameter(SLD). All other lesions were identified as non-TLs and recorded at baseline. PD for TLs was defined as ≥ 20% increase in the SLD, taking as reference the smallest SLD recorded since treatment started or the appearance of 1 or more new lesions. PD for non-TLs was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing non-TLs. Patients with neither PD nor death were censored at the date of the last tumor assessment that confirmed no PD. Patients who underwent surgical resection with curative intent without prior progression were censored at the date of surgery.


Secondary Outcome Measures:
  • Progression-free survival (PFS) as assessed by the Independent Review Committee according to Response Evaluation Criteria in Solid Tumors (RECIST) [ Time Frame: Baseline to the 10 Feb 2005 data cut-off (up to 1 year 7 months) ] [ Designated as safety issue: No ]
    PFS is defined as the time from randomization to disease progression (PD) or death due to any cause. Patients with neither disease progression nor death were censored at the last date of the last tumor assessment that confirmed that their disease had not progressed. Patients who underwent surgical resection with curative intent without prior progression were censored at the date of surgery. PFS was analyzed on the basis of the tumor response assessments made by the Independent Review Committee.

  • Best overall response (BOR) as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) [ Time Frame: Baseline to the 10 Feb 2005 data cut-off (up to 1 year 7 months) ] [ Designated as safety issue: No ]
    BOR in an individual patient was defined as the best response recorded from the start of the treatment until disease progression or recurrence. Only tumor assessments by the investigator made up to 28 days after the last study treatment in the primary study treatment phase not later than the date of the first curative surgery were included in the analysis. Responders were defined as the percentage of patients with a complete response (CR) or partial response (PR). For target lesions (TL), a CR was defined as the disappearance of all TLs and a PR was defined as ≥ 30% decrease in the SLD of target lesions, taking as reference the baseline SLD. For non-TLs, a CR was defined as the disappearance of all non-TLs and a PR was defined as the persistence of 1 or more non-TLs.

  • Best overall response (BOR) as assessed by the Independent Review Committee according to Response Evaluation Criteria in Solid Tumors (RECIST) [ Time Frame: Baseline to the 10 Feb 2005 data cut-off (up to 1 year 7 months) ] [ Designated as safety issue: No ]
    Only tumor assessments by the Independent Review Committee made up to 28 days after the last study treatment in the primary study treatment phase not later than the date of the first curative surgery were included in the analysis. Responders were defined as the percentage of patients with a complete response (CR) or partial response (PR).

  • Overall survival [ Time Frame: Baseline to the 30 May 2008 data cut-off (up to 4 years 10 months) ] [ Designated as safety issue: No ]
    Overall survival was defined as the time from the date of randomization to the date of death. Patients who were not reported to have died at the time of the clinical cut-off date for the analysis were censored using the date they were last known to be alive.

  • Time to response as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) [ Time Frame: Baseline to the 10 Feb 2005 data cut-off (up to 1 year 7 months) ] [ Designated as safety issue: No ]
    For patients whose best overall response was CR or PR, time to response was defined as the time from randomization to the first time when the measurement criteria for CR or PR (whichever status is recorded first) were met. Results are reported as the percentage of patients achieving a response in 8 time categories from Week 1 to Week 54.

  • Duration of response as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) [ Time Frame: Baseline to the 10 Feb 2005 data cut-off (up to 1 year 7 months) ] [ Designated as safety issue: No ]
    Duration of response was defined as the time that measurement criteria are first met for complete response (CR) or partial response (PR) (whichever status is recorded first) until the first date that progressive disease (PD) or death is documented. PD for target lesions was defined as ≥ 20% increase in the sum of the longest diameter, taking as reference the smallest sum of the longest diameter recorded since treatment started or the appearance of 1 or more new lesions. PD for non-target lesions was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing non-targets.

  • Duration of complete response as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) [ Time Frame: Baseline to the 10 Feb 2005 data cut-off (up to 1 year 7 months) ] [ Designated as safety issue: No ]
    Duration of complete response was defined as the time measurement criteria are first met for a complete response until the date that progressive disease (or death) is documented.

  • Time to treatment failure as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) [ Time Frame: Baseline to the 10 Feb 2005 data cut-off (up to 1 year 7 months) ] [ Designated as safety issue: No ]
    Time to treatment failure was defined as the time from the date of randomization to the date of discontinuation of the primary study treatment phase due to adverse event/intercurrent illness, insufficient therapeutic response, death, failure to return, refusing treatment/being unwilling to cooperate, or withdrawing consent; discontinuation of the post study treatment phase due to adverse event, progressive disease, death, patient refusal/administrative reasons, or withdrawing consent; documented disease progression; or death due to any cause, whichever occurs first.


Enrollment: 2035
Study Start Date: July 2003
Study Completion Date: April 2009
Primary Completion Date: January 2006 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: XELOX (oxaliplatin+capecitabine)
Patients in the 2-arm part of the study received oxaliplatin 130 mg/m^2 intravenously (iv) on Day 1 of every 3 week cycle + capecitabine 1000 mg/m^2 orally twice a day for the first 2 weeks of every 3 week cycle. Patients in the 4-arm part of the study received the same treatments plus placebo for bevacizumab 7.5 mg/kg iv on Day 1 of every 3 week cycle.
Drug: Oxaliplatin 130 mg/m^2
Oxaliplatin was administered in a 2 h infusion before the first dose of capecitabine.
Other Name: Eloxatin
Drug: Capecitabine 1000 mg/m^2
Capecitabine was taken within 30 min after the end of breakfast and dinner.
Other Name: Xeloda
Drug: Placebo for bevacizumab 7.5 mg/kg
Placebo control for bevacizumab (volume equivalent to 7.5 mg/kg bevacizumab) was administered in a 30 to 90 min infusion.
Experimental: XELOX (oxaliplatin+capecitabine) + bevacizumab
Patients in the 4-arm part of the study received oxaliplatin 130 mg/m^2 intravenously (iv) on Day 1 of every 3 week cycle + capecitabine 1000 mg/m^2 orally twice a day for the first 2 weeks of every 3 week cycle + bevacizumab 7.5 mg/kg iv on Day 1 of every 3 week cycle.
Drug: Oxaliplatin 130 mg/m^2
Oxaliplatin was administered in a 2 h infusion before the first dose of capecitabine.
Other Name: Eloxatin
Drug: Capecitabine 1000 mg/m^2
Capecitabine was taken within 30 min after the end of breakfast and dinner.
Other Name: Xeloda
Drug: Bevacizumab 7.5 mg/kg
Bevacizumab was administered in a 30 to 90 min infusion.
Other Name: Avastin
Active Comparator: FOLFOX-4 (oxaliplatin+leucovorin+fluorouracil)
Patients in the 2-arm part of the study received oxaliplatin 85 mg/m^2 intravenously (iv) + leucovorin 200 mg/m^2 iv on Day 1 of every 2 week cycle + fluorouracil 400 mg/m^2 bolus injection over 2 to 4 min followed by 600 mg/m^2 continuous infusion over 22 h on Days 1 and 2 of every 2 week cycle. Patients in the 4-arm part of the study received the same treatments plus placebo for bevacizumab 5 mg/kg iv on Day 1 of every 2 week cycle.
Drug: Oxaliplatin 85 mg/m^2
Oxaliplatin 85 mg/m^2 was administered simultaneously with leucovorin in a 2 h infusion.
Other Name: Eloxatin
Drug: Leucovorin 200 mg/m^2
Leucovorin was administered simultaneously with oxaliplatin 85 mg/m^2 in a 2 h infusion.
Drug: Fluorouracil 400 mg/m^2
Other Name: Efudex
Drug: Placebo for bevacizumab 5 mg/kg
Placebo control for bevacizumab (volume equivalent to 5 mg/kg bevacizumab) was administered in a 30 to 90 min infusion.
Active Comparator: FOLFOX-4 (oxaliplatin+leucovorin+fluorouracil) + bevacizumab
Patients in the 4-arm part of the study received oxaliplatin 85 mg/m^2 intravenously (iv) + leucovorin 200 mg/m^2 iv + bevacizumab 5 mg/kg iv on Day 1 of every 2 week cycle + fluorouracil 400 mg/m^2 bolus injection over 2 to 4 min followed by 600 mg/m^2 continuous infusion over 22 h on Days 1 and 2 of every 2 week cycle.
Drug: Oxaliplatin 85 mg/m^2
Oxaliplatin 85 mg/m^2 was administered simultaneously with leucovorin in a 2 h infusion.
Other Name: Eloxatin
Drug: Leucovorin 200 mg/m^2
Leucovorin was administered simultaneously with oxaliplatin 85 mg/m^2 in a 2 h infusion.
Drug: Fluorouracil 400 mg/m^2
Other Name: Efudex
Drug: Bevacizumab 5 mg/kg
Bevacizumab was administered in a 30 to 90 min infusion.
Other Name: Avastin

Detailed Description:

This study was conducted in 2 parts: An initial 2-arm part in which patients were randomized to 1 of 2 different treatment groups (XELOX or FOLFOX-4), and a subsequent 2 x 2 factorial part, added to the study through a protocol amendment, in which additional patients were randomized into one of 4 different treatment groups (XELOX + placebo, FOLFOX-4 + placebo, XELOX + bevacizumab, or FOLFOX-4 + bevacizumab). Due to the comparison of the oral agent capecitabine with bolus and infused fluorouracil, the study was not blinded with respect to these 2 treatments. The study was double-blind with regard to the administration of bevacizumab, ie, there was a placebo control for bevacizumab in the second part of the study.

The study consisted of 3 phases, a Primary Study Treatment Phase, a Post-Study Treatment Phase, and a Follow-Up Phase.

Primary Study Treatment Phase

Patients were to receive up to 16 cycles (2-arm part of the study) or 24 cycles (4-arm part of the study) of treatment during the Primary Study Treatment Phase (48 weeks).

Post-Study Treatment Phase

Patients who completed the 48-week primary study treatment phase without progressive disease were eligible to enter the post-study treatment phase at the discretion of the investigator and the sponsor. Patients who entered this phase were to continue treatment on the same regimen to which they were initially randomized until either progression of disease was documented, unacceptable toxicity occurred, or the patient withdrew consent.

Follow-up Phase

Patients who terminated study treatment during the primary or post-study treatment phase were followed until disease progression or death.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Adult patients ≥ 18 years of age.
  • Metastatic colorectal cancer.
  • ≥ 1 target lesion.

Exclusion Criteria:

  • Previous treatment with oxaliplatin or bevacizumab.
  • Previous systemic chemotherapy or immunotherapy for advanced or metastatic disease.
  • Progressive disease during or within 6 months of completion of previous adjuvant therapy.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00069095

  Show 236 Study Locations
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
Study Director: Clinical Trials Hoffmann-La Roche
  More Information

No publications provided

Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT00069095     History of Changes
Other Study ID Numbers: NO16966
Study First Received: September 15, 2003
Last Updated: January 30, 2013
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Fluorouracil
Capecitabine
Oxaliplatin
Bevacizumab
Leucovorin
Levoleucovorin
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antimetabolites, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Vitamin B Complex
Vitamins
Micronutrients
Growth Substances

ClinicalTrials.gov processed this record on July 28, 2014