Clinical trial NCT00069095: A Study of Capecitabine (Xeloda) and Bevacizumab as a First-line Therapy in Patients With Metastatic Colorectal Cancer
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Colorectal Cancer
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2003-09-18
Enrollment: 2035
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

Brief summary: 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).

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 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.

Primary outcomes:
measure: Progression-free Survival (PFS) as Assessed by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) by General Approach (Participants With Curative Surgery Censored): Non-inferiority of XELOX Versus FOLFOX-4
timeFrame: Baseline until disease progression or death, approximately 2 years 6 months
measure: PFS as Assessed by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) by General Approach (Participants With Curative Surgery Censored) - Superiority of Chemotherapy Plus BV Over Chemotherapy Alone
timeFrame: Baseline until disease progression or death, approximately 2 years 6 months
Secondary outcomes:
measure: PFS as Assessed by the Independent Review Committee (IRC) (General Approach, Participants With Curative Surgery Censored) - Non-inferiority of XELOX Versus FOLFOX-4
timeFrame: Baseline until disease progression or death, approximately 2 years 6 months
measure: PFS as Assessed by the Independent Review Committee (IRC) (General Approach, Participants With Curative Surgery Censored) - Superiority of Chemotherapy Plus BV Over Chemotherapy Alone
timeFrame: Baseline until disease progression or death, approximately 2 years 6 months
measure: PFS (On-treatment Approach): Non-inferiority of XELOX Versus FOLFOX-4
timeFrame: Baseline until disease progression or death, approximately 2 years 6 months
measure: PFS (On-treatment Approach): Superiority of Chemotherapy Plus BV Over Chemotherapy Alone
timeFrame: Baseline until disease progression or death, approximately 2 years 6 months
measure: PFS by General Approach, Participants With Curative Surgery Not Censored: Non-inferiority of XELOX Versus FOLFOX-4
timeFrame: Baseline until disease progression or death, approximately 2 years 6 months
measure: PFS by General Approach, Participants With Curative Surgery Not Censored: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone
timeFrame: Baseline until disease progression or death, approximately 2 years 6 months
measure: Overall Survival: Non-inferiority of XELOX Versus FOLFOX-4
timeFrame: Baseline until disease progression or death, approximately 2 years 6 months
measure: Overall Survival: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone
timeFrame: Baseline until disease progression or death, approximately 2 years 6 months
measure: Best Overall Response (BOR) as Assessed by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST): Non-inferiority of XELOX Versus FOLFOX-4
timeFrame: From baseline until disease progression/recurrence, approximately 2 years 6 months
measure: Best Overall Response (BOR) as Assessed by the Investigator According to RECIST: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone
timeFrame: From baseline until disease progression/recurrence, approximately 2 years 6 months
measure: BOR as Assessed by the IRC According to RECIST: Non-inferiority of XELOX Versus FOLFOX-4
timeFrame: From baseline until disease progression/recurrence, approximately 2 years 6 months
measure: BOR as Assessed by the IRC According to RECIST: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone
timeFrame: From baseline until disease progression/recurrence, approximately 2 years 6 months
measure: Time to Treatment Failure (TTF) as Assessed by the Investigator According to RECIST: Non-inferiority of XELOX Versus FOLFOX-4
timeFrame: From baseline until disease progression/recurrence, approximately 2 years 6 months
measure: Time to Treatment Failure as Assessed by the Investigator According to RECIST: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone
timeFrame: From baseline until disease progression/recurrence, approximately 2 years 6 months
measure: Time to Response as Assessed by the Investigator According to RECIST: Non-inferiority of XELOX Versus FOLFOX-4
timeFrame: Week 1 to Week 54
measure: Time to Response as Assessed by the Investigator According to RECIST: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone
timeFrame: Week 1 to Week 54
measure: Duration of Overall Response as Assessed by the Investigator According to RECIST: Non-inferiority of XELOX Versus FOLFOX-4
timeFrame: From baseline until disease progression/recurrence, approximately 2 years 6 months
measure: Duration of Overall Response as Assessed by the Investigator According to RECIST: Superiority Analysis of Chemotherapy Plus Bevacizumab Versus Chemotherapy Alone
timeFrame: From baseline until disease progression/recurrence, approximately 2 years 6 months
measure: Duration of Complete Response as Assessed by the Investigator According to RECIST: Non-inferiority of XELOX Versus FOLFOX-4
timeFrame: From baseline until disease progression/recurrence, approximately 2 years 6 months
measure: Duration of Complete Response as Assessed by the Investigator According to RECIST: Superiority of Chemotherapy Plus BV Over Chemotherapy Alone
timeFrame: From baseline until disease progression/recurrence, approximately 2 years 6 months
Other outcomes:
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city: København
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city: Odense
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city: Helsinki
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city: Tampere
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city: Turku
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city: Besancon
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city: Bobigny
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city: Boulogne-billancourt
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city: Brest
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city: Chambray Les Tours
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city: Colmar
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city: Bochum
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city: Tel Aviv
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city: Zerifin
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city: Genova
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city: Modena
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city: Padova
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city: Parma
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city: Pavia
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city: Reggio Emilia
country: Italy
city: Sassari
country: Italy
city: Seoul
country: Korea, Republic of
city: Mexico City
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city: Bergen
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city: Oslo
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city: Tromsø
country: Norway
city: Panama City
country: Panama
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city: Lisboa
country: Portugal
city: San Juan
country: Puerto Rico
city: Moscow
country: Russian Federation
city: Moscow
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city: Moscow
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city: St Petersburg
country: Russian Federation
city: St Petersburg
country: Russian Federation
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city: Pretoria
country: South Africa
city: Sandton
country: South Africa
city: Barcelona
country: Spain
city: Barcelona
country: Spain
city: Córdoba
country: Spain
city: Granada
country: Spain
city: Leganes
country: Spain
city: Madrid
country: Spain
city: Madrid
country: Spain
city: Madrid
country: Spain
city: Madrid
country: Spain
city: Madrid
country: Spain
city: Málaga
country: Spain
city: Santander
country: Spain
city: Valencia
country: Spain
city: Valencia
country: Spain
city: Valencia
country: Spain
city: Zaragoza
country: Spain
city: Gaevle
country: Sweden
city: Karlstad
country: Sweden
city: Stockholm
country: Sweden
city: Uppsala
country: Sweden
city: Västerås
country: Sweden
city: Bern
country: Switzerland
city: Geneve
country: Switzerland
city: Kueishan
country: Taiwan
city: Taipei
country: Taiwan
city: Taipei
country: Taiwan
city: Taipei
country: Taiwan
city: Bangkok
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city: Bangkok
country: Thailand
city: Khon Kaen
country: Thailand
city: Istanbul
country: Turkey
city: Izmir
country: Turkey
city: Aberdeen
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city: Birmingham
country: United Kingdom
city: Cardiff
country: United Kingdom
city: Derby
country: United Kingdom
city: Glasgow
country: United Kingdom
city: Guildford
country: United Kingdom
city: Hull
country: United Kingdom
city: London
country: United Kingdom
city: Maidstone
country: United Kingdom
city: Newcastle Upon Tyne
country: United Kingdom
city: Northwood
country: United Kingdom
city: Nottingham
country: United Kingdom
city: Plymouth
country: United Kingdom
city: Salisbury
country: United Kingdom
city: Southampton
country: United Kingdom
city: Sutton
country: United Kingdom
city: Taunton
country: United Kingdom
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: