Combination Chemotherapy and Bevacizumab as First-Line Therapy in Treating Patients With Metastatic Colorectal Cancer

NCT ID: NCT00719797

Last Updated: 2015-03-11

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 509 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-07-31

Brief Summary

RATIONALE: Drugs used in chemotherapy, such as irinotecan, oxaliplatin, leucovorin, and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Giving combination chemotherapy together with bevacizumab may kill more tumor cells.

PURPOSE: This randomized phase III trial is comparing two combination chemotherapy regimens given together with bevacizumab to see how well they work as first-line therapy in treating patients with metastatic colorectal cancer that cannot be removed by surgery.

Detailed Description

OBJECTIVES:

Primary

• To compare the progression-free survival of bevacizumab in combination with oxaliplatin, irinotecan hydrochloride, fluorouracil, and leucovorin calcium (FOLFOXIRI) versus bevacizumab in combination with irinotecan hydrochloride, fluorouracil, and leucovorin calcium (FOLFIRI) in patients with unresectable, metastatic colorectal cancer.

Secondary

• To evaluate the safety profile, including long-term adverse events of these regimens in these patients.
• To compare the overall response rate, duration of response, and secondary R0 surgery rates of metastases and overall survival between treatment arms.
• To evaluate potential surrogate markers predictive of bevacizumab activity.

OUTLINE: This is a multicenter study. Patients are stratified according to ECOG performance status (0 vs 1-2), prior adjuvant chemotherapy (yes vs no), and participating center. Patients are randomized to 1 of 2 treatment arms.

• Arm I (FOLFOXIRI): Patients receive irinotecan hydrochloride IV over 1 hour, oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and bevacizumab IV on day 1. Patients also receive fluorouracil IV continuously over 48 hours beginning on day 1.
• Arm II (FOLFIRI): Patients receive irinotecan hydrochloride IV over 1 hour, leucovorin calcium IV over 2 hours, and bevacizumab IV on day 1. Patients also receive fluorouracil IV continuously over 48 hours beginning on day 1.

In both arms, treatment repeats every 2 weeks for up to 12 courses. Treatment with bevacizumab, fluorouracil, and leucovorin calcium continues in the absence of disease progression or unacceptable toxicity.

Patients undergo serum extraction and blood sample collection periodically for genotyping studies. Patients also undergo collection of tumoral sections from paraffin embedded primary and/or metastatic lesions periodically for immunohistochemical analyses.

After completion of study treatment, patients are followed every 8 weeks.

Conditions

Colorectal Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Arm I (FOLFOXIRI)

Patients receive irinotecan hydrochloride IV over 1 hour, oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and bevacizumab IV on day 1. Patients also receive fluorouracil IV continuously over 48 hours beginning on day 1.

Group Type: EXPERIMENTAL

bevacizumab

Intervention Type: BIOLOGICAL

Given IV

fluorouracil

Intervention Type: DRUG

Given IV

irinotecan hydrochloride

Intervention Type: DRUG

Given IV

leucovorin calcium

Intervention Type: DRUG

Given IV

oxaliplatin

Intervention Type: DRUG

Given IV

Arm II (FOLFIRI)

Patients receive irinotecan hydrochloride IV over 1 hour, leucovorin calcium IV over 2 hours, and bevacizumab IV on day 1. Patients also receive fluorouracil IV continuously over 48 hours beginning on day 1.

Group Type: EXPERIMENTAL

bevacizumab

Intervention Type: BIOLOGICAL

Given IV

fluorouracil

Intervention Type: DRUG

Given IV

irinotecan hydrochloride

Intervention Type: DRUG

Given IV

leucovorin calcium

Intervention Type: DRUG

Given IV

Interventions

bevacizumab

Given IV

Intervention Type: BIOLOGICAL

fluorouracil

Given IV

Intervention Type: DRUG

irinotecan hydrochloride

Given IV

Intervention Type: DRUG

leucovorin calcium

Given IV

Intervention Type: DRUG

oxaliplatin

Given IV

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• ECOG performance status (PS) 0-2 (≤ 70 years of age) OR ECOG PS 0 (71-75 years of age)
• Life expectancy ≥ 12 weeks
• Neutrophils ≥ 1.5 x 10^9/L
• Platelet count ≥ 100 x 10^9/L
• Hemoglobin > 9 g/dL
• Total bilirubin ≤ 1.5 times upper limit of normal (ULN)
• AST and ALT ≤ 2.5 times ULN (≤ 5 times ULN if f liver metastases present)
• Alkaline phosphatase ≤ 2.5 times ULN (≤ 5 times ULN if liver metastases present)
• Creatinine clearance > 50 mL/min OR serum creatinine ≤ 1.5 times ULN
• Proteinuria < 2+ by dipstick OR urine protein ≤ 1 g by 24-hr urine collection
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception

Exclusion Criteria

• Serious, nonhealing wound, ulcer, or bone fracture
• Evidence of bleeding diathesis or coagulopathy
• Uncontrolled hypertension
• Clinically significant (i.e., active) cardiovascular disease, including any of the following:

• Cerebrovascular accidents within the past 6 months
• Myocardial infarction within the past 6 months
• Unstable angina
• New York Heart Association class II-IV congestive heart failure
• Serious cardiac arrhythmia requiring medication
• Known allergy to Chinese hamster ovary cell proteins or any of the components of the study medications
• Other co-existing malignancy or malignancy diagnosed within the past 5 years, except for basal cell or squamous cell carcinoma, or carcinoma in situ of the cervix
• Symptomatic peripheral neuropathy ≥ grade 1 according to the NCI Common Toxicity Criteria
• Lack of physical integrity of the upper gastrointestinal tract
• Malabsorption syndrome
• Inability to take oral medication
• Significant traumatic injury within the past 28 days

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• More than 4 weeks since prior radiotherapy
• More than 10 days since prior and no concurrent ongoing treatment with anticoagulants for therapeutic purposes
• More than 28 days since prior and no concurrent major surgical procedure
• More than 28 days since prior open biopsy
• More than 30 days since prior investigational agents
• No concurrent chronic daily high-dose acetylsalicylic acid (> 325 mg/day)

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Gruppo Oncologico del Nord-Ovest

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Alfredo Falcone, MD

Role: PRINCIPAL_INVESTIGATOR

Presidio Ospedaliero di Livorno

Locations

Ospedale Civile Ss. Antonio E Biagio Di Alessandria - Alessandria (Al) Oncologia Medica

Alessandria, , Italy

A.O. Universitaria Ospedali Riuniti - Ospedale Umberto I Di Ancona - Ancona (An) Oncologia Medica

Ancona, , Italy

P.O. Zona Aretina - Ospedale S. Donato Di Arezzo - Arezzo (Ar) Oncologia Medica

Arezzo, , Italy

Irccs Centro Di Riferimento Oncologico (Cro) - Aviano (Pn) Oncologia Medica

Aviano, , Italy

Ospedale S. Orsola F.B.F. - Brescia - Brescia (Bs) Oncologia Medica

Brescia, , Italy

Istituto Ospedaliero Fondazione Poliambulanza Di Brescia - Brescia (Bs) Oncologia Medica

Brescia, , Italy

Stabilimento "Perrino" - Brindisi - Brindisi (Br) Oncologia Medica

Brindisi, , Italy

Azienda Ospedaliera S. Elia - Caltanissetta (Cl) Oncologia Medica

Caltanissetta, , Italy

Ausl 1 Di Massa E Carrara - Carrara (Ms) Oncologia Medica

Carrara, , Italy

Ospedale Cecina - Cecina (Li) Oncologia Medica

Cecina, , Italy

Istituti Ospitalieri - Cremona - Cremona (Cr) Oncologia Medica

Cremona, , Italy

Azienda Ospedaliera S. Croce E Carle Di Cuneo - Cuneo (Cn) Oncoematologia

Cuneo, , Italy

Ausl 11 Di Empoli (Fi) - Empoli (Fi) Oncologia Medica

Empoli, , Italy

U.S.L.N.6 -Ospedale Civile 'E.Profili'-F - Fabriano (An) Oncologia Medica

Fabriano, , Italy

Ausl 10 Di Firenze - Firenze (Fi) Oncologia Medica

Florence, , Italy

Irccs Istituto Nazionale Per La Ricerca Sul Cancro (Ist) - Genova (Ge) Oncologia Medica

Genova, , Italy

Ausl Le Di Lecce - Lecce (Le) Oncologia Medica

Lecce, , Italy

Aulss 21 Di Legnago (Vr) - Legnago (Vr) Oncologia Medica

Legnano, , Italy

Ausl 12 Di Viareggio (Lu) - Lido Di Camaiore (Lu) Oncologia Medica

Lido di Camaiore, , Italy

Ospedale Livorno - Livorno (Li), Oncologia Medica

Livorno, , Italy

Presidio Ospedaliero Piana Di Lucca - Lucca (Lu) Oncologia Medica

Lucca, , Italy

Irccs Fondazione Centro S. Raffaele Del Monte Tabor - Milano (Mi) Oncologia Medica

Milan, , Italy

Ospedale Ca' Granda-Niguarda - Milano - Milano (Mi) Oncologia Medica

Milan, , Italy

S.Gerardo - Monza - Monza (Mi) Oncologia Medica

Monza, , Italy

A.O. Universitaria Federico Ii Di Napoli Oncologia Medica

Napoli, , Italy

A.O. Universitaria Maggiore Della Carita' Di Novara Oncologia Medica

Novara, , Italy

A.O. Universitaria Di Parma Oncologia Medica

Parma, , Italy

Asl 1 Di Citta' Di Castello (Pg) - Citta' Di Castello (Pg) Oncologia Medica

Perugia, , Italy

A.O. Di Perugia - Ospedale S. Maria Della Misericordia (Ex Silvestrini) - Perugia (Pg) Oncologia Medica

Perugia, , Italy

Azienda Ospedaliera San Salvatore - Pesaro (Pu) Oncologia Medica

Pesaro, , Italy

Ospedale Della Valdinievole - Pescia (Pt) Oncologia Medica

Pescia, , Italy

Ospedale Piombino - Piombino (Li) Oncologia Medica

Piombino, , Italy

A.O. Universitaria Pisana Oncologia Medica

Pisa, , Italy

Ausl 5 Di Pisa - Pisa (Pi) Oncologia Medica

Pisa, , Italy

Alfredo Falcone A.O. Universitaria Pisana - Pisa (Pi) Oncologia Medica

Pisa, , Italy

Ausl 3 Di Pistoia - Pistoia (Pt) Oncologia Medica

Pistoia, , Italy

Ausl 4 Di Prato - Prato (Po) Oncologia Medica

Prato, , Italy

Ospedale Di S. Maria Nuova - Reggio Nell'Emilia (Re) Oncologia Medica

Reggio Emilia, , Italy

Policlinico Universitario Campus Bio-Medico Di Roma Oncologia Medica

Rome, , Italy

Policlinico Umberto I Di Roma Oncologia Medica

Rome, , Italy

Policlinico Universitario Gemelli Di Roma Oncologia Medica

Rome, , Italy

A.O. Universitaria Senese Oncologia Medica

Siena, , Italy

Ospedale Civile - Sondrio - Sondrio (So) Oncologia Medica

Sondrio, , Italy

A.O. Universitaria S. Giovanni Battista-Molinette Di Torino Oncologia Medica

Torino, , Italy

Countries

Italy

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Other Identifiers

GONO-TRIBE

Identifier Type: -

Identifier Source: secondary_id

ASL608LIOM04

Identifier Type: -

Identifier Source: secondary_id

EUDRACT:2008-001537-10

Identifier Type: -

Identifier Source: secondary_id

CDR0000598582

Identifier Type: -

Identifier Source: org_study_id