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

Colorectal Cancer Clinical Trial

— TRIBE  

Official title:

A PHASE III RANDOMIZED TRIAL OF FOLFOXIRI + BEVACIZUMAB VERSUS FOLFIRI + BEVACIZUMAB AS FIRST- LINE TREATMENT FOR METASTATIC COLORECTAL CANCER

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00719797
• Other study ID #: CDR0000598582
• Secondary ID: GONO-TRIBEASL608
• Status: Completed
• Phase: Phase 3
• First received: July 19, 2008
• Last updated: March 10, 2015
• Start date: July 2008

Study information

• Verified date: March 2015
• Source: Gruppo Oncologico del Nord-Ovest
• Contact: n/a
• Is FDA regulated: No
• Health authority: Italy: Ethics Committee
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 509
• Est. primary completion date: May 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 75 Years

Eligibility

DISEASE CHARACTERISTICS:

• Histologically confirmed colorectal cancer

• Unresectable metastatic disease

• Measurable disease, defined as = 1 measurable lesion according to RECIST criteria

• No prior chemotherapy for metastatic disease

• No untreated brain metastases, spinal cord compression, or primary brain tumors

• No history or evidence of CNS disease by physical examination unless adequately treated (e.g., uncontrolled seizure despite standard medical therapy or history of stroke)

PATIENT CHARACTERISTICS:

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)

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Colorectal Cancer
• Colorectal Neoplasms

Intervention

Biological:
• bevacizumab
Given IV

Drug:
• fluorouracil
Given IV
• irinotecan hydrochloride
Given IV
• leucovorin calcium
Given IV
• oxaliplatin
Given IV

Locations

Country	Name	City	State
Italy	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	Istituto Ospedaliero Fondazione Poliambulanza Di Brescia - Brescia (Bs) Oncologia Medica	Brescia
Italy	Ospedale S. Orsola F.B.F. - 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	Firenze
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	Milano
Italy	Ospedale Ca` Granda-Niguarda - Milano - Milano (Mi) Oncologia Medica	Milano
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	A.O. Di Perugia - Ospedale S. Maria Della Misericordia (Ex Silvestrini) - Perugia (Pg) Oncologia Medica	Perugia
Italy	Asl 1 Di Citta' Di Castello (Pg) - Citta' Di Castello (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	Alfredo Falcone A.O. Universitaria Pisana - Pisa (Pi) Oncologia Medica	Pisa
Italy	Ausl 5 Di Pisa - 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 Umberto I Di Roma Oncologia Medica	Rome
Italy	Policlinico Universitario Campus Bio-Medico 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

Sponsors (1)

Lead Sponsor	Collaborator
Gruppo Oncologico del Nord-Ovest

Country where clinical trial is conducted

Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression free survival	To compare the progression free survival of bevacizumab in combination with oxaliplatin, irinotecan and infusional 5FU/LV ("GONO" FOLFOXIRI regimen) to bevacizumab in combination with irinotecan and infusional 5FU/LV (FOLFIRI regimen)	up to 54 months	No
Secondary	Overall response rate		up to 54 months	No
Secondary	Duration of response		up to 54 months	No
Secondary	Secondary R0 surgery rates of metastases		up to 54 months	No
Secondary	Overall survival		up to 54 months	No
Secondary	Surrogate markers predictive of bevacizumab activity		up to 54 months	No