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

NCT00719797 | Completed Phase 3 DMC

• 4 other identifiers: CDR0000598582GONO-TRIBEASL608LIOM04EUDRACT:2008-001537-10
• Study Type: interventional
• Target: 509
• Locations: 1 country
• Sites: 44

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.

Conditions

Colorectal Cancer

Keywords

stage IV rectal cancer; stage IV colon cancer; stage III rectal cancer; stage III colon cancer

Outcome Measures

Primary Outcomes (1)

• 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

Secondary Outcomes (5)

• Overall response rate

  up to 54 months

• Duration of response

  up to 54 months

• Secondary R0 surgery rates of metastases

  up to 54 months

• Overall survival

  up to 54 months

• Surrogate markers predictive of bevacizumab activity

  up to 54 months

Study Arms (2)

Arm I (FOLFOXIRI)

EXPERIMENTAL

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.

Biological: bevacizumab; Drug: fluorouracil; Drug: irinotecan hydrochloride; Drug: leucovorin calcium; Drug: oxaliplatin

Arm II (FOLFIRI)

EXPERIMENTAL

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.

Biological: bevacizumab; Drug: fluorouracil; Drug: irinotecan hydrochloride; Drug: leucovorin calcium

Interventions

bevacizumab BIOLOGICAL

Given IV

Arm I (FOLFOXIRI); Arm II (FOLFIRI)

fluorouracil DRUG

Given IV

Arm I (FOLFOXIRI); Arm II (FOLFIRI)

irinotecan hydrochloride DRUG

Given IV

Arm I (FOLFOXIRI); Arm II (FOLFIRI)

leucovorin calcium DRUG

Given IV

Arm I (FOLFOXIRI); Arm II (FOLFIRI)

oxaliplatin DRUG

Given IV

Arm I (FOLFOXIRI)

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Gruppo Oncologico del Nord-Ovest: lead

Study Sites (44)

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

Alessandria, 15100, Italy

Location

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

Ancona, 60100, Italy

Location

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

Arezzo, 52100, Italy

Location

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

Aviano, 33081, Italy

Location

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

Brescia, 25122, Italy

Location

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

Brescia, 25124, Italy

Location

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

Brindisi, 72100, Italy

Location

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

Caltanissetta, 93100, Italy

Location

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

Carrara, 54033, Italy

Location

Ospedale Cecina - Cecina (Li) Oncologia Medica

Cecina, 57023, Italy

Location

Istituti Ospitalieri - Cremona - Cremona (Cr) Oncologia Medica

Cremona, 26100, Italy

Location

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

Cuneo, 12100, Italy

Location

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

Empoli, 50053, Italy

Location

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

Fabriano, 60044, Italy

Location

Ausl 10 Di Firenze - Firenze (Fi) Oncologia Medica

Florence, 50122, Italy

Location

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

Genova, 16132, Italy

Location

Ausl Le Di Lecce - Lecce (Le) Oncologia Medica

Lecce, 73100, Italy

Location

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

Legnano, 37045, Italy

Location

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

Lido di Camaiore, 55053, Italy

Location

Ospedale Livorno - Livorno (Li), Oncologia Medica

Livorno, 57100, Italy

Location

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

Lucca, 25124, Italy

Location

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

Milan, 20132, Italy

Location

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

Milan, 20162, Italy

Location

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

Monza, 20052, Italy

Location

A.O. Universitaria Federico Ii Di Napoli Oncologia Medica

Napoli, 80131, Italy

Location

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

Novara, 28100, Italy

Location

A.O. Universitaria Di Parma Oncologia Medica

Parma, 43100, Italy

Location

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

Perugia, 06012, Italy

Location

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

Perugia, 06156, Italy

Location

Azienda Ospedaliera San Salvatore - Pesaro (Pu) Oncologia Medica

Pesaro, 61100, Italy

Location

Ospedale Della Valdinievole - Pescia (Pt) Oncologia Medica

Pescia, 51017, Italy

Location

Ospedale Piombino - Piombino (Li) Oncologia Medica

Piombino, 57100, Italy

Location

A.O. Universitaria Pisana Oncologia Medica

Pisa, 56100, Italy

Location

Ausl 5 Di Pisa - Pisa (Pi) Oncologia Medica

Pisa, 56100, Italy

Location

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

Pisa, 56126, Italy

Location

Ausl 3 Di Pistoia - Pistoia (Pt) Oncologia Medica

Pistoia, 51100, Italy

Location

Ausl 4 Di Prato - Prato (Po) Oncologia Medica

Prato, 59100, Italy

Location

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

Reggio Emilia, 42100, Italy

Location

Policlinico Universitario Campus Bio-Medico Di Roma Oncologia Medica

Rome, 00155, Italy

Location

Policlinico Umberto I Di Roma Oncologia Medica

Rome, 00161, Italy

Location

Policlinico Universitario Gemelli Di Roma Oncologia Medica

Rome, 00168, Italy

Location

A.O. Universitaria Senese Oncologia Medica

Siena, 53100, Italy

Location

Ospedale Civile - Sondrio - Sondrio (So) Oncologia Medica

Sondrio, 23100, Italy

Location

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

Torino, 10134, Italy

Location

Related Publications (11)

• Rossini D, Germani MM, Lonardi S, Pietrantonio F, Dell'Aquila E, Borelli B, Allegrini G, Maddalena G, Randon G, Marmorino F, Zaniboni A, Buonadonna A, Boccaccino A, Conca V, Antoniotti C, Passardi A, Masi G, Cremolini C. Treatments after second progression in metastatic colorectal cancer: A pooled analysis of the TRIBE and TRIBE2 studies. Eur J Cancer. 2022 Jul;170:64-72. doi: 10.1016/j.ejca.2022.04.019. Epub 2022 May 17.

  PMID: 35594613 DERIVED

• Antoniotti C, Germani MM, Rossini D, Lonardi S, Pietrantonio F, Santini D, Marmorino F, Allegrini G, Daniel F, Raimondi A, Borelli B, Zaniboni A, Conca V, Abraham J, Spetzler D, Maiello E, Boccaccino A, Passardi A, Giordano M, Tamburini E, Korn MW, Masi G, Cremolini C. FOLFOXIRI and bevacizumab in patients with early-onset metastatic colorectal cancer. A pooled analysis of TRIBE and TRIBE2 studies. Eur J Cancer. 2022 May;167:23-31. doi: 10.1016/j.ejca.2022.02.031. Epub 2022 Mar 30.

  PMID: 35366570 DERIVED

• Cremolini C, Antoniotti C, Stein A, Bendell J, Gruenberger T, Rossini D, Masi G, Ongaro E, Hurwitz H, Falcone A, Schmoll HJ, Di Maio M. Individual Patient Data Meta-Analysis of FOLFOXIRI Plus Bevacizumab Versus Doublets Plus Bevacizumab as Initial Therapy of Unresectable Metastatic Colorectal Cancer. J Clin Oncol. 2020 Aug 20:JCO2001225. doi: 10.1200/JCO.20.01225. Online ahead of print.

  PMID: 32816630 DERIVED

• Tokunaga R, Cao S, Naseem M, Lo JH, Battaglin F, Puccini A, Berger MD, Soni S, Millstein J, Zhang W, Stintzing S, Loupakis F, Cremolini C, Heinemann V, Falcone A, Lenz HJ. Prognostic Effect of Adenosine-related Genetic Variants in Metastatic Colorectal Cancer Treated With Bevacizumab-based Chemotherapy. Clin Colorectal Cancer. 2019 Mar;18(1):e8-e19. doi: 10.1016/j.clcc.2018.09.003. Epub 2018 Sep 13.

  PMID: 30293873 DERIVED

• Cremolini C, Antoniotti C, Lonardi S, Bergamo F, Cortesi E, Tomasello G, Moretto R, Ronzoni M, Racca P, Loupakis F, Zaniboni A, Tonini G, Buonadonna A, Marmorino F, Allegrini G, Granetto C, Masi G, Zagonel V, Sensi E, Fontanini G, Boni L, Falcone A. Primary tumor sidedness and benefit from FOLFOXIRI plus bevacizumab as initial therapy for metastatic colorectal cancer. Retrospective analysis of the TRIBE trial by GONO. Ann Oncol. 2018 Jul;29(7):1528-1534. doi: 10.1093/annonc/mdy140. Epub 2018 Apr 20.

  PMID: 29873679 DERIVED

• Cremolini C, Del Re M, Antoniotti C, Lonardi S, Bergamo F, Loupakis F, Borelli B, Marmorino F, Citi V, Cortesi E, Moretto R, Ronzoni M, Tomasello G, Zaniboni A, Racca P, Buonadonna A, Allegrini G, Ricci V, Di Donato S, Zagonel V, Boni L, Falcone A, Danesi R. DPYD and UGT1A1 genotyping to predict adverse events during first-line FOLFIRI or FOLFOXIRI plus bevacizumab in metastatic colorectal cancer. Oncotarget. 2017 Dec 21;9(8):7859-7866. doi: 10.18632/oncotarget.23559. eCollection 2018 Jan 30.

  PMID: 29487697 DERIVED

• Cremolini C, Casagrande M, Loupakis F, Aprile G, Bergamo F, Masi G, Moretto R R, Pietrantonio F, Marmorino F, Zucchelli G, Tomasello G, Tonini G, Allegrini G, Granetto C, Ferrari L, Urbani L, Cillo U, Pilati P, Sensi E, Pellegrinelli A, Milione M, Fontanini G, Falcone A. Efficacy of FOLFOXIRI plus bevacizumab in liver-limited metastatic colorectal cancer: A pooled analysis of clinical studies by Gruppo Oncologico del Nord Ovest. Eur J Cancer. 2017 Mar;73:74-84. doi: 10.1016/j.ejca.2016.10.028. Epub 2016 Dec 13.

  PMID: 27986363 DERIVED

• Cremolini C, Loupakis F, Masi G, Lonardi S, Granetto C, Mancini ML, Chiara S, Moretto R, Rossini D, Vitello S, Allegrini G, Tonini G, Bergamo F, Tomasello G, Ronzoni M, Buonadonna A, Bustreo S, Barbara C, Boni L, Falcone A. FOLFOXIRI or FOLFOXIRI plus bevacizumab as first-line treatment of metastatic colorectal cancer: a propensity score-adjusted analysis from two randomized clinical trials. Ann Oncol. 2016 May;27(5):843-9. doi: 10.1093/annonc/mdw052. Epub 2016 Feb 9.

  PMID: 26861604 DERIVED

• Cremolini C, Loupakis F, Antoniotti C, Lupi C, Sensi E, Lonardi S, Mezi S, Tomasello G, Ronzoni M, Zaniboni A, Tonini G, Carlomagno C, Allegrini G, Chiara S, D'Amico M, Granetto C, Cazzaniga M, Boni L, Fontanini G, Falcone A. FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study. Lancet Oncol. 2015 Oct;16(13):1306-15. doi: 10.1016/S1470-2045(15)00122-9. Epub 2015 Aug 31.

  PMID: 26338525 DERIVED

• Cremolini C, Loupakis F, Antoniotti C, Lonardi S, Masi G, Salvatore L, Cortesi E, Tomasello G, Spadi R, Zaniboni A, Tonini G, Barone C, Vitello S, Longarini R, Bonetti A, D'Amico M, Di Donato S, Granetto C, Boni L, Falcone A. Early tumor shrinkage and depth of response predict long-term outcome in metastatic colorectal cancer patients treated with first-line chemotherapy plus bevacizumab: results from phase III TRIBE trial by the Gruppo Oncologico del Nord Ovest. Ann Oncol. 2015 Jun;26(6):1188-1194. doi: 10.1093/annonc/mdv112. Epub 2015 Feb 23.

  PMID: 25712456 DERIVED

• Loupakis F, Cremolini C, Masi G, Lonardi S, Zagonel V, Salvatore L, Cortesi E, Tomasello G, Ronzoni M, Spadi R, Zaniboni A, Tonini G, Buonadonna A, Amoroso D, Chiara S, Carlomagno C, Boni C, Allegrini G, Boni L, Falcone A. Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. N Engl J Med. 2014 Oct 23;371(17):1609-18. doi: 10.1056/NEJMoa1403108.

  PMID: 25337750 DERIVED

MeSH Terms

Conditions

Colorectal Neoplasms; Rectal Neoplasms; Colonic Neoplasms

Interventions

Bevacizumab; Fluorouracil; Irinotecan; Leucovorin; Oxaliplatin

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Uracil; Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Camptothecin; Alkaloids; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Coenzymes; Enzymes and Coenzymes; Coordination Complexes; Organic Chemicals

Study Officials

• Alfredo Falcone, MD

  Presidio Ospedaliero di Livorno

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 19, 2008
• First Posted: July 22, 2008
• Study Start: July 1, 2008
• Primary Completion: May 1, 2011
• Last Updated: March 11, 2015

Record last verified: 2015-03

Locations

IT (44)