Combination Chemotherapy and Bevacizumab as First-Line Therapy in Treating Patients With Metastatic Colorectal Cancer (TRIBE)
10 maart 2015 bijgewerkt door: Gruppo Oncologico del Nord-Ovest
A PHASE III RANDOMIZED TRIAL OF FOLFOXIRI + BEVACIZUMAB VERSUS FOLFIRI + BEVACIZUMAB AS FIRST- LINE TREATMENT FOR METASTATIC COLORECTAL CANCER
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.
Studie Overzicht
Toestand
Voltooid
Conditie
Gedetailleerde beschrijving
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.
Studietype
Ingrijpend
Inschrijving (Werkelijk)
509
Fase
- Fase 3
Contacten en locaties
In dit gedeelte vindt u de contactgegevens van degenen die het onderzoek uitvoeren en informatie over waar dit onderzoek wordt uitgevoerd.
Studie Locaties
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Alessandria, Italië, 15100
- Ospedale Civile Ss. Antonio E Biagio Di Alessandria - Alessandria (Al) Oncologia Medica
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Ancona, Italië, 60100
- A.O. Universitaria Ospedali Riuniti - Ospedale Umberto I Di Ancona - Ancona (An) Oncologia Medica
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Arezzo, Italië, 52100
- P.O. Zona Aretina - Ospedale S. Donato Di Arezzo - Arezzo (Ar) Oncologia Medica
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Aviano, Italië, 33081
- Irccs Centro Di Riferimento Oncologico (Cro) - Aviano (Pn) Oncologia Medica
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Brescia, Italië, 25122
- Ospedale S. Orsola F.B.F. - Brescia - Brescia (Bs) Oncologia Medica
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Brescia, Italië, 25124
- Istituto Ospedaliero Fondazione Poliambulanza Di Brescia - Brescia (Bs) Oncologia Medica
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Brindisi, Italië, 72100
- Stabilimento "Perrino" - Brindisi - Brindisi (Br) Oncologia Medica
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Caltanissetta, Italië, 93100
- Azienda Ospedaliera S. Elia - Caltanissetta (Cl) Oncologia Medica
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Carrara, Italië, 54033
- Ausl 1 Di Massa E Carrara - Carrara (Ms) Oncologia Medica
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Cecina, Italië, 57023
- Ospedale Cecina - Cecina (Li) Oncologia Medica
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Cremona, Italië, 26100
- Istituti Ospitalieri - Cremona - Cremona (Cr) Oncologia Medica
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Cuneo, Italië, 12100
- Azienda Ospedaliera S. Croce E Carle Di Cuneo - Cuneo (Cn) Oncoematologia
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Empoli, Italië, 50053
- Ausl 11 Di Empoli (Fi) - Empoli (Fi) Oncologia Medica
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Fabriano, Italië, 60044
- U.S.L.N.6 -Ospedale Civile 'E.Profili'-F - Fabriano (An) Oncologia Medica
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Firenze, Italië, 50122
- Ausl 10 Di Firenze - Firenze (Fi) Oncologia Medica
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Genova, Italië, 16132
- Irccs Istituto Nazionale Per La Ricerca Sul Cancro (Ist) - Genova (Ge) Oncologia Medica
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Lecce, Italië, 73100
- Ausl Le Di Lecce - Lecce (Le) Oncologia Medica
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Legnano, Italië, 37045
- Aulss 21 Di Legnago (Vr) - Legnago (Vr) Oncologia Medica
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Lido di Camaiore, Italië, 55053
- Ausl 12 Di Viareggio (Lu) - Lido Di Camaiore (Lu) Oncologia Medica
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Livorno, Italië, 57100
- Ospedale Livorno - Livorno (Li), Oncologia Medica
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Lucca, Italië, 25124
- Presidio Ospedaliero Piana Di Lucca - Lucca (Lu) Oncologia Medica
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Milano, Italië, 20132
- Irccs Fondazione Centro S. Raffaele Del Monte Tabor - Milano (Mi) Oncologia Medica
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Milano, Italië, 20162
- Ospedale Ca' Granda-Niguarda - Milano - Milano (Mi) Oncologia Medica
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Monza, Italië, 20052
- S.Gerardo - Monza - Monza (Mi) Oncologia Medica
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Napoli, Italië, 80131
- A.O. Universitaria Federico Ii Di Napoli Oncologia Medica
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Novara, Italië, 28100
- A.O. Universitaria Maggiore Della Carita' Di Novara Oncologia Medica
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Parma, Italië, 43100
- A.O. Universitaria Di Parma Oncologia Medica
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Perugia, Italië, 06012
- Asl 1 Di Citta' Di Castello (Pg) - Citta' Di Castello (Pg) Oncologia Medica
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Perugia, Italië, 06156
- A.O. Di Perugia - Ospedale S. Maria Della Misericordia (Ex Silvestrini) - Perugia (Pg) Oncologia Medica
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Pesaro, Italië, 61100
- Azienda Ospedaliera San Salvatore - Pesaro (Pu) Oncologia Medica
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Pescia, Italië, 51017
- Ospedale Della Valdinievole - Pescia (Pt) Oncologia Medica
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Piombino, Italië, 57100
- Ospedale Piombino - Piombino (Li) Oncologia Medica
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Pisa, Italië, 56100
- Ausl 5 Di Pisa - Pisa (Pi) Oncologia Medica
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Pisa, Italië, 56100
- A.O. Universitaria Pisana Oncologia Medica
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Pisa, Italië, 56126
- Alfredo Falcone A.O. Universitaria Pisana - Pisa (Pi) Oncologia Medica
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Pistoia, Italië, 51100
- Ausl 3 Di Pistoia - Pistoia (Pt) Oncologia Medica
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Prato, Italië, 59100
- Ausl 4 Di Prato - Prato (Po) Oncologia Medica
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Reggio Emilia, Italië, 42100
- Ospedale Di S. Maria Nuova - Reggio Nell'Emilia (Re) Oncologia Medica
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Rome, Italië, 00155
- Policlinico Universitario Campus Bio-Medico Di Roma Oncologia Medica
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Rome, Italië, 00161
- Policlinico Umberto I Di Roma Oncologia Medica
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Rome, Italië, 00168
- Policlinico Universitario Gemelli Di Roma Oncologia Medica
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Siena, Italië, 53100
- A.O. Universitaria Senese Oncologia Medica
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Sondrio, Italië, 23100
- Ospedale Civile - Sondrio - Sondrio (So) Oncologia Medica
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Torino, Italië, 10134
- A.O. Universitaria S. Giovanni Battista-Molinette Di Torino Oncologia Medica
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Deelname Criteria
Onderzoekers zoeken naar mensen die aan een bepaalde beschrijving voldoen, de zogenaamde geschiktheidscriteria. Enkele voorbeelden van deze criteria zijn iemands algemene gezondheidstoestand of eerdere behandelingen.
Geschiktheidscriteria
Leeftijden die in aanmerking komen voor studie
18 jaar tot 75 jaar (Volwassen, Oudere volwassene)
Accepteert gezonde vrijwilligers
Nee
Geslachten die in aanmerking komen voor studie
Allemaal
Beschrijving
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)
Studie plan
Dit gedeelte bevat details van het studieplan, inclusief hoe de studie is opgezet en wat de studie meet.
Hoe is de studie opgezet?
Ontwerpdetails
- Primair doel: Behandeling
- Toewijzing: Gerandomiseerd
- Interventioneel model: Parallelle opdracht
- Masker: Geen (open label)
Wapens en interventies
Deelnemersgroep / Arm |
Interventie / Behandeling |
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Experimenteel: 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.
|
IV gegeven
IV gegeven
IV gegeven
IV gegeven
IV gegeven
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|
Experimenteel: 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.
|
IV gegeven
IV gegeven
IV gegeven
IV gegeven
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Wat meet het onderzoek?
Primaire uitkomstmaten
Uitkomstmaat |
Maatregel Beschrijving |
Tijdsspanne |
|---|---|---|
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Progression free survival
Tijdsspanne: up to 54 months
|
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)
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up to 54 months
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Secundaire uitkomstmaten
Uitkomstmaat |
Tijdsspanne |
|---|---|
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Overall response rate
Tijdsspanne: up to 54 months
|
up to 54 months
|
|
Duration of response
Tijdsspanne: up to 54 months
|
up to 54 months
|
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Secondary R0 surgery rates of metastases
Tijdsspanne: up to 54 months
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up to 54 months
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Overall survival
Tijdsspanne: up to 54 months
|
up to 54 months
|
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Surrogate markers predictive of bevacizumab activity
Tijdsspanne: up to 54 months
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up to 54 months
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Medewerkers en onderzoekers
Hier vindt u mensen en organisaties die betrokken zijn bij dit onderzoek.
Sponsor
Onderzoekers
- Hoofdonderzoeker: Alfredo Falcone, MD, Presidio Ospedaliero Di Livorno
Publicaties en nuttige links
De persoon die verantwoordelijk is voor het invoeren van informatie over het onderzoek stelt deze publicaties vrijwillig ter beschikking. Dit kan gaan over alles wat met het onderzoek te maken heeft.
Algemene publicaties
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
Studie record data
Deze datums volgen de voortgang van het onderzoeksdossier en de samenvatting van de ingediende resultaten bij ClinicalTrials.gov. Studieverslagen en gerapporteerde resultaten worden beoordeeld door de National Library of Medicine (NLM) om er zeker van te zijn dat ze voldoen aan specifieke kwaliteitscontrolenormen voordat ze op de openbare website worden geplaatst.
Bestudeer belangrijke data
Studie start
1 juli 2008
Primaire voltooiing (Werkelijk)
1 mei 2011
Studieregistratiedata
Eerst ingediend
19 juli 2008
Eerst ingediend dat voldeed aan de QC-criteria
19 juli 2008
Eerst geplaatst (Schatting)
22 juli 2008
Updates van studierecords
Laatste update geplaatst (Schatting)
11 maart 2015
Laatste update ingediend die voldeed aan QC-criteria
10 maart 2015
Laatst geverifieerd
1 maart 2015
Meer informatie
Termen gerelateerd aan deze studie
Trefwoorden
Aanvullende relevante MeSH-voorwaarden
- Ziekten van het spijsverteringsstelsel
- Neoplasmata
- Neoplasmata per site
- Gastro-intestinale neoplasmata
- Neoplasmata van het spijsverteringsstelsel
- Gastro-intestinale aandoeningen
- Colon Ziekten
- Darmziekten
- Intestinale neoplasmata
- Rectale ziekten
- Colorectale neoplasmata
- Fysiologische effecten van medicijnen
- Moleculaire mechanismen van farmacologische werking
- Enzymremmers
- Antimetabolieten, antineoplastische
- Antimetabolieten
- Antineoplastische middelen
- Immunosuppressieve middelen
- Immunologische factoren
- Beschermende middelen
- Topoisomeraseremmers
- Antineoplastische middelen, immunologisch
- Angiogenese-remmers
- Angiogenese modulerende middelen
- Groei stoffen
- Groeiremmers
- Micronutriënten
- Vitaminen
- Calciumregulerende hormonen en middelen
- Topoisomerase I-remmers
- Tegengif
- Vitamine B-complex
- Fluoruracil
- Oxaliplatine
- Bevacizumab
- Leucovorin
- Irinotecan
- Calcium
- Levoleucovorine
Andere studie-ID-nummers
- CDR0000598582
- GONO-TRIBE
- ASL608LIOM04
- EUDRACT:2008-001537-10
Deze informatie is zonder wijzigingen rechtstreeks van de website clinicaltrials.gov gehaald. Als u verzoeken heeft om uw onderzoeksgegevens te wijzigen, te verwijderen of bij te werken, neem dan contact op met register@clinicaltrials.gov. Zodra er een wijziging wordt doorgevoerd op clinicaltrials.gov, wordt deze ook automatisch bijgewerkt op onze website .