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Colorectal CancerPhase 3TRIBENCT00719797

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

A Phase 3 study testing bevacizumab, fluorouracil and irinotecan hydrochloride in people with Colorectal Cancer, run by Gruppo Oncologico del Nord-Ovest at 44 sites in Italy.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

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. Read more about this study

Who is it for?
Ages 18 to 75 years
Conditions the study is for
Colorectal Cancer
What is being tested?
bevacizumab, fluorouracil and irinotecan hydrochloride
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
509 participants
Where
44 sitesItaly
Study dates
Jul 2008to May 2011
Phase
Phase 3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 75 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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)
Show all 13Show fewer
  • 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

Who cannot join

  • 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
Show all 24Show fewer
  • 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)

Trial locations and contacts

44 sites in 1 country.

44 sites in 1 country

Italy44 sites

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

    Alessandria, 15100

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

    Ancona, 60100

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

    Arezzo, 52100

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

    Aviano, 33081

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

    Brescia, 25122

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

    Brescia, 25124

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

    Brindisi, 72100

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

    Caltanissetta, 93100

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

    Carrara, 54033

  • Ospedale Cecina - Cecina (Li) Oncologia Medica

    Cecina, 57023

  • Istituti Ospitalieri - Cremona - Cremona (Cr) Oncologia Medica

    Cremona, 26100

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

    Cuneo, 12100

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

    Empoli, 50053

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

    Fabriano, 60044

  • Ausl 10 Di Firenze - Firenze (Fi) Oncologia Medica

    Florence, 50122

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

    Genova, 16132

  • Ausl Le Di Lecce - Lecce (Le) Oncologia Medica

    Lecce, 73100

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

    Legnano, 37045

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

    Lido di Camaiore, 55053

  • Ospedale Livorno - Livorno (Li), Oncologia Medica

    Livorno, 57100

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

    Lucca, 25124

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

    Milan, 20132

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

    Milan, 20162

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

    Monza, 20052

  • A.O. Universitaria Federico Ii Di Napoli Oncologia Medica

    Naples, 80131

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

    Novara, 28100

  • A.O. Universitaria Di Parma Oncologia Medica

    Parma, 43100

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

    Perugia, 06012

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

    Perugia, 06156

  • Azienda Ospedaliera San Salvatore - Pesaro (Pu) Oncologia Medica

    Pesaro, 61100

  • Ospedale Della Valdinievole - Pescia (Pt) Oncologia Medica

    Pescia, 51017

  • Ospedale Piombino - Piombino (Li) Oncologia Medica

    Piombino, 57100

  • A.O. Universitaria Pisana Oncologia Medica

    Pisa, 56100

  • Ausl 5 Di Pisa - Pisa (Pi) Oncologia Medica

    Pisa, 56100

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

    Pisa, 56126

  • Ausl 3 Di Pistoia - Pistoia (Pt) Oncologia Medica

    Pistoia, 51100

  • Ausl 4 Di Prato - Prato (Po) Oncologia Medica

    Prato, 59100

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

    Reggio Emilia, 42100

  • Policlinico Universitario Campus Bio-Medico Di Roma Oncologia Medica

    Rome, 00155

  • Policlinico Umberto I Di Roma Oncologia Medica

    Rome, 00161

  • Policlinico Universitario Gemelli Di Roma Oncologia Medica

    Rome, 00168

  • A.O. Universitaria Senese Oncologia Medica

    Siena, 53100

  • Ospedale Civile - Sondrio - Sondrio (So) Oncologia Medica

    Sondrio, 23100

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

    Torino, 10134

Other trials in Italy

About this study

Official title: 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.

Read the 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.

Keywords
stage IV rectal cancer, stage IV colon cancer, stage III rectal cancer, stage III colon cancer
Medical subject headings
Colorectal Neoplasms, Rectal Neoplasms, Colonic Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Study groups in NCT00719797
Study groupRoleWhat they receive
Arm I (FOLFOXIRI)ExperimentalPatients 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.
Receives: Biological: bevacizumab; Drug: fluorouracil; Drug: irinotecan hydrochloride; Drug: leucovorin calcium; Drug: oxaliplatin
Arm II (FOLFIRI)ExperimentalPatients 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.
Receives: Biological: bevacizumab; Drug: fluorouracil; Drug: irinotecan hydrochloride; Drug: leucovorin calcium

What is being measured

The primary outcome is the main question the study is designed to answer.

  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)

    Measured: up to 54 months

Secondary outcomes (5)

  1. Overall response rate

    Measured: up to 54 months

  2. Duration of response

    Measured: up to 54 months

  3. Secondary R0 surgery rates of metastases

    Measured: up to 54 months

  4. Overall survival

    Measured: up to 54 months

  5. Surrogate markers predictive of bevacizumab activity

    Measured: up to 54 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted22 Jul 2008 (estimated)
  2. Study startJul 2008
  3. Primary completionMay 2011

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
509 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00719797
Sponsor's protocol ID
CDR0000598582
Other IDs
GONO-TRIBE, ASL608LIOM04, EUDRACT:2008-001537-10
Acronym
TRIBE
Status last verified
Mar 2015
First submitted
19 Jul 2008
Last updated
11 Mar 2015
Results posted
No
Data monitoring committee
Yes

Publications

  • 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.

    PubMed 35594613

  • 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.

    PubMed 35366570

  • 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.

    PubMed 32816630

  • 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.

    PubMed 30293873

  • 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.

    PubMed 29873679

  • 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.

    PubMed 29487697

  • 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.

    PubMed 27986363

  • 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.

    PubMed 26861604

  • 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.

    PubMed 26338525

  • 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.

    PubMed 25712456

  • 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.

    PubMed 25337750

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing bevacizumab, fluorouracil and irinotecan hydrochloride in people with Colorectal Cancer, run by Gruppo Oncologico del Nord-Ovest at 44 sites in Italy.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 13 inclusion and 24 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 11 Mar 2015. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 44 sites in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Progression free survival (time frame: up to 54 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00719797, which also lists 11 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Mar 2015.

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