Clinical trial NCT00719797: Combination Chemotherapy and Bevacizumab as First-Line Therapy in Treating Patients With Metastatic Colorectal Cancer
Official title: A PHASE III RANDOMIZED TRIAL OF FOLFOXIRI + BEVACIZUMAB VERSUS FOLFIRI + BEVACIZUMAB AS FIRST- LINE TREATMENT FOR METASTATIC COLORECTAL CANCER
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Colorectal Cancer
Keywords: stage IV rectal cancer
stage IV colon cancer
stage III rectal cancer
stage III colon cancer
Lead sponsor: Gruppo Oncologico del Nord-Ovest
Sponsor class: OTHER
First posted: 2008-07-22
Enrollment: 509
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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)

Primary outcomes:
measure: Progression free survival
timeFrame: up to 54 months
Secondary outcomes:
measure: Overall response rate
timeFrame: up to 54 months
measure: Duration of response
timeFrame: up to 54 months
measure: Secondary R0 surgery rates of metastases
timeFrame: up to 54 months
measure: Overall survival
timeFrame: up to 54 months
measure: Surrogate markers predictive of bevacizumab activity
timeFrame: up to 54 months
Other outcomes:
Locations:
city: Alessandria
country: Italy
facility: Ospedale Civile Ss. Antonio E Biagio Di Alessandria - Alessandria (Al) Oncologia Medica
city: Ancona
country: Italy
facility: A.O. Universitaria Ospedali Riuniti - Ospedale Umberto I Di Ancona - Ancona (An) Oncologia Medica
city: Arezzo
country: Italy
facility: P.O. Zona Aretina - Ospedale S. Donato Di Arezzo - Arezzo (Ar) Oncologia Medica
city: Aviano
country: Italy
facility: Irccs Centro Di Riferimento Oncologico (Cro) - Aviano (Pn) Oncologia Medica
city: Brescia
country: Italy
facility: Ospedale S. Orsola F.B.F. - Brescia - Brescia (Bs) Oncologia Medica
city: Brescia
country: Italy
facility: Istituto Ospedaliero Fondazione Poliambulanza Di Brescia - Brescia (Bs) Oncologia Medica
city: Brindisi
country: Italy
facility: Stabilimento "Perrino" - Brindisi - Brindisi (Br) Oncologia Medica
city: Caltanissetta
country: Italy
facility: Azienda Ospedaliera S. Elia - Caltanissetta (Cl) Oncologia Medica
city: Carrara
country: Italy
facility: Ausl 1 Di Massa E Carrara - Carrara (Ms) Oncologia Medica
city: Cecina
country: Italy
facility: Ospedale Cecina - Cecina (Li) Oncologia Medica
city: Cremona
country: Italy
facility: Istituti Ospitalieri - Cremona - Cremona (Cr) Oncologia Medica
city: Cuneo
country: Italy
facility: Azienda Ospedaliera S. Croce E Carle Di Cuneo - Cuneo (Cn) Oncoematologia
city: Empoli
country: Italy
facility: Ausl 11 Di Empoli (Fi) - Empoli (Fi) Oncologia Medica
city: Fabriano
country: Italy
facility: U.S.L.N.6 -Ospedale Civile 'E.Profili'-F - Fabriano (An) Oncologia Medica
city: Firenze
country: Italy
facility: Ausl 10 Di Firenze - Firenze (Fi) Oncologia Medica
city: Genova
country: Italy
facility: Irccs Istituto Nazionale Per La Ricerca Sul Cancro (Ist) - Genova (Ge) Oncologia Medica
city: Lecce
country: Italy
facility: Ausl Le Di Lecce - Lecce (Le) Oncologia Medica
city: Legnano
country: Italy
facility: Aulss 21 Di Legnago (Vr) - Legnago (Vr) Oncologia Medica
city: Lido di Camaiore
country: Italy
facility: Ausl 12 Di Viareggio (Lu) - Lido Di Camaiore (Lu) Oncologia Medica
city: Livorno
country: Italy
facility: Ospedale Livorno - Livorno (Li), Oncologia Medica
city: Lucca
country: Italy
facility: Presidio Ospedaliero Piana Di Lucca - Lucca (Lu) Oncologia Medica
city: Milano
country: Italy
facility: Irccs Fondazione Centro S. Raffaele Del Monte Tabor - Milano (Mi) Oncologia Medica
city: Milano
country: Italy
facility: Ospedale Ca' Granda-Niguarda - Milano - Milano (Mi) Oncologia Medica
city: Monza
country: Italy
facility: S.Gerardo - Monza - Monza (Mi) Oncologia Medica
city: Napoli
country: Italy
facility: A.O. Universitaria Federico Ii Di Napoli Oncologia Medica
city: Novara
country: Italy
facility: A.O. Universitaria Maggiore Della Carita' Di Novara Oncologia Medica
city: Parma
country: Italy
facility: A.O. Universitaria Di Parma Oncologia Medica
city: Perugia
country: Italy
facility: Asl 1 Di Citta' Di Castello (Pg) - Citta' Di Castello (Pg) Oncologia Medica
city: Perugia
country: Italy
facility: A.O. Di Perugia - Ospedale S. Maria Della Misericordia (Ex Silvestrini) - Perugia (Pg) Oncologia Medica
city: Pesaro
country: Italy
facility: Azienda Ospedaliera San Salvatore - Pesaro (Pu) Oncologia Medica
city: Pescia
country: Italy
facility: Ospedale Della Valdinievole - Pescia (Pt) Oncologia Medica
city: Piombino
country: Italy
facility: Ospedale Piombino - Piombino (Li) Oncologia Medica
city: Pisa
country: Italy
facility: A.O. Universitaria Pisana Oncologia Medica
city: Pisa
country: Italy
facility: Ausl 5 Di Pisa - Pisa (Pi) Oncologia Medica
city: Pisa
country: Italy
facility: Alfredo Falcone A.O. Universitaria Pisana - Pisa (Pi) Oncologia Medica
city: Pistoia
country: Italy
facility: Ausl 3 Di Pistoia - Pistoia (Pt) Oncologia Medica
city: Prato
country: Italy
facility: Ausl 4 Di Prato - Prato (Po) Oncologia Medica
city: Reggio Emilia
country: Italy
facility: Ospedale Di S. Maria Nuova - Reggio Nell'Emilia (Re) Oncologia Medica
city: Rome
country: Italy
facility: Policlinico Universitario Campus Bio-Medico Di Roma Oncologia Medica
city: Rome
country: Italy
facility: Policlinico Umberto I Di Roma Oncologia Medica
city: Rome
country: Italy
facility: Policlinico Universitario Gemelli Di Roma Oncologia Medica
city: Siena
country: Italy
facility: A.O. Universitaria Senese Oncologia Medica
city: Sondrio
country: Italy
facility: Ospedale Civile - Sondrio - Sondrio (So) Oncologia Medica
city: Torino
country: Italy
facility: A.O. Universitaria S. Giovanni Battista-Molinette Di Torino Oncologia Medica
Study officials:
affiliation: Presidio Ospedaliero di Livorno
name: Alfredo Falcone, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
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