Combination Chemotherapy and Bevacizumab as First-Line Therapy in Treating Patients With 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.

Sex

All

Minimum age

18 Years

Maximum age

75 Years

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)

• DERIVEDRossini 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
• DERIVEDAntoniotti 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
• DERIVEDCremolini 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
• DERIVEDTokunaga 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
• DERIVEDCremolini 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.