Second-Line Combination Chemotherapy With or Without Bevacizumab in Treating Patients With Metastatic Colorectal Cancer Who Have Received First-Line Chemotherapy and Bevacizumab (BEBYP)

AN OPEN-LABEL, MULTICENTER, RANDOMIZED PHASE III STUDY OF SECOND-LINE CHEMOTHERAPY WITH OR WITHOUT BEVACIZUMAB IN METASTATIC COLORECTAL CANCER PATIENTS WHO HAVE RECEIVED FIRST-LINE CHEMOTHERAPY PLUS BEVACIZUMAB.

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. It is not yet known whether combination chemotherapy is more effective with or without bevacizumab in treating metastatic colorectal cancer.

PURPOSE: This randomized phase III trial is studying second-line combination chemotherapy to see how well it works compared with or without bevacizumab in treating patients with metastatic colorectal cancer who have received first-line chemotherapy and bevacizumab.

Study Overview

• Status: Terminated
• Conditions: Colorectal Cancer
• Intervention / Treatment: Biological: bevacizumab; Drug: oxaliplatin; Drug: leucovorin calcium; Drug: fluorouracil; Drug: irinotecan hydrochloride

Detailed Description

OBJECTIVES:

Primary

• To compare the progression-free survival of second-line chemotherapy with or without bevacizumab in patients with metastatic colorectal cancer who have received first-line chemotherapy with bevacizumab.

Secondary

• To compare the overall survival, response rate, and safety profile of second-line chemotherapy of these regimens in these patients.
• To conduct pharmacogenomics assessment of candidate variants in the VEGF gene and evaluate their association with progression-free survival and other study outcomes.

OUTLINE: This is a multicenter study. Patients are stratified according to participating center, ECOG performance status (0 vs 1-2), disease-free interval from the last administration of first-line chemotherapy for metastatic disease (≤ 3 months vs > 3 months), and type of second-line chemotherapy (irinotecan hydrochloride, leucovorin calcium, and fluorouracil [FOLFIRI] vs oxaliplatin, leucovorin calcium, and fluorouracil [mFOLFOX-6]). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive either irinotecan hydrochloride over 1 hour or oxaliplatin over 1 hour on day 1. Patients also receive leucovorin calcium IV over 2 hours and fluorouracil IV over 46 hours continuously beginning on day 1.
• Arm II: Patients receive combination chemotherapy as in arm I and bevacizumab IV on day 1.

Treatment in both arms repeats every 2 weeks for up to 12 courses in the absence of disease progression or unacceptable toxicity.

Existing formalin-fixed paraffin-embedded tumor tissue samples are assessed for pharmacogenomics and markers predictive of response, resistance to, or toxicity from bevacizumab. Samples are analyzed via RT-PCR, array comparative genomic hybridization, fluorescence in situ hybridization, sequencing of candidate genes, and immunohistochemistry.

After completion of study treatment, patients are followed for 1 year.

• Study Type: Interventional
• Enrollment (Actual): 184
• Phase: Phase 3

Contacts and Locations

Study Locations

• Italy
  • Ancona, Italy, 60100
    • Università Politecnica delle Marche
  • Arezzo, Italy, 52100
    • Azienda Usl 8 Arezzo
  • Biella, Italy, 13900
    • Ospedale degli Infermi - ASL 12
  • Brindisi, Italy, 72100
    • A. Perrino Hospital
  • Caltanissetta, Italy, 93100
    • Azienda Ospedaliera S. Elia
  • Cuneo, Italy, 12100
    • Ospedale Santa Croce
  • Empoli, Italy, 50053
    • Ospedale San Giuseppe
  • Fabriano, Italy, 60044
    • Ospedale E. Profili
  • Fano, Italy, 61032
    • Ospedale Civile S. Croce
  • Florence, Italy, 50139
    • Azienda Ospedaliero Careggi
  • Florence, Italy, 50011
    • Azienda Ospedaliera di Firenze
  • Genoa, Italy, 16132
    • Istituto Nazionale per la Ricerca sul Cancro
  • La Spezia, Italy, 19100
    • Ospendale S. Andrea EST
  • Lecce, Italy, 73100
    • Azienda Ospedaliera Vito Fazzi
  • Lido di Camaiore, Italy, 55043
    • Azienda USL12 Versilia
  • Lucca, Italy, 55100
    • Ospedale Campo Di Marte Lucca
  • Novara, Italy, 28100
    • Azienda Ospedaliera Maggiore Della Carita
  • Pisa, Italy, 56126
    • Azienda Ospedaliera Pisana
  • Reggio Emilia, Italy, 42100
    • Arcispedale S. Maria Nuova
  • Siena, Italy, 53100
    • Azienda Ospedaliera Universitaria Senese
  • Siena, Italy, 53100
    • Dipartimento Oncologico

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Histologically confirmed colorectal adenocarcinoma

  • Metastatic or unresectable disease

• Progressive disease based on the following criteria:

  • Progression during or after first-line chemotherapy for metastatic disease, including any of the following:

    • Fluoropyrimidine-based monotherapy with bevacizumab
    • Fluoropyrimidine and irinotecan hydrochloride-based doublet with bevacizumab
    • Fluoropyrimidine and oxaliplatin-based doublet with bevacizumab
  • Progression after more than 3 months from the last administration of first-line chemotherapy for metastatic disease with a fluoropyrimidine, irinotecan hydrochloride, and oxaliplatin triplet (FOLFOXIRI) with bevacizumab to which the patient had previously responded
• Measurable disease, as assessed by RECIST criteria
• No prior or concurrent CNS metastasis

PATIENT CHARACTERISTICS:

• ECOG performance status 0-2
• Life expectancy > 3 months
• ANC ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3
• Hemoglobin ≥ 9 g/dL
• INR ≤ 1.5 times upper limit of normal (ULN)
• aPTT ≤ 1.5 ULN
• Serum bilirubin ≤ 1.5 times ULN
• AST and ALT ≤ 2.5 times ULN (< 5 times ULN if liver metastases present)
• Alkaline phosphatase ≤ 2.5 times ULN (< 5 times ULN if liver metastases present)
• Serum creatinine ≤ 1.5 times ULN
• Proteinuria < 2+ OR protein ≤ 1g by 24-hour urine
• Not pregnant or nursing
• Fertile patients must use effective contraception
• No bowel obstruction or subobstruction
• No history of inflammatory enteropathy
• No prior extensive intestinal resection (i.e., > hemicolectomy or extensive small intestine resection with chronic diarrhea)
• No symptomatic peripheral neuropathy > grade 2
• No active uncontrolled infection
• No active disseminated intravascular coagulation
• No prior or concurrent malignancy, except for curatively treated basal cell and squamous cell carcinoma of the skin, or in situ carcinoma of the cervix

• No clinically significant cardiovascular disease, including any of the following:

  • Cerebrovascular accident within the past 6 months
  • Myocardial infarction within the past 6 months
  • Unstable angina
  • NYHA class II-IV chronic heart failure
  • Uncontrolled arrhythmia
• No uncontrolled hypertension
• No thromboembolic or hemorrhagic events within the past 6 months
• No evidence of bleeding diathesis or coagulopathy
• No serious, non healing wound/ulcer or serious bone fracture
• No significant traumatic injury within the past 28 days

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• At least 6 weeks since prior radiotherapy
• At least 4 weeks since prior surgery
• No prior first-line chemotherapy for metastatic disease without bevacizumab
• No prior cetuximab or other investigational agents
• More than 28 days since prior open biopsy
• More than 28 days since prior and no concurrent major surgical procedure

• No concurrent therapeutic anticoagulation, antiplatelet agents, or NSAID with anti-platelet activity

  • Acetylsalicylic acid ≤ 325 mg/day allowed

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm I; Patients receive either irinotecan hydrochloride over 1 hour or oxaliplatin over 1 hour on day 1. Patients also receive leucovorin calcium IV over 2 hours and fluorouracil IV over 46 hours continuously beginning on day 1. Treatment repeats every 2 weeks for up to 12 courses in the absence of disease progression or unacceptable toxicity.	Drug: oxaliplatin; Given IV; Drug: leucovorin calcium; Given IV; Drug: fluorouracil; Given IV; Drug: irinotecan hydrochloride; Given IV
Experimental: Arm II; Patients receive combination chemotherapy as in arm I and bevacizumab IV on day 1. Treatment repeats every 2 weeks for up to 12 courses in the absence of disease progression or unacceptable toxicity.	Biological: bevacizumab; Given IV; Drug: oxaliplatin; Given IV; Drug: leucovorin calcium; Given IV; Drug: fluorouracil; Given IV; Drug: irinotecan hydrochloride; Given IV

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Progression-free survival	last progression of the last patient

Secondary Outcome Measures

Outcome Measure	Time Frame
Overall survival	the end of the stady
Response rate	last visit of the last patient
Safety	the end of the study

Collaborators and Investigators

• Sponsor: Gruppo Oncologico del Nord-Ovest
• Investigators: Principal Investigator: Alfredo Falcone, MD, Presidio Ospedaliero di Livorno

Publications and helpful links

General Publications

• Masi G, Salvatore L, Boni L, Loupakis F, Cremolini C, Fornaro L, Schirripa M, Cupini S, Barbara C, Safina V, Granetto C, Fea E, Antonuzzo L, Boni C, Allegrini G, Chiara S, Amoroso D, Bonetti A, Falcone A; BEBYP Study Investigators. Continuation or reintroduction of bevacizumab beyond progression to first-line therapy in metastatic colorectal cancer: final results of the randomized BEBYP trial. Ann Oncol. 2015 Apr;26(4):724-730. doi: 10.1093/annonc/mdv012. Epub 2015 Jan 18.

Study record dates

Study Major Dates

• Study Start: June 1, 2008
• Primary Completion (Actual): February 1, 2013
• Study Completion (Actual): March 1, 2014

Study Registration Dates

• First Submitted: July 19, 2008
• First Submitted That Met QC Criteria: July 19, 2008
• First Posted (Estimate): July 22, 2008

Study Record Updates

• Last Update Posted (Estimate): March 11, 2015
• Last Update Submitted That Met QC Criteria: March 10, 2015
• Last Verified: March 1, 2015

More Information

Terms related to this study

• Keywords: adenocarcinoma of the rectum; stage IV rectal cancer; stage IV colon cancer; adenocarcinoma of the colon; recurrent colon cancer; recurrent rectal cancer; stage III colon cancer; stage III rectal cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Micronutrients; Vitamins; Calcium-Regulating Hormones and Agents; Topoisomerase I Inhibitors; Antidotes; Vitamin B Complex; Fluorouracil; Oxaliplatin; Bevacizumab; Leucovorin; Irinotecan; Calcium; Levoleucovorin
• Other Study ID Numbers: CDR0000598567; GONO-BEBYP-ASL607LIOM03; GONO-AIFA - FARM5C4FB4; EUDRACT:2007-002886-11