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

Colorectal Cancer Clinical Trial

— BEBYP  

Official title:

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.

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00720512
• Other study ID #: CDR0000598567
• Secondary ID: GONO-BEBYP-ASL60
• Status: Terminated
• Phase: Phase 3
• First received: July 19, 2008
• Last updated: March 10, 2015
• Start date: June 2008
• Est. completion date: March 2014

Study information

• Verified date: March 2015
• Source: Gruppo Oncologico del Nord-Ovest
• Contact: n/a
• Is FDA regulated: No
• Health authority: Italy: Agenzia Italiana del Farmaco (AIFA)
• Study type: Interventional

Clinical 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. 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 184
• Est. completion date: March 2014
• Est. primary completion date: February 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 75 Years

Eligibility

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 Design

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Colorectal Cancer
• Colorectal Neoplasms

Intervention

Biological:
• bevacizumab
Given IV

Drug:
• fluorouracil
Given IV
• irinotecan hydrochloride
Given IV
• leucovorin calcium
Given IV
• oxaliplatin
Given IV

Locations

Country	Name	City	State
Italy	Universita Politecnica Delle Marche	Ancona
Italy	Azienda Usl 8 Arezzo	Arezzo
Italy	Ospedale degli Infermi - ASL 12	Biella
Italy	A. Perrino Hospital	Brindisi
Italy	Azienda Ospedaliera S. Elia	Caltanissetta
Italy	Ospedale Santa Croce	Cuneo
Italy	Ospedale San Giuseppe	Empoli
Italy	Ospedale E. Profili	Fabriano
Italy	Ospedale Civile S. Croce	Fano
Italy	Azienda Ospedaliera di Firenze	Florence
Italy	Azienda Ospedaliero Careggi	Florence
Italy	Istituto Nazionale per la Ricerca sul Cancro	Genoa
Italy	Ospendale S. Andrea EST	La Spezia
Italy	Azienda Ospedaliera Vito Fazzi	Lecce
Italy	Azienda USL12 Versilia	Lido di Camaiore
Italy	Ospedale Campo Di Marte Lucca	Lucca
Italy	Azienda Ospedaliera Maggiore Della Carita	Novara
Italy	Azienda Ospedaliera Pisana	Pisa
Italy	Arcispedale S. Maria Nuova	Reggio Emilia
Italy	Azienda Ospedaliera Universitaria Senese	Siena
Italy	Dipartimento Oncologico	Siena

Sponsors (1)

Lead Sponsor	Collaborator
Gruppo Oncologico del Nord-Ovest

Country where clinical trial is conducted

Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-free survival		last progression of the last patient	No
Secondary	Overall survival		the end of the stady	No
Secondary	Response rate		last visit of the last patient	No
Secondary	Safety		the end of the study	Yes