A Study of Bevacizumab in Combination With Capecitabine and Cisplatin as First-line Therapy in Patients With Advanced Gastric Cancer

NCT ID: NCT00548548

Last Updated: 2017-06-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 774 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2007-09-30
• Study Completion Date: 2013-11-30

Brief Summary

This study will compare treatment with bevacizumab in combination with capecitabine and cisplatin versus placebo in combination with capecitabine and cisplatin, as first-line therapy in patients with locally advanced or metastatic gastric cancer who had not received prior chemotherapy for advanced or metastatic disease.

Detailed Description

This is a 2 arm, randomized, double-blind, multicenter phase III study. Patients will be randomized (1:1) to capecitabine/cisplatin plus bevacizumab or capecitabine/cisplatin plus placebo. This is an event-driven trial with the primary analysis planned after approximately 517 deaths had been observed. After the primary analysis, the study will remain open and patients can continue with study treatment until progressive disease or earlier at the investigator's discretion. After discontinuation of the last patient, the study will end globally.

Conditions

Adenocarcinoma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Bevacizumab

Participants received intravenous (IV) bevacizumab 7.5 mg/kg every 3 weeks, oral capecitabine 1,000 mg/m˄2 twice daily for 14 days every 3 weeks, or 5-fluorouracil (5-FU) at a dose of 800 mg/m˄2/day as a continuous IV infusion over the first 5 days of every 3 week cycle, and cisplatin 80 mg/m˄2 as an IV infusion every 3 weeks for a maximum of 6 cycles. Bevacizumab and capecitabine/5-FU were administered until disease progression or unacceptable toxicity.

Group Type: EXPERIMENTAL

Bevacizumab

Intervention Type: DRUG

Intravenous bevacizumab 7.5 mg/kg once every 3 weeks, given until disease progression or unmanageable toxicity.

Capecitabine

Intervention Type: DRUG

Oral capecitabine 1,000 mg/m˄2 twice daily for 14 days every 3 weeks, given until disease progression or unmanageable toxicity.

Cisplatin

Intervention Type: DRUG

Cisplatin 80 mg/m˄2 as a 2 hr intravenous infusion with hyper-hydration and pre-medication (steroids and anti-emetics), given every 3 weeks for a maximum of 6 cycles or until disease progression or unmanageable toxicity.

5-fluorouracil

Intervention Type: DRUG

For participants with difficulty swallowing, malabsorption, or other conditions that could affect intake of oral capecitabine medication, 5-fluorouracil was administered instead, at a dose of 800 mg/m˄2/day as a continuous intravenous infusion over 5 days (days 1 to 5 of each cycle), every 3 weeks.

Placebo

Participants received intravenous (IV) placebo infusion every 3 weeks, oral capecitabine 1,000 mg/m˄2 twice daily for 14 days every 3 weeks, or 5-fluorouracil (5-FU) at a dose of 800 mg/m˄2/day as a continuous IV infusion over the first 5 days of every 3 week cycle, and cisplatin 80 mg/m˄2 as an IV infusion every 3 weeks for a maximum of 6 cycles. The placebo and capecitabine/5-FU were administered until disease progression or unacceptable toxicity.

Group Type: PLACEBO_COMPARATOR

Capecitabine

Intervention Type: DRUG

Oral capecitabine 1,000 mg/m˄2 twice daily for 14 days every 3 weeks, given until disease progression or unmanageable toxicity.

Cisplatin

Intervention Type: DRUG

Cisplatin 80 mg/m˄2 as a 2 hr intravenous infusion with hyper-hydration and pre-medication (steroids and anti-emetics), given every 3 weeks for a maximum of 6 cycles or until disease progression or unmanageable toxicity.

Placebo

Intervention Type: DRUG

Intravenous placebo every 3 weeks, given until disease progression or unmanageable toxicity.

5-fluorouracil

Intervention Type: DRUG

For participants with difficulty swallowing, malabsorption, or other conditions that could affect intake of oral capecitabine medication, 5-fluorouracil was administered instead, at a dose of 800 mg/m˄2/day as a continuous intravenous infusion over 5 days (days 1 to 5 of each cycle), every 3 weeks.

Interventions

Bevacizumab

Intravenous bevacizumab 7.5 mg/kg once every 3 weeks, given until disease progression or unmanageable toxicity.

Intervention Type: DRUG

Capecitabine

Oral capecitabine 1,000 mg/m˄2 twice daily for 14 days every 3 weeks, given until disease progression or unmanageable toxicity.

Intervention Type: DRUG

Cisplatin

Cisplatin 80 mg/m˄2 as a 2 hr intravenous infusion with hyper-hydration and pre-medication (steroids and anti-emetics), given every 3 weeks for a maximum of 6 cycles or until disease progression or unmanageable toxicity.

Intervention Type: DRUG

Placebo

Intravenous placebo every 3 weeks, given until disease progression or unmanageable toxicity.

Intervention Type: DRUG

5-fluorouracil

For participants with difficulty swallowing, malabsorption, or other conditions that could affect intake of oral capecitabine medication, 5-fluorouracil was administered instead, at a dose of 800 mg/m˄2/day as a continuous intravenous infusion over 5 days (days 1 to 5 of each cycle), every 3 weeks.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Written informed consent obtained prior to any study specific procedures.
• Age ≥ 18 years.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
• Life expectancy of at least 3 months.
• Able to comply with the protocol.
• Histologically confirmed adenocarcinoma of the stomach or gastro-oesophageal junction with inoperable, locally advanced, or metastatic disease, not amenable to curative therapy.
• Measurable disease or non-measurable but evaluable disease, according to the Response Evaluation Criteria in Solid Tumours (RECIST).
• Patient not receiving anticoagulant medication must have an International normalized ratio (INR) ≤ 1.5 and activated partial thromboplastin time (aPTT) ≤ 1.5 x Upper Limit of Normal (ULN) within 7 days prior to randomisation.

Exclusion Criteria

• Previous chemotherapy for locally advanced or metastatic gastric cancer. Patients may have received prior neoadjuvant or adjuvant chemotherapy as long as it was completed at least 6 months prior to randomisation.
• Previous platinum or anti-angiogenic therapy (ie, anti-vascular endothelial growth factor [VEGF] or VEGF receptor tyrosine kinase inhibitor, etc.).
• Patients with locally advanced disease who are candidates for curative therapy (including operation and/or chemotherapy and/or radiotherapy).
• Radiotherapy within 28 days of randomisation.
• Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to randomisation, or anticipation of the need for major surgery during the course of the study treatment (planned elective surgery).
• Minor surgical procedures within 2 days prior to randomisation.
• Evidence of central nervous system (CNS) metastasis at baseline.
• History or evidence upon physical/neurological examination of CNS disease unrelated to cancer unless adequately treated with standard medical therapy, eg, uncontrolled seizures.
• History of another malignancy which could affect compliance with the protocol or interpretation of results.
• Inadequate bone marrow function.
• Inadequate liver function.
• Inadequate renal function.
• Uncontrolled hypertension or clinically significant (ie, active) cardiovascular disease.
• Active infection requiring intravenous antibiotics at randomisation.
• History or evidence of inherited bleeding diathesis or coagulopathy with the risk of bleeding.
• Serious or non-healing wound, peptic ulcer, or (incompletely healed) bone fracture.
• Active gastrointestinal bleeding.
• History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months of randomisation.
• Neuropathy (eg, impairment of hearing and balance) ≥ grade II according to Common Terminology Criteria for Adverse Events (CTCAE) v3.0.
• Chronic daily treatment with aspirin or clopidogrel.
• Chronic daily treatment with oral corticosteroids; inhaled steroids and short courses of oral steroids for anti-emesis or as an appetite stimulant are allowed.
• Known hypersensitivity to any of the study drugs or excipients or to Chinese hamster ovary cell products or to other recombinant human or humanised antibodies.
• Known dihydropyrimidine dehydrogenase (DPD) deficiency.
• Evidence of any other disease, metabolic or psychological dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates use of an investigational drug, or that may affect patient compliance with the study, or place the patient at high risk from treatment complications.
• Known acute or chronic-active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV).
• Pregnant or lactating females.
• Women of childbearing potential not using effective nonhormonal (intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal jelly, or surgically sterile) means of contraception.
• Sexually active men unwilling to practice contraception during the study.
• Current or recent (within the 28 days prior to randomisation) treatment with another investigational drug or participation in another investigational study.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Hoffmann-La Roche

INDUSTRY

Sponsor Role: collaborator

Chugai Pharmaceutical

INDUSTRY

Sponsor Role: collaborator

Genentech, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Eric Hedrick, MD

Role: STUDY_DIRECTOR

Genentech, Inc.

Locations

Tower Cancer Research Fnd

Beverly Hills, California, United States

Moores UCSD Cancer Center

La Jolla, California, United States

Kenmar Research Institute LLC

Los Angeles, California, United States

USC/Norris Cancer Center

Los Angeles, California, United States

Georgetown University

Washington D.C., District of Columbia, United States

Florida Cancer Specialists

Fort Myers, Florida, United States

H. Lee Moffitt Cancer

Tampa, Florida, United States

Cancer Center of Kansas

Wichita, Kansas, United States

Methodist Cancer Center Onc

Omaha, Nebraska, United States

Memorial Sloan Kettering

New York, New York, United States

Duke Univ Medical Center

Durham, North Carolina, United States

South Carolina Oncology Assoc

Columbia, South Carolina, United States

The Sarah Cannon Research Inst

Nashville, Tennessee, United States

Countries

United States

References

Han K, Jin J, Maia M, Lowe J, Sersch MA, Allison DE. Lower exposure and faster clearance of bevacizumab in gastric cancer and the impact of patient variables: analysis of individual data from AVAGAST phase III trial. AAPS J. 2014 Sep;16(5):1056-63. doi: 10.1208/s12248-014-9631-6. Epub 2014 Jun 19.

Reference Type: DERIVED

PMID: 24942210 (View on PubMed)

Ohtsu A, Shah MA, Van Cutsem E, Rha SY, Sawaki A, Park SR, Lim HY, Yamada Y, Wu J, Langer B, Starnawski M, Kang YK. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol. 2011 Oct 20;29(30):3968-76. doi: 10.1200/JCO.2011.36.2236. Epub 2011 Aug 15.

Reference Type: DERIVED

PMID: 21844504 (View on PubMed)

Other Identifiers

BO20904

Identifier Type: OTHER

Identifier Source: secondary_id

AVF4200g

Identifier Type: -

Identifier Source: org_study_id