Clinical trial NCT00548548: A Study of Bevacizumab in Combination With Capecitabine and Cisplatin as First-line Therapy in Patients With Advanced Gastric Cancer
Official title: A Double-blind, Randomised, Multicenter, Phase III Study of Bevacizumab in Combination With Capecitabine and Cisplatin Versus Placebo in Combination With Capecitabine and Cisplatin, as First-line Therapy in Patients With Advanced Gastric Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Adenocarcinoma
Keywords: Avastin
Metastatic Adenocarcinoma
AVAGAST
Lead sponsor: Genentech, Inc.
Sponsor class: INDUSTRY
Collaborators: name: Hoffmann-La Roche
name: Chugai Pharmaceutical
First posted: 2007-10-24
Enrollment: 774
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Overall Survival
timeFrame: From randomization until death, up to 26 months
Secondary outcomes:
measure: Progression-free Survival
timeFrame: From randomization until disease progression or death, up to 26 months.
measure: Progression-free Survival During First-line Therapy
timeFrame: From randomization until 28-days after the last study treatment was administered, up to 26 months.
measure: Time to Disease Progression
timeFrame: From randomization until disease progression; assessed every 6 weeks for the first year and every 12 weeks thereafter, up to 26 months.
measure: Participants With a Best Overall Response of Complete or Partial Response
timeFrame: From randomization until the end of study, up to 26 months.
measure: Duration of Response
timeFrame: From randomization to the end of study, up to 26 months
measure: Participants With Disease Control
timeFrame: From randomization until the end of study, up to 26 months.
measure: Participants With Adverse Events
timeFrame: From randomization until 3 months after last dose (up to 26 months)
Other outcomes:
Locations:
city: Beverly Hills
country: United States
facility: Tower Cancer Research Fnd
state: California
city: La Jolla
country: United States
facility: Moores UCSD Cancer Center
state: California
city: Los Angeles
country: United States
facility: Kenmar Research Institute LLC
state: California
city: Los Angeles
country: United States
facility: USC/Norris Cancer Center
state: California
city: Washington, D.C.
country: United States
facility: Georgetown University
state: District of Columbia
city: Fort Myers
country: United States
facility: Florida Cancer Specialists
state: Florida
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer
state: Florida
city: Wichita
country: United States
facility: Cancer Center of Kansas
state: Kansas
city: Omaha
country: United States
facility: Methodist Cancer Center Onc
state: Nebraska
city: New York
country: United States
facility: Memorial Sloan Kettering
state: New York
city: Durham
country: United States
facility: Duke Univ Medical Center
state: North Carolina
city: Columbia
country: United States
facility: South Carolina Oncology Assoc
state: South Carolina
city: Nashville
country: United States
facility: The Sarah Cannon Research Inst
state: Tennessee
Study officials:
affiliation: Genentech, Inc.
name: Eric Hedrick, MD
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.