Back to resultsA Study of Bevacizumab in Combination With Capecitabine and Cisplatin as First-line Therapy in Patients With Advanced Gastric Cancer (AVAGAST)
Primary Purpose
Adenocarcinoma
Status
Completed
Phase
Phase 3
Locations
United States
Study Type
Interventional
Intervention
Bevacizumab
Capecitabine
Cisplatin
Placebo
5-fluorouracil
Sponsored by
About this trial
This is an interventional treatment trial for Adenocarcinoma focused on measuring Avastin, Metastatic Adenocarcinoma, AVAGAST
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.
Sites / Locations
- Tower Cancer Research Fnd
- Moores UCSD Cancer Center
- Kenmar Research Institute LLC
- USC/Norris Cancer Center
- Georgetown University
- Florida Cancer Specialists
- H. Lee Moffitt Cancer
- Cancer Center of Kansas
- Methodist Cancer Center Onc
- Memorial Sloan Kettering
- Duke Univ Medical Center
- South Carolina Oncology Assoc
- The Sarah Cannon Research Inst
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
Bevacizumab
Placebo
Arm Description
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.
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.
Outcomes
Primary Outcome Measures
Overall Survival
The primary efficacy endpoint for this study was overall survival (time to death), defined as the time between randomization and the date of death irrespective of the cause of death. Patients for whom no death was captured on the clinical database were censored at the most recent date they were known to be alive. Median survival was estimated by the Kaplan-Meier method.
Secondary Outcome Measures
Progression-free Survival
Progression-free survival (PFS) is defined as the time between randomization and the date of first documented disease progression or death, whichever occurs first. Patients who neither progressed nor died at the time of study completion or who were lost to follow-up were censored at the date of the last tumor assessment or last follow up for progression of disease. Median PFS was estimated using the Kaplan-Meier method.
Progression-free Survival During First-line Therapy
Progression-free survival (PFS) during first-line therapy is defined as the time between randomization and the date of first documented disease progression or death, whichever occurs first and only if it occurs no later than 28 days after last confirmed intake of any study medication and only if it occurs before the start of non-study antineoplastic treatment. Participants who did not progress or die in this interval or were lost to follow-up were censored at the date of the last tumor assessment within this time window. Median PFS was estimated using the Kaplan-Meier method.
Time to Disease Progression
Time to progression is defined as the time from randomization to the first occurrence of progressive disease (PD). PD was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria and defined as at least a 20% increase in the sum of the longest diameter of target lesions, or appearance of ≥1 new lesions and/or unequivocal progression of existing non-target lesions. Patients with no PD at study completion (including those who died before PD) were censored at the date of the last tumor assessment. Median time to PD was estimated using the Kaplan-Meier method.
Participants With a Best Overall Response of Complete or Partial Response
Best overall response during first-line therapy is defined as the occurrence of either a confirmed complete (CR) or a partial (PR) best overall response, as determined by the RECIST criteria. CR is defined as the disappearance of all target and non-target lesions and PR is defined as at least a 30% decrease in the sum of the longest diameter of target lesions and no new or progression of non-target lesions, or the disappearance of all target lesions and persistence of one or more non-target lesion(s).
Duration of Response
Duration of response during first line therapy is defined as the time from when response (CR or PR) was first documented to first documented disease progression or death (whichever occurs first) during first line therapy. This was only be calculated for participants who achieved a best overall response of CR or PR. Participants who did not progress or die after they had a confirmed response were censored at the date of their last tumor measurement or last follow up for progression of disease during first line therapy. Median duration of response was estimated using the Kaplan-Meier method.
Participants With Disease Control
Disease control for participants with measurable disease was defined as a complete response (CR), partial response (PR) or stable disease (SD) for 6 weeks or longer, as determined by the RECIST criteria. For participants without measurable disease, disease control was defined as no disease progression for ≥ 6 weeks.
Participants With Adverse Events
The intensity of Adverse Events (AEs) was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 3.0 on a five-point scale from Grade 1 (Mild) to Grade 5 (Death). A serious AE (SAE) was defined as any event that is fatal, life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, is medically significant or requires intervention to prevent one or other of the outcomes listed above.
Full Information
NCT ID
NCT00548548
First Posted
October 23, 2007
Last Updated
May 16, 2017
Sponsor
Genentech, Inc.
Collaborators
Hoffmann-La Roche, Chugai Pharmaceutical
1. Study Identification
Unique Protocol Identification Number
NCT00548548
Brief Title
A Study of Bevacizumab in Combination With Capecitabine and Cisplatin as First-line Therapy in Patients With Advanced Gastric Cancer
Acronym
AVAGAST
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
2. Study Status
Record Verification Date
May 2017
Overall Recruitment Status
Completed
Study Start Date
September 2007 (Actual)
Primary Completion Date
November 2009 (Actual)
Study Completion Date
November 2013 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Genentech, Inc.
Collaborators
Hoffmann-La Roche, Chugai Pharmaceutical
4. Oversight
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Adenocarcinoma
Keywords
Avastin, Metastatic Adenocarcinoma, AVAGAST
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
774 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Bevacizumab
Arm Type
Experimental
Arm Description
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.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Bevacizumab
Intervention Description
Intravenous bevacizumab 7.5 mg/kg once every 3 weeks, given until disease progression or unmanageable toxicity.
Intervention Type
Drug
Intervention Name(s)
Capecitabine
Intervention Description
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
Intervention Name(s)
Cisplatin
Intervention Description
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
Intervention Name(s)
Placebo
Intervention Description
Intravenous placebo every 3 weeks, given until disease progression or unmanageable toxicity.
Intervention Type
Drug
Intervention Name(s)
5-fluorouracil
Intervention Description
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.
Primary Outcome Measure Information:
Title
Overall Survival
Description
The primary efficacy endpoint for this study was overall survival (time to death), defined as the time between randomization and the date of death irrespective of the cause of death. Patients for whom no death was captured on the clinical database were censored at the most recent date they were known to be alive. Median survival was estimated by the Kaplan-Meier method.
Time Frame
From randomization until death, up to 26 months
Secondary Outcome Measure Information:
Title
Progression-free Survival
Description
Progression-free survival (PFS) is defined as the time between randomization and the date of first documented disease progression or death, whichever occurs first. Patients who neither progressed nor died at the time of study completion or who were lost to follow-up were censored at the date of the last tumor assessment or last follow up for progression of disease. Median PFS was estimated using the Kaplan-Meier method.
Time Frame
From randomization until disease progression or death, up to 26 months.
Title
Progression-free Survival During First-line Therapy
Description
Progression-free survival (PFS) during first-line therapy is defined as the time between randomization and the date of first documented disease progression or death, whichever occurs first and only if it occurs no later than 28 days after last confirmed intake of any study medication and only if it occurs before the start of non-study antineoplastic treatment. Participants who did not progress or die in this interval or were lost to follow-up were censored at the date of the last tumor assessment within this time window. Median PFS was estimated using the Kaplan-Meier method.
Time Frame
From randomization until 28-days after the last study treatment was administered, up to 26 months.
Title
Time to Disease Progression
Description
Time to progression is defined as the time from randomization to the first occurrence of progressive disease (PD). PD was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria and defined as at least a 20% increase in the sum of the longest diameter of target lesions, or appearance of ≥1 new lesions and/or unequivocal progression of existing non-target lesions. Patients with no PD at study completion (including those who died before PD) were censored at the date of the last tumor assessment. Median time to PD was estimated using the Kaplan-Meier method.
Time Frame
From randomization until disease progression; assessed every 6 weeks for the first year and every 12 weeks thereafter, up to 26 months.
Title
Participants With a Best Overall Response of Complete or Partial Response
Description
Best overall response during first-line therapy is defined as the occurrence of either a confirmed complete (CR) or a partial (PR) best overall response, as determined by the RECIST criteria. CR is defined as the disappearance of all target and non-target lesions and PR is defined as at least a 30% decrease in the sum of the longest diameter of target lesions and no new or progression of non-target lesions, or the disappearance of all target lesions and persistence of one or more non-target lesion(s).
Time Frame
From randomization until the end of study, up to 26 months.
Title
Duration of Response
Description
Duration of response during first line therapy is defined as the time from when response (CR or PR) was first documented to first documented disease progression or death (whichever occurs first) during first line therapy. This was only be calculated for participants who achieved a best overall response of CR or PR. Participants who did not progress or die after they had a confirmed response were censored at the date of their last tumor measurement or last follow up for progression of disease during first line therapy. Median duration of response was estimated using the Kaplan-Meier method.
Time Frame
From randomization to the end of study, up to 26 months
Title
Participants With Disease Control
Description
Disease control for participants with measurable disease was defined as a complete response (CR), partial response (PR) or stable disease (SD) for 6 weeks or longer, as determined by the RECIST criteria. For participants without measurable disease, disease control was defined as no disease progression for ≥ 6 weeks.
Time Frame
From randomization until the end of study, up to 26 months.
Title
Participants With Adverse Events
Description
The intensity of Adverse Events (AEs) was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 3.0 on a five-point scale from Grade 1 (Mild) to Grade 5 (Death). A serious AE (SAE) was defined as any event that is fatal, life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, is medically significant or requires intervention to prevent one or other of the outcomes listed above.
Time Frame
From randomization until 3 months after last dose (up to 26 months)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Eric Hedrick, MD
Organizational Affiliation
Genentech, Inc.
Official's Role
Study Director
Facility Information:
Facility Name
Tower Cancer Research Fnd
City
Beverly Hills
State/Province
California
ZIP/Postal Code
90211-1850
Country
United States
Facility Name
Moores UCSD Cancer Center
City
La Jolla
State/Province
California
ZIP/Postal Code
92093
Country
United States
Facility Name
Kenmar Research Institute LLC
City
Los Angeles
State/Province
California
ZIP/Postal Code
90057
Country
United States
Facility Name
USC/Norris Cancer Center
City
Los Angeles
State/Province
California
ZIP/Postal Code
90089
Country
United States
Facility Name
Georgetown University
City
Washington, D.C.
State/Province
District of Columbia
ZIP/Postal Code
20007
Country
United States
Facility Name
Florida Cancer Specialists
City
Fort Myers
State/Province
Florida
ZIP/Postal Code
33916
Country
United States
Facility Name
H. Lee Moffitt Cancer
City
Tampa
State/Province
Florida
ZIP/Postal Code
33612
Country
United States
Facility Name
Cancer Center of Kansas
City
Wichita
State/Province
Kansas
ZIP/Postal Code
67214-3728
Country
United States
Facility Name
Methodist Cancer Center Onc
City
Omaha
State/Province
Nebraska
ZIP/Postal Code
68114
Country
United States
Facility Name
Memorial Sloan Kettering
City
New York
State/Province
New York
ZIP/Postal Code
10021
Country
United States
Facility Name
Duke Univ Medical Center
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States
Facility Name
South Carolina Oncology Assoc
City
Columbia
State/Province
South Carolina
ZIP/Postal Code
10595
Country
United States
Facility Name
The Sarah Cannon Research Inst
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37203
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
24942210
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.
Results Reference
derived
PubMed Identifier
21844504
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.
Results Reference
derived
Learn more about this trial
A Study of Bevacizumab in Combination With Capecitabine and Cisplatin as First-line Therapy in Patients With Advanced Gastric Cancer
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