A Study of Bevacizumab in Combination With Capecitabine and Cisplatin as First-line Therapy in Patients With Advanced Gastric Cancer (AVAGAST)
This study is ongoing, but not recruiting participants.
Sponsor:
Genentech
Collaborators:
Roche Pharma AG
Chugai
Information provided by (Responsible Party):
Genentech
ClinicalTrials.gov Identifier:
NCT00548548
First received: October 23, 2007
Last updated: December 15, 2011
Last verified: December 2011
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Purpose
To 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.
| Condition | Intervention | Phase |
|---|---|---|
|
Adenocarcinoma |
Drug: Bevacizumab Drug: Capecitabine Drug: Cisplatin Drug: Placebo Drug: 5-fluorouracil |
Phase 3 |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Investigator) Primary Purpose: Treatment |
| Official Title: | 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 |
Resource links provided by NLM:
Further study details as provided by Genentech:
Primary Outcome Measures:
- Overall Survival [ Time Frame: From randomization until death, up to 26 months ] [ Designated as safety issue: No ]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 [ Time Frame: From randomization until disease progression or death, up to 26 months. ] [ Designated as safety issue: No ]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 [ Time Frame: From randomization until 28-days after the last study treatment was administered, up to 26 months. ] [ Designated as safety issue: No ]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 Frame: From randomization until disease progression; assessed every 6 weeks for the first year and every 12 weeks thereafter, up to 26 months. ] [ Designated as safety issue: No ]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 [ Time Frame: From randomization until the end of study, up to 26 months. ] [ Designated as safety issue: No ]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 [ Time Frame: From randomization to the end of study, up to 26 months ] [ Designated as safety issue: No ]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 [ Time Frame: From randomization until the end of study, up to 26 months. ] [ Designated as safety issue: No ]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 [ Time Frame: From randomization until 3 months after last dose (up to 26 months) ] [ Designated as safety issue: No ]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.
| Enrollment: | 774 |
| Study Start Date: | September 2007 |
| Primary Completion Date: | November 2009 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: 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.
|
Drug: Bevacizumab
Intravenous bevacizumab 7.5 mg/kg once every 3 weeks, given until disease progression or unmanageable toxicity.
Drug: Capecitabine
Oral capecitabine 1,000 mg/m˄2 twice daily for 14 days every 3 weeks, until disease progression or unmanageable toxicity.
Drug: Cisplatin
Cisplatin 80 mg/m˄2 as a 2 hr intravenous infusion with hyper-hydration and pre-medication (steroids and anti-emetics), every 3 weeks for a maximum of 6 cycles or until disease progression or unmanageable toxicity.
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.
|
|
Placebo Comparator: 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.
|
Drug: Capecitabine
Oral capecitabine 1,000 mg/m˄2 twice daily for 14 days every 3 weeks, until disease progression or unmanageable toxicity.
Drug: Cisplatin
Cisplatin 80 mg/m˄2 as a 2 hr intravenous infusion with hyper-hydration and pre-medication (steroids and anti-emetics), every 3 weeks for a maximum of 6 cycles or until disease progression or unmanageable toxicity.
Drug: Placebo
Intravenous placebo every 3 weeks, given until disease progression or unmanageable toxicity
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.
|
Detailed Description:
This was a two arm, randomized, double-blind, multicenter phase III study. Patients were randomized (1:1) to capecitabine/cisplatin plus bevacizumab or capecitabine/cisplatin plus placebo. This was an event-driven trial with the final analysis (triggering the end of the study) planned after approximately 517 deaths had been observed. After final analysis the study will remain open and patients can continue with study treatment until progressive disease or earlier at the investigators discretion. After discontinuation of the last patient, the study will end globally.
Eligibility| Ages Eligible for Study: | 18 Years and older |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
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 (i.e. anti-VEGF or VEGFR 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, e.g. 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 (i.e. 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 (e.g. 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
Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00548548
Locations
| United States, California | |
| Tower Cancer Research Fnd | |
| Beverly Hills, California, United States, 90211-1850 | |
| Moores UCSD Cancer Center | |
| La Jolla, California, United States, 92093 | |
| Kenmar Research Institute LLC | |
| Los Angeles, California, United States, 90057 | |
| USC/Norris Cancer Center | |
| Los Angeles, California, United States, 90089 | |
| United States, District of Columbia | |
| Georgetown University | |
| Washington, District of Columbia, United States, 20007 | |
| United States, Florida | |
| Florida Cancer Specialists | |
| Fort Myers, Florida, United States, 33916 | |
| H. Lee Moffitt Cancer | |
| Tampa, Florida, United States, 33612 | |
| United States, Kansas | |
| Cancer Center of Kansas | |
| Wichita, Kansas, United States, 67214-3728 | |
| United States, Nebraska | |
| Methodist Cancer Center Onc | |
| Omaha, Nebraska, United States, 68114 | |
| United States, New York | |
| Memorial Sloan Kettering | |
| New York, New York, United States, 10021 | |
| United States, North Carolina | |
| Duke Univ Medical Center | |
| Durham, North Carolina, United States, 27710 | |
| United States, South Carolina | |
| South Carolina Oncology Assoc | |
| Columbia, South Carolina, United States, 10595 | |
| United States, Tennessee | |
| The Sarah Cannon Research Inst | |
| Nashville, Tennessee, United States, 37203 | |
Sponsors and Collaborators
Genentech
Roche Pharma AG
Chugai
Investigators
| Study Director: | Eric Hedrick, M.D. | Genentech |
More Information
Additional Information:
No publications provided by Genentech
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | Genentech |
| ClinicalTrials.gov Identifier: | NCT00548548 History of Changes |
| Other Study ID Numbers: | AVF4200g, BO20904 |
| Study First Received: | October 23, 2007 |
| Results First Received: | December 15, 2011 |
| Last Updated: | December 15, 2011 |
| Health Authority: | United States: Food and Drug Administration |
Keywords provided by Genentech:
|
Avastin Metastatic Adenocarcinoma AVAGAST |
Additional relevant MeSH terms:
|
Adenocarcinoma Adenocarcinoma, Mucinous Stomach Neoplasms Carcinoma Neoplasms, Glandular and Epithelial Neoplasms by Histologic Type Neoplasms Neoplasms, Cystic, Mucinous, and Serous Gastrointestinal Neoplasms Digestive System Neoplasms Neoplasms by Site Digestive System Diseases Gastrointestinal Diseases Stomach Diseases Capecitabine |
Bevacizumab Cisplatin Fluorouracil Antineoplastic Agents Therapeutic Uses Pharmacologic Actions Radiation-Sensitizing Agents Physiological Effects of Drugs Antimetabolites Molecular Mechanisms of Pharmacological Action Antimetabolites, Antineoplastic Immunosuppressive Agents Immunologic Factors Angiogenesis Inhibitors Angiogenesis Modulating Agents |
ClinicalTrials.gov processed this record on June 17, 2013