Esophageal Neoplasms, Neoplasm Metastasis, Stomach Neoplasms
Conditions
Keywords
metastatic esophagogastric adenocarcinomas, ESOPHAGEAL CANCER, GASTRIC CANCER, ADENOCARCINOMA, TARGTED THERAPY, BEVACIZUMAB, CAPECITBAINE, OXALIPLATIN, METASTATIC
Brief summary
The purpose of this study is to evaluate the progression free survival of capecitabine (Xeloda), oxaliplatin and bevacizumab (Avastin) in previously untreated metastatic esophagogastric adenocarcinomas.
Detailed description
The number of new cases of esophageal and gastric cancers in the United States in 2005 is 14520 for esophageal cancer and 21860 for gastric cancer. Unfortunately, esophageal and gastric cancers will also account for 13570 and 11550 deaths, respectively, in 2005. The 5 year survival rates for metastatic gastroesophageal, GE junctional, and gastric cancers are less than 5%. The major current treatment modality for patients with advanced esophageal, GE junctional, and gastric adenocarcinomas is systemic chemotherapy. We seek to investigate the efficacy of capecitabine and oxaliplatin in combination with bevacizumab as first line treatment for metastatic esophagogastric cancers. The choice of capecitabine and oxaliplatin is made to develop a user-friendly biologically-based regimen, offering patients oral capecitabine in place of continuous 5FU infusion pumps. Since capecitabine can be given crushed this regimen may both be active and user-friendly. Preliminary data in colorectal cancer suggest that the regimen of capecitabine, oxaliplatin, and bevacizumab has comparable activity to FOLFOX-bevacizumab. The goal of the proposed regimen is to define a capecitabine and oxaliplatin-based regimen that optimizes biological approaches over cytotoxic approaches. The addition of bevacizumab to chemotherapy regimens for metastatic colorectal cancer, metastatic non-small cell lung cancer, and metastatic breast cancer has shown to improve response rates and overall survival. If active, this regimen could serve as a first line comparator to the capecitabine, oxaliplatin, and epirubicin combination. This approach will also help to simplify regimen development across gastrointestinal cancers. In addition to the primary efficacy endpoint of this protocol, several correlative endpoints will also be examined in an exploratory manner. The importance of developing blood-based and tumor biomarkers has been extensively reviewed. However, the role of such predictive markers has not been well studied for XELOX-A. This information is important since it may help define which populations are most likely to benefit and most likely to suffer significant toxicity from this important GI cancer regimen. This biomarker approach may also help understand and define mechanisms of sensitivity, resistance, and toxicity that may be used to guide future hypothesis-driven studies designed to improve the efficacy and safety of this regimen. The correlative biomarker endpoints include serum, plasma and urine biomarkers (e.g. VEGF and bFGF), a wound healing model of angiogenesis, and tumor biopsy studies .
Interventions
DRUGcapecitabine (Xeloda), oxaliplatin and bevacizumab (Avastin)
Capecitabine will be administered orally at a twice daily dose of 850 mg/m2 (equivalent to a total daily dose of 1700 mg/m2) given days 1-14 of the three week cycle. Oxaliplatin will be administered at the dose of 130 mg/m2 given as a 2-hour intravenous infusion on day 1 of a three week cycle. Bevacizumab will be administered at a dose of 15 mg/kg given as a 30-90 minute intravenous infusion on day 1 of a three week cycle following the administration of oxaliplatin.
Sponsors
Hoffmann-La Roche
Sanofi
Genentech, Inc.
Duke University
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Primary Inclusion Criteria: * Histologically or cytologically documented and radiographically measurable adenocarcinoma of the esophagus or stomach that is metastatic/recurrent and not amenable to potentially curative treatment * No prior therapy for metastatic disease * Prior radiation therapy is permitted, provided it is completed \> 28 days prior to day 1 of study drug * Normal organ and marrow function * Karnofsky Performance Status 70-100% Primary
Exclusion criteria
* Unstable or poorly controlled hypertension \> 150/100 mm Hg * Arterial thromboembolic events within 6 months * Clinically significant uncontrolled cardiac disease * Significant proteinuria at baseline * Grade 2 or greater peripheral neuropathy * History of abdominal fistula, GI perforation, or intra-abdominal abscess within 6 months
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Median Progression-Free Survival (PFS) | 5 years from study start date | Time in months from the start of study treatment to the date of first progression (PD) according to the RECIST criteria, or death due to any cause. PER RECIST, a PD is indicated when there is at least a 20% increase in the sum of the longest diameters from target lesions relative to the smallest sum recorded since treatment is initiated. Median PFS was estimated using a Kaplan-Meier curve, and is the time at which 50% of patients remain alive without disease progression. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| To Assess the Safety and Tolerability of the Combination of Bevacizumab, Oxaliplatin and Capecitabine in Patients With Previously Untreated Metastatic Esophagogastric Adenocarcinoma | Every 21 days | Number of subjects who experienced an adverse event |
| Response Rate | Every 9 weeks for up to 1 year | The proportion of patients for whom the best overall response is complete response (CR) or partial response (PR). A CR occurs when all lesions disappear; whereas, a PR is indicated when there is at least a 30% decrease in the sum of the longest diameters (LD) of the target lesion. A PD (progressive disese) occurs when there is at least a 20% increase in the sum of the LD relative to the smallest sum LD recorded since treatment is initiated. Disease is considered stable if there is no response and no PD. All patients were assigned a best response for inclusion in this calculation in accordance with the protocol. |
| Median Survival | 5 years after study start date | Time in months from the start of study treatment to date of death due to any cause. Median survival was estimated using a Kaplan-Meier curve and is the time point at which 50% of patients remain alive. |
Countries
United States
Participant flow
Pre-assignment details
81 subjects consented, 21 were screen failures, 60 subjects were considered enrolled.
Participants by arm
| Arm | Count |
|---|---|
| 1- Capecitabine (Xeloda), Oxaliplatin and Bevacizumab (Avastin capecitabine (Xeloda), oxaliplatin and bevacizumab (Avastin): Capecitabine will be administered orally at a twice daily dose of 850 mg/m2 (equivalent to a total daily dose of 1700 mg/m2) given days 1-14 of the three week cycle.
Oxaliplatin will be administered at the dose of 130 mg/m2 given as a 2-hour intravenous infusion on day 1 of a three week cycle.
Bevacizumab will be administered at a dose of 15 mg/kg given as a 30-90 minute intravenous infusion on day 1 of a three week cycle following the administration of oxaliplatin. | 60 |
| Total | 60 |
Baseline characteristics
| Characteristic | 1- Capecitabine (Xeloda), Oxaliplatin and Bevacizumab (Avastin |
|---|---|
| Age, Continuous | 58 years STANDARD_DEVIATION 12 |
| Sex: Female, Male Female | 13 Participants |
| Sex: Female, Male Male | 47 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 56 / 58 |
| serious Total, serious adverse events | 33 / 58 |
Outcome results
Primary
Median Progression-Free Survival (PFS)
Time in months from the start of study treatment to the date of first progression (PD) according to the RECIST criteria, or death due to any cause. PER RECIST, a PD is indicated when there is at least a 20% increase in the sum of the longest diameters from target lesions relative to the smallest sum recorded since treatment is initiated. Median PFS was estimated using a Kaplan-Meier curve, and is the time at which 50% of patients remain alive without disease progression.
Time frame: 5 years from study start date
Population: All patients with at least one scheduled restaging who received treatment. However, an additional 3 patients who progressed before treatment are not included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 1- Capecitabine (Xeloda), Oxaliplatin and Bevacizumab (Avastin | Median Progression-Free Survival (PFS) | 6.97 survival time in months |
Secondary
Median Survival
Time in months from the start of study treatment to date of death due to any cause. Median survival was estimated using a Kaplan-Meier curve and is the time point at which 50% of patients remain alive.
Time frame: 5 years after study start date
Population: All patients who received treatment are included in the analysis population. However, 2 patients who never started treatment before leaving the study were excluded from this analysis of survival time.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 1- Capecitabine (Xeloda), Oxaliplatin and Bevacizumab (Avastin | Median Survival | 10.51 survival time in months |
Secondary
Response Rate
The proportion of patients for whom the best overall response is complete response (CR) or partial response (PR). A CR occurs when all lesions disappear; whereas, a PR is indicated when there is at least a 30% decrease in the sum of the longest diameters (LD) of the target lesion. A PD (progressive disese) occurs when there is at least a 20% increase in the sum of the LD relative to the smallest sum LD recorded since treatment is initiated. Disease is considered stable if there is no response and no PD. All patients were assigned a best response for inclusion in this calculation in accordance with the protocol.
Time frame: Every 9 weeks for up to 1 year
Population: All eligible patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 1- Capecitabine (Xeloda), Oxaliplatin and Bevacizumab (Avastin | Response Rate | 41.7 percentage of participants |
Secondary
To Assess the Safety and Tolerability of the Combination of Bevacizumab, Oxaliplatin and Capecitabine in Patients With Previously Untreated Metastatic Esophagogastric Adenocarcinoma
Number of subjects who experienced an adverse event
Time frame: Every 21 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 1- Capecitabine (Xeloda), Oxaliplatin and Bevacizumab (Avastin | To Assess the Safety and Tolerability of the Combination of Bevacizumab, Oxaliplatin and Capecitabine in Patients With Previously Untreated Metastatic Esophagogastric Adenocarcinoma | 56 participants |