Esophageal Cancer, Stomach Cancer
Conditions
Keywords
TPCA, Taxotere, Platinum, Avastin, Camptosar, gastric cancer
Brief summary
The purpose of this research study is to determine if the combination of docetaxel, cisplatin, irinotecan and bevacizumab will help shrink metastatic esophageal or gastric cancer and how the cancer responds to this combination. Bevacizumab is a new drug that is believed to stop the formation of new blood vessels that carry nutrients to tumors. Bevacizumab is approved for use in metastatic colon and rectal cancer. Docetaxel, cisplatin and irinotecan are traditional chemotherapy agents that have been tested together in another clinical trial for esophageal and gastric cancer. It is hoped that adding bevacizumab to this regimen will make the treatment more effective.
Detailed description
OBJECTIVES: Primary To determine the 10-month progression-free survival rate for the combination of TPC and Bevacizumab in patients with metastatic esophageal or gastric cancer Secondary * To determine the response rate (RECIST) and median duration of response * To determine overall survival * To determine toxicity Exploratory * To explore if 7/7 and 7/6 UGT1A1 polymorphisms correlate with grade III/IV irinotecan-related diarrhea and neutropenia when irinotecan is given at relatively low dose to patients with esophageal and gastric cancer * To correlate expression of tumoral and serum VEGF with response and survival * To correlate TGF alpha levels and tumor microvessel density with clinical activity * To examine circulating endothelial cells (CECs) as surrogate markers of antitumor activity of bevacizumab DESIGN This trial will use a single stage design to differentiate a \>/= 50% rate of 10-month progression-free survival from a \</= 30% rate. The proposed regimen would be promising if at least 15 of 35 patients were alive and progression-free at 10 months.
Interventions
DRUGBevacizumab
DRUGDocetaxel
DRUGCisplatin
DRUGIrinotecan
Sponsors
Brigham and Women's Hospital
Massachusetts General Hospital
Genentech, Inc.
Dana-Farber Cancer Institute
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed, unresectable esophageal or gastric carcinoma (carcinoma=adenocarcinoma or squamous cell carcinoma) * Measurable disease greater than or equal to 1 cm (longest diameter) by spiral computed tomography (CT) scan or 2 cm or greater by other radiographic technique * Lesions must be measurable in at least one dimension * Bone lesions, ascites, and effusions are not measurable * 18 years of age or older * ECOG performance status 0 or 1 * Life expectancy of at least 12 weeks * Adequate bone marrow function * Adequate renal function * Adequate liver function
Exclusion criteria
* Prior chemotherapy (except as part of pre- or post-operative therapy, completed more than 1 year prior to start day of this protocol) * History of severe hypersensitivity to bevacizumab, docetaxel, cisplatin, irinotecan, or drugs formulated with polysorbate 80 * Current, recent (within 4 weeks) or planned participation in an experimental drug study * Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 0, or anticipation of need for major surgical procedure during the course of the study * Minor surgical procedures, such as fine needle aspirations, port-a-cath placement, or core biopsies within 7 days prior to Day 0 of study * Myocardial infarction or stroke in past 6 months * Blood pressure of \> 150/100 mmHg * Unstable angina * New York Heart Association (NYHA) grade II or greater congestive heart failure * Clinically significant peripheral vascular disease * Persistent bleeding from primary tumor, while off anticoagulants, requiring repeated transfusions * Evidence of bleeding diathesis or coagulopathy * Uncontrolled serious medical or psychiatric illness * Uncontrolled diarrhea * Peripheral neuropathy \> grade 1 * Clinically apparent central nervous system metastases or carcinomatous meningitis * Other active malignancy other than non-melanoma skin cancer or in situ cervical carcinoma. * Urine protein: creatinine ratio of 1.0 or greater at screening * History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to Day 1 * Serious non-healing wound, ulcer, or bone fracture * Pregnant or breast-feeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 10-month Progression-Free Survival Rate | Disease was evaluated radiologically at baseline and every 2 cycles on treatment; Treatment continued until disease progression or unacceptable toxicity. Relevant for this endpoint was disease status at 10 months. | 10-month progression-free survival rate is the probability of patients remaining alive and progression-free at 10-months from study entry estimated using Kaplan-Meier methods. Per RECIST 1.0 criteria: progressive disease (PD) is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Best Response | Disease was evaluated radiologically at baseline and every 2 cycles on treatment. Treatment continued until disease progression or unacceptable toxicity. Treatment duration was a median of 6 cycles/18 weeks given 3-week cycle length (range 1-26 cycles). | Best response on treatment was based on RECIST 1.0 criteria: Complete Response (CR) is complete disappearance of all target lesions; Partial Response (PR) is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. Both require confirmation no fewer than 4 weeks apart. CR/PR assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions. Progressive disease (PD) is at least a 20% increase in the sum of longest diameter of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions. Stable disease is defined as any condition not meeting above criteria. |
| Overall Survival | Patients in the study cohort were followed for a median of 12.2 month (up to 40 months). | Overall survival is defined as the time from study entry to death or date last known alive and estimate using Kaplan-Meier (KM) methods. |
| Progression-Free Survival | Disease was evaluated radiologically at baseline and every 2 cycles on treatment. Treatment continued until disease progression or unacceptable toxicity. Treatment duration was a median of 6 cycles/18 weeks given 3-week cycle length (range 1-26 cycles). | Progression-free survival based on the Kaplan-Meier method is defined as the duration of time from study entry to documented disease progression (PD) requiring removal from the study or death. Patients alive and progression-free at last follow-up are censored. Per RECIST 1.0 criteria: progressive disease is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions. |
Countries
United States
Participant flow
Recruitment details
Patients (n=38) were enrolled between September 2006 and March 2008.
Participants by arm
| Arm | Count |
|---|---|
| Docetaxel, Cisplatin, Irinotecan and Bevacizumab (TPCA) Patients received bevacizumab 10 mg/kg IV on day 1 every 3 weeks while on study. Additionally, they received docetaxel 30 mg/m2 IV over 30 minutes, followed by cisplatin 25 mg/m2 IV over 30 minutes, followed by irinotecan 50 mg/m2 IV over 30 minutes on days 1 and 8 of each 3-week cycle until disease progression or unacceptable toxicity. Dose reductions were not permitted for bevacizumab although treatment could be held up to 2 months. If bevacizumab was discontinued, treatment with other agents could continue. When docetaxel, cisplatin, or irinotecan was held on day 1 of a cycle, all agents were held. | 38 |
| Total | 38 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 2 |
| Overall Study | Alternative Therapy | 1 |
Baseline characteristics
| Characteristic | Docetaxel, Cisplatin, Irinotecan and Bevacizumab (TPCA) |
|---|---|
| Age, Continuous | 58 years |
| Primary Site of Disease Esophageal | 13 Participants |
| Primary Site of Disease Gastric | 16 Participants |
| Primary Site of Disease Gastroesophageal junction | 9 Participants |
| Race/Ethnicity, Customized Black or African American | 2 Participants |
| Race/Ethnicity, Customized Hispanic | 3 Participants |
| Race/Ethnicity, Customized White | 33 Participants |
| Region of Enrollment United States | 38 Participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 32 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 37 / 38 |
| serious Total, serious adverse events | 30 / 38 |
Outcome results
Primary
10-month Progression-Free Survival Rate
10-month progression-free survival rate is the probability of patients remaining alive and progression-free at 10-months from study entry estimated using Kaplan-Meier methods. Per RECIST 1.0 criteria: progressive disease (PD) is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions.
Time frame: Disease was evaluated radiologically at baseline and every 2 cycles on treatment; Treatment continued until disease progression or unacceptable toxicity. Relevant for this endpoint was disease status at 10 months.
Population: The analysis dataset is comprised of all enrolled patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Docetaxel, Cisplatin, Irinotecan and Bevacizumab (TPCA) | 10-month Progression-Free Survival Rate | 40.0 probability (%) |
Secondary
Best Response
Best response on treatment was based on RECIST 1.0 criteria: Complete Response (CR) is complete disappearance of all target lesions; Partial Response (PR) is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. Both require confirmation no fewer than 4 weeks apart. CR/PR assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions. Progressive disease (PD) is at least a 20% increase in the sum of longest diameter of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions. Stable disease is defined as any condition not meeting above criteria.
Time frame: Disease was evaluated radiologically at baseline and every 2 cycles on treatment. Treatment continued until disease progression or unacceptable toxicity. Treatment duration was a median of 6 cycles/18 weeks given 3-week cycle length (range 1-26 cycles).
Population: The analysis dataset is comprised of all treated and evaluable patients.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Docetaxel, Cisplatin, Irinotecan and Bevacizumab (TPCA) | Best Response | Partial Response | 23 participants |
| Docetaxel, Cisplatin, Irinotecan and Bevacizumab (TPCA) | Best Response | Stable Disease | 7 participants |
| Docetaxel, Cisplatin, Irinotecan and Bevacizumab (TPCA) | Best Response | Progressive Disease | 5 participants |
Secondary
Overall Survival
Overall survival is defined as the time from study entry to death or date last known alive and estimate using Kaplan-Meier (KM) methods.
Time frame: Patients in the study cohort were followed for a median of 12.2 month (up to 40 months).
Population: The analysis dataset is comprised of all enrolled patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Docetaxel, Cisplatin, Irinotecan and Bevacizumab (TPCA) | Overall Survival | 14.9 months |
Secondary
Progression-Free Survival
Progression-free survival based on the Kaplan-Meier method is defined as the duration of time from study entry to documented disease progression (PD) requiring removal from the study or death. Patients alive and progression-free at last follow-up are censored. Per RECIST 1.0 criteria: progressive disease is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions.
Time frame: Disease was evaluated radiologically at baseline and every 2 cycles on treatment. Treatment continued until disease progression or unacceptable toxicity. Treatment duration was a median of 6 cycles/18 weeks given 3-week cycle length (range 1-26 cycles).
Population: The analysis dataset is comprised of all enrolled patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Docetaxel, Cisplatin, Irinotecan and Bevacizumab (TPCA) | Progression-Free Survival | 8.9 months |