Cisplatin, Irinotecan and Bevacizumab (PCA) Versus Docetaxel, Cisplatin, Irinotecan and Bevacizumab (TPCA) in Metastatic Esophageal and Gastric Cancer

Study Overview
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Brief Summary
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There is no clear standard of care for metastatic stomach or esophageal cancer in the United States. The purpose of this research study is to determine the differences between two regimens of chemotherapy; Arm A: PCA (Cisplatin, Irinotecan and Bevacizumab) and Arm B: TPCA (Docetaxel, Cisplatin, Irinotecan and Bevacizumab). Docetaxel, Cisplatin, and Irinotecan are traditional chemotherapy drugs. Bevacizumab is an antibody (a protein that attacks a foreign substance in the body). Bevacizumab is believed to stop the formation of new blood vessels that carry nutrients to tumors. Both of the chemotherapy regimens (PCA and TPCA) have been studied in patients with esophageal and gastric cancer, and we are trying to determine if one regimen will keep your cancer from growing and improve how long you can live.

Detailed Description
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OBJECTIVES: Primary * To evaluate progression-free survival at 7 months in metastatic esophageal and gastric patients treated with either PCA or TPCA Secondary To determine overall survival To determine the response rate (RECIST) in measurable disease patients To evaluate type and severity of toxicities associated with each regimen Exploratory: To correlate expression of tumoral and serum VEGF with response and survival To correlate TGF alpha levels and tumor microvessel density with clinical activity of the combination of PCA or TPCA To examine circulating endothelial cells (CECs) as surrogate markers of antitumor activity of bevacizumab 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 DESIGN: This trial was designed to compare 7-month progression-free survival between arms. The hypothesis was that TPCA would have superior outcome over PCA (70% vs 50%). With 40 eligible patients per arm followed for 1 year there was 80% power to detect a hazard ratio of 0.48 using the log-rank test at a one-sided type I error rate of 5%. Stratification factors were ECOG performance status 0/1 vs 2 and site of primary tumor (gastric vs GE junction/esophageal).

Official Title
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A Randomized, Multicenter, Phase II Trial of Cisplatin, Irinotecan and Bevacizumab (PCA) vs. Docetaxel, Cisplatin, Irinotecan and Bevacizumab (TPCA) in Metastatic Esophageal and Gastric Cancer

Conditions
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Esophageal Cancer, Gastric Cancer, Stomach Cancer

Intervention / Treatment
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* Drug: Bevacizumab
* Drug: Cisplatin
* Drug: Irinotecan
* Device: Docetaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed, unresectable esophageal, GE junction or gastric adenocarcinoma (including adenosquamous, or undifferentiated carcinoma). Measurable disease is not required. 18 years of age or older ECOG Performance Status=2 Life expectancy of 12 weeks or greater Adequate bone marrow, renal and liver function as outlined in the protocol. Men and women of childbearing potential must use adequate contraception Exclusion Criteria: Prior chemotherapy (except as part of pre- or post-operative therapy, completed at least 1 prior to start of this protocol). Squamous cell carcinoma histology of esophageal, GE junction or gastric tumor Known history of allergy or hypersensitivity to Chinese hamster ovary products, polysorbate 80, or any of the study drugs Treatment or planned participation in an experimental drug study within 4 weeks of C1 D1. Concurrent use of herbal medications or other alternative therapies Major surgical procedures, such as fine needle aspirations, port-a-cath placement, or core biopsies, within 7 days of cycle 1 day 1 Palliative radiation to 25% or less of bone marrow, must be completed > 2 weeks prior to day 1, palliative radiation to > 25% of bone marrow, must be completed > 4 weeks prior to day 1 Myocardial infarction, unstable angina, CVA or TIA or other thrombotic event in the past six months Inadequately controlled hypertension (defined as systolic blood pressure of >150mmHg and/or diastolic blood pressure of > 100mmHg). Initiation of antihypertensive medication is recommended, however adequate control of blood pressure must be documented prior to C1 D1 No history of prior hypertensive crisis or hypertensive encephalopathy NYHA Grade II or greater congestive heart failure Clinically significant peripheral vascular disease Active bleeding from primary tumor Evidence of bleeding diatheses or coagulopathy (other than deep venous thrombosis, portal vein thrombosis, pulmonary embolism, or atrial fibrillation). Patients on therapeutic anticoagulation may be enrolled provided they have been clinically stable on anticoagulation for a least 2 weeks prior to C1 D1. Uncontrolled serious medical or psychiatric illness Uncontrolled diarrhea Peripheral neuropathy No known brain or other CNS metastasis by history or clinical examination Other active malignancy other than non-melanoma skin cancer or in-situ cervical carcinoma. A resected or previously treated cancer (other than in-situ carcinoma) must have demonstrated no evidence of recurrence for at least 3 years Urine protein:creatinine ratio 1.0 or greater at screening History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess with 6 months of C1 D1 Serious, non-healing wound, ulcer or bone fracture Pregnant or breast feeding Inability to comply with study and/or follow-up procedures History of HIV seropositivity, hepatitis C virus, acute or chronic hepatitis B, or other serious chronic infection

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A: PCA<br>Patients first received bevacizumab 10 mg/kg IV on day 1 of every cycle (cycle length=21 days) at approximately 0.5 mg/kg/minute. Additionally, on days 1 and 8 of each cycle, patients received cisplatin 30 mg/m2 IV over 30 minutes and then irinotecan 65 mg/m2 IV over 30 minutes of each 3-week cycle. Treatment could continue until disease progression or unacceptable toxicity. | Drug: Bevacizumab<br> <br> * Other names: Avastin;Drug: Cisplatin<br> <br> * Other names: Platinol;Drug: Irinotecan<br> <br> * Other names: Camptosar;|
| Active Comparator: Arm B: TPCA<br>Patients first received bevacizumab 10 mg/kg IV on day 1 of every cycle (cycle length=21 days) at approximately 0.5 mg/kg/minute. Additionally on days 1 and 8 of each cycle, patients received docetaxel 30 mg/m2 IV over 30 minutes followed by cisplatin 25 mg/m2 IV over 30 minutes and then irinotecan 50 mg/m2 IV over 30 minutes of each 3-week cycle. | Drug: Cisplatin<br> <br> * Other names: Platinol;Drug: Irinotecan<br> <br> * Other names: Camptosar;Device: Docetaxel<br> <br> * Other names: Docefrez;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 7-month Progression-Free Survival | 7-month progression-free survival is the probability of patients remaining alive and progression-free at 7-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. | Disease was evaluated radiologically at baseline and every 2 cycles on treatment; Relevant for this endpoint was disease status at 7 months of follow-up. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Patients in the study cohort were followed up to approximately 2.5 years as of this analysis. | 
| 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. | Disease was evaluated radiologically at baseline and every 2 cycles on treatment; Treatment duration was a median of 5 cycles (up to approximately 1 year) in this study cohort as of this analysis.. | 
| Overall Response (OR) Rate | Overall response (OR) rate was defined as achieving partial response (PR) or complete response (CR) based on RECIST 1.0 criteria on treatment. Per RECIST 1.0 for target lesions, CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. To be assigned a status of CR or PR, changes in tumor measurements must be confirmed by repeat assessments performed no fewer than 4 weeks after the response criteria are first met. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions. | Disease was evaluated radiologically at baseline and every 2 cycles on treatment; Treatment duration was a median of 5 cycles (up to approximately 1 year) in this study cohort as of this analysis. | 
| 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. | Disease was evaluated radiologically at baseline and every 2 cycles on treatment; Patients were followed for up to 2.5 years as of this analysis. |