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

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.

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