Avastin and Tarceva for Upper Gastrointestinal Cancers

Primary Objective

• To determine the median time to progression (TTP) and response rate (RR) of the combination of erlotinib and bevacizumab in patients with advanced upper gastro-intestinal carcinomas, refractory or intolerant to standard systemic therapy.

Secondary Objective

• To determine safety, tolerability and toxicity.
• To determine median and overall survival (OS).
• To correlate efficacy of treatment with the expression of tumor markers obtained in serum (EFGR, bFGF, p-VEGF-A, and sVEGF-R2), in paraffin embedded tumor tissue (micro vessel density (MVD), and expression of VEGFR and EGFR, after immunostaining), and in fresh frozen tumor biopsies (micro array-based analyses of patterns of gene expression).

Treatment:

Bevacizumab (AvastinÒ) will be given intravenously at 10 mg/kg every other week.

Erlotinib is given as an orally daily dose and most be taken at least one hour before or two hours after ingestion of food.

Inclusion criteria

• Histologically or cytologically verified carcinoma of the gall bladder or bile ducts.
• PS 0-1 (ECOG scale)
• Age > 18 years
• Life expectancy > 3 months
• Sufficient organ function, defined as:

• Platelets > 100 x 109/liter
• Leukocytes > 3,0 x 109/liter
• ACN > 1,5 x 109/liter
• ASAT and/or ALAT < 3 x upper normal limit
• Bilirubin < 1,5 x upper normal limit
• EDTA clearance > 45 ml/min
• APTT and INR < normal limit
• Fertile females must use oral contraceptive, IUD (intrauterine device) or preservatives. Fertile males must use preservatives.

Exclusion criteria

• Radiotherapy or chemotherapy within the last 4 weeks
• Co-medication that may interfere with study results; e.g. immuno-suppressive agents other than corticosteroids
• Any prior EGFR- or VEGFR-based therapy
• Any condition (medical, social, psychological), which would prevent adequate information and follow-up
• Tumor located close to major blood vessels and judged to possess a high risk of serious bleeding
• Any other active malignancy, except basal or squamous cell carcinoma of the skin, or carcinoma in situ
• Any significant cardiac disease (New York Heart Association Class II or greater), significant arrythmia, congestive heart failure, acute myocardial infarction within 6 months or unstable angina pectoris
• Clinically significant peripheral vascular disease
• Evidence of coagulopathy
• Use of ASA, NSAIDs or clopidogrel
• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to treatment, anticipation of need for major surgical procedure during the curse of the study

o Minor surgical procedures, fine needle aspirations or core biopsies within 7 days prior to treatment

• History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 6 month prior to treatment
• Any ongoing infection, uncontrolled diabetes mellitus, serious non-healing wound or ulcer
• Pregnancy or breast feeding
• Ongoing therapeutic anti-coagulation
• Hypertension with blood pressure > 150/100 mmHg