Gemcitabine, Oxaliplatin in Combination With Bevacizumab in Patients With Hepatocellular Carcinoma

Phase II Study of Gemcitabine, Oxaliplatin in Combination With Bevacizumab (Avastin) in Patients With Hepatocellular Carcinoma

Dana-Farber Cancer Institute, Beth Israel Deaconess Medical Center, Brigham and Women's Hospital, Genentech, Inc., Sanofi-Synthelabo, Eli Lilly and Company

The purpose of this study is to test the safety of bevacizumab when given in combination with gemcitabine and oxaliplatin and to see what effects (good or bad) it has on patients with hepatocellular carcinoma.

Treatment is given in cycles, each cycle (except for cycle 1) is 4 weeks long. Cycle 1 is only 2 weeks long. During cycle one only, bevacizumab will be given intravenously on day one. Two weeks after receiving bevacizumab, the patient will return to the clinic for treatment with all 3 study drugs. During cycle 2 and every cycle thereafter patients will receive; bevacizumab intravenously on day one and day 15; gemcitabine intravenously on day 2 and day 16; oxaliplatin intravenously on day 2 and day 16. The following evaluations will be conducted on day 1 and day 15 of each cycle (once every 2 weeks): physical examination, vital signs, medical history, blood tests and urine tests. Tumor measurements done by CT and/or MRI will be repeated at the end of cycle 3 and every 2 cycles thereafter. Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI) of the liver and Perfusions CT scans will also be done on days 10-12 following bevacizumab treatment during cycle 1, and the Perfusion CT will be repeated at the end of cycle 3. Once study treatment is stopped the following evaluations will be performed: physical exam, vital signs, blood work, urine tests, CT scan of chest, abdomen and pelvis, and tumor measurements by CT or MRI scans. Follow-up will consist of physical examinations and blood tests every 6 months. Patients will continue to receive study treatment as long as there is no disease progression or unacceptable side affects.

Unresectable hepatocellular carcinoma, Metastatic hepatocellular carcinoma, gemcitabine, oxaliplatin, bevacizumab, Avastin

For cycle 1 (14 days), bevacizumab 10 mg/kg was administered alone on day 1. For cycle 2 and beyond (28 days/cycle), bevacizumab 10 mg/kg was administered on days 1 and 15, gemcitabine 1,000 mg/m2 was administered as a dose rate infusion at 10 mg/m2/min followed by oxaliplatin at 85 mg/m2 on days 2 and 16. All drugs were administered intravenously until progression, intolerance, patient withdrawal, or death.

Time to disease progression of gemcitabine, oxaliplatin and bevacizumab regimen in patients with hepatocellular carcinoma.

From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 years

Inclusion Criteria: Unresectable or metastatic hepatocellular carcinoma Measurable tumors Adequate hepatic function: total bilirubin < 3.0mg/dl; AST < 7x ULN Adequate bone marrow function: ANC > 1,000/mm3; platelets > 75,000/mm3 INR < 1.5 for those who are not on anticoagulation Up to two prior chemotherapy regimens for hepatocellular carcinoma 18 years of age or older ECOG performance status of 0-1 Life expectancy of > 12 weeks Exclusion Criteria: Clinically apparent central nervous system metastases or carcinomatous meningitis Uncontrolled serious medical or psychiatric illness Pregnant or lactating women Current or recent (within 4 weeks of first study infusion) participation in experimental study drug Uncontrolled hypertension Significant proteinuria Serious, non-healing wound, ulcer, or bone fracture Evidence of bleeding diathesis or coagulopathy