Dose Finding and Early Efficacy Study of Gemcitabine Plus Capecitabine in Combination With Bevacizumab Plus Erlotinib in Advanced Pancreatic Cancer

• Published in: Journal of clinical oncology Vol. 27; no. 33; pp. 5499 - 5505
• Main Authors: STARLING, Naureen, WATKINS, David, CUNNINGHAM, David, THOMAS, Janet, WEBB, Janine, BROWN, Gina, THOMAS, Karen, OATES, Jacqui, CHAU, Ian
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Society of Clinical Oncology 20.11.2009
• Subjects: Adult; Aged; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - adverse effects; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Bevacizumab; Biological and medical sciences; Capecitabine; Deoxycytidine - administration & dosage; Deoxycytidine - adverse effects; Deoxycytidine - analogs & derivatives; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Erlotinib Hydrochloride; Female; Fluorouracil - administration & dosage; Fluorouracil - adverse effects; Fluorouracil - analogs & derivatives; Follow-Up Studies; Gastroenterology. Liver. Pancreas. Abdomen; Humans; Infusions, Intravenous; Kaplan-Meier Estimate; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; Maximum Tolerated Dose; Medical sciences; Middle Aged; Neoplasm Invasiveness - pathology; Neoplasm Staging; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - mortality; Pancreatic Neoplasms - pathology; Probability; Quinazolines - administration & dosage; Quinazolines - adverse effects; Risk Assessment; Survival Analysis; Time Factors; Treatment Outcome; Tumors; Antineoplastic agent; Gemcitabine; Capecitabine; Quinazoline derivatives; Monoclonal antibody; Bevacizumab; Cancerology; Pancreas cancer; Advanced stage; Antiangiogenic agent; Protein-tyrosine kinase; Pyrimidine nucleoside; Dose; Pancreatic disease; Drug combination; Enzyme; Tyrosine kinase inhibitor; Fluoropyrimidine derivatives; Transferases; Treatment efficiency; Enzyme inhibitor; Malignant tumor; Prodrug; Vascular endothelium growth factor; Antimetabolic; Erlotinib; Pyrimidine derivatives; Digestive diseases; Early; Fluorine Organic compounds; Cancer
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/JCO.2008.21.5384

This study evaluated safety and efficacy of chemotherapy (gemcitabine plus capecitabine) plus bevacizumab/erlotinib in advanced pancreatic cancer because dual epidermal growth factor receptor/vascular endothelial growth factor blockade has a rational biologic basis in this malignancy. Patients with untreated, unresectable, locally advanced or metastatic pancreatic carcinoma were enrolled onto one of the following four sequential dose levels (DLs) of escalating capecitabine doses (days 1 to 21): DL1, 910 mg/m(2); DL2, 1,160 mg/m(2); DL3, 1,400 mg/m(2); or DL4, 1,660 mg/m(2). Doses of coadministered gemcitabine (1,000 mg/m(2) on days 1, 8, and 15), bevacizumab (5 mg/kg on days 1 and 15), and erlotinib (100 mg/d) every 28 days (up to six cycles) were fixed. Using a 3+3 study design, dose-limiting toxicity (DLT) was assessed in cycle 1. Results Twenty assessable patients were enrolled (DL1, n = 8; DL2, n = 3; DL3, n = 6; and DL4, n = 3); 97 cycles were administered. Median age was 63 years (range, 33 to 77 years), and male-to-female ratio was 10:10. Performance status was 0 and 1 in two and 17 patients, respectively; and nine and 11 patients had locally advanced and metastatic disease, respectively. DLT occurred in one patient at DL1 (grade 3 epistaxis) and two patients at DL4 (grade 3 diarrhea and grade 3 skin rash > 7 days). Common grade 3 and 4 toxicities (10% to 20%) were diarrhea, hand-foot syndrome, stomatitis, and skin rash. Grade 3 lethargy and grade 3 or 4 neutropenia occurred in 40% and 45% of patients, respectively. No GI perforation, grade 3 GI hemorrhage/hypertension, or pneumonitis occurred. Ten partial responses were observed. Median overall and progression-survival times (all patients) were 12.5 and 9.0 months, respectively. The maximum-tolerated dose of capecitabine was 1,660 mg/m(2). The recommended capecitabine dose in this cytotoxic doublet/biologic doublet regimen is 1,440 mg/m(2); this regimen is under evaluation in an ongoing phase II study.