Combination therapy: intermittent sorafenib with bevacizumab yields activity and decreased toxicity

• Published in: British journal of cancer Vol. 102; no. 3; pp. 495 - 499
• Main Authors: LEE, J.-M, SAROSY, G. A, ANNUNZIATA, C. M, AZAD, N, MINASIAN, L, KOTZ, H, SQUIRES, J, HOUSTON, N, KOHN, E. C
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 02.02.2010
• Subjects: Adult; Aged; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - adverse effects; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Benzenesulfonates - administration & dosage; Benzenesulfonates - adverse effects; Bevacizumab; Biological and medical sciences; Blood pressure; Cancer research; Cancer therapies; Chemotherapy; Clinical Study; Creatinine; Female; Female genital diseases; Growth factors; Gynecology. Andrology. Obstetrics; Humans; Hypertension; Immunotherapy; Kinases; Maximum Tolerated Dose; Medical research; Medical sciences; Middle Aged; Neoplasms, Glandular and Epithelial - drug therapy; Niacinamide - analogs & derivatives; Oncology; Ovarian cancer; Ovarian Neoplasms - drug therapy; Patients; Phenylurea Compounds; Proteins; Pyridines - administration & dosage; Pyridines - adverse effects; Response rates; Toxicity; Tumors; Urine; United States > US; Antineoplastic agent; Tyrosine kinase inhibitor; Toxicity; ovarian cancer; Ovary cancer; Enzyme inhibitor; Monoclonal antibody; Malignant tumor; Biological activity; Female genital diseases; Bevacizumab; Ovarian diseases; Cancerology; Vascular endothelium growth factor; Sorafenib; anti-angiogenesis; Combined treatment; Multikinase inhibitor; Antiangiogenic agent; Cancer
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/sj.bjc.6605514

We previously reported preliminary results of our phase I study of continuous daily sorafenib with bevacizumab every other week for solid tumours. Toxicity was moderate, leading to additional dose levels (DL) testing intermittent sorafenib dosing. Seventeen patients with advanced solid tumours were treated on three additional DLs testing sorafenib days 1-5 per week. Dose level 4 was sorafenib 200 mg twice daily (b.i.d.) and bevacizumab 5 mg kg(-1). DL5 alternated between bevacizumab 10 mg kg(-1)-sorafenib 200 mg b.i.d. (A) and sorafenib 400 mg b.i.d. with bevacizumab 5 mg kg(-1) (B). Outcome and toxicity data from 19 epithelial ovarian cancer (EOC) patients from DL 1-5 were analysed. Fewer patients required sorafenib dose reduction with the intermittent schedule (41 vs 74% daily, P=0.01). Hand-foot skin reaction (HFSR) remained the primary cause of dose reduction (n=5). Partial responses (12%) or disease stabilisation > or =4 months (53%; median 6 (4-26)) occurred in most patients on the intermittent schedule. Partial response occurred in 47% EOC patients treated in pooled analysis of duration 4-37 months. Intermittent sorafenib dosing with bevacizumab has promising clinical activity and less sorafenib dose reduction and side effects, but does not ameliorate HFSR. We are conducting a phase II clinical trial with intermittent sorafenib and bevacizumab in patients with EOC.