BAY 43-9006 (Sorafenib) and Bevacizumab (Avastin) To Treat Solid Tumors

Summary

Background: * BAY 43-9006 is an inhibitor of wild-type and mutant B-Raf and c-Raf kinase isoforms in vitro, but it also inhibits p38, c-kit, VEGFR-2 and PDGFR-Beta affecting tumor growth as well as possibly promoting apoptosis by events downstream of c-Raf. * Bevacizumab is a humanized IgG1 monoclonal antibody (MAb) that binds all biologically active isoforms of human vascular endothelial growth factor (VEGF, or VEGF-A) with high affinity (k(d)= 1.1nM) * The most common adverse events associated with bevacizumab of any severity include asthenia, pain, headache, hypertension, diarrhea, stomatitis, constipation, epistaxis, dyspnea, dermatitis and proteinuria. * This Phase I trial is open to patients with all solid tumors. Objectives: * Determine the safety and toxicity of the combination of BAY 43-9006 (Sorafenib) and bevacizumab. * Determine estimates of biochemical changes in the Ras-Raf-MAPK and VEGF signal transduction pathways in tumor and stromal cells in response to treatment at the MTD, at least in a pilot fashion, if those changes are statistically significant. Eligibility: * Adults with histologically documented solid tumor malignancy that is metastatic or unresectable and for which standard curative therapies do not exist or are no longer effective. * Patients must be off prior chemotherapy, radiation therapy, hormonal therapy, or biological therapy for at least 4 weeks. * All patients enrolling in cohort 2 must have at least one lesion amenable to biopsy. * ECOG performance status 0 or 1 and adequate organ and marrow function. Design: * Cohort I will receive BAY 43-9006 and bevacizumab together at the start of study in a dose escalation fashion. * Cohort II will be randomized as to which agent they receive for cycle one. Cycles 2 and beyond are treated using both agents. * Tumor biopsies will be obtained from patients in Cohort II before treatment, two weeks into mono-therapy, and two weeks into combinatorial therapy. * DCE-MRI studies will be obtained on patients in Cohort II before treatment, two weeks into monotherapy, four weeks into monotherapy, and two weeks into combinatorial therapy. * FDG-PET studies will be obtained on patients in Cohort II before treatment, two weeks into mono-therapy, and two weeks into combinatorial therapy. * Patients will be evaluated for toxicity in clinic every 2 weeks for Cycles 1 and 2, and then every 4 weeks. * Patients will be evaluated for response every 8 weeks using the RECIST criteria. * Approximately 62 patients will be needed to achieve the objectives of the trial.

Timeline

Start

2004-11-02

Primary completion

2005-11-01

Completion

2012-07-20

Publications

• Background Campbell SL, Khosravi-Far R, Rossman KL, Clark GJ, Der CJ. Increasing complexity of Ras signaling. Oncogene. 1998 Sep 17;17(11 Reviews):1395-413. doi: 10.1038/sj.onc.1202174.
• Background Cohen Y, Xing M, Mambo E, Guo Z, Wu G, Trink B, Beller U, Westra WH, Ladenson PW, Sidransky D. BRAF mutation in papillary thyroid carcinoma. J Natl Cancer Inst. 2003 Apr 16;95(8):625-7. doi: 10.1093/jnci/95.8.625.
• Background Chong H, Vikis HG, Guan KL. Mechanisms of regulating the Raf kinase family. Cell Signal. 2003 May;15(5):463-9. doi: 10.1016/s0898-6568(02)00139-0.

Drugs

Indications