A Phase I Trial of BAY 43-9006 (Sorafenib) and Bevacizumab in Refractory Solid Tumors With Biologic and Proteomic Analysis

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.