The results from a recent Phase I solid tumor clinical trial indicate that combination targeted therapy with sorafenib and bevacizumab produces anti-tumor activity (and enhanced toxicity) with respect to 43% of the ovarian cancer patients enrolled in that trial. Sorafenib (Nexavar®) inhibits the Raf kinase and vascular endothelial growth factor (VEGF) receptor. Bevacizumab (Avastin®) is a monoclonal antibody targeted against VEGF.

Dr. Elise Kohn, Principal Trial Investigator, NCI Center for Cancer Research

The results from a recent Phase I solid tumor clinical trial indicate that combination targeted therapy with sorafenib and bevacizumab produces antitumor activity (and enhanced toxicity) with respect to 43% of the ovarian cancer patients enrolled in that trial. Sorafenib (Nexavar®) inhibits the Raf kinase and vascular endothelial growth factor (VEGF) receptor. Bevacizumab (Avastin®) is a monoclonal antibody targeted against VEGF. The trial is sponsored by the National Cancer Institute (NCI) and Elise Kohn is the principal trial investigator.

The patients enrolled in the trial had advanced solid tumors, with Eastern Cooperative Oncology Group performance status of 0 to 1. A phase I dose-escalation trial of sorafenib and bevacizumab was initiated at below-recommended single-agent doses because of possible overlapping toxicity: sorafenib 200 mg orally twice daily and bevacizumab intravenously at 5 mg/kg (dose level (DL1)) or 10 mg/kg (dose level (DL2)) every 2 weeks. Additional patients were enrolled at the maximum-tolerated dose (MTD).

Thirty-nine patients were treated under the trial protocol. DL1 was the MTD and was administered to 27 patients. Dose-limiting toxicity in DL2 was grade 3 proteinuria and thrombocytopenia. Adverse events included hypertension, hand-foot syndrome, diarrhea, transaminitis, and fatigue. Partial responses (PRs) were seen in six (43%) of 13 patients with ovarian cancer (response duration range, 4 to 22+ months) and one of three patients with renal cell cancer (response duration, 14 months). PR or disease stabilization ≥ 4 months (median, 6 months; range, 4 to 22+ months) was seen in 22 (59%) of 37 assessable patients. The majority (74%) required sorafenib dose reduction to 200 mg/orally at a median of four cycles (range, one to 12 cycles).

The trial investigators concluded that combination therapy with sorafenib and bevacizumab has promising clinical activity, especially in patients with ovarian cancer. The trial investigators also noted that the rapidity and frequency of sorafenib dose reductions indicates that sorafenib at 200 mg twice daily with bevacizumab 5 mg/kg every 2 weeks may not be tolerable long term, and alternate sorafenib dosing schedules should be explored.

Source: Combination targeted therapy with sorafenib and bevacizumab results in enhanced toxicity and antitumor activity; Azad NS et. al., J Clin Oncol. 2008 Aug 1;26(22):3709-14.

Additional Information:

• Phase I solid tumor clinical trial protocol underlying study discussed above: Phase I Randomized Study of Sorafenib and Bevacizumab in Patients With Refractory, Metastatic, or Unresectable Solid Tumors.
• Targeted Combination Therapy for Advanced Solid Tumors, Featured Clinical Trials, Cancer Studies Highlighted in the NCI Cancer Bulletin, National Cancer Institute, July 19, 2005.
• For a list of open ovarian cancer clinical trials using sorafenib & bevacizumab, click here.
• For a list of open solid tumor clinical trials using sorafenib & bevacizumab, click here.
• For National Cancer Institute (NCI) patient information regarding sorafenib, click here.
• For National Cancer Institute (NCI) patient information regarding bevacizumab, click here.