Sorafenib in combination with gemcitabine in recurrent epithelial ovarian cancer: a study of the Princess Margaret Hospital Phase II Consortium.

OBJECTIVES: Antiangiogenic strategies have demonstrated efficacy in epithelial ovarian cancer (EOC). Sorafenib is a novel multitargeted kinase inhibitor with antiangiogenic activity. Gemcitabine has known activity against EOC. A phase 1 clinical trial of this combination suggested activity in ovarian cancer with no dose-limiting toxicity. This phase 2 study was designed to examine the safety and efficacy of gemcitabine and sorafenib in patients with recurrent EOC. METHODS: Patients with recurrent EOC after platinum-based chemotherapy and who had subsequently received up to 3 prior chemotherapy regimens were eligible. Gemcitabine (1000 mg/m intravenous [IV]) was administered weekly for 7 of 8 weeks in the first cycle, then weekly for 3 weeks of each subsequent 4-week cycle. Sorafenib (400 mg p.o. bid) was given continuously. The primary end point for this trial was objective response rate by the Response Evaluation Criteria in Solid Tumors. Secondary endpoints included Gynecologic Cancer Intergroup (GCIG) CA-125 response, time to progression, overall survival, and toxicity. RESULTS: Forty-three patients were enrolled, and 33 completed at least 1 cycle. Two patients had a partial response (Response Evaluation Criteria in Solid Tumors objective response rate = 4.7%). Ten patients (23.3%) maintained response or stable disease for at least 6 months. GCIG CA-125 response was 27.9%. The median time to progression was 5.4 months, and the median overall survival was 13.0 months. Hematologic toxicity was common but manageable. The most common nonhematologic adverse events were hand-foot syndrome, fatigue, hypokalemia, and diarrhea. CONCLUSION: This trial of gemcitabine and sorafenib in recurrent EOC did not meet its primary efficacy end point, but the combination was associated with encouraging rates of prolonged stable disease and CA-125 response.

Relevant molecular markers and targets.

Ovarian cancer is a heterogeneous disease with extensive cytogenetic and molecular heterogeneity including aneuploidy, chromosomal alterations, mutations and overexpression as well as a natural propensity to disseminate and spread, making it difficult to diagnose at an early stage. Insights into the molecular mechanisms operative in cancer development, progression and metastasis have uncovered a wide array of targets for therapeutic intervention. In the absence of a common driving oncogene in ovarian cancer, single targeted therapy for this disease is unlikely to yield significant clinical benefit. Tailored approaches that combine molecular targeting agents with cytotoxic regimens hold great promise when used in primary treatment, during consolidation and maintenance therapy, and in the treatment of persistent or recurrent disease. The most promising treatment strategies are those that target the drivers of tumorigenesis and enhance the activity of cytotoxic agents. Receptor tyrosine kinases, non-receptor tyrosine kinases, serine/threonine kinases, transferases, proteases and deacetylases are among the relevant molecular markers and targets for ovarian cancer that are discussed. Collaboration, coordination, creativity and aggressive outreach to patients and their advocates are essential for success in running the concurrent trials with multiple clinical end points and embedded translational research that are needed to evaluate the array of promising targeted therapeutics and combinations. Validated biomarkers, surrogate specimens and end points, and additional clinically relevant in vitro and in vivo models for ovarian cancer are needed to facilitate the drug development and evaluation process, and ultimately to make meaningful improvements in the diagnosis, prevention and management of ovarian cancer.