Purpose: A CTEP-sponsored phase II trial was performed to evaluate safety and clinical activity of combination therapy with CCI-779 (temsirolimus) and bevacizumab in patients with advanced melanoma. Experimental Design: Seventeen patients with unresectable stage III to IV melanoma were treated intravenously with temsirolimus 25mg weekly and bevacizumab 10 mg every 2 weeks. Adverse events were recorded using CTCAE v3.0. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors, and overall survival was recorded. Correlative studies measured changes in protein kinases and histology of tumor biopsies, and immunologic changes in peripheral blood. Results: Treatment was well-tolerated in most patients; 2 patients had grade 4 lymphopenia and one patient developed reversible grade 2 leukoencephalopathy. Among 17 patients, best overall response was partial response (PR) in three patients (18%), stable disease at 8 weeks (SD) in 9 patients, and progressive disease (PD) in 4 patients. One patient was not evaluable for clinical response. Maximal response duration was 35 months. Ten evaluable patients had BRAFWT tumors, among whom 3 had PRs, 5 had SD, and 2 had PD. Correlative studies in tumor biopsies revealed decreased phospho-S6K (d2 and d23 vs d1, p<0.001), and decreased mitotic (Ki67+) melanoma cells by d23 (p=0.007). Effects on immune functions were mixed, with decreased alloreactive T cell responses and decreased circulating CD4+FoxP3+ cells. Conclusions: These data provide evidence for clinical activity of combination therapy with temsirolimus and bevacizumab, that may be greater in patients with BRAFwt melanoma. Preservation of immunologic function also supports combination with immune therapies.
- Received December 27, 2012.
- Revision received March 27, 2013.
- Accepted April 9, 2013.
- Copyright © 2013, American Association for Cancer Research.