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Slingluff CL Jr , Petroni GR , Molhoek KR , Brautigan DL , Chianese-Bullock KA , Shada AL , Smolkin ME , Olson WC , Gaucher A , Chase CM , Grosh WW , Weiss GR , Wagenseller AG , Olszanski AJ , Martin L , Shea SM , Erdag G , Ram P , Gershenwald JE , Weber MJ
Clinical activity and safety of combination therapy with temsirolimus and bevacizumab for advanced melanoma: a phase II trial (CTEP 7190/Mel47)
Clin Cancer Res. 2013 Jul 1;19(13) :3611-20
PMID: 23620404    PMCID: PMC3700572    URL: https://www.ncbi.nlm.nih.gov/pubmed/23620404
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PURPOSE: A CTEP-sponsored phase II trial was conducted to evaluate safety and clinical activity of combination therapy with CCI-779 (temsirolimus) and bevacizumab in patients with advanced melanoma. EXPERIMENTAL DESIGN: Patients with unresectable stage III to IV melanoma were treated intravenously with temsirolimus 25 mg 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 protein kinases and histology of tumor biopsies and immune function in peripheral blood. RESULTS: Seventeen patients were treated. Most patients tolerated treatment well, but 2 had grade 4 lymphopenia and 1 developed reversible grade 2 leukoencephalopathy. Best clinical response was partial response (PR) in 3 patients [17.7%, 90% confidence interval (CI) 5, 0-39.6], stable disease at 8 weeks (SD) in 9 patients, progressive disease (PD) in 4 patients, and not evaluable in 1 patient. Maximal response duration for PR was 35 months. Ten evaluable patients had BRAF(WT) tumors, among whom 3 had PRs, 5 had SD, and 2 had PD. Correlative studies of tumor biopsies revealed decreased phospho-S6K (d2 and d23 vs. d1, P < 0.001), and decreased mitotic rate (Ki67(+)) among 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. CONCLUSION: These data provide preliminary evidence for clinical activity of combination therapy with temsirolimus and bevacizumab, which may be greater in patients with BRAF(wt) melanoma. Mixed effects on immunologic function also support combination with immune therapies.
Slingluff, Craig L Jr Petroni, Gina R Molhoek, Kerrington R Brautigan, David L Chianese-Bullock, Kimberly A Shada, Amber L Smolkin, Mark E Olson, Walter C Gaucher, Alison Chase, Cheryl Murphy Grosh, William W Weiss, Geoffrey R Wagenseller, Aubrey G Olszanski, Anthony J Martin, Lainie Shea, Sofia M Erdag, Gulsun Ram, Prahlad Gershenwald, Jeffrey E Weber, Michael J eng R01 GM56362/GM/NIGMS NIH HHS/ P30 CA44579/CA/NCI NIH HHS/ Clinical Trial, Phase II Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Clin Cancer Res. 2013 Jul 1;19(13):3611-20. doi: 10.1158/1078-0432.CCR-12-3919. Epub 2013 Apr 25.