Clinical Activity and Safety of Combination Therapy with Temsirolimus and Bevacizumab for Advanced Melanoma: A Phase II Trial (CTEP 7190/Mel47)

Abstract

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 Patients with unresectable stage III to IV melanoma were treated intravenously with temsirolimus 25mg weekly and bevacizumab 10mg 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 two had grade 4 lymphopenia and one developed reversible grade 2 leukoencephalopathy. Best clinical response was partial response (PR) in three patients (17.7%, 90%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 BRAFWT 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 BRAFwt melanoma. Mixed effects on immunologic function also support combination with immune therapies.

Rapalogs Efficacy Relies on the Modulation of Antitumor T-cell Immunity

“…Our choice of models was based on rapalogs indications in renal and breast carcinoma (4,5,7) and their current evaluation in melanoma (41). In contrast with that in RENCA and 4T1 tumors, we observed that T-cell subsets can differentially shape the efficacy of rapalogs against B16-OVA tumor growth.…”

Management of hyperhidrosis

“…With a prevalence of approximately 2.8% of the US population (1.4% axillary and 0.5% palmar, by national survey),3 HH is an often overlooked disorder that has significant impact on psychosocial functioning of affected patients 4–6. A family history is often reported by patients affected by HH, supporting a basis of genetic transmission that has been explored by Ro et al7 in a recent study 2.…”

“…The diagnosis of primary HH, which is, by definition, not associated with an underlying condition, requires that other (potentially more serious) causative pathologies be ruled out 4. Secondary HH, in contrast, may be attributed to a number of other conditions, including endocrine disturbances, drugs, certain malignancies, and central nervous system abnormalities 4. HH can be further distinguished by anatomic distribution of affected regions and by laterality: unilateral versus bilateral and symmetrical 4.…”

Angiogenesis in melanoma: an update with a focus on current targeted therapies

“…Similarly, the Cancer Therapy Evaluation Program trial led by Slingluff et al showed that temsirolimus and bevacizumab elicited an objective clinical response in patients with BRAF/RAS−wild-type melanomas. These results suggest that the combination of an angiogenesis inhibitor with an mTOR pathway inhibitor (25 mg temsirolimus weekly and 10 mg bevacizumab every 2 weeks) is a promising a regimen for a subset of melanoma patients who lack activating mutations in both BRAF and RAS and for whom no targeted therapies are currently available 86. However, no study has shown that bevacizumab as monotherapy offers a significant survival benefit over conventional therapies.…”