2005;56:47C60. grade 2 leukoencephalopathy. Best clinical response was partial response (PR) in three patients (17.7%, 90%CI 5,0C39.6), 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). Brimonidine 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. with a combination of mTOR inhibition (rapamycin) and VEGF blockade (bevacizumab) in VEGFR2+ melanomas [7]. Additional anti-tumor synergy was expected by blocking VEGF-mediated angiogenesis. Thus, Brimonidine we performed a Cancer Therapy Evaluation Program (CTEP)-sponsored phase II clinical trial of combination therapy with temsirolimus and bevacizumab in patients with advanced melanoma (NCI protocol # 7190, “type”:”clinical-trial”,”attrs”:”text”:”NCT00397982″,”term_id”:”NCT00397982″NCT00397982). This combination had the potential to impact systemic immune function: temsirolimus is usually converted in vivo to sirolimus in vivo, and sirolimus has known immunosuppressive effects [12C16], but also can improve CD8+ T cell memory [17C19]. Also VEGF blockade can improve T cell immunity and dendritic cell function [20C23]. Combinations of immune and targeted therapies can be considered if the targeted therapies preserve or potentiate immune function. The primary aim of the study was to estimate the objective response rate (ORR) with the combination therapy. Other aims included toxicity assessment and correlative studies of mTOR signaling and histologic changes in tumor, as well as effects on Rabbit Polyclonal to Caspase 6 (phospho-Ser257) immune function, to guide future combinations of molecular targeted therapy with immune therapy. Methods Patients Patients with American Joint Committee on Cancer stage III to IV melanoma, with measurable disease, were eligible. Other inclusion criteria included age 18 or older, weight at least 110 pounds, Eastern Cooperative Oncology Group performance status 0C1, adequate hepatic, renal, and hematopoietic function (details in Supplemental Text), and ability to provide informed consent. Exclusion criteria included other therapy in the preceding 4 weeks, nitrosoureas or mitomycin C within 6 weeks, uncontrolled brain metastases, allergy to or prior treatment with temsirolimus or bevacizumab, other acute illness, clinically significant cardiovascular disease, pregnancy or nursing, HIV or Hepatitis C contamination, and uncontrolled diabetes. The study also required tumor accessible for biopsy at three time points but was modified after 11 patients were enrolled, to allow enrollment without biopsiable disease. Patients were studied after informed consent and with institutional review board (#12471) and US Food and Drug Administration approval (CTEP IND# 61010 & 7921). The trial was registered with ClinicalTrials.gov (“type”:”clinical-trial”,”attrs”:”text”:”NCT00397982″,”term_id”:”NCT00397982″NCT00397982). Clinical Trial Design The main objective of this study was to estimate the objective response (CR + PR) rate (ORR) in participants treated with CCI-779 (temsirolimus, 25 mg IV weekly) and bevacizumab (10 mg IV every 2 weeks). Secondary objectives included: to describe the adverse event profile, and to obtain preliminary assessments of pre- and post-treatment measurements of biomarkers and vascular and immune system parameters in these participants. Tumor biopsies were obtained pretreatment (Cycle 1, Day 1, C1D1, 0h), 24h after temsirolimus only (C1D2, at 24h), and 24h after treatment with both brokers (C2D8, D23) (Schema, Physique 1). Treatment lasted up to 26 cycles (1 year). Open in a separate window Physique 1 Clinical trial schematicDrug treatment (top row) and tissue and blood collection (bottom row) are indicated. DLT, dose-limiting toxicity. The study was designed to differentiate between objective response rates (ORR) of 5% and 25%, with a two-stage design. For the first stage, 13 eligible participants Brimonidine were accrued. If no objective responses had been observed in Brimonidine the first 13 participants, accrual would halt, and the null hypothesis would be accepted. If 1 or more (8%) objective responses were observed, accrual would continue to the second stage, with up to 7 additional eligible participants..