The most common toxicities were myelosuppression, nausea, vomiting, and fatigue. Phase Rucaparib clinical trial II studies have shown clinical activity as a single agent in patients with hematologic malignancies. Together, these observations coalesced to motivate inves tigation of the FTI R115777 in patients with advanced melanoma. Inasmuch as there was limited experience in evaluating tumor tissue for effective Inhibitors,Modulators,Libraries biochemical target in hibition, an integral part of the current study involved obtaining sizable tumor tissue before and during R115777 administration to measure FT enzymatic activity directly and also to assess effects on specific signaling pathways ex vivo. Many of the signaling pathways involved in melano magenesis are also involved in T cell activation, includ ing the RAS pathway.

We recently have shown that cytokine production and proliferation of T cells in re sponse to T cell receptor engagement is blocked in vitro by FTIs, suggesting that these compounds could theoretically inhibit T cell function in treated patients. Given the importance of the immune system to participate in melanoma growth control, the effect of signal Inhibitors,Modulators,Libraries transduction inhibitors on lymphocyte function has become a critical parameter to consider in the can cer context. This may be particularly relevant, Inhibitors,Modulators,Libraries given the recent data suggesting that selective inhibition of BRAFV600E may increase T cell recognition of melanoma antigens in vitro. Therefore, an additional goal of the current study was to assess whether T cell function in treated patients was affected ex vivo.

Patients and methods Study design This was a multicenter phase II clinical trial of R115777 in patients with metastatic melanoma carried out by the CALGB melanoma working group. The primary objectives were to estimate the clinical response rate and to evaluate the toxicity of this agent Inhibitors,Modulators,Libraries in this patient population. The sec ondary objectives were to measure FT activity and effects on signaling events in tumor tissue, and to assess effects on T cell activation ex vivo from the peripheral blood. Trial Conduct CALGB developed and coordinated this trial. Institu tional review board approval and patient informed con sent were required at each participating center. Inhibitors,Modulators,Libraries Patient registration and data collection were managed by the CALGB Statistical Center. Data quality was ensured by careful review of data by CALGB Statistical Center staff and by the study chairperson.

Statistical analyses were performed by CALGB statisticians. As part of the quality assurance program of the CALGB, members of the Audit Committee visit all par ticipating institutions at least once every three years to review source documents. The auditors verify compli ance with federal regulations and protocol requirements, www.selleckchem.com/products/jq1.html including those pertaining to eligibility, treatment, ad verse events, tumor response, and outcome in a sample of protocols at each institution.