Essentially the most common toxicities had been myelosuppression, nausea, vomiting, and fatigue. Phase II research have shown clinical activity as a single agent in individuals with hematologic malignancies. Collectively, these observations coalesced to motivate inves tigation of the FTI R115777 in patients with advanced melanoma. Inasmuch as there was limited expertise in evaluating tumor tissue for efficient biochemical target in hibition, an integral part of the present study involved acquiring sizable tumor tissue just before and through R115777 administration to measure FT enzymatic activity directly and also to assess effects on certain signaling pathways ex vivo. A lot of of the signaling pathways involved in melano magenesis are also involved in T cell activation, includ ing the RAS pathway.
We not too long ago have shown that cytokine production and proliferation of T cells in re sponse to T cell receptor engagement is blocked in the know in vitro by FTIs, suggesting that these compounds could theoretically inhibit T cell function in treated individuals. Offered the importance from the immune program to take part in melanoma development control, the effect of signal transduction inhibitors on lymphocyte function has turn out to be a critical parameter to consider inside the can cer context. This may be particularly relevant, offered the recent data suggesting that selective inhibition of BRAFV600E could increase T cell recognition of melanoma antigens in vitro. Consequently, an additional aim of the existing study was to assess no matter whether T cell function in treated patients was affected ex vivo.
Individuals and techniques Study design This was a multicenter phase II clinical trial of R115777 in individuals with metastatic melanoma carried out by the CALGB melanoma operating group. The main objectives were to estimate GDC0941 the clinical response price and to evaluate the toxicity of this agent within this patient population. The sec ondary objectives had been to measure FT activity and effects on signaling events in tumor tissue, and to assess effects on T cell activation ex vivo in the peripheral blood. Trial Conduct CALGB created and coordinated this trial. Institu tional assessment board approval and patient informed con sent have been necessary at every single participating center. Patient registration and data collection had been managed by the CALGB Statistical Center. Data high quality was ensured by careful assessment of data by CALGB Statistical Center employees and by the study chairperson.
Statistical analyses had been performed by CALGB statisticians. As a part of the excellent assurance system of your CALGB, members from the Audit Committee go to all par ticipating institutions at the least after just about every three years to review supply documents. The auditors confirm compli ance with federal regulations and protocol specifications, which includes those pertaining to eligibility, treatment, ad verse events, tumor response, and outcome within a sample of protocols at each and every institution.