Staining in tensity was scored as: 0, no staining; 1, weak staining, 2, moderat

6 hours following IV adminis tration of dinaciclib, and CL appeared to be dose inde pendent. Dose related increases in exposure to dinaciclib were observed as doses increased from 0. 33 to 14 mg m2. Exposure to dinaciclib was similar on days 1 and 15 after once weekly dosing, with a mean AUC ratio キナーゼ 阻害剤 of 1. 04, Plasma concentrations at the end of each 2 hour infusion were also similar within each subject, These data suggest that dinaciclib does not accumulate in plasma and pharmacokinetics do not appear to be time dependent over the time course evaluated in this study. Pharmacokinetic parameter means at each dose level, assessed on day 1 and day 15, are available as supplemental information, Tumor response There were no observed complete or partial responses based on RECIST guidelines in subjects with solid tumors following treatment with dinaciclib.<br><br> Ten patients achieved stable disease through at least 4 cycles of treatment with dinaciclib, including 2 subjects with NSCLC and 2 subjects with adenoid cystic carcinoma, One subject, with sarcoma, demonstrated pro longed SD through オーダー Lenalidomide 12 treatment cycles. In this study, the CDK inhibitor dinaciclib was adminis tered once weekly for 3 weeks followed by a 1 week recov ery period and had an acceptable safety and tolerability profile for subjects with solid tumors. The MAD for dinaciclib, administered at a 2 hour IV infusion, was 14 mg m2, and the DLTs experienced at this dose level were orthostatic hypotension and elevated uric acid.<br><br> Hypotension may be associated with cytokine release syndrome, which has been observed in patients with hematologic malignancies and advanced solid tumors treated with the CDK inhibitor flavopiridol, and has also been identified LY2603618 Checkpoint 阻害剤 as a DLT, The most frequently reported treatment related AEs at all dose levels tested were nausea and anemia, and 16 subjects experienced grade 3 or 4 treatment related AEs. Anemia, neutropenia, and fatigue were the most common AEs related to study drug reported at the RP2D of 12 mg m2. The most fre quent SAEs among the 17 subjects who reported experi encing SAEs were deep vein thrombosis, sepsis, and anemia. Adverse events led to the discontinuation of treatment in 6 subjects and 4 subjects died due to AEs that were deemed unrelated to dinaciclib.<br><br> Dinaciclib effectively inhibited peripheral blood lympho cyte proliferation, as measured by an ex vivo lymphocyte stimulation assay, demonstrating PD activity when ad ministered at the RP2D as a 2 hour IV infu sion. One mechanism by which CDK1 and CDK2 may regulate the cell cycle is via phosphorylation of the Rb tumor suppressor family of proteins, In our study, treatment with dinaciclib did not result in substantial decreases in the phosphorylation of the Rb protein in skin biopsies, indicating that no subject had a PD response to dinaciclib treatment based on the protocol specified criteria that required complete suppression of Rb phos phorylation. It is unlikely that the lack of an observed PD effect using phospho Rb staining of skin biopsies was due to a limited effect of dinaciclib activity in inhibiting the cell cycle, since dinaciclib treatment inhibited ex vivo lymphocyte proliferation.