Subjects con tinued on treatment until there was disease progression, unaccepta

11 mg m2 infusion dose died of cardiac arrest, one subject treated with the 14 mg m2 infusion died of bowel perforations, and an other subject also treated at the 14 mg m2 dose level died of unknown cause. All 4 AEs leading to death were ABT-737 構造 deemed unlikely related to dinaciclib treatment by the investigator. A total of 6 subjects reported AEs leading to discontinuation of treatment, but in 4 of the 6 subjects, AEs leading to discontinuation were consid ered unlikely related to dinaciclib. Pharmacodynamics and pharmacokinetics of dinaciclib Lymphocyte proliferation data were available from 46 of the 48 treated subjects.<br><br> Following treatment at the RP2D of 12 mg m2, lympho cyte proliferation was generally inhibited compared with proliferation levels observed pretreatment, although there was some variability, The inhibition of ex vivo PHA stimulated lymphocyte proliferation correlated with the observed plasma concentrations オーダー AEB071 from 46 subjects, The majority of samples had BrdU incorpor ation of less than 5% at plasma concentration of 100 ng mL, BrdU incorporation was completely inhibited at plasma concentration 200 ng mL. Complete inhibition of BrdU uptake was achieved at dinaciclib plasma concentrations greater than 100 ng mL at about 2 hours after the start of IV infusion with dinaciclib, Additionally, 10 of the 11 subjects treated with dinaciclib at the RP2D had both pretreatment and cycle 1 day 22 SUVmax data, and were therefore evaluable for response by PET CT analysis. One subject at the RP2D was classified as a PET CT responder with the best SUVmax decrease be ing greater than 30% , the PET CT response rate at the RP2D is 10.<br><br> 0% based on the 10 evaluable sub jects, Analysis of subject skin biopsy samples demonstrated pretreatment phospho Rb staining. Mean IHC scores were calculated before and after treatment for the 11 subjects who were treated at the RP2D of 12 mg m2. Before dinaciclib treatment, these subjects had a mean H score of 18. 55, following treatment, the overall H score de creased to 17. 64. Therefore, supplier AG-014699 as no subjects demonstrated complete loss of phospho Rb staining following treatment with dinaciclib, no subjects were deemed to have achieved a response based on phospho Rb staining, as defined in the study protocol. Of the 48 treated subjects, 47 subjects were evaluable for the PK analysis, one subject who received IV infusion for less than 1 hour—resulting in less than 3.<br><br> 63 mg m2 dose of dinaciclib on day 1 of cycle 1—and had no concentration versus time data on day 15 of cycle 1 was excluded from the analysis. Following 2 hour IV adminis tration of dinaciclib, Cmax was observed at approximately 2 hours after the initiation of the infusion, and dinaciclib exhibited rapid distribution and elimination phases after the end of an infusion, Terminal half life values ranged from 1. 5 to 3. 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 of 1.