A phase I and pharmacokinetic (PK) study of continuous daily administration of P1446A-05, a potent and specific oral Cdk4 inhibitor.

3013 Background: P1446A-05 is a novel oral inhibitor of Cdk4-D1, Cdk1-B, and Cdk9-T, and has been shown to inhibit tumor growth both in vitro and in vivo. Pharmacodynamic studies demonstrate that activation of Cdk1 reappears within 48 hours after P1446A-05 is withdrawn, suggesting the need for prolonged administration hence, we sought to evaluate the feasibility, safety and tolerability of a continuous daily schedule of P1446A-05 in patients (pts) with advanced malignancies. Methods: P1446A-05 was given at escalating doses of 75, 150, 250, 350 and 500mg. Samples were collected for PK at multiple time points over 24 hours on cycle 1 day 1 and 15, as well as at single time points on cycle 1 day 8, 22 and cycle 2 day 1. Results: Thirty-nine pts (median age=63 years, 51% male, 51% ECOG PS=1) collectively received more than 100 cycles of P1446A-05. The majority of drug-related toxicities were ≤Grade 2, the most common of which were diarrhea (n=54), nausea/vomiting (n=27/17), fatigue (n=22) and anorexia (n=16). Two pts developed study-drug related diarrhea with hypokalemia/elevated creatinine and died during cycle 1. Dose-limiting toxicities (DLT) at 500mg (Table) led to subsequent de-escalation and expansion of the 350mg cohort. A total of 24 pts were treated at 350mg; only one patient experienced dose-limiting diarrhea. PK data are summarized below. Accumulation ratios across dose levels suggest moderate accumulation with continuous dosing. Nine pts achieved stable disease (SD) for at least 2 cycles. One pt with alveolar soft tissue sarcoma, whose disease was progressing at enrollment, remains on treatment with SD after 11 cycles. Conclusions: The recommend phase II dose of P1446A-05 is 350mg. Further phase II studies at this dose will be conducted with potential enrichment strategies. [Table: see text]