A phase I dose-escalation study of the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of a novel cyclin-dependent kinase inhibitor administered weekly in subjects with advanced malignancies

3535 Background: SCH 727965 is a potent and selective inhibitor of the cyclin-dependent kinases CDK1,2,5 and 9 with IC50's of < 5nM. SCH 727965 induces apoptosis in a broad array of tumor cell lines, causes tumor growth inhibition or regression in various xenograft models, and has a greater therapeutic index than flavopiridol in an in vivo screening model. SCH 727965 was advanced into clinical trials. Methods: SCH 727965 was administered by 2-hour IV infusion on days 1, 8 and 15 of a 28-day cycle. Doses were escalated with an accelerated titration algorithm to define the maximally administered dose (MAD) and the recommended phase 2 dose (RPTD). PD assessments included an ex vivo PHA lymphocyte stimulation assay, skin biopsies for IHC measurement of retinoblastoma protein phosphorylation, and functional imaging using FDG-PET/CT scans. PK and PD data were obtained during Cycle 1. Results: 43 subjects have been treated at doses ranging from 0.33 to 14 mg/m2. The most common treatment-emergent adverse events were nausea, anemia, and fatigue. The MAD was 14 mg/m2 defined by a DLT of grade 3 hypotension in one subject and transient grade 4 hyperuricemia in another subject. The RPTD was 12 mg/m2. Grade 3 or 4 treatment related adverse events were uncommon. Grade 3 or 4 neutropenia was seen in only 3 subjects. SCH 727965 inhibition of lymphocyte proliferation was dose-dependent, indicating a PD effect, and was sustained up to 8 hours post-dose at the RPTD. Drug exposure was dose-proportional. SCH 727965 was rapidly eliminated with a terminal half-life of 1.5 to 3 hours. No objective responses by RECIST criteria have yet been observed although PET SUV signal decreases as large as >30% have been observed in some subjects. Conclusions: SCH 727965 is safe and well tolerated at the recommended phase 2 dose of 12 mg/m2. The AE profile of weekly dosing differed from that seen in an every -21 day dosing schedule, and plasma concentrations at the RPTD or lower doses were above those required for in vivo efficacy in xenograft tumor models. PD activity was verified in an ex vivo lymphocyte proliferation assay, and preliminary changes on PET/CT suggest drug related modulation of tumor metabolic activity. [Table: see text]