A phase I dose-escalation study of the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of the novel cyclin-dependent kinase inhibitor SCH 727965 administered every 3 weeks in subjects with advanced malignancies

3532 Background: SCH 727965 is a novel pyrazolo1,5-apyrimidine which potently and selectively inhibits the cyclin- dependent kinases CDK1, CDK2, CDK5 and CDK9 with IC50’s of 100 tumor cell lines (including NCI 60) and results in tumor growth inhibition or regression in multiple xenograft models. SCH 727965 was advanced into clinical trials because of its CDK inhibition specificity, broad anti-tumor activity, and safety. Methods: SCH 727965 was administered by 2-hour IV infusion on day 1 of a 21-day cycle utilizing an accelerated titration design for dose escalation. PD assessments include an ex vivo PHA lymphocyte stimulation assay and functional imaging using FDG-PET/CT scans. PK and PD data were obtained during cycle 1 of treatment. Results: 23 subjects treated at doses from 1.85 to 58mg/m2. The most common treatment-emergent adverse events are nausea/vomiting, diarrhea, neutropenia, and fatigue. Neutropenia, complicated by fever or infection, represented the dose limiting toxicity in 2 of 3 subjects at 58mg/m2. The most common grade 3 or 4 treatment related adverse event is neutropenia. SCH 727965 is rapidly eliminated with a terminal half-life of 1.5 to 3 hours. Exposure is dose-proportional. Inhibition of lymphocyte proliferation (measured by BrdU uptake) correlates with drug concentration and indicates a PD effect. Decreased cycle 1 day 8 PET signal, measured by SUV, is observed in some subjects, although no objective responses by RECIST criteria are observed to date. Conclusions: SCH 727965 is safe and well tolerated at dose levels below the maximum administered dose of 58mg/m2. The study is ongoing. Subjects are exposed to plasma concentrations above those required for in vivo efficacy in xenograft tumor models. Lymphocyte proliferation assay data verify drug exposures at current doses are associated with PD activity. Preliminary changes on PET/CT suggest drug related modulation of tumor metabolic activity. SCH 727965 will be evaluated further in phase 2 studies. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Schering-Plough Schering-Plough