A phase 1 study of the selective cyclin dependent kinase inhibitor P276–00 in patients with advanced refractory neoplasms
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14117 Background: In human cancers, genetic and epigenetic events result in over-expression of cyclins or absence or diminished levels of Cdk inhibitors, providing tumor cells with selective growth advantage. This has prompted the development of pharmacological Cdk inhibitors that could potentially produce anti-tumor effect. P276–00 is a selective Cdk4-D1 and Cdk1-B inhibitor. This study was designed to determine the maximum tolerated dose (MTD), toxicity profile, pharmacokinetics, and antitumour activity of P276–00 given intravenously to patients with advanced refractory solid tumours. Methods: P276–00 was administered in escalating doses to cohorts of eligible patients (pts), starting with a dose of 9 mg/m2 as a 30 minute iv infusion day 1 to 5, and day 8 to 12, q 3 weekly. To date 22 pts have been entered on the study (cohort 1 - 4 pts at 9 mg/m2, cohort 2 - 4 pts at 12.6 mg/m2, cohort 3 - 6 pts at 17.6 mg/m2, cohort 4 - 8 pts at 24.6 mg/m2) with PS 0–2, and mean age of 56 years. Pharmacokinetic profiles were obtained on cycle 1 days 1 and 5. Skin biopsies were obtained immediately prior to starting study treatment and on day 21 of cycle 2 and will be analyzed for Ki67, cleaved caspase 3, phospho-Rb, cyclin D1 and cdk4, and microarray. Results: To date dose limiting toxicity has occurred in one pt. Grade 3 fatigue occurred in 1 pt at 17.6 mg/m2. The most common drug-related adverse events, which were all grade 1 or 2, were fatigue, nausea, hypotension, sweating, and dry mouth. No Grade 3 biochemical toxicities have been reported so far. There have been no responses noted to date. 4 pts have stable disease after 2 cycles. Pharmacokinetic results: The Cmax, t1/2, and AUC0–8 on day 1 were as follows: 9 mg/m2- 315 ng/mL, 6.6 hr, 883 ng.h/mL; 12.6 mg/m2- 402 ng/mL, 5.5 hr, 848 ng.h/mL; 17.6 mg/m2- 589 ng/mL, 5.3 hr, 1289 ng.h/mL; 24.6 mg/m2- 621 ng/mL, 5.6 hr, 1286 ng.h/mL. Conclusions: P276–00 is well tolerated, but grade 3 fatigue has been noted in 1 pt at 17.6 mg/m2 dose level. We have observed confirmed stable disease in one patient. PK results indicate that at 9 mg/m2,12.6 mg/m2, 17.6 mg/m2 and 24.6 mg/m2 we are able to cross the cdk4 enzyme IC50 approximately 10, 13, 19 and 20 times and cross the anti-proliferative IC50 1.1, 1.4, 2.1 and 2.2 times respectively. Accrual continues at the 34.4 mg/m2 dose level. No significant financial relationships to disclose.
