A Phase I Study Of R547, A Novel, Selective Inhibitor Of Cell Cycle And Transcriptional Cyclin Dependent Kinases (Cdks)

3528 Background: R547, a potent inhibitor of CDKs 1, 2, 4, 7, and 9, has shown broad antitumor activity in preclinical models. This phase Ia study assessed safety, pharmacokinetic (PK), and pharmacodynamic (PD) endpoints. Methods: R547 given as a 90 or 180 min infusion D1, D8 (21 day cycle). Key inclusion criteria: ECOG 0–2, adequate hematologic, hepatic, and renal function. Exclusion: brain metastases, NYHA III/IV CHF, CVA, current antihypertensive therapy. Blood samples on cycle 1, D1, D8 for PK and PD. PD endpoint is inhibition of retinoblastoma phosphorylation (pRB) in PBMCs. Results: 41 pts received R547 over dose range 8.6 - 195 mg/m2; 31 pts on 90 min and 10 pts on 180 min schedule. Mean age 53.4 yrs (20–81), 25F:16M. Mean R547 cycles 3.1(<1- 8) for 18 evaluable pts receiving doses ≥ 155 mg/m2. Toxicities: principal related events were nausea (54%), fatigue (34%), emesis (34%), headache (34%), and hypotension (32%). All of these limited to gr 1/ 2, except 4 gr 3 fatigue (1 in cycle 1) and 1 gr 3 nausea. DLTs: 90 min- gr 3 somnolence, gr 3 confusion, gr 3 fatigue, 1 pt each, all at 195 mg/m2; 180 min- 1 DLT of prolonged gr 3 pruritis at 195 mg/m2. PK: Mean AUC for 20 pts with PK receiving ≥ 155 mg/m2 R547 exceeds exposures efficacious in xenograft studies. At equivalent doses, the 180 min schedule produces equivalent AUC but 30% reduction of Cmax. PD: for pts with available data (n=21), an exposure-dependent decrease in pRB/total RB ratio was observed 1.5 to 24 hrs post R547. Activity: tumor regression in 1 pt with metastatic squamous ca skin; 8 additional pts received ≥ 4 cycles. Conclusions: Treatment with R547 is tolerable at a dose of 155 mg/m2 on D1, D8 (21 day cycle) for both 90 and 180 min schedules. Nausea, emesis, headache, and transient hypotension are manageable with anti-emetic, analgesic, and iv fluid support. The DLTs observed in the 90 min schedule have not occurred in pts receiving 180 min infusions, a schedule which maintains R547 exposure but reduces Cmax. Exposures predictive of preclinical efficacy have been achieved. Inhibition of a relevant PD marker (pRB) and antitumor activity have each been confirmed in the clinic. Phase II trials in advanced solid tumors and hematologic malignancies are planned. No significant financial relationships to disclose.