A phase I dose escalation trial of a daily oral CDK 4/6 inhibitor PD-0332991

Abstract

3550 Background: PD-0332991 is a novel oral inhibitor of CDK 4/6, which is active against Rb positive tumors and has never before been tested in humans. A phase I dose escalation trial of PD-0332991 administered as a daily oral single agent was conducted to investigate safety, pharmacokinetics and pharmacodynamics in patients with advanced cancer. Methods: PD-0332991 was administered daily for 21 days in 28-day cycles (Schedule 3/1) to patients in successive dose escalating cohorts at doses from 25 mg to 150 mg QD. An alternative schedule of 14 days dosing in 21-day cycles (Schedule 2/1) was tested at 100 mg to 225 mg QD. Patients with advanced Rb positive solid tumors were enrolled in the study. Results: Fifty-seven patients have been enrolled into the study. The most common tumor types were: breast, colorectal, liposarcoma, and melanoma. The median age across the study was 57 years. For Schedule 3/1, the MTD/RP2D was determined to be 125 mg QD. For Schedule 2/1, the MTD/RP2D is still to be identified but the maximum administered dose (MAD) was determined to be 225 mg QD. Six DLTs have been observed, all relating to myelosuppression. The most common AEs were neutropenia, anemia, fatigue, nausea, constipation, vomiting and diarrhea. Concentrations were moderately variable (% CV range in AUC on Day 8 of Cycle 1 was 14–64%) with dose-dependent increases in exposure observed following PD-0332991 administration (mean AUC(0–10 hr) values were 724 and 1,500 ng.hr/mL at the 125 mg and 225 mg dose levels, respectively). The effect of food on PD-0332991 pharmacokinetics is currently being evaluated. In Schedule 3/1, there have been 6 patients with stable disease (= 10 cycles) with 3 patients (one each with breast cancer, colon cancer and ovarian cancer) with stable disease for at least 20 cycles. In Schedule 2/1, one patient has had stable disease for at least 10 cycles. Updated data will be presented. Conclusions: The principal and dose limiting toxicity of PD- 0332991 is myelosuppression. The RP2D for Schedule 3/1 is 125 mg QD. The MAD has been determined for Schedule 2/1 as 225 mg QD and the dose in this schedule has been de-escalated to 200 mg QD to evaluate the MTD. Tumor specimens, when available, from patients in both schedules are also being tested for pharmacodynamic modulation of phospho-RB protein. No significant financial relationships to disclose.