Phase 1, Dose-escalation Trial of the Oral Cyclin-dependent Kinase 4/6 Inhibitor PD 0332991, Administered Using a 21-day Schedule in Patients with Advanced Cancer
Mené sur 41 patients atteints d'une tumeur solide avancée Rb+, cet essai de phase I évalue la dose maximale tolérable d'un inhibiteur de CDK4/6 administré par voie orale pendant quatre semaines
Purpose: To identify the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of the first-in-class, oral CDK4/6 inhibitor PD 0332991 administered once daily (QD) for 21 of 28 days (3/1 Schedule) in patients with retinoblastoma protein (Rb)-positive advanced solid tumors, and to describe pharmacokinetic-pharmacodynamic relationships relative to drug effects. Experimental Design: This open-label phase 1 study (NCT00141297) enrolled patients who received PD 0332991 orally in 6 dose-escalation cohorts in a standard 3+3 design. Results: Forty-one patients were enrolled. DLTs were observed in five patients (12%) overall; at the 75, 125, and 150 mg QD dose levels. The MTD and recommended phase 2 dose of PD 0332991 was 125 mg QD. Neutropenia was the only dose-limiting effect. After cycle 1, grade 3 neutropenia, anemia, and leukopenia occurred in five (12%), three (7%), and one (2%) patient(s), respectively. The most common non-hematologic AEs included fatigue, nausea, and diarrhea. Thirty-seven patients were evaluable for tumor response; 10 (27%) had stable disease for ≥4 cycles of whom six derived prolonged benefit (≥10 cycles). PD 0332991 was slowly absorbed (median Tmax 5.5 hours), and slowly eliminated (mean half-life was 25.9 hrs) with a large volume of distribution (mean 2793 L). The AUC increased linearly with dose. Using an Emax model, neutropenia was shown to be proportional to exposure. Conclusions: