Data from Phase I, 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

Abstract

<div>Abstract<p><b>Purpose:</b> 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 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.</p><p><b>Experimental Design:</b> This open-label phase I study (NCT00141297) enrolled patients who received PD 0332991 orally in six dose-escalation cohorts in a standard 3 + 3 design.</p><p><b>Results:</b> Forty-one patients were enrolled. DLTs were observed in five patients (12%) overall; at the 75, 125, and 150 mg once daily dose levels. The MTD and recommended phase II dose of PD 0332991 was 125 mg once daily. 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 adverse events 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 <i>T</i><sub>max</sub>, 5.5 hours), and slowly eliminated (mean half-life was 25.9 hours) with a large volume of distribution (mean, 2,793 L). The area under the concentration–time curve increased linearly with dose. Using an <i>E</i><sub>max</sub> model, neutropenia was shown to be proportional to exposure.</p><p><b>Conclusions:</b> PD 0332991 warrants phase II testing at 125 mg once daily, at which dose neutropenia was the sole significant toxicity. <i>Clin Cancer Res; 18(2); 568–76. ©2011 AACR</i>.</p></div>