Abstract
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. 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. 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 T(max), 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 E(max) model, neutropenia was shown to be proportional to exposure. PD 0332991 warrants phase II testing at 125 mg once daily, at which dose neutropenia was the sole significant toxicity.
Highlights
Phosphorylation of the retinoblastoma protein (Rb), mediated by cyclin-dependent kinase 4 (CDK4) or CDK6, is required for entry of a cell into the cell cycle
This study shows that an inhibitor of CDK4/6 may be administered with a tolerable toxicity profile and a pharmacokinetic–pharmacodynamic relationship that shows an expected cellular response
Study population Eligible patients were men and women aged !18 years with Rb-positive solid tumors or non–Hodgkin lymphoma, confirmed histologically or cytologically at original diagnosis, that were refractory to standard therapy or for whom no standard-of-care therapy was available
Summary
Phosphorylation of the retinoblastoma protein (Rb), mediated by cyclin-dependent kinase 4 (CDK4) or CDK6 (complexed with the activating subunit cyclin D), is required for entry of a cell into the cell cycle. Phosphorylation of Rb early in the G1 phase initiates the changes in gene transcription that carry a cell through the G1–S tran-. Authors' Affiliations: 1Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania; 2Karmanos Cancer Institute, Detroit, Michigan; 3Pfizer Oncology, San Diego, California; and 4Memorial Sloan-Kettering Cancer Center, New York. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Current address for K.T. Flaherty: Massachusetts General Hospital Cancer Center, Boston, MA; and current address for V.G. Abramson: Vanderbilt University School of Medicine, Nashville, TN. CDK4 and/or CDK6 are pivotal regulators of cell division
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