Phase I Study of PD 0332991, a Novel, Oral, Cyclin-D Kinase (CDK) 4/6 Inhibitor in Combination with Letrozole, for First-Line Treatment of Metastatic Post-Menopausal, Estrogen Receptor-Positive (ER+), Human Epidermal Growth Factor Receptor 2 (HER2)-Negative Breast Cancer.
Authors: Finn R. , Hurvitz S. , Allison M. , Applebaum S. , Glaspy J. , DiCarlo B. , Courtney R. , Shaik N. , Kim S. , Fowst C. , Slamon D. 
Published: December 2010

Abstract
Background: PD 0332991 is a potent, oral, small molecule inhibitor of CDK 4/6 kinase. Preclinical studies identified that human luminal ER+ breast cancer cell lines were uniquely sensitive to G0/G1 arrest and growth inhibition by PD 0332991 and this appears to be related to an intact Rb pathway in this subtype (Finn, SABCS 2008, abstract 5064). These studies also identified the ability of PD 0332991 to act synergistically with anti-hormonal treatment in vitro and to restore sensitivity to hormonal treatment in models of acquired resistance. Based on these observations, a phase I/II randomized study of PD 0332991 in combination with letrozole versus letrozole alone as first-line treatment of metastatic ER+ breast cancer was launched.Methods: Post-menopausal women with ER+, HER2-negative breast cancer were eligible. Other eligibility criteria included Eastern Cooperative Oncology Group performance status of 0 or 1, no brain metastases, and adequate organ function. The phase I part of the study was conducted to assess the safety and tolerability of the combination including dose-limiting toxicities (DLTs). Enrollment in phase I is planned for up to 12 patients. The starting dose was PD 0332991 125 mg daily for 3 weeks followed by 1 week off (Schedule 3/1) and letrozole 2.5 mg daily. Cycle 1 consisted of PD 0332991 administered for 2 weeks alone followed by 1 week off. Subsequent cycles consisted of PD 0332991 on Schedule 3/1 and letrozole administered continuously. Pharmacokinetic samples were collected to assess the potential for a drug–drug interaction (DDI). Archival tumor tissue was required for biomarker evaluation. The tumor assessments were performed every 8 weeks.Results: Nine patients have currently been enrolled and treated; median duration of treatment was 3 months (range &lt;1–9). Eight patients remain on study, and 1 patient has discontinued treatment due to progressive disease. One DLT (grade 4 neutropenia) has been reported to date. Most commonly reported adverse events include neutropenia, leukopenia, and fatigue. Of the 6 patients evaluable for response, 2 achieved a partial response and 4 stable disease. Preliminary pharmacokinetic data (mean area under the plasma concentration–time curve from 0 to 24 hours) to date for PD 0332991 in the absence and presence of letrozole (1893 vs. 1904 ng.hr/mL [n=6]) and letrozole in the absence and presence of PD 0332991 (1816 vs. 1615 ng.hr/mL [n=5]) suggest no DDI, although there was a minor reduction in letrozole exposure in combination with PD 0332991.Conclusions: The combination of PD 0332991 and letrozole is well tolerated. Encouraging activity is seen with the combination and a randomized phase II part of the study will be initiated. Updated results on the phase I cohort will be presented at the meeting.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5069.