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

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 Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5069.