P1-17-06: A Phase II Trial of the CDK 4/6 Inhibitor PD0332991 in Women with Advanced Breast Cancer.
Authors: DeMichele A , Clark A , Randolph S , Christensen J , Gallagher M , Lal P , Feldman M , Zhang P , Perini R , Velders L , Domchek S , Kaplan-Tweed C , Gogineni K , Keefe S , Fox K , O'Dwyer P 
Published: June 2012

Abstract
Background: Dysregulation of the G1/S checkpoint of the cell cycle is a feature of many breast cancers. PD0332991, a potent oral inhibitor of cyclin-dependent kinases (CDKs) 4 and 6 is well-tolerated and has demonstrated activity in a phase I trial in a variety of solid tumors at a phase II dose of 125 mg daily on a 3 week on/1 week off schedule. Preclinical data suggest that this agent is most active in ER+ (luminal) breast cancers. We are performing a phase II study of PD0332991 in women with advanced breast cancer, one of several parallel disease cohorts under study.
Methods: Patients with histologically-confirmed stage IV breast cancer were eligible if they had primary or metastatic tumor which stained positive for retinoblastoma (Rb) protein by immunohistochemistry, disease measureable by RECIST criteria and adequate organ function/performance status. Treatment was initiated with PD0332991 at 125 mg orally, days 1 - 21 of a 28-day treatment cycle. Tumor assessments occurred after every 2 cycles (8-week intervals). The primary objective was to determine the safety and response rates in cohorts of 15 patients per tumor type; 15 patients per arm provided 80% power to detect a 15% (1/15) response rate per disease that would lead to further cohort expansion. Secondary objectives include PK, PD and predictive biomarker assessment.
Results: 36 patients were screened, 32 (89%) stained positive for Rb, and 14 have enrolled on study. The only reported toxicites are neutropenia (7 patients, 4 grade 3/4), thrombocytopenia (1 patient, grade 1) and fatigue (1 patient, grade 2). 3 patients (23%) have had dose interruptions and 5 (38%) have had dose-reduction for neutropenia, though no episodes of febrile neutropenia have occurred. Among 11 patients assessable for response to date, there is 1(7%) partial response (PR), 6 (43%) with stable disease (SD) and 4 (29%) with progressive disease (PD). 3 of 6 patients with stable disease have received greater than 6 months of therapy, and these sustained responses have occurred with dosing as low as 50 mg/day. All PR/SD have occurred in patients with ER+ tumors; all PD have been in patients with triple negative (ER-/PR-/Her2-) disease. The cyclin D1 status of all patients are being assessed. Of the 10 ER+ patients, 3 are cyclin D1 amplified, 5 are non-amplified and 2 are pending assessment. 2 in 4 cyclin D1 non-amplified patients had SD, while 2 of 2 evaluable patients with amplification had SD. PK and PD analyses are in progress.
Conclusions: PD 0332991 is an extremely well-tolerated, oral CDK 4/6 inhibitor that demonstrates prolonged single-agent activity in ER+ breast cancer patients who have progressed on hormonal therapy. These data have prompted expansion of this breast cancer cohort to further delineate activity and translational studies examining predictors of response are underway.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-17-06.