Abstract 4718: A randomized phase 2 study of the cyclin-dependent kinase (CDK) inhibitor dinaciclib (SCH 727965) in patients with advanced breast cancer
Authors: Mita Monica , Joy Anil A. , Mita Alain , Sankhala Kamalesh , Moseley Jennifer , Zhang Da , Statkevich Paul , Jou Ying-Ming , Yao Siu-Long , Navarro Mark , Warren Stephen L. , Bannerji Rajat , Shapiro Charles L. 
Published: June 2012

Abstract
Dinaciclib is a potent, selective inhibitor of CDKs 1, 2, 5, and 9 with preclinical activity in breast cancer cell lines and tumor xenografts. A randomized, multicenter, open-label phase 2 study was conducted to compare the efficacy of dinaciclib and capecitabine (1250 mg PO) in patients (pts) with advanced, previously treated breast cancer (BC). Dinaciclib 50 mg/m2 was administered by 2-hour i.v. infusion once every 21 days. Key inclusion criteria included ≤2 prior chemotherapy regimens, prior treatment with a taxane and anthracycline, and measurable disease.
According to the original design, 20 pts were to be randomized 1:1 and thereafter pts were to be randomized using an adaptive Bayesian algorithm that adjusts the randomization ratio in favor of the more active arm. The protocol was amended to continue 1:1 randomization in lieu of the adaptive approach to obtain more experience with upfront dinaciclib. Patients were allowed to cross-over to dinaciclib after progressing on capecitabine. This design provides a comparison of dinaciclib versus capecitabine and an assessment of dinaciclib activity in patients who progressed on capecitabine. Time-to-progression (TTP) was the primary endpoint for pts receiving upfront treatment, and response rate (RR) was the primary endpoint for pts who crossed over to dinaciclib.
Twenty-eight pts were treated (13 dinaciclib, 15 capecitabine). Data on 19 dinaciclib treated pts, including 6 that crossed over, are presented. Their median age was 53 (34-80) with a median of 2 (1-2) prior chemotherapy regimens and median ECOG performance status of 1(0-1). ER+/PR+/Her2 receptor status is available for 10/13 pts treated with dinaciclib, including five with ER+/PR+/Her2-, one with ER-/PR-/Her2-, two with ER-/PR-/Her2+ and two with ER+/PR-/Her2-. The median number of treatment cycles was 3 (1-11). 17 pts received more than one cycle of dinaciclib treatement.
Investigators reported partial responses (PR) in 2/12 (17%) evaluable subjects receiving upfront dinaciclib; both with ER+/HER2- tumors. One confirmed PR had a complete resolution of a 4 cm chest wall mass. No responses were reported on the cross over arm. Four of fifteen (27%) evaluable subjects receiving capecitabine were reported to have PR. Analysis of TTP will be presented at the meeting.
Treatment-related grade 1 and 2 toxicities, occurring in &gt;30% of pts, included diarrhea (67%), nausea (67%), vomiting (61%), neutropenia (50%) and decreased appetite (44%). The most common treatment-related grade 3 and 4 toxicities, occurring in 2 or more pts, were neutropenia (64%), leukopenia (29%), AST increased (14%) and febrile neutropenia (14%). PK results will be included in the final abstract.
Dinaciclib monotherapy showed some anti-tumor activity, with acceptable safety and tolerability, in patients with ER+/Her2- BC, warranting further exploration in the combination setting.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4718. doi:10.1158/1538-7445.AM2011-4718