Abstract 2242: A randomized phase 2 study of the cyclin-dependent kinase (CDK) inhibitor Dinaciclib (SCH 727965) in patients with non-small cell lung cancer (NSCLC)
Authors: Warren Stephen L. , Nemunaitis John , Stephenson Joe , Samson Benoit , Joy Anil A. , Zhang Da , Statkevich Paul , Jou Ying-Ming , Yao Siu-Long , Navarro Mark , Bannerji Rajat , Edelman Martin J. 
Published: June 2012

Abstract
Dinaciclib is a potent, selective inhibitor of CDKs 1, 2, 5, and 9 with preclinical activity against NSCLC cell lines and tumor xenografts. NSCLC tumors have numerous defects in cell cycle regulation (abnormal p16/cyclin D/Rb pathway, cyclin E overexpression, loss of p27/KIP1). The rationale for this study is that abnormal cell cycle regulation may predispose NSCLC cells to the pro-apoptotic effects of dinaciclib. A randomized, multicenter, open-label phase 2 study was conducted to compare the efficacy of dinaciclib and erlotinib (150 mg PO QD) in patients (pts) with locally advanced previously treated Non-Small Cell Lung Cancer (NSCLC). Dinaciclib 50 mg/m2 was administered by 2-hour i.v. infusion once every 21 days. Key inclusion criteria included ≤ 2 prior chemotherapy regimens and measurable disease.
Patients were randomized to treatment with dinaciclib or erlotinib using an adaptive Bayesian design to adjust the randomization ratio in favor of the more active arm. Patients could cross-over to dinaciclib after progressing on erlotinib. This design provides a comparison of dinaciclib versus erlotinib and assesses dinaciclib activity in patients who've progressed on erlotinib. Primary endpoints: Time-to-progression (TTP) for pts receiving upfront treatment; and response rate (RR) for pts who crossed over to dinaciclib.
Sixty-four pts received upfront treatment with either erlotinib (n=49) or dinaciclib (n=15). Seventeen patients crossed over from upfront erlotinib arm to dinaciclib. Median age was 65 (range 46-82) with a median of 1 (range 1-2) prior chemotherapy regimens and median ECOG performance status of 1 (0-2). The median number of treatment cycles was 2 (range 1-19), with 27/32 treated pts receiving &gt; 1 cycle of treatment with dinaciclib. Tumor responses were assessed using RECIST. No dinaciclib responses were observed in either upfront or cross over arms. Two of forty-nine (4%) evaluable subjects receiving upfront erlotinib were reported to have partial responses (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 (76%), neutropenia (66%), vomiting (59%), nausea (55%), fatigue (38%) and leukopenia (38%). The most common treatment-related grade 3 and 4 toxicities, occurring in 2 or more pts were neutropenia (60%), leukopenia (32%), vomiting (20%), diarrhea (16%), fatigue (12%), nausea (12%), electrolyte imbalance (8%) and hyperuricemia (8%). PK results are pending and will be included in the final abstract.
Dinaciclib has acceptable safety and tolerability in patients with NSCLC but did not demonstrate anti-tumor activity. In accordance with pre-specified rules of the adaptive design, patient enrollment was stopped initially in the crossover stage and in the upfront stage of the trial.
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 2242. doi:10.1158/1538-7445.AM2011-2242