Abstract CT209: A phase I study with the oral pan-CDK inhibitor BAY 1000394 in patients with advanced stage small cell lung or ovarian cancer
Authors: Bahleda Rastilav , Barlesi Fabrice , Audebert Christine , Perol Maurice , Ray-Coquard Isabelle , Strumberg Dirk , Schultheis Beate , Govindan Ramaswamy , Dy Grace K. , Zalcman Gerard , Walter Annette O. , Kornacker Martin , Ocker Matthias , Soria Jean-Charles 
Published: May 2015

Abstract
Background: BAY 1000394 (BAY) is an oral pan-CDK inhibitor targeting CDKs 1, 2, 4, 7 and 9 in the low nanomolar range. The recommended phase 2 dose was identified in the previously reported dose escalation part of this multicenter phase I study. We report here additional data on pharmacodynamics (PD) biomarker and clinical outcome of patients with advanced SCLC and ovarian cancer (OC).
Methods: BAY was orally administered as monotherapy on a 3-days on/4-days off schedule at 5 mg bid in continuous 21 day cycles. A novel PCR-based PD assay using whole blood obtained on days 1 and 10 of the first treatment cycle was performed. Response rate was assessed every second cycle using RECIST 1.1.
Results: A total of 25 pre-treated patients with extensive stage SCLC and 25 patients with advanced OC (stage IIIB/IV) were enrolled to this study. In addition, 6 patients with distinct genetic profiles (e.g. cyclin E amplification) related to the mode of action of BAY were included at Gustave Roussy, Paris, France. The overall disease control rate (DCR, includes stable disease or better) according to RECIST was 32.3% in the total study population with 20 SD. On average, patients with SD or better stayed on treatment for 103.5 days (4.9 cycles). DCRs were 29% (n=9) for SCLC, 36% for ovarian cancer (n=9) and 33.3% for patients harboring tumor specific mutations (n=2), respectively. Levels of Proliferating Cell Nuclear Antigen (PCNA) were analyzed in the blood as surrogate biomarker and reduction of PCNA expression was detected at the recommended phase 2 dose of 5 mg bid. Nausea and diarrhea (CTCAE grades 1 and 2) were commonly observed but proved to be clinically manageable with standard medication. While the dose escalation trial confirmed MTD at 7.5 mg bid, the occurrence of four thromboembolic events at this dose level led to the reduction of the recommended phase 2 dose to 5 mg bid. No additional drug related thromboses were observed at the lower dose and the overall incidence rate (7.9%) of thromboembolic events at 5 mg bid is below the expected rate in this patient population. Conclusion: The continuous oral treatment with the pan-CDK inhibitor BAY 1000394 is feasible and showed signs of efficacy and pharmacodynamic activity at 5 mg bid on a 3-days on/4-days off treatment schedule in a non-biomarker selected expansion population of phase I patients with advanced stage SCLC or ovarian cancer.
Citation Format: Rastilav Bahleda, Fabrice Barlesi, Christine Audebert, Maurice Perol, Isabelle Ray-Coquard, Dirk Strumberg, Beate Schultheis, Ramaswamy Govindan, Grace K. Dy, Gerard Zalcman, Annette O. Walter, Martin Kornacker, Matthias Ocker, Jean-Charles Soria. A phase I study with the oral pan-CDK inhibitor BAY 1000394 in patients with advanced stage small cell lung or ovarian cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT209. doi:10.1158/1538-7445.AM2014-CT209