Abstract CT102: Phase Ib safety, preliminary anti-leukemic activity and biomarker analysis of the polo-like kinase 1 (PLK1) inhibitor, onvansertib, in combination with low-dose cytarabine or decitabine in patients with relapsed or refractory acute myeloid leukemia
Authors: Zeidan Amer M. , Becker Pamela , Spira Alexander I. , Patel Prapti A. , Schiller Gary J. , Tsai Michaela L. , Lin Tara L. , Ridinger Maya , Erlander Mark , Silberman Sandra L. , Cortes Jorge E. 
Published: August 2019

Abstract
Background: Despite recent advances in the understanding of the biology and development of new agents for patients with acute myeloid leukemia (AML), prognosis remains poor with most patients (pts) succumbing to their disease. PLK1 is a serine/threonine kinase, a master regulator of cell-cycle progression, and is overexpressed in numerous cancer types including AML. Onvansertib is a third generation, orally active and highly selective PLK1 inhibitor with a ~24-hour half-life that demonstrates activity in preclinical AML models both as a single agent and in combination with low-dose cytarabine (LDAC). A Phase I study showed that Onvansertib was well tolerated in pts with solid tumors.
Methods: The goal of this Phase Ib (NCT03303339) study is to test the safety of Onvansertib in combination with either LDAC or Decitabine in relapsed or refractory AML. Efficacy, pharmacokinetics and pharmacodynamics of the combination are secondary endpoints. Pts are treated with Onvasertib for 5 days in combination with either LDAC (20 mg/m2 SC qd x 10d) or Decitabine (20 mg/m2 IV qd x 5d) over a flexible 21 to 28-day cycle, with the next cycle initiated based on recovery of cell counts. Each arm follows a standard dose escalation design with 50% increments in successive cohorts of 3 pts. Dose limiting toxicity (DLT) is evaluated during the 1stcycle. As of January 2, 2019, 21 pts have enrolled. The starting dose of Onvansertib was 12mg/m2 and was escalated to 18, 27 and 40mg/m2 in subsequent cohorts. In both arms, no treatment-related serious adverse events and deaths or DLTs occurred at the first 3 doses and treatment at 40mg/m2 is ongoing. Additional objectives include pharmacokinetics, preliminary anti-leukemic activity and correlative biomarker and pharmacodynamics analyses. Assessment of PLK1 inhibition is being determined in pts by changes in phosphorylation status of the translationally controlled tumor protein (TCTP), which is a PLK1 substrate, and is being evaluated not only in terms of response to treatment, but also as a potentially identifiable marker ex vivo for pts that may be more responsive to therapy. Genomic and gene expression analysis are assessed to identify biomarkers that may also be associated with response to treatment.
Citation Format: Amer M. Zeidan, Pamela Becker, Alexander I. Spira, Prapti A. Patel, Gary J. Schiller, Michaela L. Tsai, Tara L. Lin, Maya Ridinger, Mark Erlander, Sandra L. Silberman, Jorge E. Cortes. Phase Ib safety, preliminary anti-leukemic activity and biomarker analysis of the polo-like kinase 1 (PLK1) inhibitor, onvansertib, in combination with low-dose cytarabine or decitabine in patients with relapsed or refractory acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT102.