Meeting Abstract | 2020 ASCO Annual Meeting I


Background: LY2880070 (LY) is an oral, selective competitive inhibitor of checkpoint kinase 1 (Chk1). Chk1 inhibitors are known to increase the anti-tumor efficacy of agents such as gemcitabine (GEM), which induce replication stress. Synergy between these two agents has been applied to the clinical setting. Methods: This two-part, open-label multi-center study explores the safety, pharmacokinetics (PK), and anti-tumor activity of LY in patients with advanced or metastatic cancers. The primary objective of this study was to determine the maximum tolerated dose (MTD) for multiple escalating oral doses of LY in combination with GEM. Secondary objectives were to: 1) Characterize the dose-limiting toxicities (DLTs) and overall safety profile for LY; 2) Evaluate the PK of LY; and 3) Evaluate the anti-tumor activity of LY. Patients received LY in a variety of different dose regimens, in combination with GEM (50 to 800 mg/m2) on days 1, 8, and 15 (optional) of a 21-day cycle. Results: The combination of LY with GEM required lower doses of both LY (vs 200 mg BID monotherapy RP2D dose) and GEM (vs approved doses). The dose levels explored ranged from LY:GEM of 10 mg QD:800 mg/m2 to 50 mg BID:100 mg/m2. BID dosing of LY was implemented in order to maximize the total daily dose and avoid the adverse events that appeared to correlate with Cmax. Treatment-emergent adverse events in > 40% of patients included vomiting, nausea, and fatigue. DLTs included reduced platelet count (Gr2), fatigue (Gr3), diarrhea (Gr3), and thrombocytopenia (x2, Gr2). The t1/2 of LY was ~ 5 h, and was not significantly affected by combination with GEM. Two patients had a best overall response of SD for a duration of ≥ 6 cycles, and a confirmed PR was observed in an ovarian cancer patient who had failed multiple regimens. Conclusions: LY was tolerated in combination with lower dose GEM. The toxicity profile can be modulated by changing the dosing frequency from QD to BID while administering the same daily dose. LY may be good candidate for combination therapy with DNA damaging agents. Clinical trial information: NCT02632448.

© 2020 American Society of Clinical Oncology

Research Sponsor:

Esperas Pharma Inc.


No companion articles


DOI: 10.1200/JCO.2020.38.15_suppl.3581 Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020) 3581-3581.

Published online May 25, 2020.

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