Abstract LB-200: Dose and schedule determination of the Chk1/2 inhibitor LY2606368 in patients with solid tumors.
Authors: Bendell Johanna C. , Janku Filip , Infante Jeffrey , Jones Suzanne , Burris Howard , Golden Lisa , Hynes Scott M. , Lin Ji , Bence Aimee K. , Tse Susan , Kurzrock Razelle , Hong David 
Published: August 2014

Abstract
Background: LY2606368 mesylate hydrate (LY2606368) is a Chk1/2 inhibitor. In addition to its role in DNA damage response, Chk1 also phosphorylates multiple downstream targets that regulate DNA replication, chromosome alignment, spindle checkpoints, and exit from cytokinesis. Since potent inhibition of Chk1 is predicted to generate DNA damage and mitotic catastrophe, this study evaluated LY2606368 as a single agent.
Methods: Two schedules of LY2606368 were assessed in this dose escalation study: dosing on days 1-3 every 14 days (Schedule [Sch] 1) and dosing on day 1 every 14 days (Sch 2). Patients were assessed for safety, tolerability, pharmacokinetics (PK), pharmacodynamic (PD), and dose-limiting toxicities (DLT).
Results: A total of 45 patients were enrolled, 27 of which were treated on Sch 1 at doses of 10-50 mg/m2 while 18 patients were treated on Sch 2 at doses of 40-130 mg/m2. The most frequently reported AE, regardless of schedule, was a transient (typically &lt; 5 days) decrease in neutrophil count, which occurred in 93% of patients (Grade 4 in 73% of patients). A total of 3 patients (6.7%) experienced febrile neutropenia. Other common toxicities, regardless of causality, included white blood cell decrease (84%), anemia (73%), fatigue (56%), platelet count decreased (53%), nausea (36%), constipation (29%), anorexia (27%), vomiting (27%), dyspnea (20%), and fever (20%). The majority of the non-hematologic toxicities were CTCAE Grade 1/2 in severity. Hematologic toxicity was the dose limiting toxicity on both schedules. The MTD for Sch 1 was 40 mg/m2 and for Sch 2 was 105 mg/m2. The systemic exposure of LY2606368 increased in a dose-dependent manner across the dose range of 10-130 mg/m2 for both schedules. The LY2606368 half-life is suitable for achieving acceptable exposure while minimizing intra- and intercycle accumulation for either schedule. The exposure at MTD for both schedules is in the range that correlates to the minimal tumor response in nonclinical xenograft models. The nonclinical PK/PD model predicts an average pChk1% inhibition of ∼50% and ∼70% for 72 hours is required for minimum and maximum tumor responses, respectively. Simulations of human PK/PD profiles predict that the exposure and average pChk1% inhibition at the MTD of each schedule achieve the requirements for the minimum tumor response. One patient with SCC of the anus achieved a PR (60% reduction). Ten of the 45 patients (22%) achieved SD including 4/7 (57%) HNSCC patients (range on treatment: 3-7.5mo) that had received multiple prior therapies.
Conclusions: Based on the nonclinical PK/PD model, clinical human PK, human PD simulations, the similar safety profile, and the increased patient convenience, a dose of 105 mg/m2 of LY2606368, administered once every 14 days was selected as the schedule to further evaluate in Part B of the study, a dose expansion component which will focus on patients with squamous histology tumors.
Citation Format: Johanna C. Bendell, Filip Janku, Jeffrey Infante, Suzanne Jones, Howard Burris, Lisa Golden, Scott M. Hynes, Ji Lin, Aimee K. Bence, Susan Tse, Razelle Kurzrock, David Hong. Dose and schedule determination of the Chk1/2 inhibitor LY2606368 in patients with solid tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-200. doi:10.1158/1538-7445.AM2013-LB-200