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Background: 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, LY2606368 was evaluated as a single agent in expansion cohorts of patients with recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN). Methods: This was a phase I, multicenter, nonrandomized, open-label study in patients with advanced cancer (NCT01115790). Based on results from the dose-escalation phase, dose-expansion cohorts were comprised of patients with SCC given LY2606368 at the maximum tolerated dose (MTD) of 105 mg/m2 on day 1 of a 14-day schedule. Cohorts were defined by tumor location and by line of treatment. Patients were assessed for safety, tolerability, and preliminary efficacy. Pretreatment biopsies were obtained for pharmacogenomic analysis, including human papillomavirus (HPV) status. Aggregate results from patients with recurrent/metastatic SCCHN are presented. Results: Fifty-seven patients with recurrent/metastatic SCCHN were enrolled in the dose-expansion phase. Over 50% of patients had received ≥2 prior lines of treatment (median of 3 cycles; range: 1 to 5) in the recurrent/metastatic setting. The most frequently reported adverse event (AE) was a transient (typically 10% of patients included thrombocytopenia (44%), anemia (25%), fatigue (23%), and headache (14%). The majority of non-hematologic AEs were grade 1 or 2 (per Common Terminology Criteria) in severity. Three patients (5%) had a partial response and 25 patients (44%) had stable disease for at least 3 cycles. The duration of response ranged from 4.8-7.8+ months, and the median progression-free survival (PFS) was 1.6 months (90% confidence interval: 1.4, 2.8). Biopsy samples were evaluable from 34 patients. The median PFS by HPV status was 4.5 months in 15 patients who were HPV positive, and 1.4 months in 19 patients who were HPV negative (log-rank test, p = .0012). Conclusions: LY2606368 has an acceptable safety profile and demonstrates modest preliminary activity in a subset of patients with recurrent/metastatic SCCHN. The MTD of 105 mg/m2 is confirmed as the recommended dose for phase II testing. Citation Format: Johanna Bendell, Stefan Grant, Filip Janku, Jeffrey Infante, William N. William, Todd M. Bauer, Sarina Piha-Paul, Ricardo Martinez, Sameera Wijayawardana, Ji Lin, Lisa Golden, Aimee Bence Lin, David Hong. Checkpoint kinase (CHK) 1/2 inhibitor LY2606368 in a phase I dose-expansion study in patients with squamous cell carcinoma of the head and neck. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT240. doi:10.1158/1538-7445.AM2015-CT240

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 < 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