Abstract CT240: 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
Authors: Bendell Johanna , Grant Stefan , Janku Filip , Infante Jeffrey , William William N. , Bauer Todd M. , Piha-Paul Sarina , Martinez Ricardo , Wijayawardana Sameera , Lin Ji , Golden Lisa , Lin Aimee Bence , Hong David 
Published: August 2015

Abstract
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 &lt;5 days) decrease in neutrophil/leukocyte count, which occurred in 91% of patients (grade 4 in 63% of patients). Ten patients (18%) experienced febrile neutropenia. Other study drug-related AEs occurring in &gt;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