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Phase I Study of LY2606368, a Checkpoint Kinase 1 Inhibitor, in Patients With Advanced Cancer

2016; Lippincott Williams & Wilkins; Volume: 34; Issue: 15 Linguagem: Inglês

10.1200/jco.2015.64.5788

1527-7755

David S. Hong, Jeffrey R. Infante, Filip Janků, Suzanne F. Jones, Ly M. Nguyen, Howard A. Burris, Aung Naing, Todd M. Bauer, Sarina A. Piha‐Paul, Faye M. Johnson, Razelle Kurzrock, Lisa Golden, Scott M. Hynes, Ji Lin, Aimee Bence Lin, Johanna C. Bendell,

Cancer therapeutics and mechanisms

Purpose The primary objective was to determine safety, toxicity, and a recommended phase II dose regimen of LY2606368, an inhibitor of checkpoint kinase 1, as monotherapy. Patients and Methods This phase I, nonrandomized, open-label, dose-escalation trial used a 3 + 3 dose-escalation scheme and included patients with advanced solid tumors. Intravenous LY2606368 was dose escalated from 10 to 50 mg/m 2 on schedule 1 (days 1 to 3 every 14 days) or from 40 to 130 mg/m 2 on schedule 2 (day 1 every 14 days). Safety measures and pharmacokinetics were assessed, and pharmacodynamics were measured in blood, hair follicles, and circulating tumor cells. Results Forty-five patients were treated; seven experienced dose-limiting toxicities (all hematologic). The maximum-tolerated doses (MTDs) were 40 mg/m 2 (schedule 1) and 105 mg/m 2 (schedule 2). The most common related grade 3 or 4 treatment-emergent adverse events were neutropenia, leukopenia, anemia, thrombocytopenia, and fatigue. Grade 4 neutropenia occurred in 73.3% of patients and was transient (typically < 5 days). Febrile neutropenia incidence was low (7%). The LY2606368 exposure over the first 72 hours (area under the curve from 0 to 72 hours) at the MTD for each schedule coincided with the exposure in mouse xenografts that resulted in maximal tumor responses. Minor intra- and intercycle accumulation of LY2606368 was observed at the MTDs for both schedules. Two patients (4.4%) had a partial response; one had squamous cell carcinoma (SCC) of the anus and one had SCC of the head and neck. Fifteen patients (33.3%) had a best overall response of stable disease (range, 1.2 to 6.7 months), six of whom had SCC. Conclusion An LY2606368 dose of 105 mg/m 2 once every 14 days is being evaluated as the recommended phase II dose in dose-expansion cohorts for patients with SCC.