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Ref Type Journal Article
PMID (27044938)
Authors Hong D, Infante J, Janku F, Jones S, Nguyen LM, Burris H, Naing A, Bauer TM, Piha-Paul S, Johnson FM, Kurzrock R, Golden L, Hynes S, Lin J, Lin AB, Bendell J
Title Phase I Study of LY2606368, a Checkpoint Kinase 1 Inhibitor, in Patients With Advanced Cancer.
Journal Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Vol 34
Issue 15
Date 2016 May 20
URL
Abstract Text 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.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.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.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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown head and neck squamous cell carcinoma not applicable Prexasertib Phase I Actionable In a Phase I trial, Prexasertib (LY2606368) treatment resulted in partial response in a patient with head and neck squamous cell carcinoma (PMID: 27044938; NCT0115790). 27044938
Unknown unknown anal squamous cell carcinoma not applicable Prexasertib Phase I Actionable In a Phase I trial, Prexasertib (LY2606368) treatment resulted in partial response in a patient with anal squamous cell carcinoma (PMID: 27044938). 27044938
Unknown unknown squamous cell carcinoma not applicable Prexasertib Phase I Actionable In a Phase I trial, Prexasertib (LY2606368) treatment resulted in partial response in 2 patients with squamous cell carcinoma (SCC), and 40% (6/15) of solid tumor patients who achieved stable disease had SCC (PMID: 27044938; NCT0115790). 27044938
Unknown unknown Advanced Solid Tumor not applicable Prexasertib Phase I Actionable In a Phase I trial, Prexasertib (LY2606368) treatment resulted in partial response in 4.4% (2/45) and stable disease ranging from 1.2 to 6.7 months in 33.3% (15/45) of patients with advanced solid tumors (PMID: 27044938). 27044938