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|Ref Type||Journal Article|
|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|
|Date||2016 May 20|
|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.|
|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|