title: Phase I Study of LY2606368, a Checkpoint Kinase 1 Inhibitor, in Patients With Advanced Cancer.
abstract: 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.
authors.affiliation: David Hong, Filip Janku, Ly M. Nguyen, Aung Naing, Sarina Piha-Paul, Faye M. Johnson, and Razelle Kurzrock, The University of Texas MD Anderson Cancer Center, Houston, TX; Jeffrey Infante, Suzanne Jones, Howard Burris, Todd M. Bauer, and Johanna Bendell, Sarah Cannon Research Institute; Jeffrey Infante, Howard Burris, Todd M. Bauer, and Johanna Bendell, Tennessee Oncology, Nashville, TN; and Lisa Golden, Scott Hynes, Ji Lin, and Aimee Bence Lin, Eli Lilly, Indianapolis, IN. dshong@mdanderson.org.
authors.forename: David
authors.initials: D
authors.lastname: Hong
authors.affiliation: David Hong, Filip Janku, Ly M. Nguyen, Aung Naing, Sarina Piha-Paul, Faye M. Johnson, and Razelle Kurzrock, The University of Texas MD Anderson Cancer Center, Houston, TX; Jeffrey Infante, Suzanne Jones, Howard Burris, Todd M. Bauer, and Johanna Bendell, Sarah Cannon Research Institute; Jeffrey Infante, Howard Burris, Todd M. Bauer, and Johanna Bendell, Tennessee Oncology, Nashville, TN; and Lisa Golden, Scott Hynes, Ji Lin, and Aimee Bence Lin, Eli Lilly, Indianapolis, IN.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Infante
authors.affiliation: David Hong, Filip Janku, Ly M. Nguyen, Aung Naing, Sarina Piha-Paul, Faye M. Johnson, and Razelle Kurzrock, The University of Texas MD Anderson Cancer Center, Houston, TX; Jeffrey Infante, Suzanne Jones, Howard Burris, Todd M. Bauer, and Johanna Bendell, Sarah Cannon Research Institute; Jeffrey Infante, Howard Burris, Todd M. Bauer, and Johanna Bendell, Tennessee Oncology, Nashville, TN; and Lisa Golden, Scott Hynes, Ji Lin, and Aimee Bence Lin, Eli Lilly, Indianapolis, IN.
authors.forename: Filip
authors.initials: F
authors.lastname: Janku
authors.affiliation: David Hong, Filip Janku, Ly M. Nguyen, Aung Naing, Sarina Piha-Paul, Faye M. Johnson, and Razelle Kurzrock, The University of Texas MD Anderson Cancer Center, Houston, TX; Jeffrey Infante, Suzanne Jones, Howard Burris, Todd M. Bauer, and Johanna Bendell, Sarah Cannon Research Institute; Jeffrey Infante, Howard Burris, Todd M. Bauer, and Johanna Bendell, Tennessee Oncology, Nashville, TN; and Lisa Golden, Scott Hynes, Ji Lin, and Aimee Bence Lin, Eli Lilly, Indianapolis, IN.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Jones
authors.affiliation: David Hong, Filip Janku, Ly M. Nguyen, Aung Naing, Sarina Piha-Paul, Faye M. Johnson, and Razelle Kurzrock, The University of Texas MD Anderson Cancer Center, Houston, TX; Jeffrey Infante, Suzanne Jones, Howard Burris, Todd M. Bauer, and Johanna Bendell, Sarah Cannon Research Institute; Jeffrey Infante, Howard Burris, Todd M. Bauer, and Johanna Bendell, Tennessee Oncology, Nashville, TN; and Lisa Golden, Scott Hynes, Ji Lin, and Aimee Bence Lin, Eli Lilly, Indianapolis, IN.
authors.forename: Ly M
authors.initials: LM
authors.lastname: Nguyen
authors.affiliation: David Hong, Filip Janku, Ly M. Nguyen, Aung Naing, Sarina Piha-Paul, Faye M. Johnson, and Razelle Kurzrock, The University of Texas MD Anderson Cancer Center, Houston, TX; Jeffrey Infante, Suzanne Jones, Howard Burris, Todd M. Bauer, and Johanna Bendell, Sarah Cannon Research Institute; Jeffrey Infante, Howard Burris, Todd M. Bauer, and Johanna Bendell, Tennessee Oncology, Nashville, TN; and Lisa Golden, Scott Hynes, Ji Lin, and Aimee Bence Lin, Eli Lilly, Indianapolis, IN.
authors.forename: Howard
authors.initials: H
authors.lastname: Burris
authors.affiliation: David Hong, Filip Janku, Ly M. Nguyen, Aung Naing, Sarina Piha-Paul, Faye M. Johnson, and Razelle Kurzrock, The University of Texas MD Anderson Cancer Center, Houston, TX; Jeffrey Infante, Suzanne Jones, Howard Burris, Todd M. Bauer, and Johanna Bendell, Sarah Cannon Research Institute; Jeffrey Infante, Howard Burris, Todd M. Bauer, and Johanna Bendell, Tennessee Oncology, Nashville, TN; and Lisa Golden, Scott Hynes, Ji Lin, and Aimee Bence Lin, Eli Lilly, Indianapolis, IN.
authors.forename: Aung
authors.initials: A
authors.lastname: Naing
authors.affiliation: David Hong, Filip Janku, Ly M. Nguyen, Aung Naing, Sarina Piha-Paul, Faye M. Johnson, and Razelle Kurzrock, The University of Texas MD Anderson Cancer Center, Houston, TX; Jeffrey Infante, Suzanne Jones, Howard Burris, Todd M. Bauer, and Johanna Bendell, Sarah Cannon Research Institute; Jeffrey Infante, Howard Burris, Todd M. Bauer, and Johanna Bendell, Tennessee Oncology, Nashville, TN; and Lisa Golden, Scott Hynes, Ji Lin, and Aimee Bence Lin, Eli Lilly, Indianapolis, IN.
authors.forename: Todd M
authors.initials: TM
authors.lastname: Bauer
authors.affiliation: David Hong, Filip Janku, Ly M. Nguyen, Aung Naing, Sarina Piha-Paul, Faye M. Johnson, and Razelle Kurzrock, The University of Texas MD Anderson Cancer Center, Houston, TX; Jeffrey Infante, Suzanne Jones, Howard Burris, Todd M. Bauer, and Johanna Bendell, Sarah Cannon Research Institute; Jeffrey Infante, Howard Burris, Todd M. Bauer, and Johanna Bendell, Tennessee Oncology, Nashville, TN; and Lisa Golden, Scott Hynes, Ji Lin, and Aimee Bence Lin, Eli Lilly, Indianapolis, IN.
authors.forename: Sarina
authors.initials: S
authors.lastname: Piha-Paul
authors.affiliation: David Hong, Filip Janku, Ly M. Nguyen, Aung Naing, Sarina Piha-Paul, Faye M. Johnson, and Razelle Kurzrock, The University of Texas MD Anderson Cancer Center, Houston, TX; Jeffrey Infante, Suzanne Jones, Howard Burris, Todd M. Bauer, and Johanna Bendell, Sarah Cannon Research Institute; Jeffrey Infante, Howard Burris, Todd M. Bauer, and Johanna Bendell, Tennessee Oncology, Nashville, TN; and Lisa Golden, Scott Hynes, Ji Lin, and Aimee Bence Lin, Eli Lilly, Indianapolis, IN.
authors.forename: Faye M
authors.initials: FM
authors.lastname: Johnson
authors.affiliation: David Hong, Filip Janku, Ly M. Nguyen, Aung Naing, Sarina Piha-Paul, Faye M. Johnson, and Razelle Kurzrock, The University of Texas MD Anderson Cancer Center, Houston, TX; Jeffrey Infante, Suzanne Jones, Howard Burris, Todd M. Bauer, and Johanna Bendell, Sarah Cannon Research Institute; Jeffrey Infante, Howard Burris, Todd M. Bauer, and Johanna Bendell, Tennessee Oncology, Nashville, TN; and Lisa Golden, Scott Hynes, Ji Lin, and Aimee Bence Lin, Eli Lilly, Indianapolis, IN.
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
authors.affiliation: David Hong, Filip Janku, Ly M. Nguyen, Aung Naing, Sarina Piha-Paul, Faye M. Johnson, and Razelle Kurzrock, The University of Texas MD Anderson Cancer Center, Houston, TX; Jeffrey Infante, Suzanne Jones, Howard Burris, Todd M. Bauer, and Johanna Bendell, Sarah Cannon Research Institute; Jeffrey Infante, Howard Burris, Todd M. Bauer, and Johanna Bendell, Tennessee Oncology, Nashville, TN; and Lisa Golden, Scott Hynes, Ji Lin, and Aimee Bence Lin, Eli Lilly, Indianapolis, IN.
authors.forename: Lisa
authors.initials: L
authors.lastname: Golden
authors.affiliation: David Hong, Filip Janku, Ly M. Nguyen, Aung Naing, Sarina Piha-Paul, Faye M. Johnson, and Razelle Kurzrock, The University of Texas MD Anderson Cancer Center, Houston, TX; Jeffrey Infante, Suzanne Jones, Howard Burris, Todd M. Bauer, and Johanna Bendell, Sarah Cannon Research Institute; Jeffrey Infante, Howard Burris, Todd M. Bauer, and Johanna Bendell, Tennessee Oncology, Nashville, TN; and Lisa Golden, Scott Hynes, Ji Lin, and Aimee Bence Lin, Eli Lilly, Indianapolis, IN.
authors.forename: Scott
authors.initials: S
authors.lastname: Hynes
authors.affiliation: David Hong, Filip Janku, Ly M. Nguyen, Aung Naing, Sarina Piha-Paul, Faye M. Johnson, and Razelle Kurzrock, The University of Texas MD Anderson Cancer Center, Houston, TX; Jeffrey Infante, Suzanne Jones, Howard Burris, Todd M. Bauer, and Johanna Bendell, Sarah Cannon Research Institute; Jeffrey Infante, Howard Burris, Todd M. Bauer, and Johanna Bendell, Tennessee Oncology, Nashville, TN; and Lisa Golden, Scott Hynes, Ji Lin, and Aimee Bence Lin, Eli Lilly, Indianapolis, IN.
authors.forename: Ji
authors.initials: J
authors.lastname: Lin
authors.affiliation: David Hong, Filip Janku, Ly M. Nguyen, Aung Naing, Sarina Piha-Paul, Faye M. Johnson, and Razelle Kurzrock, The University of Texas MD Anderson Cancer Center, Houston, TX; Jeffrey Infante, Suzanne Jones, Howard Burris, Todd M. Bauer, and Johanna Bendell, Sarah Cannon Research Institute; Jeffrey Infante, Howard Burris, Todd M. Bauer, and Johanna Bendell, Tennessee Oncology, Nashville, TN; and Lisa Golden, Scott Hynes, Ji Lin, and Aimee Bence Lin, Eli Lilly, Indianapolis, IN.
authors.forename: Aimee Bence
authors.initials: AB
authors.lastname: Lin
authors.affiliation: David Hong, Filip Janku, Ly M. Nguyen, Aung Naing, Sarina Piha-Paul, Faye M. Johnson, and Razelle Kurzrock, The University of Texas MD Anderson Cancer Center, Houston, TX; Jeffrey Infante, Suzanne Jones, Howard Burris, Todd M. Bauer, and Johanna Bendell, Sarah Cannon Research Institute; Jeffrey Infante, Howard Burris, Todd M. Bauer, and Johanna Bendell, Tennessee Oncology, Nashville, TN; and Lisa Golden, Scott Hynes, Ji Lin, and Aimee Bence Lin, Eli Lilly, Indianapolis, IN.
authors.forename: Johanna
authors.initials: J
authors.lastname: Bendell
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000071877:Checkpoint Kinase 1 / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011719:Pyrazines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011720:Pyrazoles / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D011720:Pyrazoles; C000608121:prexasertib; D000071877:Checkpoint Kinase 1