title: Phase I dose-escalation study to examine the safety and tolerability of LY2603618, a checkpoint 1 kinase inhibitor, administered 1 day after pemetrexed 500 mg/m(2) every 21 days in patients with cancer.
abstract: OBJECTIVE
  This phase I study aims at assessing the safety and tolerability of LY2603618, a selective inhibitor of Checkpoint Kinase 1, in combination with pemetrexed and determining the maximum tolerable dose and the pharmacokinetic parameters.
  
  
  METHODS
  This was an open-label, multicenter, dose-escalation study in patients with advanced solid tumors. Increasing doses of LY2603618 (40-195 mg/m(2)) were combined with 500 mg/m(2) of pemetrexed. LY2603618 was administered on Days 1 and 9 and pemetrexed on Day 8 in a 28-day cycle. For all subsequent 21-day cycles, pemetrexed was administered on Day 1 and LY2603618 on Day 2. Antitumor activity was evaluated as per Response Evaluation Criteria in Solid Tumors 1.0.
  
  
  RESULTS
  A total of 31 patients were enrolled into six cohorts (three at 40 mg/m(2) over 4.5-hour infusion, 1-hour infusion in subsequent cohorts: three each at 40 mg/m(2), 70 mg/m(2), and 195 mg/m(2); 13 at 105 mg/m(2); six at 150 mg/m(2)). Four patients experienced a dose-limiting toxicity: diarrhea (105 mg/m(2)); reversible infusion-related reaction (150 mg/m(2)); thrombocytopenia (195 mg/m(2)); and fatigue (195 mg/m(2)). The maximum tolerated dose was defined as 150 mg/m(2). The pharmacokinetic data demonstrated that the exposure of LY2603618 increased in a dose-dependent manner, displayed a suitable half-life for maintaining required human exposures while minimizing the intra- and inter-cycle accumulation, and was unaffected by the pemetrexed administration. The pharmacokinetic-defined biologically efficacious dose was achieved at doses ≥105 mg/m(2).
  
  
  CONCLUSIONS
  LY2603618 administered approximately 24 h after pemetrexed showed acceptable safety and pharmacokinetic profiles.
authors.affiliation: Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare/TGen, 10510 N 92nd St, Ste 200, Scottsdale, AZ 85258, USA. gweiss@tgen.org
authors.forename: Glen J
authors.initials: GJ
authors.lastname: Weiss
authors.forename: Ross C
authors.initials: RC
authors.lastname: Donehower
authors.forename: Tara
authors.initials: T
authors.lastname: Iyengar
authors.forename: Ramesh K
authors.initials: RK
authors.lastname: Ramanathan
authors.forename: Karen
authors.initials: K
authors.lastname: Lewandowski
authors.forename: Eric
authors.initials: E
authors.lastname: Westin
authors.forename: Karla
authors.initials: K
authors.lastname: Hurt
authors.forename: Scott M
authors.initials: SM
authors.lastname: Hynes
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Anthony
authors.forename: Scott
authors.initials: S
authors.lastname: McKane
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000071877:Checkpoint Kinase 1; D005260:Female; D005971:Glutamates / Q000008:administration & dosage; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy*; D000068437:Pemetrexed; D010671:Phenylurea Compounds / Q000008:administration & dosage; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011494:Protein Kinases; D011719:Pyrazines / Q000008:administration & dosage
chemical_list: D005971:Glutamates; C582547:LY2603618; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D000068437:Pemetrexed; D006147:Guanine; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1