title: A phase II study to evaluate LY2603618 in combination with gemcitabine in pancreatic cancer patients.
abstract: The aim of this study was to determine whether checkpoint kinase 1 inihibitor (CHK1), LY2603618, and gemcitabine prolong overall survival (OS) compared to gemcitabine alone in patients with unresectable pancreatic cancer.
  
  
  
  Patients with Stage II-IV locally advanced or metastatic pancreatic cancer were randomized (2:1) to either 230 mg of LY2603618/1000 mg/m2gemcitabine combined or 1000 mg/m2gemcitabine alone. OS was assessed using both a Bayesian augment control model and traditional frequentist analysis for inference. Progression-free survival (PFS), overall response rate (ORR), duration of response, pharmacokinetics (PK), and safety (Common Terminology Criteria for Adverse Events [AEs] v 3.0) were also evaluated.
  
  
  
  Ninety-nine patients (n = 65, LY2603618/gemcitabine; n = 34, gemcitabine) were randomized (intent-to-treat population). The median OS (months) was 7.8 (range, 0.3-18.9) with LY2603618/gemcitabine and 8.3 (range, 0.8-19.1+) with gemcitabine. Similarly, in a Bayesian analysis, the study was not positive since the posterior probability that LY2603618/gemcitabine was superior to gemcitabine in improving OS was 0.3, which did not exceed the prespecified threshold of 0.8. No significant improvements in PFS, ORR, or duration of response were observed. Drug-related treatment-emergent AEs in both arms included nausea, thrombocytopenia, fatigue, and neutropenia. The severity of AEs with LY2603618/gemcitabine was comparable to gemcitabine. The LY2603618 exposure targets (AUC(0-∞)≥21,000 ng∙hr/mL and Cmax≥2000 ng/mL) predicted for maximum pharmacodynamic response were achieved after 230 mg of LY2603618.
  
  
  
  LY2603618/gemcitabine was not superior to gemcitabine for the treatment of patients with pancreatic cancer.
  
  
  
  NCT00839332 . Clinicaltrials.gov. Date of registration: 6 February 2009.
authors.affiliation: Institut Català d'Oncologia-IDIBELL (Institut d'Investigació Biomèdica de Bellvitge), Barcelona, Spain.
authors.forename: Berta
authors.initials: B
authors.lastname: Laquente
authors.affiliation: University Hospital and Research Institute, Madrid, Spain.
authors.forename: Jose
authors.initials: J
authors.lastname: Lopez-Martin
authors.affiliation: US Oncology Research, Tyler, USA.
authors.forename: Donald
authors.initials: D
authors.lastname: Richards
authors.affiliation: Hematology, Onkology, and Palliative Care, Klinikum Stuttgart, Stuttgart, Germany.
authors.forename: Gerald
authors.initials: G
authors.lastname: Illerhaus
authors.affiliation: Virginia Oncology Associates, Eastern Virginia Medical School, US Oncology Research, Hampton, VA, USA.
authors.forename: David Z
authors.initials: DZ
authors.lastname: Chang
authors.affiliation: 21st Century Oncology, University of Florida Health Oncology, Jacksonville, USA.
authors.forename: George
authors.initials: G
authors.lastname: Kim
authors.affiliation: St. Joseph Mercy Hospital, Ypsilanti, MI, USA.
authors.forename: Philip
authors.initials: P
authors.lastname: Stella
authors.affiliation: Academic Medical Center, Amsterdam, Netherlands.
authors.forename: Dirk
authors.initials: D
authors.lastname: Richel
authors.affiliation: Department of Oncology, Military Institute of Medicine, Warsaw, Poland.
authors.forename: Cezary
authors.initials: C
authors.lastname: Szcylik
authors.affiliation: Department of Oncology and Hematology, Universitá di Modena e Reggio Emilia, Policlinico di Modena, Modena, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Cascinu
authors.affiliation: Department of Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
authors.forename: G L
authors.initials: GL
authors.lastname: Frassineti
authors.affiliation: Institute of Oncology Ion Chiricuta, University of Medicine and Pharmacy Iuliu Hatieganu, Cluj Napoca, Romania.
authors.forename: Tudor
authors.initials: T
authors.lastname: Ciuleanu
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Karla
authors.initials: K
authors.lastname: Hurt
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Hynes
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Ji
authors.initials: J
authors.lastname: Lin
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Aimee Bence
authors.initials: AB
authors.lastname: Lin
authors.affiliation: Translational Genomics Research Institute (TGen) and HonorHealth Research Institute, Phoenix, AZ, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Von Hoff
authors.affiliation: START Madrid-CIOCC, Centro Integral Oncológico Clara Campal, Medical Oncology Division, Hospital Universitario Madrid Norte Sanchinarro, Calle Oña, 10, 28050, Madrid, Spain. emiliano.calvo@start.stoh.com.
authors.forename: Emiliano
authors.initials: E
authors.lastname: Calvo
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010671:Phenylurea Compounds / Q000008:administration & dosage; D011379:Prognosis; D011719:Pyrazines / Q000008:administration & dosage; D015996:Survival Rate; D000093542:Gemcitabine
chemical_list: C582547:LY2603618; D010671:Phenylurea Compounds; D011719:Pyrazines; D003841:Deoxycytidine; D000093542:Gemcitabine
keywords: CHK1; LY2603618; cancer; gemcitabine; phase II