title: Phase I study of oral gemcitabine prodrug (LY2334737) in Japanese patients with advanced solid tumors.
abstract: OBJECTIVE
  LY2334737 is an oral gemcitabine prodrug. This Phase I study assessed the safety and tolerability of LY2334737 in Japanese patients with solid tumors and evaluated pharmacokinetics (PK), pharmacodynamics, and antitumor activity.
  
  
  METHODS
  Patients with advanced/metastatic solid tumors received escalating doses of LY2334737 once daily for 14 days, followed by a 7-day drug-free period. Cycles were repeated until discontinuation criteria were met.
  
  
  RESULTS
  Of 13 patients treated, 3 received 20 mg/day, 6 received 30 mg/day, 4 received 40 mg/day. On the 40 mg dose, 3 patients experienced dose-limiting toxicities (DLTs): hepatic toxicities (e.g., Grade [G]3/4 transaminase and G1-3 bilirubin elevation) and G4 thrombocytopenia; all 3 showed features of disseminated intravascular coagulation. One additional DLT occurred on the 30 mg dose (G3 transaminase elevation). Exploratory pharmacogenetic analyses identified a genetic variation in the CES2 gene potentially associated with these DLTs. PK data showed no clear relationship between the AUC of gemcitabine and its incorporation into leukocyte DNA; 2 of the 3 DLT patients had high incorporation. Two patients (30 mg/day) achieved stable disease with progression-free survival lasting 135 and 155 days.
  
  
  CONCLUSIONS
  LY2334737 was tolerated by Japanese patients up to 30 mg/day. The toxicities observed at the 40 mg dose may require the development of alternative dosing schedules.
authors.affiliation: Division of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Noboru
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nokihara
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Yamada
authors.forename: Kazunori
authors.initials: K
authors.lastname: Uenaka
authors.forename: Risa
authors.initials: R
authors.lastname: Sekiguchi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Makiuchi
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Slapak
authors.forename: Karim A
authors.initials: KA
authors.lastname: Benhadji
authors.forename: Tomohide
authors.initials: T
authors.lastname: Tamura
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D043182:Carboxylesterase / Q000235:genetics; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D003857:Deoxyuridine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D011355:Prodrugs / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D000093542:Gemcitabine
chemical_list: C569272:LY2334737; D011355:Prodrugs; D003841:Deoxycytidine; C517204:CES2 protein, human; D043182:Carboxylesterase; D003857:Deoxyuridine; D000093542:Gemcitabine