title: Phase I study of Oral gemcitabine prodrug (LY2334737) alone and in combination with erlotinib in patients with advanced solid tumors.
abstract: OBJECTIVE
  LY2334737 is an orally available prodrug of gemcitabine. The objective of this study was to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of daily administration of LY2334737 with or without erlotinib.
  
  
  METHODS
  Patients with advanced or metastatic cancer were treated with escalating doses of LY2334737 monotherapy or in combination with continuous daily administration of 100 mg erlotinib. LY2334737 was given once daily for 14 days of a 21-day cycle. The study was extended with a bioequivalence trial to investigate a novel LY2334737 drug formulation.
  
  
  RESULTS
  A total of 65 patients were treated in this study. The MTD was 40 mg LY2334737. Fatigue was the most frequent DLT for LY2334737 monotherapy (4 patients) followed by elevated transaminase levels (2 patients), both observed at the 40- to 50-mg dose levels. Among the 10 patients in the combination arm, 2 had DLTs at the 40-mg dose level. These were fatigue and elevated liver enzyme levels. The most common adverse events were fatigue (n = 38), nausea (n = 27), vomiting (n = 24), diarrhea (n = 23), anorexia (n = 20), pyrexia (n = 18), and elevated transaminase levels (n = 14). The pharmacokinetics showed dose proportional increase in LY2334737 and gemcitabine exposure. The metabolite 2',2'-difluorodeoxyuridine accumulated with an accumulation index of 4.3 (coefficient of variation: 20%). In one patient, complete response in prostate-specific antigen was observed for 4 cycles, and stable disease was achieved in 22 patients overall. Pharmacokinetic analysis showed that the 2 investigated LY2334737 drug formulations were bioequivalent.
  
  
  CONCLUSIONS
  LY2334737 displays linear pharmacokinetics and the MTD is 40 mg with or without daily administration of 100 mg erlotinib. Signs of antitumor activity warrant further development.
authors.affiliation: Division of Clinical Pharmacology, The Netherlands Cancer Institute, The Netherlands. stijnkoolen@gmail.com
authors.forename: Stijn L W
authors.initials: SL
authors.lastname: Koolen
authors.forename: Petronella O
authors.initials: PO
authors.lastname: Witteveen
authors.forename: Robert S
authors.initials: RS
authors.lastname: Jansen
authors.forename: Marlies H G
authors.initials: MH
authors.lastname: Langenberg
authors.forename: Roelien H
authors.initials: RH
authors.lastname: Kronemeijer
authors.forename: Annemarie
authors.initials: A
authors.lastname: Nol
authors.forename: Ignacio
authors.initials: I
authors.lastname: Garcia-Ribas
authors.forename: Sophie
authors.initials: S
authors.lastname: Callies
authors.forename: Karim A
authors.initials: KA
authors.lastname: Benhadji
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Slapak
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: Emile E
authors.initials: EE
authors.lastname: Voest
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000378:metabolism; D003857:Deoxyuridine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011355:Prodrugs / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult; D000093542:Gemcitabine
chemical_list: C569272:LY2334737; D011355:Prodrugs; D011799:Quinazolines; D003841:Deoxycytidine; D000069347:Erlotinib Hydrochloride; D003857:Deoxyuridine; D000093542:Gemcitabine