title: A phase I, first in man study of OSI-7836 in patients with advanced refractory solid tumors: IND.147, a study of the Investigational New Drug Program of the National Cancer Institute of Canada Clinical Trials Group.
abstract: OBJECTIVE
  To determine the maximum tolerated dose (MTD), recommended phase II dose (RP2D), safety, tolerability, toxicity profile, dose-limiting toxicities (DLTs), anti-tumor activity and pharmacokinetics of OSI-7836 given IV on day 1 and day 8 every 3 weeks in patients with advanced incurable cancer.
  
  
  METHODS
  Twenty-seven previously treated patients with advanced or metastatic solid tumors were enrolled in this phase I study conducted by the National Cancer Institute of Canada Clinical Trial Group (NCIC CTG). OSI-7836 was administered IV on day 1 and day 8 every 3 weeks. The dose was initially escalated from 100 to 600 mg/m2 and finally de-escalated to 200 mg/m2 in seven cohorts of patients. Patients were evaluated every other cycle of treatment for radiological response. Pharmacokinetics were performed on day 1 and day 8 of cycle 1 for all patients.
  
  
  RESULTS
  Twenty-six patients were evaluable for toxicity. All patients experienced reversible Grade 3 lymphopenia beginning at cycle 1. The maximal delivered dose was 600 mg/m2. MTD was reached at 400 mg/m2. DLTs included fever, fatigue, rash, herpes simplex infection, nausea and vomiting. The RP2D was 200 mg/m2. No objective responses were seen in 21 evaluable patients. Pharmacokinetics were dose proportional, with a mean half-life of 46.0 min and a clearance of 34 l/(h.m2).
  
  
  CONCLUSIONS
  OSI-7836 given at 200 mg/m2 on day 1 and day 8 every 3 weekly is associated with manageable toxicity and is recommended for further study. While no objective responses were seen, the significant treatment related lymphopenia suggests that hematologic malignancies may warrant further investigation.
authors.affiliation: The Ottawa Hospital Regional Cancer Centre, 501 Smyth Road, Ottawa, ON, Canada, K1H 8L6. ggoss@ottawahospital.on.ca
authors.forename: G
authors.initials: G
authors.lastname: Goss
authors.forename: L L
authors.initials: LL
authors.lastname: Siu
authors.forename: I
authors.initials: I
authors.lastname: Gauthier
authors.forename: E X
authors.initials: EX
authors.lastname: Chen
authors.forename: A M
authors.initials: AM
authors.lastname: Oza
authors.forename: R
authors.initials: R
authors.lastname: Goel
authors.forename: J
authors.initials: J
authors.lastname: Maroun
authors.forename: J
authors.initials: J
authors.lastname: Powers
authors.forename: W
authors.initials: W
authors.lastname: Walsh
authors.forename: M
authors.initials: M
authors.lastname: Maclean
authors.forename: D W
authors.initials: DW
authors.lastname: Drolet
authors.forename: J
authors.initials: J
authors.lastname: Rusk
authors.forename: L K
authors.initials: LK
authors.lastname: Seymour
mesh_terms: D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D001087:Arabinonucleosides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D002170:Canada; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D015507:Drugs, Investigational / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D005334:Fever / Q000139:chemically induced; D006207:Half-Life; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D001087:Arabinonucleosides; D015507:Drugs, Investigational; C411255:4'-thio-arabinofuranosylcytosine