title: Phase 1 study of the safety, tolerability, and pharmacokinetics of TH-302, a hypoxia-activated prodrug, in patients with advanced solid malignancies.
abstract: OBJECTIVE
  The objectives of this phase 1, first-in-human study were to determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), safety, pharmacokinetics, and preliminary activity of the hypoxia-activated prodrug TH-302 in patients with advanced solid tumors.
  
  
  METHODS
  TH-302 was administered intravenously over 30 to 60 minutes in two regimens: three times weekly dosing followed by 1 week off (arm A) and every 3-week dosing (arm B).
  
  
  RESULTS
  Fifty-seven patients enrolled (arm A: N = 37 and arm B: N = 20). The TH-302 dose was escalated from 7.5 to 670 mg/m(2) in arm A and from 670 to 940 mg/m(2) in arm B. The most common adverse events were nausea, skin rash, fatigue, and vomiting. Hematologic toxicity was mild and limited. Grade 3 skin and mucosal toxicities were dose limiting at 670 mg/m(2) in arm A; the MTD was 575 mg/m(2). In arm B, grade 3 fatigue and grade 3 vaginitis/proctitis were dose limiting at 940 mg/m(2); the MTD was 670 mg/m(2). Plasma concentrations of TH-302 and the active metabolite Br-IPM (brominated version of isophosphoramide mustard) increased proportionally with dose. Two partial responses were noted in patients with metastatic small cell lung cancer (SCLC) and melanoma in arm A at 480 and 670 mg/m(2). Stable disease was observed in arms A and B in 18 and 9 patients, respectively.
  
  
  CONCLUSIONS
  The MTD of TH-302 was 575 mg/m(2) weekly and 670 mg/m(2) every 3 weeks. Skin and mucosal toxicities were DLTs. On the basis of responses in metastatic melanoma and SCLC, further investigations in these indications were initiated.
authors.affiliation: Virginia G Piper Cancer Center at Scottsdale Healthcare/TGen, Scottsdale, Arizona 85238, USA. gweiss@tgen.org
authors.forename: Glen J
authors.initials: GJ
authors.lastname: Weiss
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Infante
authors.forename: E Gabriela
authors.initials: EG
authors.lastname: Chiorean
authors.forename: Mitesh J
authors.initials: MJ
authors.lastname: Borad
authors.forename: Johanna C
authors.initials: JC
authors.lastname: Bendell
authors.forename: Julian R
authors.initials: JR
authors.lastname: Molina
authors.forename: Raoul
authors.initials: R
authors.lastname: Tibes
authors.forename: Ramesh K
authors.initials: RK
authors.lastname: Ramanathan
authors.forename: Karen
authors.initials: K
authors.lastname: Lewandowski
authors.forename: Suzanne F
authors.initials: SF
authors.lastname: Jones
authors.forename: Mario E
authors.initials: ME
authors.lastname: Lacouture
authors.forename: Virginia K
authors.initials: VK
authors.lastname: Langmuir
authors.forename: Hank
authors.initials: H
authors.lastname: Lee
authors.forename: Stew
authors.initials: S
authors.lastname: Kroll
authors.forename: Howard A
authors.initials: HA
authors.lastname: Burris
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009593:Nitroimidazoles / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D010752:Phosphoramide Mustards / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D011355:Prodrugs / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D009593:Nitroimidazoles; D010752:Phosphoramide Mustards; D011355:Prodrugs; C552526:TH 302