title: A phase I study of the safety and pharmacokinetics of the hypoxia-activated prodrug TH-302 in combination with doxorubicin in patients with advanced soft tissue sarcoma.
abstract: OBJECTIVE
  The purpose of this study was to determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), safety, pharmacokinetics and preliminary activity of TH-302, a hypoxia-activated prodrug, in combination with doxorubicin in patients with advanced soft tissue sarcoma.
  
  
  METHODS
  TH-302 was administered intravenously on days 1 and 8 and doxorubicin 75 mg/m² on day 1 (2 h after TH-302) of every 3-week cycle. TH-302 starting dose was 240 mg/m² with a classic 3 + 3 dose escalation. Pharmacokinetics were assessed on days 1 and 8 of cycle 1. Tumor assessments were performed after every second cycle.
  
  
  RESULTS
  Sixteen patients enrolled. Prophylactic growth factor support was added due to grade 4 neutropenia. The MTD was 300 mg/m². DLTs at 340 mg/m² were neutropenia-associated infection and grade 4 thrombocytopenia. Common adverse events included fatigue, nausea and skin rash. There was no evidence of pharmacokinetic interaction between TH-302 and doxorubicin. Five of 15 (33%) evaluable patients had a partial response by RECIST (Response Evaluation Criteria in Solid Tumors) criteria.
  
  
  CONCLUSIONS
  The hematologic toxicity of doxorubicin is increased when combined with TH-302. This can be mitigated by prophylactic growth factor support. Toxicities were manageable and there was evidence of antitumor activity.
authors.affiliation: Stanford University Medical Center, Stanford, Calif., USA. kganjoo@stanford.edu
authors.forename: Kristen N
authors.initials: KN
authors.lastname: Ganjoo
authors.forename: Lee D
authors.initials: LD
authors.lastname: Cranmer
authors.forename: James E
authors.initials: JE
authors.lastname: Butrynski
authors.forename: Daniel
authors.initials: D
authors.lastname: Rushing
authors.forename: Douglas
authors.initials: D
authors.lastname: Adkins
authors.forename: Scott H
authors.initials: SH
authors.lastname: Okuno
authors.forename: Gustavo
authors.initials: G
authors.lastname: Lorente
authors.forename: Stew
authors.initials: S
authors.lastname: Kroll
authors.forename: Virginia K
authors.initials: VK
authors.lastname: Langmuir
authors.forename: Sant P
authors.initials: SP
authors.lastname: Chawla
mesh_terms: D000038:Abscess / Q000209:etiology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000740:Anemia / Q000139:chemically induced; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D002481:Cellulitis / Q000139:chemically induced; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000009:adverse effects* / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D003875:Drug Eruptions; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use; D006801:Humans; D008231:Lymphopenia / Q000139:chemically induced; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009503:Neutropenia / Q000139:chemically induced* / Q000188:drug therapy; D009593:Nitroimidazoles / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D010752:Phosphoramide Mustards / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D012509:Sarcoma / Q000188:drug therapy* / Q000601:surgery; D013280:Stomatitis / Q000139:chemically induced; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D009593:Nitroimidazoles; D010752:Phosphoramide Mustards; C552526:TH 302; D016179:Granulocyte Colony-Stimulating Factor; D004317:Doxorubicin; C010013:adriamycinol