title: Phase I study of cisdiamminedichloroplatinum in combination with azidothymidine in the treatment of patients with advanced malignancies.
abstract: OBJECTIVE
  Azidothymidine (AZT, zidovudine) has been shown to reverse cisplatin resistance in cell culture. This phase I study was performed to determine the maximally tolerated dose (MTD) and dose-limiting toxicities of AZT when administered by continuous intravenous infusion in combination with cisplatin (CDDP), and to evaluate the pharmacokinetics of AZT in this setting.
  
  
  METHODS
  Entered in the study were 61 patients with advanced, histologically confirmed malignancies which were unresponsive to or for which no "standard" chemotherapeutic regimen existed. AZT was administered as a 72-h infusion on days 1-3 and 14-16 of a 28-day cycle at dose levels from 400 through 14,364 mg/m(2) per day. CDDP at dose levels of 30, 45, or 60 mg/m(2) was administered at hour 36 of each AZT infusion. The plasma pharmacokinetics of AZT were determined in patients treated at representative dose levels.
  
  
  RESULTS
  Of the 61 patients who completed 125 courses of therapy, 21 had stable disease for a median of four cycles (range two to eight), 33 progressed on therapy, and 7 were not assessable for response. The major observed toxicity was myelosuppression. The MTD of AZT was 8135 mg/m(2) per day when administered on this schedule. Escalation of CDDP did not result in additive toxicity. The mean steady-state level of AZT at the MTD was 44 microM (range 35-51 microM).
  
  
  CONCLUSIONS
  Steady-state concentrations of AZT increased with dose. The plasma levels achieved at the MTD exceeded those required for drug resistance reversal in vitro. The administration of CDDP had no effect on AZT steady-state levels. The dose-limiting toxicity of this drug combination is myelosuppression. AZT may be useful in further studies utilizing combination therapy to achieve increased chemotherapy effectiveness.
authors.affiliation: Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, 1500 E. Duarte Rd, Duarte, CA 91010, USA. rmorgan@coh.org
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Morgan
authors.forename: Edward M
authors.initials: EM
authors.lastname: Newman
authors.forename: Lawrence
authors.initials: L
authors.lastname: Sowers
authors.forename: Kevin
authors.initials: K
authors.lastname: Scanlon
authors.forename: Jonathan
authors.initials: J
authors.lastname: Harrison
authors.forename: Steven
authors.initials: S
authors.lastname: Akman
authors.forename: Lucille
authors.initials: L
authors.lastname: Leong
authors.forename: Kim
authors.initials: K
authors.lastname: Margolin
authors.forename: Joyce
authors.initials: J
authors.lastname: Niland
authors.forename: James
authors.initials: J
authors.lastname: Raschko
authors.forename: George
authors.initials: G
authors.lastname: Somlo
authors.forename: Mary
authors.initials: M
authors.lastname: Carroll
authors.forename: Warren
authors.initials: W
authors.lastname: Chow
authors.forename: Merry
authors.initials: M
authors.lastname: Tetef
authors.forename: Victor
authors.initials: V
authors.lastname: Hamasaki
authors.forename: Yun
authors.initials: Y
authors.lastname: Yen
authors.forename: James H
authors.initials: JH
authors.lastname: Doroshow
mesh_terms: D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D015215:Zidovudine / Q000008:administration & dosage
chemical_list: D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D015215:Zidovudine; D002945:Cisplatin