title: A phase I and pharmacokinetic study of high dose tamoxifen and weekly cisplatin in patients with metastatic melanoma.
abstract: BACKGROUND
  The authors have previously demonstrated that tamoxifen (TAM) is synergistic with cisplatin (DDP) in patients with metastatic melanoma. In vitro studies have demonstrated that TAM/DDP synergy is dependent on a TAM effect that is currently under investigation. In an attempt to improve the complete response rate of this regimen, the authors initiated a Phase I trial to determine the maximum tolerated dose (MTD) of TAM that could be safely administered with weekly DDP.
  
  
  METHODS
  TAM was started on Day 1 at a dose of 80 mg/day and was increased by 40 mg to the MTD in groups of 3 patients. DDP (80 mg/m2) was begun on Day 2 and repeated weekly for a total of 3 weeks. During Week 4, the patients were not treated with DDP but instead evaluated for response. If disease stabilization or regression was documented, the patients received a second 3-week cycle of DDP and were then reevaluated for response. Patients with progressive disease were removed from the study.
  
  
  RESULTS
  In 25 consecutive patients, the overall response rate was 20%. No responses were observed in patients treated with TAM at a dose of <240 mg/day. Among 13 patients treated at or above this dose, there were 2 complete responses, 3 partial responses, 2 mixed responses, and 6 patients with progressive disease. The overall response rate for patients treated with 240 mg of TAM or higher was 38.5%. Dose-limiting toxicity, which occurred at a TAM dose of 280 mg/day, was primarily hematologic and gastrointestinal in nature. There was one toxic death (due to septic neutropenia) at this dose. There were no episodes of thrombosis.
  
  
  CONCLUSIONS
  A TAM dose of 240 mg/day is the recommended Phase II dose. Based on the 38.5% overall response rate at this dose, the authors have initiated a Phase II study.
authors.affiliation: Department of Medicine, Hollings Cancer Center, Medical University of South Carolina, Charleston 29403, USA.
authors.forename: E F
authors.initials: EF
authors.lastname: McClay
authors.forename: M E
authors.initials: ME
authors.lastname: McClay
authors.forename: J A
authors.initials: JA
authors.lastname: Jones
authors.forename: P J
authors.initials: PJ
authors.lastname: Winski
authors.forename: R D
authors.initials: RD
authors.lastname: Christen
authors.forename: S B
authors.initials: SB
authors.lastname: Howell
authors.forename: P D
authors.initials: PD
authors.lastname: Hall
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects; D002945:Cisplatin / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy*; D008875:Middle Aged; D013629:Tamoxifen / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D013629:Tamoxifen; D002945:Cisplatin