title: Dose escalation study of intravenous estramustine phosphate in combination with Paclitaxel and Carboplatin in patients with advanced prostate cancer.
abstract: OBJECTIVE
  The purpose is to determine a safe weekly dose of i.v. estramustine phosphate (EMP) to combine with weekly paclitaxel and monthly carboplatin in patients with advanced prostate cancer.
  
  
  METHODS
  Patients with advanced prostate cancer (castrate and noncastrate) were administered escalating doses of weekly 1-h infusion of i.v. EMP (500-1000-1500 mg/m(2)) in combination with weekly paclitaxel (100 mg/m(2) over 1 h) and i.v. carboplatin (area under the curve 6 mg/ml-min every 4 weeks). Four weeks of therapy were considered one cycle. In the first three cohorts, EMP was given i.v. 3 h before paclitaxel. Cohorts 4 and 5 reversed the administration order: EMP (doses 1000-1500 mg/m(2)) was given immediately after the end of paclitaxel infusion. Plasma levels of EMP and its metabolites, estramustine and estromustine, were monitored at time 0, at 120 min, and approximately at 20, 21, and 168 h from the start of EMP infusion. Paclitaxel concentrations were determined at basal (0), 30, 60, 90, and 120 min and 18 h after the start of paclitaxel infusion, and a concentration-time curve was estimated. Pharmacokinetic evaluation was performed in cycles 1 and 2 during the first week of therapy.
  
  
  RESULTS
  Nineteen patients were entered on the initial three dose levels (cohorts 1-3). Dose-limiting transient hepatic toxicity was encountered in cohort 3 (EMP = 1500 mg/m(2)). An additional 13 patients were treated with paclitaxel (100 mg/m(2)) first, followed by i.v. EMP at 1000 mg/m(2) (cohort 4), and 1500 mg/m(2) (cohort 5). No dose-limiting toxicities were seen, and cohort 5 was determined safe for Phase II studies. Thromboembolic events were observed in 9% of patients (no prophylactic coumadin was used). Plasma concentrations of EMP and metabolites increased proportionally with dose. In all cohorts, there was a slight decrease in EMP and estramustine plasma concentrations between cycles 1 and 2. Although not significant, higher levels of estromustine at cycle 2 were observed in comparison to cycle 1. Decreased clearance of paclitaxel leading to higher than expected paclitaxel plasma concentrations was observed during the first cycle of therapy. Paclitaxel plasma concentrations were lower during cycle 2. In 17 patients with androgen-independent disease, 59% had >/=50% posttherapy decline in PSA and 22% showed measurable disease regression.
  
  
  CONCLUSIONS
  The regimen of weekly i.v. EMP in combination with paclitaxel and carboplatin can be safely administered with hepatic toxicity being transient and reversible. Pharmacokinetic results suggest that EMP competitively inhibits the biotransformation of paclitaxel after the first administration. This effect is counterbalanced, after repeated administrations, by a possible induction of the metabolic system caused by EMP. Phase II testing is ongoing to evaluate the efficacy of this combination.
authors.affiliation: Genitourinary Oncology Service, Division of Solid Tumor, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA. kellyw@mskcc.org
authors.forename: William Kevin
authors.initials: WK
authors.lastname: Kelly
authors.forename: Andrew X
authors.initials: AX
authors.lastname: Zhu
authors.forename: Howard
authors.initials: H
authors.lastname: Scher
authors.forename: Tracey
authors.initials: T
authors.lastname: Curley
authors.forename: Mary
authors.initials: M
authors.lastname: Fallon
authors.forename: Susan
authors.initials: S
authors.lastname: Slovin
authors.forename: Lawrence
authors.initials: L
authors.lastname: Schwartz
authors.forename: Steve
authors.initials: S
authors.lastname: Larson
authors.forename: William
authors.initials: W
authors.lastname: Tong
authors.forename: Beryl
authors.initials: B
authors.lastname: Hartley-Asp
authors.forename: Cinzia
authors.initials: C
authors.lastname: Pellizzoni
authors.forename: Maurizio
authors.initials: M
authors.lastname: Rocchetti
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D004961:Estramustine / Q000008:administration & dosage / Q000097:blood; D006801:Humans; D008297:Male; D008875:Middle Aged; D017239:Paclitaxel / Q000008:administration & dosage / Q000097:blood; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D016896:Treatment Outcome
chemical_list: D004961:Estramustine; D003577:Cytochrome P-450 Enzyme System; D016190:Carboplatin; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D017239:Paclitaxel