title: A phase I study of paclitaxel, estramustine phosphate and vinorelbine (Pacl-E-Vin) in advanced malignancies: triple tubulin targeting.
abstract: Anti-tubulin couplets have activity in hormone-resistant prostate cancer. This study was designed to define the dose-limiting toxicity (DLT) and recommended phase II dose (RPTD) of the unique triplet combination of paclitaxel, estramustine phosphate (EMP) and vinorelbine (Pacl-E-Vin). Patients with advanced malignancies who had failed standard therapy, ECOG performance status (PS 0-2) and adequate organ function were included. Dose of EMP was fixed at 300 mg/m2/dose p.o. t.i.d. on days 1-3 and 8-10. Vinorelbine dose was 20 mg/m2/day i.v. on days 3 and 10. Paclitaxel was dose escalated from 40 to 50 mg/m /day i.v. on days 3 and 10. Cycles were repeated every 3 weeks. Twelve adults (median age 72) were entered on this study. Primary tumors included prostate (n=7), cervix (n=2), melanoma (n=1), colon (1) and lung with synchronous prostate cancer (n=1). Nine patients had received no prior chemotherapy, one had received a prior regimen and two had received two or more prior regimens. Of four evaluable patients at dose level 1, one patient had grade 3 neutropenia leading to the day 10 dose being withheld. Of five evaluable patients at dose level 2, there was one DLT (febrile neutropenia) and two grade 3 neutropenias leading to the day 10 dose being withheld. One patient had a lower extremity deep vein thrombosis. Other side effects were mild and reversible. Nine patients were evaluable for efficacy: three with prostate cancer had a greater than 50% prostate-specific antigen (PSA) response, and a patient with synchronous prostate and lung cancer had a greater than 50% PSA response. We conclude that the DLT of Pacl-E-Vin is neutropenia. RPTD is vinorelbine 20 mg/m2, paclitaxel 40 mg/m2, both administered on days 3 and 10, and EMP 900 mg/m2/day on days 1-3 and 8-10, q3w. Dose omission at day 10 followed by 20% dose reduction of paclitaxel and vinorelbine is recommended in the event of grade 3 neutropenia. Activity in hormone-refractory prostate cancer is promising and warrants phase II evaluation.
authors.affiliation: New York University School of Medicine/Kaplan Comprehensive Cancer Center, NY 10016, USA.
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Sewak
authors.forename: Abraham
authors.initials: A
authors.lastname: Chachoua
authors.forename: Anne
authors.initials: A
authors.lastname: Hamilton
authors.forename: Samir
authors.initials: S
authors.lastname: Taneja
authors.forename: Janet
authors.initials: J
authors.lastname: Lee
authors.forename: Minerva
authors.initials: M
authors.lastname: Utate
authors.forename: Joan
authors.initials: J
authors.lastname: Sorich
authors.forename: Franco M
authors.initials: FM
authors.lastname: Muggia
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D016503:Drug Delivery Systems / Q000379:methods*; D004961:Estramustine / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000503:physiopathology; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects; D014404:Tubulin; D014747:Vinblastine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D000077235:Vinorelbine
chemical_list: D014404:Tubulin; D004961:Estramustine; D014747:Vinblastine; D017239:Paclitaxel; D000077235:Vinorelbine