PURPOSE: To determine the maximally tolerated dose (MTD) and pharmacokinetics of carboplatin plus KOS-862 (Epothilone D) a novel cytotoxic macrolide capable of causing mitotic arrest, in patients with advanced solid malignancies. EXPERIMENTAL DESIGN: Patients who have progressed on standard regimens were treated at four different levels of KOS-862(mg/m(2))/Carboplatin(AUC): 50/5,75/5, 75/6 and 100/6 in a "3 + 3" phase I study study design to determine MTD. Patients received KOS-862 on Days 1 and 8, and carboplatin on day 1, of 3-week cycles. Pharmacokinetics of KOS-862 and Carboplatin were studied. RESULTS: Twenty-seven patients enrolled in the study. At the top dose level, 2 out of the 9 patients experienced Dose Limiting Toxicity. (grade 3 peripheral motor neuropathy in both patients) Twenty-seven patients had sufficient plasma data points for pharmacokinetic analysis Both the parent drug, KOS-862, and the major inactive metabolite Seco-D KOS-862 (KOS-1965) were quantified in plasma. Kinetics of KOS-862 were the same as seen in monotherapy studies using the same route and time of administration. Two patients had tumor response after study treatment. Ten of 20 evaluable patients had stable disease after 2 cycles of study treatment. The MTD in the present study was KOS-862 100 mg/m(2) + carboplatin AUC = 6. CONCLUSIONS: The pharmacokinetics of KOS-862 were similar in this combination study to those seen in previous monotherapy studies using the same route and time of administration. We have described the MTD of this schedule. The neurotoxicity seen with this regimen should be considered prior to its administration in unselected populations.
PURPOSE: To determine the maximally tolerated dose (MTD) and pharmacokinetics of carboplatin plus KOS-862 (Epothilone D) a novel cytotoxic macrolide capable of causing mitotic arrest, in patients with advanced solid malignancies. EXPERIMENTAL DESIGN:Patients who have progressed on standard regimens were treated at four different levels of KOS-862(mg/m(2))/Carboplatin(AUC): 50/5,75/5, 75/6 and 100/6 in a "3 + 3" phase I study study design to determine MTD. Patients received KOS-862 on Days 1 and 8, and carboplatin on day 1, of 3-week cycles. Pharmacokinetics of KOS-862 and Carboplatin were studied. RESULTS: Twenty-seven patients enrolled in the study. At the top dose level, 2 out of the 9 patients experienced Dose Limiting Toxicity. (grade 3 peripheral motor neuropathy in both patients) Twenty-seven patients had sufficient plasma data points for pharmacokinetic analysis Both the parent drug, KOS-862, and the major inactive metabolite Seco-D KOS-862 (KOS-1965) were quantified in plasma. Kinetics of KOS-862 were the same as seen in monotherapy studies using the same route and time of administration. Two patients had tumor response after study treatment. Ten of 20 evaluable patients had stable disease after 2 cycles of study treatment. The MTD in the present study was KOS-862 100 mg/m(2) + carboplatin AUC = 6. CONCLUSIONS: The pharmacokinetics of KOS-862 were similar in this combination study to those seen in previous monotherapy studies using the same route and time of administration. We have described the MTD of this schedule. The neurotoxicity seen with this regimen should be considered prior to its administration in unselected populations.
Authors: T C Chou; O A O'Connor; W P Tong; Y Guan; Z G Zhang; S J Stachel; C Lee; S J Danishefsky Journal: Proc Natl Acad Sci U S A Date: 2001-07-03 Impact factor: 11.205
Authors: T C Chou; X G Zhang; C R Harris; S D Kuduk; A Balog; K A Savin; J R Bertino; S J Danishefsky Journal: Proc Natl Acad Sci U S A Date: 1998-12-22 Impact factor: 11.205
Authors: K C Nicolaou; N Winssinger; J Pastor; S Ninkovic; F Sarabia; Y He; D Vourloumis; Z Yang; T Li; P Giannakakou; E Hamel Journal: Nature Date: 1997-05-15 Impact factor: 49.962
Authors: Tomasz M Beer; Celestia S Higano; Mansoor Saleh; Robert Dreicer; Gary Hudes; Joel Picus; Mark Rarick; Louis Fehrenbacher; Alison L Hannah Journal: Invest New Drugs Date: 2007-07-07 Impact factor: 3.850
Authors: Sandro Pignata; Sabino De Placido; Rosalbino Biamonte; Giovanni Scambia; Giovanni Di Vagno; Giuseppe Colucci; Antonio Febbraro; Marco Marinaccio; Alessandra Vernaglia Lombardi; Luigi Manzione; Giacomo Cartenì; Mario Nardi; Saverio Danese; Maria Rosaria Valerio; Andrea de Matteis; Bruno Massidda; Giampietro Gasparini; Massimo Di Maio; Carmela Pisano; Francesco Perrone Journal: BMC Cancer Date: 2006-01-07 Impact factor: 4.430