Dose-finding study of valspodar (PSC 833) with daunorubicin and cytarabine to reverse multidrug resistance in elderly patients with previously untreated acute myeloid leukemia
(2000) The Hematology Journal — Vol. 1, n° 6, p. 411-421 (2000)
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- Introduction: This trial was designed to determine the maximum tolerated dose of intravenous daunorubicin (DNR) in combination with valspodar and to test the feasibility of P-glycoprotein modulation using valspodar in elderly patients with previously untreated acute myelogenous leukemia receiving standard induction chemotherapy. Methods: Patients ≥60 years of age with previously untreated AML received valspodar (10 mg/kg/24 h by continuous intravenous infusion [CIV] on days 1-4 with a 2-mg/kg loading dose on day 1) in conjunction with two cycles of induction chemotherapy consisting of cytarabine (200 mg/m<sup>2</sup> CIV on days 1-7), and DNR (35 mg/m<sup>2</sup> [cohort 1] or 45 mg/m<sup>2</sup> [cohort 2] on days 1-3, intravenous bolus). Patients were assessed for dose-limiting toxicities (DLT), response rate, event-free and overall survival, and pharmacokinetics of valspodar and DNR. Results: Valspodar was well tolerated at the lower DNR dose level (ie, 35 mg/m<sup>2</sup>) resulting in a 21% rate of DLT and only three toxic deaths. Treatment-related mortality was unacceptably high at the 45 mg/m<sup>2</sup> DNR dose level. The complete response rate was 49% overall and similar in both cohorts. The median overall survival of patients was 333 days in cohort 1 compared to 98 days in cohort 2. At baseline, 70% of assessable patients were P-glycoprotein positive. Conclusion: Substantial inhibition of P-glycoprotein activity can be achieved in this patient population at clinically tolerable doses of valspodar and DNR. The maximum tolerated dose of DNR was established as 35 mg/m<sup>2</sup>. This regimen is being further evaluated in phase III trials.
Citations
Sonneveld, P., Burnett, A., Vossebeld, P., Ben-Am, M., Rosenkranz, G., Pfister, C., Verhoef, G., Dekker, A., Ossenkoppele, G., Ferrant, C., Yin, L., Gratwohl, A., Kovacsovics, T., Vellenga, E., Capdeville, R., & Löwenberg, B. (2000). Dose-finding study of valspodar (PSC 833) with daunorubicin and cytarabine to reverse multidrug resistance in elderly patients with previously untreated acute myeloid leukemia. The Hematology Journal, 1(6), 411-421. https://hdl.handle.net/2078.5/187051 (Original work published 2000)