Phase 1 and pharmacokinetic study of bolus-infusion flavopiridol followed by cytosine arabinoside and mitoxantrone for acute leukemias

摘要: Flavopiridol is a protein bound, cytotoxic, cyclin-dependent kinase inhibitor. given by 1-hour bolus at 50 mg/m(2) daily 3 times followed cytosine arabinoside and mitoxantrone (FLAM) active in adults with poor-risk acute leukemias. A pharmacologically derived "hybrid" schedule (30-minute 4-hour infusion) of flavopiridol was more effective than administration refractory chronic lymphocytic leukemia. Our phase 1 trial "hybrid FLAM" 55 relapsed/refractory leukemias began total dose per day (20-mg/m(2) bolus, 30-mg/m(2) infusion). Dose-limiting toxicity occurred level 6 (30-mg/m(2) 70-mg/m(2) tumor lysis, hyperbilirubinemia, mucositis. Death 5 patients (9%). Complete remission 22 (40%) across all doses. Overall disease-free survivals for complete are 60% 2 years. Pharmacokinetics demonstrated dose-response unbound plasma unrelated to protein, albumin, peripheral blast count, or toxicity. Pharmacodynamically, inhibited mRNAs multiple cell cycle regulators, but uniform increases bcl-2. "Hybrid leukemias, recommended 30 infusion 60 days. This clinical registered www.clinicaltrials.gov as #NCT00470197.