Phase 1 and pharmacokinetic study of bolus-infusion flavopiridol followed by cytosine arabinoside and mitoxantrone for acute leukemias
| Autor: | Jacqueline Greer, Judith E. Karp, Dwella Moton-Nelson, Biju Joseph, Steven D. Gore, Hetty E. Carraway, Amanda L. Blackford, John J. Wright, Katrina Alino, Linda S. Resar, Janet Briel, Michael A. McDevitt, B. Douglas Smith, Mark J. Levis, Karen Mackey, L. Austin Doyle, Lorena Bagain, Ming Zhao, Michelle A. Rudek |
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| Rok vydání: | 2011 |
| Předmět: |
Adult
Male Clinical Trials and Observations medicine.drug_class medicine.medical_treatment Immunology Pharmacology Biochemistry Antimetabolite Drug Administration Schedule Young Adult chemistry.chemical_compound Bolus (medicine) Piperidines Pharmacokinetics Antineoplastic Combined Chemotherapy Protocols medicine Humans Infusion Pumps Aged Flavonoids Acute leukemia Chemotherapy Mitoxantrone Leukemia Dose-Response Relationship Drug business.industry Cytarabine Cell Biology Hematology Middle Aged Alvocidib chemistry Chemotherapy Adjuvant Acute Disease Female business medicine.drug |
| Zdroj: | Blood. 117:3302-3310 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2010-09-310862 |
| Popis: | Flavopiridol is a protein bound, cytotoxic, cyclin-dependent kinase inhibitor. Flavopiridol given by 1-hour bolus at 50 mg/m2 daily 3 times followed by cytosine arabinoside and mitoxantrone (FLAM) is active in adults with poor-risk acute leukemias. A pharmacologically derived “hybrid” schedule (30-minute bolus followed by 4-hour infusion) of flavopiridol was more effective than bolus administration in refractory chronic lymphocytic leukemia. Our phase 1 trial “hybrid FLAM” in 55 adults with relapsed/refractory acute leukemias began at a total flavopiridol dose of 50 mg/m2 per day 3 times (20-mg/m2 bolus, 30-mg/m2 infusion). Dose-limiting toxicity occurred at level 6 (30-mg/m2 bolus, 70-mg/m2 infusion) with tumor lysis, hyperbilirubinemia, and mucositis. Death occurred in 5 patients (9%). Complete remission occurred in 22 (40%) across all doses. Overall and disease-free survivals for complete remission patients are more than 60% at more than 2 years. Pharmacokinetics demonstrated a dose-response for total and unbound plasma flavopiridol unrelated to total protein, albumin, peripheral blast count, or toxicity. Pharmacodynamically, flavopiridol inhibited mRNAs of multiple cell cycle regulators, but with uniform increases in bcl-2. “Hybrid FLAM” is active in relapsed/refractory acute leukemias, with a recommended “hybrid” dose of bolus 30 mg/m2 followed by infusion of 60 mg/m2 daily for 3 days. This clinical trial is registered at www.clinicaltrials.gov as #NCT00470197. |
| Databáze: | OpenAIRE |
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