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Phase I and pharmacokinetic study of flavopiridol followed by 1-beta-D-arabinofuranosylcytosine and mitoxantrone in relapsed and refractory adult acute leukemias.

AbstractPURPOSE:
The serine/threonine kinase inhibitor flavopiridol targets multiple cyclin-dependent kinases, induces checkpoint arrest, and interrupts transcriptional elongation. We designed a phase I clinical trial using a timed sequential therapy approach where flavopiridol was given for the dual purpose of initial cytoreduction and enhancing cell cycle progression of the remaining leukemia cell cohort followed by cycle-dependent drugs 1-beta-D-arabinofuranosylcytosine (ara-C) and mitoxantrone.
EXPERIMENTAL DESIGN:
Flavopiridol was given by 1-hour infusion daily for 3 days beginning day 1 followed by 2 g/m2/72 h ara-C beginning day 6 and 40 mg/m2 mitoxantrone beginning day 9. In vivo correlates included pharmacokinetics, modulation of blast cycle regulators, and serum and marrow supernatant vascular endothelial growth factor levels.
RESULTS:
Of 34 adults receiving induction therapy, 16 (47%) evinced direct leukemia cytotoxicity with > or =50% drop in peripheral blast counts and tumor lysis in 9 (26%). Four (12%) died during therapy (two fungal infections and two sudden death). Dose-limiting toxicity occurred at 60 mg/m2/d with profound neutropenia >40 days duration, and maximal tolerated dose was 50 mg/m2/d. Overall response rate was 31% in 26 acute myelogenous leukemia and 12.5% in acute lymphoblastic leukemia. Pharmacokinetics showed that a linear two-compartment model with first-order elimination provided the best fit of the observed concentration versus time data. Flavopiridol down-regulated one or more target proteins in marrow blasts in vivo. Vascular endothelial growth factor was detected in sera and marrow supernatant pretreatment, and sera obtained on day 3 inhibited bovine aortic endothelial cell proliferation by a mean of 32% (range, 10-80%).
CONCLUSIONS:
Our data suggest that flavopiridol is cytotoxic to leukemic cells and, when followed by ara-C and mitoxantrone, exerts biological and clinical effects in patients with relapsed and refractory acute leukemias. These findings warrant continuing development of flavopiridol at 50 mg/m2/d x 3 days in combination with cytotoxic and biological agents for acute leukemias.
AuthorsJudith E Karp, Antonino Passaniti, Ivana Gojo, Scott Kaufmann, Keith Bible, Tushar S Garimella, Jacqueline Greer, Janet Briel, B Douglas Smith, Steven D Gore, Michael L Tidwell, Douglas D Ross, John J Wright, A Dimitrios Colevas, Kenneth S Bauer
JournalClinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 11 Issue 23 Pg. 8403-12 (Dec 01 2005) ISSN: 1078-0432 [Print] United States
PMID16322302 (Publication Type: Clinical Trial, Phase I, Journal Article)
Chemical References
  • Antineoplastic Agents
  • Flavonoids
  • Piperidines
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • Cytarabine
  • alvocidib
  • Mitoxantrone
Topics
  • Adult
  • Aged
  • Animals
  • Antineoplastic Agents (pharmacokinetics)
  • Antineoplastic Combined Chemotherapy Protocols (administration & dosage)
  • Bone Marrow Cells (metabolism)
  • Cattle
  • Cell Proliferation
  • Cohort Studies
  • Cytarabine (administration & dosage)
  • Endothelium, Vascular (metabolism)
  • Female
  • Flavonoids (pharmacokinetics)
  • Humans
  • Leukemia, Myeloid, Acute (drug therapy, metabolism)
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Mitoxantrone (administration & dosage)
  • Neoplasm Recurrence, Local (drug therapy, metabolism)
  • Piperidines (pharmacokinetics)
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, metabolism)
  • Salvage Therapy
  • U937 Cells
  • Vascular Endothelial Growth Factor A (metabolism)

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