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Phase I and Pharmacokinetic Study of Flavopiridol followed by 1-ß-D-Arabinofuranosylcytosine and Mitoxantrone in Relapsed and Refractory Adult Acute Leukemias

Authors' Affiliations: ¹ Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; ² University of Maryland Greenebaum Cancer Center; and ³ Baltimore Veterans Affairs Medical Center, Baltimore, Maryland; ⁴ Mayo Clinic, Rochester, Minnesota; and ⁵ Investigational Drug Branch, Clinical Trials Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland

Requests for reprints: Judith E. Karp, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 1650 Orleans Street, CRB Room 289, Baltimore, MD 21231-1000. Phone: 410-503-5399; Fax: 410-614-1005; E-mail: jkarp2{at}jhmi.edu.

Purpose: 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-ß-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 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.

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