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


METHODS
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.
Karp
Judith E
JE
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231-1000, USA.
Passaniti
Antonino
A
Gojo
Ivana
I
Kaufmann
Scott
S
Bible
Keith
K
Garimella
Tushar S
TS
Greer
Jacqueline
J
Briel
Janet
J
Smith
B Douglas
BD
Gore
Steven D
SD
Tidwell
Michael L
ML
Ross
Douglas D
DD
Wright
John J
JJ
Colevas
A Dimitrios
AD
Bauer
Kenneth S
KS
D000328:Adult; D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D001854:Bone Marrow Cells / Q000378:metabolism; D002417:Cattle; D049109:Cell Proliferation; D015331:Cohort Studies; D003561:Cytarabine / Q000008:administration & dosage; D004730:Endothelium, Vascular / Q000378:metabolism; D005260:Female; D005419:Flavonoids / Q000493:pharmacokinetics*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D008942:Mitoxantrone / Q000008:administration & dosage; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000378:metabolism; D010880:Piperidines / Q000493:pharmacokinetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism; D016879:Salvage Therapy; D020298:U937 Cells; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D000970:Antineoplastic Agents; D005419:Flavonoids; D010880:Piperidines; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D003561:Cytarabine; C077990:alvocidib; D008942:Mitoxantrone