Abstract | PURPOSE: 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:
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Authors | Judith 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 |
Journal | Clinical 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 |
PMID | 16322302
(Publication Type: Clinical Trial, Phase I, Journal Article)
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Chemical References |
- Antineoplastic Agents
- Flavonoids
- Piperidines
- VEGFA protein, human
- Vascular Endothelial Growth Factor A
- Cytarabine
- alvocidib
- Mitoxantrone
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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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