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

Judith 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

Research output: Contribution to journalArticle

Abstract

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-β-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/m 2/72 h ara-C beginning day 6 and 40 mg/m 2 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/m 2/d with profound neutropenia >40 days duration, and maximal tolerated dose was 50 mg/m 2/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/m 2/d × days in combination with cytotoxic and biological agents for acute leukemias.

Original languageEnglish (US)
Pages (from-to)8403-8412
Number of pages10
JournalClinical Cancer Research
Volume11
Issue number23
DOIs
StatePublished - Dec 1 2005

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alvocidib
Mitoxantrone
Cytarabine
Leukemia
Pharmacokinetics
Bone Marrow
Vascular Endothelial Growth Factor A
Serum
Clinical Trials, Phase I
Maximum Tolerated Dose
Cyclin-Dependent Kinases
Mycoses
Protein-Serine-Threonine Kinases
Cytotoxins
Biological Factors
Sudden Death
Neutropenia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Acute Myeloid Leukemia
Cell Cycle

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Phase I and pharmacokinetic study of flavopiridol followed by 1-β-D-arabinofuranosylcytosine and mitoxantrone in relapsed and refractory adult acute leukemias. / Karp, Judith; Passaniti, Antonino; Gojo, Ivana; Kaufmann, Scott; Bible, Keith; Garimella, Tushar S.; Greer, Jacqueline; Briel, Janet; Smith, B Douglas; Gore, Steven D.; Tidwell, Michael L.; Ross, Douglas D.; Wright, John J.; Colevas, A. Dimitrios; Bauer, Kenneth S.

In: Clinical Cancer Research, Vol. 11, No. 23, 01.12.2005, p. 8403-8412.

Research output: Contribution to journalArticle

Karp, J, Passaniti, A, Gojo, I, Kaufmann, S, Bible, K, Garimella, TS, Greer, J, Briel, J, Smith, BD, Gore, SD, Tidwell, ML, Ross, DD, Wright, JJ, Colevas, AD & Bauer, KS 2005, 'Phase I and pharmacokinetic study of flavopiridol followed by 1-β-D-arabinofuranosylcytosine and mitoxantrone in relapsed and refractory adult acute leukemias', Clinical Cancer Research, vol. 11, no. 23, pp. 8403-8412. https://doi.org/10.1158/1078-0432.CCR-05-1201
Karp, Judith ; Passaniti, Antonino ; Gojo, Ivana ; Kaufmann, Scott ; Bible, Keith ; Garimella, Tushar S. ; Greer, Jacqueline ; Briel, Janet ; Smith, B Douglas ; Gore, Steven D. ; Tidwell, Michael L. ; Ross, Douglas D. ; Wright, John J. ; Colevas, A. Dimitrios ; Bauer, Kenneth S. / Phase I and pharmacokinetic study of flavopiridol followed by 1-β-D-arabinofuranosylcytosine and mitoxantrone in relapsed and refractory adult acute leukemias. In: Clinical Cancer Research. 2005 ; Vol. 11, No. 23. pp. 8403-8412.
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abstract = "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-β-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/m 2/72 h ara-C beginning day 6 and 40 mg/m 2 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/m 2/d with profound neutropenia >40 days duration, and maximal tolerated dose was 50 mg/m 2/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/m 2/d × days in combination with cytotoxic and biological agents for acute leukemias.",
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T1 - Phase I and pharmacokinetic study of flavopiridol followed by 1-β-D-arabinofuranosylcytosine and mitoxantrone in relapsed and refractory adult acute leukemias

AU - Karp, Judith

AU - Passaniti, Antonino

AU - Gojo, Ivana

AU - Kaufmann, Scott

AU - Bible, Keith

AU - Garimella, Tushar S.

AU - Greer, Jacqueline

AU - Briel, Janet

AU - Smith, B Douglas

AU - Gore, Steven D.

AU - Tidwell, Michael L.

AU - Ross, Douglas D.

AU - Wright, John J.

AU - Colevas, A. Dimitrios

AU - Bauer, Kenneth S.

PY - 2005/12/1

Y1 - 2005/12/1

N2 - 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-β-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/m 2/72 h ara-C beginning day 6 and 40 mg/m 2 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/m 2/d with profound neutropenia >40 days duration, and maximal tolerated dose was 50 mg/m 2/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/m 2/d × days in combination with cytotoxic and biological agents for acute leukemias.

AB - 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-β-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/m 2/72 h ara-C beginning day 6 and 40 mg/m 2 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/m 2/d with profound neutropenia >40 days duration, and maximal tolerated dose was 50 mg/m 2/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/m 2/d × days in combination with cytotoxic and biological agents for acute leukemias.

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