A phase I pharmacokinetic study of pulse-dose vorinostat with flavopiridol in solid tumors

Mark Andrew Dickson, Dana E. Rathkopf, Richard D. Carvajal, Steven Grant, John D. Roberts, Joel M Reid, Matthew M. Ames, Renee M. McGovern, Robert A. Lefkowitz, Mithat Gonen, Lauren M. Cane, Heather J. Dials, Gary K. Schwartz

Research output: Contribution to journalArticle

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Abstract

Purpose: Vorinostat (V) at levels >2.5 μM enhances chemotherapy in vitro. Yet the approved oral dose of 400 mg inconsistently achieves this level in patients. We developed an intermittent oral pulse-dose schedule of V to increase serum levels. We combined V with the cyclin dependent kinase inhibitor flavopiridol (F) which increases V-induced apoptosis. Experimental Design One week before combination treatment, V alone was given daily for 3d (cycle-1). Then V was given on d1-3 and d8-10, and F on d2 and d9, every 21-d. Due to neutropenia, this was modified to V on d1-3 and d15-17, and F on d2 and d16, every 28-d. Bolus and split-dose F schedules were studied. Results 34 patients were treated. On the 21-d schedule, the maximum tolerated dose (MTD) was V 600 mg/d and F 60 mg/m 2 bolus. On the 28-d schedule, the MTD was V 800 mg/d and F 30 mg/m 2 over 30 min and 30 mg/m 2 over 4 h. V C max at the 800 mg dose was 4.8 μM (± 2.8). V C max ≥2.5 μM was achieved in 86% of patients at the MTD. F increased the C max of V by 27% (95% CI 11%-43%). F C max of ≥2 μM was achieved in 90% of patients. 8 patients had stable disease for on average 5.5 m (range 1.6-13.2 m). Conclusions Intermittent high dose oral V in combination with F is feasible and achieves target serum levels ≤2.5 μM. V concentrations higher than previously reported with oral dosing were achieved.

Original languageEnglish (US)
Pages (from-to)1004-1012
Number of pages9
JournalInvestigational New Drugs
Volume29
Issue number5
DOIs
StatePublished - Oct 2011

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alvocidib
Pharmacokinetics
Maximum Tolerated Dose
Appointments and Schedules
Neoplasms
Cyclin-Dependent Kinases
Neutropenia
Serum
Research Design
vorinostat
Apoptosis
Drug Therapy

Keywords

  • CDKs and CDK inhibitors
  • Combination chemotherapy
  • Histone deacetylase inhibitors
  • Pharmacokinetics
  • Phase I trials

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Oncology

Cite this

Dickson, M. A., Rathkopf, D. E., Carvajal, R. D., Grant, S., Roberts, J. D., Reid, J. M., ... Schwartz, G. K. (2011). A phase I pharmacokinetic study of pulse-dose vorinostat with flavopiridol in solid tumors. Investigational New Drugs, 29(5), 1004-1012. https://doi.org/10.1007/s10637-010-9447-x

A phase I pharmacokinetic study of pulse-dose vorinostat with flavopiridol in solid tumors. / Dickson, Mark Andrew; Rathkopf, Dana E.; Carvajal, Richard D.; Grant, Steven; Roberts, John D.; Reid, Joel M; Ames, Matthew M.; McGovern, Renee M.; Lefkowitz, Robert A.; Gonen, Mithat; Cane, Lauren M.; Dials, Heather J.; Schwartz, Gary K.

In: Investigational New Drugs, Vol. 29, No. 5, 10.2011, p. 1004-1012.

Research output: Contribution to journalArticle

Dickson, MA, Rathkopf, DE, Carvajal, RD, Grant, S, Roberts, JD, Reid, JM, Ames, MM, McGovern, RM, Lefkowitz, RA, Gonen, M, Cane, LM, Dials, HJ & Schwartz, GK 2011, 'A phase I pharmacokinetic study of pulse-dose vorinostat with flavopiridol in solid tumors', Investigational New Drugs, vol. 29, no. 5, pp. 1004-1012. https://doi.org/10.1007/s10637-010-9447-x
Dickson, Mark Andrew ; Rathkopf, Dana E. ; Carvajal, Richard D. ; Grant, Steven ; Roberts, John D. ; Reid, Joel M ; Ames, Matthew M. ; McGovern, Renee M. ; Lefkowitz, Robert A. ; Gonen, Mithat ; Cane, Lauren M. ; Dials, Heather J. ; Schwartz, Gary K. / A phase I pharmacokinetic study of pulse-dose vorinostat with flavopiridol in solid tumors. In: Investigational New Drugs. 2011 ; Vol. 29, No. 5. pp. 1004-1012.
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abstract = "Purpose: Vorinostat (V) at levels >2.5 μM enhances chemotherapy in vitro. Yet the approved oral dose of 400 mg inconsistently achieves this level in patients. We developed an intermittent oral pulse-dose schedule of V to increase serum levels. We combined V with the cyclin dependent kinase inhibitor flavopiridol (F) which increases V-induced apoptosis. Experimental Design One week before combination treatment, V alone was given daily for 3d (cycle-1). Then V was given on d1-3 and d8-10, and F on d2 and d9, every 21-d. Due to neutropenia, this was modified to V on d1-3 and d15-17, and F on d2 and d16, every 28-d. Bolus and split-dose F schedules were studied. Results 34 patients were treated. On the 21-d schedule, the maximum tolerated dose (MTD) was V 600 mg/d and F 60 mg/m 2 bolus. On the 28-d schedule, the MTD was V 800 mg/d and F 30 mg/m 2 over 30 min and 30 mg/m 2 over 4 h. V C max at the 800 mg dose was 4.8 μM (± 2.8). V C max ≥2.5 μM was achieved in 86{\%} of patients at the MTD. F increased the C max of V by 27{\%} (95{\%} CI 11{\%}-43{\%}). F C max of ≥2 μM was achieved in 90{\%} of patients. 8 patients had stable disease for on average 5.5 m (range 1.6-13.2 m). Conclusions Intermittent high dose oral V in combination with F is feasible and achieves target serum levels ≤2.5 μM. V concentrations higher than previously reported with oral dosing were achieved.",
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author = "Dickson, {Mark Andrew} and Rathkopf, {Dana E.} and Carvajal, {Richard D.} and Steven Grant and Roberts, {John D.} and Reid, {Joel M} and Ames, {Matthew M.} and McGovern, {Renee M.} and Lefkowitz, {Robert A.} and Mithat Gonen and Cane, {Lauren M.} and Dials, {Heather J.} and Schwartz, {Gary K.}",
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T1 - A phase I pharmacokinetic study of pulse-dose vorinostat with flavopiridol in solid tumors

AU - Dickson, Mark Andrew

AU - Rathkopf, Dana E.

AU - Carvajal, Richard D.

AU - Grant, Steven

AU - Roberts, John D.

AU - Reid, Joel M

AU - Ames, Matthew M.

AU - McGovern, Renee M.

AU - Lefkowitz, Robert A.

AU - Gonen, Mithat

AU - Cane, Lauren M.

AU - Dials, Heather J.

AU - Schwartz, Gary K.

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N2 - Purpose: Vorinostat (V) at levels >2.5 μM enhances chemotherapy in vitro. Yet the approved oral dose of 400 mg inconsistently achieves this level in patients. We developed an intermittent oral pulse-dose schedule of V to increase serum levels. We combined V with the cyclin dependent kinase inhibitor flavopiridol (F) which increases V-induced apoptosis. Experimental Design One week before combination treatment, V alone was given daily for 3d (cycle-1). Then V was given on d1-3 and d8-10, and F on d2 and d9, every 21-d. Due to neutropenia, this was modified to V on d1-3 and d15-17, and F on d2 and d16, every 28-d. Bolus and split-dose F schedules were studied. Results 34 patients were treated. On the 21-d schedule, the maximum tolerated dose (MTD) was V 600 mg/d and F 60 mg/m 2 bolus. On the 28-d schedule, the MTD was V 800 mg/d and F 30 mg/m 2 over 30 min and 30 mg/m 2 over 4 h. V C max at the 800 mg dose was 4.8 μM (± 2.8). V C max ≥2.5 μM was achieved in 86% of patients at the MTD. F increased the C max of V by 27% (95% CI 11%-43%). F C max of ≥2 μM was achieved in 90% of patients. 8 patients had stable disease for on average 5.5 m (range 1.6-13.2 m). Conclusions Intermittent high dose oral V in combination with F is feasible and achieves target serum levels ≤2.5 μM. V concentrations higher than previously reported with oral dosing were achieved.

AB - Purpose: Vorinostat (V) at levels >2.5 μM enhances chemotherapy in vitro. Yet the approved oral dose of 400 mg inconsistently achieves this level in patients. We developed an intermittent oral pulse-dose schedule of V to increase serum levels. We combined V with the cyclin dependent kinase inhibitor flavopiridol (F) which increases V-induced apoptosis. Experimental Design One week before combination treatment, V alone was given daily for 3d (cycle-1). Then V was given on d1-3 and d8-10, and F on d2 and d9, every 21-d. Due to neutropenia, this was modified to V on d1-3 and d15-17, and F on d2 and d16, every 28-d. Bolus and split-dose F schedules were studied. Results 34 patients were treated. On the 21-d schedule, the maximum tolerated dose (MTD) was V 600 mg/d and F 60 mg/m 2 bolus. On the 28-d schedule, the MTD was V 800 mg/d and F 30 mg/m 2 over 30 min and 30 mg/m 2 over 4 h. V C max at the 800 mg dose was 4.8 μM (± 2.8). V C max ≥2.5 μM was achieved in 86% of patients at the MTD. F increased the C max of V by 27% (95% CI 11%-43%). F C max of ≥2 μM was achieved in 90% of patients. 8 patients had stable disease for on average 5.5 m (range 1.6-13.2 m). Conclusions Intermittent high dose oral V in combination with F is feasible and achieves target serum levels ≤2.5 μM. V concentrations higher than previously reported with oral dosing were achieved.

KW - CDKs and CDK inhibitors

KW - Combination chemotherapy

KW - Histone deacetylase inhibitors

KW - Pharmacokinetics

KW - Phase I trials

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