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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2010-05-12

AUTHORS

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

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/m2 bolus. On the 28-d schedule, the MTD was V 800 mg/d and F 30 mg/m2 over 30 min and 30 mg/m2 over 4 h. V Cmax at the 800 mg dose was 4.8 µM (± 2.8). V Cmax ≥2.5 µM was achieved in 86% of patients at the MTD. F increased the Cmax of V by 27% (95% CI 11%–43%). F Cmax 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. More... »

PAGES

1004-1012

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/s10637-010-9447-x

DOI

http://dx.doi.org/10.1007/s10637-010-9447-x

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1043518079

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/20461440


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29 schema:description 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/m2 bolus. On the 28-d schedule, the MTD was V 800 mg/d and F 30 mg/m2 over 30 min and 30 mg/m2 over 4 h. V Cmax at the 800 mg dose was 4.8 µM (± 2.8). V Cmax ≥2.5 µM was achieved in 86% of patients at the MTD. F increased the Cmax of V by 27% (95% CI 11%–43%). F Cmax 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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36 D1-3
37 D16
38 D2
39 D9
40 I pharmacokinetic study
41 MTD
42 Results 34 patients
43 apoptosis
44 bolus
45 chemotherapy
46 combination
47 combination treatment
48 concentration
49 cyclin-dependent kinase inhibitor flavopiridol
50 disease
51 dose
52 dosing
53 flavopiridol
54 high dose
55 intermittent high dose
56 kinase inhibitor flavopiridol
57 levels
58 m2
59 maximum
60 min
61 neutropenia
62 one week
63 oral dose
64 oral dosing
65 patients
66 pharmacokinetic study
67 phase I pharmacokinetic study
68 schedule
69 serum levels
70 solid tumors
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74 tumors
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76 weeks
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