A phase I pharmacokinetic study of pulse-dose vorinostat with flavopiridol in solid tumors Journal Article
| Authors: | Dickson, M. A.; Rathkopf, D. E.; Carvajal, R. D.; Grant, S.; Roberts, J. D.; Reid, J. M.; Ames, M. M.; McGovern, R. M.; Lefkowitz, R. A.; Gonen, M.; Cane, L. M.; Dials, H. J.; Schwartz, G. K. |
| Article Title: | A phase I pharmacokinetic study of pulse-dose vorinostat with flavopiridol in solid tumors |
| Abstract: | 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. 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. 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). 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. |
| Keywords: | adult; aged; aged, 80 and over; middle aged; clinical trial; dose response; antineoplastic agents; antineoplastic agent; neoplasm; neoplasms; cohort studies; antineoplastic combined chemotherapy protocols; cohort analysis; dose-response relationship, drug; vorinostat; hydroxamic acids; flavonoid; flavonoids; flavopiridol; piperidines; phase 1 clinical trial; hydroxamic acid; piperidine derivative |
| Journal Title: | Investigational New Drugs |
| Volume: | 29 |
| Issue: | 5 |
| ISSN: | 0167-6997 |
| Publisher: | Springer |
| Date Published: | 2011-10-01 |
| Start Page: | 1004 |
| End Page: | 1012 |
| Language: | English |
| PUBMED: | 20461440 |
| PROVIDER: | scopus |
| DOI: | 10.1007/s10637-010-9447-x |
| PMCID: | PMC3545439 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 1" - "Export Date: 1 March 2012" - "Source: Scopus" |
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