Phase I Study of Vorinostat in Combination with Bortezomib for Relapsed and Refractory Multiple Myeloma
Purpose: Vorinostat, a histone deacetylase inhibitor, enhances cell death by the proteasome inhibitor bortezomib in vitro . We sought to test the combination clinically. Experimental Design: A phase I trial evaluated sequential dose escalation of bortezomib at 1 to 1.3 mg/m 2 i.v. on days 1, 4, 8, a...
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Veröffentlicht in: | Clinical cancer research 2009-08, Vol.15 (16), p.5250-5257 |
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Zusammenfassung: | Purpose: Vorinostat, a histone deacetylase inhibitor, enhances cell death by the proteasome inhibitor bortezomib in vitro . We sought to test the combination clinically.
Experimental Design: A phase I trial evaluated sequential dose escalation of bortezomib at 1 to 1.3 mg/m 2 i.v. on days 1, 4, 8, and 11 and vorinostat at 100 to 500 mg orally daily for 8 days of each 21-day cycle in relapsed/refractory
multiple myeloma patients. Vorinostat pharmacokinetics and dynamics were assessed.
Results: Twenty-three patients were treated. Patients had received a median of 7 prior regimens (range, 3-13), including autologous
transplantation in 20, thalidomide in all 23, lenalidomide in 17, and bortezomib in 19, 9 of whom were bortezomib-refractory.
Two patients receiving 500 mg vorinostat had prolonged QT interval and fatigue as dose-limiting toxicities. The most common
grade >3 toxicities were myelo-suppression ( n = 13), fatigue ( n = 11), and diarrhea ( n = 5). There were no drug-related deaths. Overall response rate was 42%, including three partial responses among nine bortezomib
refractory patients. Vorinostat pharmacokinetics were nonlinear. Serum C max reached a plateau above 400 mg. Pharmacodynamic changes in CD-138+ bone marrow cells before and on day 11 showed no correlation
between protein levels of NF-κB, IκB, acetylated tubulin, and p21CIP1 and clinical response.
Conclusions: The maximum tolerated dose of vorinostat in our study was 400 mg daily for 8 days every 21 days, with bortezomib administered
at a dose of 1.3 mg/m 2 on days 1, 4, 8, and 11. The promising antimyeloma activity of the regimen in refractory patients merits further evaluation.
(Clin Cancer Res 2009;15(16):5250–7) |
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ISSN: | 1078-0432 1557-3265 |
DOI: | 10.1158/1078-0432.CCR-08-2850 |