Phase I study of vorinostat in combination with bortezomib for relapsed and refractory multiple myeloma - PubMed (original) (raw)

Clinical Trial

. 2009 Aug 15;15(16):5250-7.

doi: 10.1158/1078-0432.CCR-08-2850. Epub 2009 Aug 11.

Angelika M Burger, Sunita Philip, Ruben Niesvizky, Sarah S Kolla, Olga Goloubeva, Carolynn Harris, James Zwiebel, John J Wright, Igor Espinoza-Delgado, Maria R Baer, Julianne L Holleran, Merrill J Egorin, Steven Grant

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Clinical Trial

Phase I study of vorinostat in combination with bortezomib for relapsed and refractory multiple myeloma

Ashraf Badros et al. Clin Cancer Res. 2009.

Abstract

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/m2 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 Cmax 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-kappaB, IkappaB, 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/m2 on days 1, 4, 8, and 11. The promising antimyeloma activity of the regimen in refractory patients merits further evaluation.

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Figures

Figure 1

Figure 1

Western blot analysis of biomarkers corresponding to HDAC inhibitor-related proteins (Figure 1, A) and apoptosis-related proteins (Figure 1, B) from CD138+ myeloma cells. Panels A, B, and C display results for baseline and day 11 bone marrow samples following vorinostat-bortezomib therapy in relationship to clinical responses. Numbers reflect densitometric scans of each protein normalized to pre-treatment values, arbitrarily designated as 1.00.

Figure 1

Figure 1

Western blot analysis of biomarkers corresponding to HDAC inhibitor-related proteins (Figure 1, A) and apoptosis-related proteins (Figure 1, B) from CD138+ myeloma cells. Panels A, B, and C display results for baseline and day 11 bone marrow samples following vorinostat-bortezomib therapy in relationship to clinical responses. Numbers reflect densitometric scans of each protein normalized to pre-treatment values, arbitrarily designated as 1.00.

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