Phase I Study of Vorinostat in Combination with Bortezomib for Relapsed and Refractory Multiple Myeloma

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/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)

HR23B is a biomarker for tumor sensitivity to HDAC inhibitor-based therapy

“…From the clinical perspective, HDAC inhibitors have been studied in combination with an increasing array of anticancer agents (6,8,16), and clinical studies in which HDAC inhibitors were combined with proteasome inhibitors yielded results that suggest additive effects (7,16,20,21). For example, the combined treatment of SAHA/vorinostat with bortezomib produced encouraging clinical effects in patients with relapsed and refractory multiple myeloma (20). Based on the results described here, we surmise that the improved clinical profile reflects the additive inhibition of the proteasome, resulting in greater levels of associated tumor cell death.…”

Safety and efficacy of vorinostat, bortezomib, doxorubicin and dexamethasone in a phase I/II study for relapsed or refractory multiple myeloma (VERUMM study: vorinostat in elderly, relapsed and unfit multiple myeloma)

“…Comparison of our VBDD results to other HDACi trials was favorable, while AEs were well manageable (Table 1A). 3,4,12,13,[16][17][18][19][20][21] With a median follow-up of 30.8 months, median PFS and OS were 9.6 and 33.8 months, respectively (Fig.1E+F). Maintenance with VD or VTD was performed in eight and four patients, respectively.…”

Cladribine in combination with entinostat synergistically elicits anti-proliferative/anti-survival effects on multiple myeloma cells

“…HDAC inhibitors exert potent anti-tumor activity in a variety of human cancers, including lymphomas. Although the underlying mechanisms are not clear, HDAC inhibitors are wildly used in combination with chemotherapeutic agents to enhance anticancer activity [46–49]. As a selective class I HDAC inhibitor, entinostat has shown promising efficacy in the treatment of B cell lymphomas [39,40,50].…”