A Phase III study of vorinostat (Zolinza?; Merck Sharp & Dohme/MSD)in combination with bortezomib (Velcade?; Millennium Pharmaceutical/Takeda Pharmaceutical)in patients with progressive multiple myeloma, demonstrated a 23% percent reduction in the risk of progression compared to the standard therapy of bortezomib (p=0.01).

Results from the Phase III trial called VANTAGE 088 (Vorinostat in Combination with Bortezomib in Patients with Relapsed/Refractory Multiple Myeloma: A Global, Randomized Phase III Trial) were presented at the 53rd Annual Meeting of the American Society of Hematology, in San Diego, CA.

Variety of clinical data
Also presented were full results from VANTAGE 095 (Vorinostat in Combination with Bortezomib in Salvage Multiple Myeloma Patients: A Global Phase IIb Trial). Additionally, investigational clinical and pre-clinical vorinostat data across a variety of hematologic cancers were presented in more than 10 oral and poster presentations at the meeting.

“Most patients with multiple myeloma eventually relapse or become resistant to treatment ,” said Meletios Dimopoulos, M.D., professor and chairman, Department of Clinical Therapeutics, University of Athens School of Medicine, Athens, Greece. “We are encouraged by the results of the investigational use of Zolinza in combination therapy in this difficult-to-treat patient population.”

Port Worthy
Axplora

Vorinostat is a histone deacetylase (HDAC) inhibitor indicated for use in the United States for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma (CTCL) who have progressive, persistent, or recurrent disease on or following two systemic therapies. Vorinostat inhibits the enzymatic activity of histone deacetylases HDAC1, HDAC2, and HDAC3 (Class I), and HDAC6 (Class II) at nanomolar concentrations (IC50<86 nM).

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Prior treatment
VANTAGE 088, a Phase III randomized, double-blinded, placebo-controlled study in patients with progressive multiple myeloma who received between one and three prior treatment regimens, was designed to demonstrate an improvement in progression-free survival (PFS) in patients treated with the combination of the investigational use of Vorinostat and bortezomib compared to bortezomib alone. The PFS endpoint was assessed by an Independent Adjudication Committee.

Based on the full analysis of 417 PFS events in 637 patients, patients treated with vorinostat (n= 317) and bortezomib (n= 320) had a 23% reduction in the risk of progression compared to bortezomib alone with a hazard ratio of 0.774 (p=0.01). The observed median PFS was 7.6 months in the vorinostat and bortezomib arm, and 6.8 months in the bortezomib arm.

A trend to overall survival
In addition to the improvement in PFS, significant improvement in overall response rate (ORR) was also observed in the combination arm (vorinostat and bortezomib, 56%; bortezomib and placebo, 41%; p<0.0001). The duration of response was 8.5 months in the combination arm and 8.4 months in the control arm. A trend in favor of overall survival (OS) was observed in the vorinostat and bortezomib arm, but the difference was not statistically significant (hazard ratio = 0.86; vorinostat and bortezomib vs. bortezomib and placebo; p=0.35).

Adverse events
In the Phase III study, significantly more patients treated with the combination of vorinostat and bortezomib versus bortezomib alone experienced thrombocytopenia (55% vs. 33%), diarrhea (62% vs. 43%t), nausea (61% vs. 39%), vomiting (45% vs. 26%) and fatigue (40% vs. 31%) (p<0.05 for all grades). No difference was observed between the discontinuation rates due to an adverse event for vorinostat compared to the placebo arm (21% vs. 22%).

Study protocol
In the VANTAGE 088 study, patients were randomized 1:1 to receive 21-day cycles of bortezomib (1.3 mg/m2 intravenously; days 1, 4, 8, and 11) in combination with oral vorinostat 400 mg/d, or matching placebo, on days 1 to 14. Patients were treated until disease progression, unacceptable toxicities, or withdrawal from the study. The primary endpoint for this trial was PFS (occurrence of 417 PFS events). Secondary and exploratory endpoints included ORR (? partial response), clinical benefit response (ORR + minimal response), overall survival, time to progression, patient-reported outcomes questionnaires (QLQ-C30, QLQ-MY20), and safety/tolerability.

Six hundred and thirty-seven patients were enrolled from 174 centers in 33 countries across the globe, making this trial one of the largest studies conducted in patients with relapsed/refractory myeloma. The median age of the study population was 62 years (range, 29-86 years). Patients had received a median of two prior regimens (range, 1-3).

The VANTAGE 095 study is an open-label, single-arm Phase IIb trial study. Researchers investigated the use of vorinostat plus bortezomib in bortezomib-refractory patients (defined as less than 25% response on therapy, or progression during or less than 60 days after completion of therapy) and patients considered to be refractory, intolerant, or ineligible for IMiD-based therapy regimens. Eligible patients were 18 years or older, had measurable secretory multiple myeloma, had received two or more prior anti-myeloma regimens, and relapsed or progressed following prior systemic therapy. Patients received 21-day cycles of bortezomib (1.3 mg/m2 intravenously; days 1, 4, 8, and 11) plus oral vorinostat 400 mg/d on days 1 to 14. If patient had no change as the best response after 4 cycles of treatment or progressive disease after two cycles of treatment, oral dexamethasone 20 mg on the day of and day after each dose of bortezomib could be added to the treatment regimen. Patients were treated until disease progression, unacceptable toxicities, or withdrawal from the study. The primary endpoint was ORR (? partial response) as assessed by an independent adjudication committee. The combination of ZOLINZA and bortezomib demonstrated an ORR of 11 percent according to the European Group for Blood and Marrow Transplant (EBMT) criteria, the primary endpoint.

In this study, one hundred and forty-three (143) patients were enrolled from 41 centers in 12 countries across Asia-Pacific, Europe, and North America, with 136 of these patients contributing to the efficacy analysis. The study population was heavily pretreated, having received a median of four prior lines of therapy (range 2-17, ? 4 prior regimens: 69%).

The most common treatment-emergent adverse events regardless of relationship to study drug were thrombocytopenia (70%), nausea (57%), diarrhea (54%) and anemia (52%).

For more information:
Study of Vorinostat (MK-0683) an HDAC Inhibitor, or Placebo in Combination With Bortezomib in Patients With Multiple Myeloma (MK-0683-088 AMJ)(VANTAGE 088)
Study of Vorinostat (MK0683), an HDAC Inhibitor, in Combination With Bortezomib in Patients With Relapsed or Refractory Multiple Myeloma (0683-095 AMJ)(VANTAGE 095).

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