Study of Vorinostat (MK0683), an HDAC Inhibitor, in Combination With Bortezomib in Patients With Relapsed or Refractory Multiple Myeloma

Condition(s) targeted: Relapsed or Refractory Multiple Myeloma

Intervention: Comparator: vorinostat (HDAC inhibitor) (Drug); Comparator: bortezomib (Drug); Comparator: dexamethasone (Drug)

Phase: Phase 2

Status: Recruiting

Sponsored by: Merck

Official(s) and/or principal investigator(s):
Medical Monitor, Study Director, Affiliation: Merck

Overall contact:
Toll Free Number, Phone: 1-888-577-8839

Study of vorinostat in combination with bortezomib in patients with relapsed or refractory multiple myeloma after at least 2 prior treatment regimens.

Histone deacetylases (HDAC) facilitate gene transcription by modulating the uncoiling of chromatin. HDAC function is dysregulated in hematologic and solid malignancies, and this dysregulation may result in over-expression of oncogenes. Thus, inhibition of HDACs may result in anti-cancer effects. HDAC inhibitors, like vorinostat, represent a new class of antitumor agents that have the ability to induce antiproliferative effects including cyto-differentiation, cell cycle growth arrest or apoptosis in various cancer cell lines. Several studies have investigated the in vitro antimyeloma activity of vorinostat in combination with bortezomib and have demonstrated that vorinostat may act synergistically with bortezomib to modulate tumor cell growth. Mitsiades et al have shown that vorinostat enhances the sensitivity of bortezomib. Pei et al found that exposure of human multiple myeloma cell lines & patient-derived multiple myeloma cells to bortezomib and vorinostat resulted in synergistic interactions as a result of: (1) Interruption of NF-kB & related signaling pathways (JNK, XIAP, Mcl-1, etc.) (2) Inhibition of Hsp90 (3) Induction of ER stress signal and (4) acetylation of Dynein/ disruption of aggresome function/formation, salvage for ubiquinated proteins. In addition a marked increase in mitochondrial injury, caspase activation, and apoptosis was also observed.

Bortezomib is indicated for the treatment of patients with multiple myeloma. Two Phase I dose-ranging studies of a regimen combining vorinostat and bortezomib among patients with relapsed as well as end-stage, refractory multiple myeloma have been conducted. These studies enrolled a total of 57 patients. In these studies, administration of vorinostat with standard doses of bortezomib resulted in responses in 20/45 (44%) evaluable patients (Weber et al 2007, Badros et al 2007). The purpose of the present study is to definitively evaluate the clinical activity of vorinostat in combination with bortezomib in patients with multiple myeloma

Official title: An International, Multicenter, Open-Label Study of Vorinostat (MK0683) in Combination With Bortezomib in Patients With Relapsed or Refractory Multiple Myeloma

Study design: Treatment, Non-Randomized, Open Label, Active Control, Single Group Assignment, Efficacy Study

Primary outcome: Response rate associated with the administration of vorinostat in combination with bortezomib

Secondary outcome: Tolerability of vorinostat administered in combination with bortezomib

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Patient is 18 years of age or older

- Patient has an established diagnosis of multiple myeloma based on myeloma diagnostic

criteria and received at least 2 prior anti-myeloma regimens

- Patient must have adequate organ function

- Patient is refractory to prior bortezomib regimen and have also been exposed to prior

IMiD (thalidimide or lenalidmide)

Exclusion Criteria:

- Patient has known hypersensitivity to any components of bortezomib or vorinostat

- Patient has had a prior allogeneic bone marrow transplant or plans to undergo any

type of bone marrow transplantation within 4 weeks of the initiation of study therapy

- Patient has known hypersensitivity to any components of bortezomib or vorinostat.

Patient has active Hepatitis B or C, plasma cell leukemia, or is HIV positive

Toll Free Number, Phone: 1-888-577-8839

Merck Sharp & Dohme (Australia) Pty Ltd., South Granville NSW 2142, Australia; Recruiting
David Woolner, Phone: 64-9-523-6075

Merck Sharp & Dohme B.V., Bruxelles 1180, Belgium; Recruiting
Nathalie Schrameijer, Phone: 32-2-373-4310

Laboratoires Merck Sharp & Dohme - Chibret, Paris Cedex 8 75114, France; Recruiting
Jean-Marie Goehrs, Phone: 33-1-4754-89-90

Msd Sharp & Dohme Gmbh, Haar 85540, Germany; Recruiting
Thomas Lang, Phone: 49-89-4561-1536

Merck Sharp & Dohme (Italia) S.P.A., Roma 191, Italy; Recruiting
Gianfranco Botta, Phone: 39 06 36 191187

MSD Korea Ltd., Seoul 121-705, Korea, Republic of; Recruiting
Steve Kim, Phone: 82-2-6363-0241

Merck Sharp & Dohme IDEA, Inc., Moscow 121059, Russian Federation; Recruiting
Tatiana Serebriakova, Phone: 7-495-941-8264

Merck Sharp & Dohme De Espana, S.A.E., Madrid 28027, Spain; Recruiting
Jorge Gonzalez-Esteban, Phone: 34-91-3210-728

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Merch Sharp & Dohme Ltd., Hoddesdon, Hertfordshire EN11 9BU, United Kingdom; Recruiting
Paul Robinson, Phone: 44 1992 452341

Call for Information, Indianapolis, Indiana 46254, United States; Recruiting

Call for Information, Boston, Massachusetts 02115, United States; Recruiting

Call for Information, Jefferson City, Missouri 65109-0000, United States; Recruiting

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Call for Information, Syracuse, New York 13210-0000, United States; Recruiting

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Call for Information, Media, Pennsylvania 19063, United States; Recruiting

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Call for Information, Philadelphia, Pennsylvania 19141, United States; Recruiting

Merck Frosst Canada Ltd., Kirkland, Quebec H9H 3L1, Canada; Recruiting
Michel Cimon, Phone: 514-428-2605

Call for Information, Knoxville, Tennessee 37920, United States; Recruiting

Call for Information, Milwaukee, Wisconsin 53226, United States; Recruiting

Starting date: October 2008
Ending date: June 2010
Last updated: October 16, 2009