Study of Vorinostat (MK0683), an Histone Deacetylase (HDAC) Inhibitor in Combination With Bortezomib in Patients With Relapsed or Refractory Multiple Myeloma (MK-0683-095)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the clinical activity of vorinostat in combination with bortezomib in participants with relapsed or refractory multiple myeloma after at least 2 prior treatment regimens. The primary objective is to define the objective response rate (RR) associated with the administration of vorinostat in combination with bortezomib to patients with relapsed and refractory multiple myeloma after at least 2 prior treatment regimens. The primary hypothesis of the study is the administration of vorinostat in combination with bortezomib will result in a clinically meaningful rate of objective response.

Detailed Description
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The protocol has been amended to indicate that the Final Analysis is designated as the time when the primary endpoint of 29 responders has been met, or the time when all participants have discontinued treatment or have been enrolled in the study for at least 6 months (if the primary endpoint is not reached by this time). Following the Final Analysis, participants will be allowed to continue study treatment in an extension as long as they have not met the criteria for discontinuation, and will be followed for overall survival and serious AEs.

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

Conditions
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Relapsed or Refractory Multiple Myeloma

Intervention / Treatment
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* Drug: Vorinostat
* Drug: Bortezomib
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has an established diagnosis of multiple myeloma based on myeloma diagnostic criteria Must have adequate organ function Is refractory to prior bortezomib regimen and have also been exposed to prior Immunomodulatory imide drugs (IMiD: thalidimide or lenalidmide) Has relapsed and refractory multiple myeloma after at least 2 prior treatment regimens Has performance status of ≤ 2 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale Has measurable disease, defined as any quantifiable serum monoclonal (M) protein value and, where applicable, urine light chain of ≥200 mg/24 hours Female participants are not pregnant and not breastfeeding, and are not a woman of childbearing potential (WOCBP) or are a WOCBP who agrees to follow contraceptive guidance during the treatment period and for at least 30 days after the last dose of study intervention Male participants must agree to use approved contraception during the treatment period and for at least 30 days after the last dose of study intervention and refrain from donating sperm during this period Is relapsed, refractory, intolerant, and/or ineligible (in the opinion of the investigator) to other therapies including an IMiD (thalidomide or lenalidomide) Is refractory to bortezomib (no response on prior bortezomib containing regimen or progression on or within 60 days of bortezomib containing regimen Exclusion Criteria: Has known hypersensitivity to any components of bortezomib or vorinostat 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 Has an active systemic infection Has acute diffuse infiltrative pulmonary disease or pericardial disease Has known hypersensitivity to any components of bortezomib or vorinostat Has active Hepatitis B or C, plasma cell leukemia, or is human immunodeficiency virus (HIV) positive Has history of a prior malignancy with the exception of cervical intraepithelial neoplasia; non-melanoma skin cancer; adequately treated localized prostate carcinoma with prostate specific antigen (PSA) < 0.1; or who has undergone potentially curative therapy with no evidence of that disease for five years, or who is deemed at low risk for recurrence by his/her treating physician Has known central nervous system (CNS) metastases and/or carcinomatous meningitis Has plasma cell leukemia defined as the presence of more than 20% plasma cells in the peripheral blood and an absolute plasma cell count of at least 2000/μL Has a history of a gastrointestinal surgery or other procedures that might, in the opinion of the Investigator, interfere with the absorption or swallowing of the study drug Has preexisting National Cancer Institute (NCI) Common Toxicity Criteria (CTC) Grade 1 neuropathy with pain or >Grade 2 neuropathy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vorinostat + Bortezomib<br>Participants receive vorinostat 400 mg, orally, once daily (QD) on Days 1-14 of each 21-day treatment cycle and bortezomib 1.3mg/m^2 intravenous (IV) injection QD on Days 1, 4, 8 and 11 of each 21-day treatment cycle for up to 26 cycles. Participants with progressive disease (PD) after 2 cycles of treatment or no change (NC) after 4 cycles of treatment receive additional treatment of Dexamethasone, 20 mg of total daily dose, orally on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day treatment cycle for up to 26 cycles. Eligible participants could receive additional treatment on an extension. | Drug: Vorinostat<br>* Four 100 mg vorinostat capsules orally, once daily (QD) by mouth on Days 1-14 of each 21-day treatment cycle.<br>* Other names: Zolinza;Drug: Bortezomib<br>* Bortezomib 1.3 mg/m^2, IV injection QD on Days 1, 4, 8, and 11 of each 21-day treatment cycle.<br>* Other names: Velcade;Drug: Dexamethasone<br>* Five 4 mg Dexamethasone tablets orally, QD on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day treatment cycle if PD is observed after 2 treatment cycles or if NC to disease is observed after 4 treatment cycles.<br>* Other names: Decadron;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (RR) | Objective RR was defined as percentage (%) of participants with complete response (CR: disappearance of original monoclonal (M) paraprotein from blood & urine on at least 2 determinations for at least 6 weeks (WKs) by immunofixation studies, <5% plasma cells in bone marrow on at least 1 determination, no increase in size/number of lytic bone lesions (LBLs) & disappearance of soft tissue plasmacytomas (STP) for at least 6 WKs on skeletal survey (SS) if available) or partial response (PR: ≥50% reduction in serum M protein for at least 2 determinations 6 WKs apart, if present, reduction in 24-hour urinary light chain excretion by ≥90% or ≤200 mg for at least 2 determinations 6 WKs apart, ≥50% reduction in STP size for at least 6 WKs, & no increase in size/number of LBLs on SS if available) as assessed by Independent Adjudication Committee (IAC) per European Blood & Marrow Transplant (EBMT) criteria. To report RR & 95% confidence intervals (CIs), exact test of binomial parameter was used. | Up to approximately 30 months (through Final Analysis data cut-off of 16-May-2011) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Experienced an Adverse Event (AE) | An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the Sponsor's product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the Sponsor's product, is also an AE. The number of participants who experienced an AE were reported. | Up to approximately 22 months | 
| Number of Participants Who Discontinued Study Treatment Due to an AE | An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the Sponsor's product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the Sponsor's product, is also an AE. The number of participants who discontinued study treatment due to an AE were reported. | Up to approximately 18 months | 
| Time To Disease Progression (TTP) as Determined by IAC Per EBMT Criteria | TTP was defined as the time from allocation to the first documented disease progression (PD) as determined by IAC per EBMT criteria or death due to myeloma, whichever occurred first. PD: >25% increase in level of serum Mparaprotein, which must also be an absolute increase of at least 5g/L (500 mg/dL) and confirmed on a repeat investigation or 25% increase in 24-hour urinary light chain excretion, which must also be an absolute increase of at least 200mg/24hour and confirmed on a repeat investigation or >25% increase in plasma cells in a bone marrow aspirate or on trephine biopsy, which must also be an absolute increase of at least 10% or definitive increase in size of existing LBLs or STP or development of hypercalcemia (corrected serum calcium >11.5 mg/dL or 2.8 mmol/L not attributable to any other cause). To report the median TTP (in months) and associated 95% CIs Kaplan-Meier method was used. | Up to approximately 30 months (through Final Analysis data cut-off of 16-May-2011) | 
| TTP as Assessed by Investigator Per EBMT Criteria | TTP was defined as the time from allocation to the first documented PD as assessed by investigator per EBMT criteria or death due to myeloma, whichever occurred first. PD: >25% increase in level of serum Mparaprotein, which must also be an absolute increase of at least 5g/L (500 mg/dL) and confirmed on a repeat investigation or 25% increase in 24-hour urinary light chain excretion, which must also be an absolute increase of at least 200mg/24hour and confirmed on a repeat investigation or >25% increase in plasma cells in a bone marrow aspirate or on trephine biopsy, which must also be an absolute increase of at least 10% or definitive increase in size of existing LBLs or STP or development of hypercalcemia (corrected serum calcium >11.5 mg/dL or 2.8 mmol/L not attributable to any other cause). To report the median TTP (in months) and associated 95% CIs Kaplan-Meier method was used. | Up to approximately 30 months (through Final Analysis data cut-off of 16-May-2011) | 
| Progression-Free Survival (PFS) as Determined by IAC Per EBMT Criteria | PFS was defined as the time from allocation to the first documents PD as determined by IAC per EBMT criteria or death due to any cause, whichever occurs first. PD: >25% increase in level of serum M-paraprotein, which must also be an absolute increase of at least 5g/L (500 mg/dL) and confirmed on a repeat investigation or 25% increase in 24-hour urinary light chain excretion, which must also be an absolute increase of at least 200mg/24hour and confirmed on a repeat investigation or >25% increase in plasma cells in a bone marrow aspirate or on trephine biopsy, which must also be an absolute increase of at least 10% or definitive increase in size of existing LBLs or STP or development of hypercalcemia (corrected serum calcium >11.5 mg/dL or 2.8 mmol/L not attributable to any other cause). To report the median PFS (in months) and associated 95%CIs Kaplan-Meier method was used. | Up to approximately 30 months (through Final Analysis data cut-off of 16-May-2011) | 
| PFS as Assessed by Investigator Per EBMT Criteria | PFS was defined as the time from allocation to the first documents PD as assessed by investigator per EBMT criteria or death due to any cause, whichever occurs first. PD: >25% increase in level of serum M-paraprotein, which must also be an absolute increase of at least 5g/L (500 mg/dL) and confirmed on a repeat investigation or 25% increase in 24-hour urinary light chain excretion, which must also be an absolute increase of at least 200mg/24hour and confirmed on a repeat investigation or >25% increase in plasma cells in a bone marrow aspirate or on trephine biopsy, which must also be an absolute increase of at least 10% or definitive increase in size of existing LBLs or STP or development of hypercalcemia (corrected serum calcium >11.5 mg/dL or 2.8 mmol/L not attributable to any other cause). To report the median PFS (in months) and associated 95%CIs Kaplan-Meier method was used. | Up to approximately 30 months (through Final Analysis data cut-off of 16-May-2011) | 
| Overall Survival (OS) | OS was defined as the time from allocation to death due to any cause. To report the median survival (in months) and the associated 95%CIs were reported using Kaplan-Meier method was used. Participants without documented death at the time of final analysis were censored at the date of the last follow up. | Up to approximately 40 months (through End of Trial data cut-off of 09-Apr-2012) |