Multiple Myeloma
Conditions
Keywords
Neoplasms, Plasma Cell, Neoplasms by Histologic Type, Neoplasms, Hemostatic Disorders, Vascular Diseases, Cardiovascular Diseases, Paraproteinemias, Blood Protein Disorders, Hematologic Diseases, Hemorrhagic Disorders, Lymphoproliferative Disorders, Immunoproliferative Disorders, Immune System Diseases, Vorinostat, Bortezomib, Anti-Inflammatory Agents, Non-Steroidal, Analgesics, Non-Narcotic, Analgesics, Sensory System Agents, Peripheral Nervous System Agents, Physiological Effects of Drugs, Pharmacologic Actions, Anti-Inflammatory Agents, Therapeutic Uses, Antirheumatic Agents, Antineoplastic Agents, Enzyme Inhibitors, Molecular Mechanisms of Pharmacological Action, Anticarcinogenic Agents
Brief summary
Study of the efficacy and safety of bortezomib administered in combination with vorinostat in patients with relapsed or refractory multiple myeloma. 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 ubiquitinated 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 asend-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 inpatients with multiple myeloma.
Interventions
DRUGVorinostat
Four 100 mg capsules vorinostat taken orally, once daily, on Days 1 through 14 of each 21-day treatment cycle.
DRUGbortezomib
1.3 mg/m2 of bortezomib by IV push, on Days 1, 4, 8, and 11 of each 21-day treatment cycle.
DRUGplacebo to vorinostat
Four placebo capsules taken orally, once daily, on Days 1 through 14 of each 21-day treatment cycle.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participant has an established diagnosis of multiple myeloma based on the myeloma diagnostic criteria. * Participant has received at least 1 but not more than 3 prior anti-myeloma regimens and has progressive disease after the most recent treatment regimen. * Participant must have adequate organ function.
Exclusion criteria
* Participant 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. * Participant has known hypersensitivity to any components of bortezomib or vorinostat. * Participant has active Hepatitis B or C, plasma cell leukemia, or is human immunodeficiency virus (HIV) positive. * Participant has had prior treatment with vorinostat or histone deacetylase (HDAC) inhibitors.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) | From randomization to event of disease progression or death assessed up to 32 months (final study analysis) | Progression-free survival was measured from the start of the treatment to the time when the criteria for progression was met or death due to any cause (whichever is first recorded). Response to study therapy was assessed using European Blood and Marrow Transplantation Group (EBMT) Criteria. A stratified Cox proportional hazards model was used with Efron's likelihood approximation to account for ties in event times. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Grade 3-5 Clinical or Laboratory Adverse Events (AEs) | Up to 722 days | An adverse event (AE) was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product/protocol-specified procedure, whether or not considered related to the medicinal product/protocol-specified procedure. Any worsening of a preexisting condition temporally associated with the use of the product was also an AE. Grades come from the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Per protocol, clinical and laboratory AEs are presented as a combined total for each grade. |
| Overall Survival | From randomization up to 32 months (final study analysis) | Overall survival was measured from the start of the treatment to death due to any cause. Overall Survival is represented as the number of deaths per 100-person- months and was computed by dividing the number of participants with an event of death that occurred during the study follow-up period by the total duration of follow-up (in 100 months) for all the participants in each cohort since participants had different lengths of follow-up. |
| Time to Progression | Baseline and at the end of each 21-day Cycle assessed up to 32 months (final study analysis) | Time to progression was measured from the start of the treatment to the time when the criteria for progression was met or death due to myeloma (whichever is first recorded). Response to study therapy was assessed using European Blood and Marrow Transplantation Group (EBMT) Criteria. A stratified Cox proportional hazards model was used with Efron's likelihood approximation to account for ties in event times. |
| Objective Response Rate | Baseline and at the end of each 21-day Cycle assessed up to 32 months (final study analysis) | Objective response rate was measured as the proportion of patients who achieved a confirmed partial response or better during the course of the study. Response to study therapy was assessed using EBMT Criteria and confirmed by Independent Adjudication Review. |
Participant flow
Recruitment details
This study enrolled participants with an established diagnosis of multiple myeloma based on standard criteria that have received at least 1 but not more than 3 prior anti-myeloma regimens and have demonstrated progressive disease after the most recent treatment regimen. Additional inclusion and exclusion criteria applied.
Pre-assignment details
637 participants were randomized to treatment and 635 participants received at least 1 dose of MK-0683 or placebo: 315 participants were treated with vorinostat + bortezomib and 320 participants were treated with placebo + bortezomib.
Participants by arm
| Arm | Count |
|---|---|
| Vorinostat + Bortezomib Participants will receive vorinostat four 100 mg capsules (400 mg total) orally 0-30 minutes after a meal on Days 1 through 14 of a 21-day treatment cycle and bortezomib 1.3 mg/m\^2 by intravenous injection on Days 1, 4, 8, and 11 of a 21-day treatment cycle. | 317 |
| Placebo + Bortezomib Participants will receive four placebo capsules orally 0-30 minutes after a meal on Days 1 through 14 of a 21-day treatment cycle and bortezomib 1.3 mg/m\^2 by intravenous injection on Days 1, 4, 8, and 11 of a 21-day treatment cycle. | 320 |
| Total | 637 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 61 | 62 |
| Overall Study | Death | 5 | 8 |
| Overall Study | Lack of Efficacy | 112 | 144 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Not Treated | 2 | 0 |
| Overall Study | Physician Decision | 26 | 18 |
| Overall Study | Protocol Violation | 2 | 2 |
| Overall Study | Withdrawal by Subject | 89 | 61 |
Baseline characteristics
| Characteristic | Placebo + Bortezomib | Vorinostat + Bortezomib | Total |
|---|---|---|---|
| Age, Continuous | 62.7 Years STANDARD_DEVIATION 10 | 60.9 Years STANDARD_DEVIATION 10 | 61.8 Years STANDARD_DEVIATION 10 |
| Age, Customized 85 years and over | 2 Participants | 1 Participants | 3 Participants |
| Age, Customized Adolescents (12-17 years) | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Adults (18-64 years) | 181 Participants | 200 Participants | 381 Participants |
| Age, Customized Children (2-11 years) | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized From 65-84 years | 137 Participants | 116 Participants | 253 Participants |
| Age, Customized Infants and toddlers (28 days-23 months) | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized In utero | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Newborns (0-27 days) | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Preterm newborn infants (gestational age < 37 wks) | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 23 Participants | 32 Participants | 55 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 297 Participants | 285 Participants | 582 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 134 Participants | 126 Participants | 260 Participants |
| Sex: Female, Male Male | 186 Participants | 191 Participants | 377 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 312 / 315 | 306 / 320 |
| serious Total, serious adverse events | 130 / 315 | 138 / 320 |
Outcome results
Primary
Progression-Free Survival (PFS)
Progression-free survival was measured from the start of the treatment to the time when the criteria for progression was met or death due to any cause (whichever is first recorded). Response to study therapy was assessed using European Blood and Marrow Transplantation Group (EBMT) Criteria. A stratified Cox proportional hazards model was used with Efron's likelihood approximation to account for ties in event times.
Time frame: From randomization to event of disease progression or death assessed up to 32 months (final study analysis)
Population: The analysis population includes all randomized participants.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Vorinostat + Bortezomib | Progression-Free Survival (PFS) | 7.63 Months | 95% Confidence Interval 6.87 |
| Placebo + Bortezomib | Progression-Free Survival (PFS) | 6.83 Months | 95% Confidence Interval 5.67 |
Comparison: Cox model stratified by myeloma stage at enrollment, history of a bone marrow transplant, and number of prior treatment regimens, with a single treatment covariate.p-value: =0.0195% CI: [0.636, 0.941]Regression, Cox
Secondary
Number of Participants With Grade 3-5 Clinical or Laboratory Adverse Events (AEs)
An adverse event (AE) was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product/protocol-specified procedure, whether or not considered related to the medicinal product/protocol-specified procedure. Any worsening of a preexisting condition temporally associated with the use of the product was also an AE. Grades come from the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Per protocol, clinical and laboratory AEs are presented as a combined total for each grade.
Time frame: Up to 722 days
Population: The analysis population includes all randomized participants who received ≥1 dose of study medication.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Vorinostat + Bortezomib | Number of Participants With Grade 3-5 Clinical or Laboratory Adverse Events (AEs) | Grade 3 | 272 Participants |
| Vorinostat + Bortezomib | Number of Participants With Grade 3-5 Clinical or Laboratory Adverse Events (AEs) | Grade 4 | 108 Participants |
| Vorinostat + Bortezomib | Number of Participants With Grade 3-5 Clinical or Laboratory Adverse Events (AEs) | Grade 5 | 11 Participants |
| Placebo + Bortezomib | Number of Participants With Grade 3-5 Clinical or Laboratory Adverse Events (AEs) | Grade 3 | 240 Participants |
| Placebo + Bortezomib | Number of Participants With Grade 3-5 Clinical or Laboratory Adverse Events (AEs) | Grade 4 | 85 Participants |
| Placebo + Bortezomib | Number of Participants With Grade 3-5 Clinical or Laboratory Adverse Events (AEs) | Grade 5 | 17 Participants |
Secondary
Objective Response Rate
Objective response rate was measured as the proportion of patients who achieved a confirmed partial response or better during the course of the study. Response to study therapy was assessed using EBMT Criteria and confirmed by Independent Adjudication Review.
Time frame: Baseline and at the end of each 21-day Cycle assessed up to 32 months (final study analysis)
Population: The analysis population includes all randomized participants who received ≥1 dose of study medication.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Vorinostat + Bortezomib | Objective Response Rate | 56.2 Percentage of Participants | 95% Confidence Interval 50.5 |
| Placebo + Bortezomib | Objective Response Rate | 40.6 Percentage of Participants | 95% Confidence Interval 35.2 |
Secondary
Overall Survival
Overall survival was measured from the start of the treatment to death due to any cause. Overall Survival is represented as the number of deaths per 100-person- months and was computed by dividing the number of participants with an event of death that occurred during the study follow-up period by the total duration of follow-up (in 100 months) for all the participants in each cohort since participants had different lengths of follow-up.
Time frame: From randomization up to 32 months (final study analysis)
Population: The analysis population includes all randomized participants.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Vorinostat + Bortezomib | Overall Survival | 1.7 Events/100-person Months | 95% Confidence Interval 1.56 |
| Placebo + Bortezomib | Overall Survival | 1.9 Events/100-person Months | 95% Confidence Interval 1.75 |
Comparison: Cox model stratified by myeloma stage at enrollment, history of a bone marrow transplant, and number of prior treatment regimens, with a single treatment covariate.p-value: 0.349695% CI: [0.622, 1.184]Regression, Cox
Secondary
Time to Progression
Time to progression was measured from the start of the treatment to the time when the criteria for progression was met or death due to myeloma (whichever is first recorded). Response to study therapy was assessed using European Blood and Marrow Transplantation Group (EBMT) Criteria. A stratified Cox proportional hazards model was used with Efron's likelihood approximation to account for ties in event times.
Time frame: Baseline and at the end of each 21-day Cycle assessed up to 32 months (final study analysis)
Population: The analysis population includes all randomized participants.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Vorinostat + Bortezomib | Time to Progression | 7.73 Months | 95% Confidence Interval 7 |
| Placebo + Bortezomib | Time to Progression | 7.03 Months | 95% Confidence Interval 6.33 |