Relapsed or Refractory Multiple Myeloma
Conditions
Brief summary
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
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.
Interventions
DRUGVorinostat
Four 100 mg vorinostat capsules orally, once daily (QD) by mouth on Days 1-14 of each 21-day treatment cycle.
DRUGBortezomib
Bortezomib 1.3 mg/m\^2, IV injection QD on Days 1, 4, 8, and 11 of each 21-day treatment cycle.
DRUGDexamethasone
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.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (RR) | Up to approximately 30 months (through Final Analysis data cut-off of 16-May-2011) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Discontinued Study Treatment Due to an AE | Up to approximately 18 months | 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. |
| Time To Disease Progression (TTP) as Determined by IAC Per EBMT Criteria | Up to approximately 30 months (through Final Analysis data cut-off of 16-May-2011) | 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. |
| TTP as Assessed by Investigator Per EBMT Criteria | Up to approximately 30 months (through Final Analysis data cut-off of 16-May-2011) | 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. |
| Number of Participants Who Experienced an Adverse Event (AE) | Up to approximately 22 months | 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. |
| PFS as Assessed by Investigator Per EBMT Criteria | Up to approximately 30 months (through Final Analysis data cut-off of 16-May-2011) | 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. |
| Overall Survival (OS) | Up to approximately 40 months (through End of Trial data cut-off of 09-Apr-2012) | 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. |
| Progression-Free Survival (PFS) as Determined by IAC Per EBMT Criteria | Up to approximately 30 months (through Final Analysis data cut-off of 16-May-2011) | 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. |
Participant flow
Pre-assignment details
Of 143 participants enrolled, 142 participants were allocated to treatment. Five participants received additional treatment for about 1 year during an extension as per investigator's discretion based on clinical benefit of the treatment received. All 5 participants discontinued extension treatment and were followed for survival up to 2 years post last dose of treatment.
Participants by arm
| Arm | Count |
|---|---|
| Vorinostat + Bortezomib 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. | 143 |
| Total | 143 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 29 |
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | Physician Decision | 8 |
| Overall Study | Progressive Disease | 82 |
| Overall Study | Protocol Violation | 2 |
| Overall Study | Withdrawal by Subject | 21 |
Baseline characteristics
| Characteristic | Vorinostat + Bortezomib |
|---|---|
| Age, Continuous | 62.1 Years STANDARD_DEVIATION 8.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 138 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 34 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 102 Participants |
| Sex: Female, Male Female | 56 Participants |
| Sex: Female, Male Male | 87 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 85 / 143 |
| other Total, other adverse events | 140 / 142 |
| serious Total, serious adverse events | 92 / 142 |
Outcome results
Primary
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.
Time frame: Up to approximately 30 months (through Final Analysis data cut-off of 16-May-2011)
Population: All participants who received at least one dose of study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vorinostat + Bortezomib | Objective Response Rate (RR) | 11.3 Percentage of Participants |
p-value: 0.419Exact Test for Binomial Parameter
Secondary
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.
Time frame: Up to approximately 18 months
Population: All participants who received at least one dose of study treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vorinostat + Bortezomib | Number of Participants Who Discontinued Study Treatment Due to an AE | 28 Participants |
Secondary
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.
Time frame: Up to approximately 22 months
Population: All participants who received at least one dose of study treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vorinostat + Bortezomib | Number of Participants Who Experienced an Adverse Event (AE) | 142 Participants |
Secondary
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.
Time frame: Up to approximately 40 months (through End of Trial data cut-off of 09-Apr-2012)
Population: All allocated participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vorinostat + Bortezomib | Overall Survival (OS) | 11.23 Months |
Secondary
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.
Time frame: Up to approximately 30 months (through Final Analysis data cut-off of 16-May-2011)
Population: All participants who received at least one dose of study treatment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vorinostat + Bortezomib | PFS as Assessed by Investigator Per EBMT Criteria | 2.83 Months |
Secondary
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.
Time frame: Up to approximately 30 months (through Final Analysis data cut-off of 16-May-2011)
Population: All participants who received at least one dose of study treatment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vorinostat + Bortezomib | Progression-Free Survival (PFS) as Determined by IAC Per EBMT Criteria | 3.13 Months |
Secondary
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.
Time frame: Up to approximately 30 months (through Final Analysis data cut-off of 16-May-2011)
Population: All participants who received at least one dose of study treatment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vorinostat + Bortezomib | Time To Disease Progression (TTP) as Determined by IAC Per EBMT Criteria | 3.47 Months |
Secondary
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.
Time frame: Up to approximately 30 months (through Final Analysis data cut-off of 16-May-2011)
Population: All participants who received at least one dose of study treatment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vorinostat + Bortezomib | TTP as Assessed by Investigator Per EBMT Criteria | 3.07 Months |