Multiple Myeloma
Conditions
Keywords
Multiple myeloma, adults, LBH589, refractory
Brief summary
This study will evaluate the efficacy and safety of LBH589B in adult patients with multiple myeloma who have received at least two prior therapies and are refractory to their last therapy. Patients must have received in prior therapy either bortezomib or lenalidomide
Interventions
DRUGLBH589
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Adults ≥ 18 years old 2. Subjects must have signed the consent form before undergoing any study specific screening procedures and before participation in this study. The subject must be fully informed by the investigator of the nature and potential risks of participation in this study. 3. Patients must have had a diagnosis of symptomatic multiple myeloma (from IMWG see (Kyle et al,2003) meeting all three of the following criteria: * Monoclonal immunoglobulin (spike on electrophoresis, or band on immunofixation) on serum or on 24 hour urine. * Bone marrow (clonal) plasma cells or plasmacytoma * Related organ or tissue impairment (anemia, hypercalcemia, lytic bone lesions, renal insufficiency, hyperviscosity or recurrent infections) (The Kyle et al 2003 definition of symptomatic Myeloma has been adapted based on the new
Exclusion criteria
defined in protocol amendment 1) 4. Subjects must have received at least two prior lines of therapy and be refractory to the most recent line of therapy according to the following definitions: Refractory to most recent line of therapy Defined by disease progression during treatment or within 60 - 100 days after the completion of the most recent line of therapy. This includes the development of disease progression during maintenance or consolidation therapy with high dose glucocorticoids, or any other specific MM therapy Sixty days is counted from the point in time when the first response assessment is performed after completion of the last line of therapy. At a maximum, disease progression should be documented within 100 days after the last day of the last dose of any anti-MM therapy, including if last regimen of the most recent line of therapy was Autologous Stem Cell Transplant (ASCT). Stable disease patients also part of the IMWG definition are not eligible for this trial. At study screening, Progressive Disease (PD) will be assessed by comparing screening values or symptoms in reference to the baseline (values or symptoms) of their last line of therapy. Should a patient have experienced an initial response on their last line of therapy, PD should be assessed in reference to the lowest values of the initial confirmed response Minimal Response(MR) / Partial Response (PR) / Complete Response (CR). Disease progression is defined by having one or more of the following: * \>25% increase in the level of serum monoclonal paraprotein, which must also be an absolute increase of at least 5 g/L and confirmed on a repeat investigation. * \>25% increase in 24-hour urinary light chain excretion, which must also be an absolute increase of at least 200 mg/24 h and confirmed on a repeat investigation. * \>25% increase in plasma cells in a bone marrow aspirate or on bone marrow biopsy, which must also be an absolute increase of at least 10% * Definite increase in the size of existing lytic bone lesions or soft tissue plasmacytomas. * Development of new bone lesions or soft tissue plasmacytomas (not including compression fracture). * Development of hypercalcemia (corrected serum calcium \> 11.5 mg/dL or 2.8 mmol/L not attributable to any other cause). 5. Subjects must have previously been treated with bortezomib and at least one of the following: lenalidomide or thalidomide 6. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤ 2 7. Patients must have the following hematological laboratory values: * Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L (or ≥1.0 x 109/L if the neutropenia is clinically related to progressive myeloma with bone marrow infiltration of \> 50% involvement * Hemoglobin ≥ 8.0 g/dl * Platelets ≥ 75.0 x 109/L (or ≥ 50.0 x 109/L x if the thrombocytopenia is clinically related to progressive myeloma with bone marrow infiltration \> 50% involvement 8. Patients must have the following renal function as shown by : * Calculated Creatinine Clearance (CrCL) \> 30ml/min (Cockcroft and Gault formula) 9. Patients must have adequate liver function as shown by: * Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤ 2.5 x Upper limit of normal (ULN) * Serum bilirubin ≤ 1.5 x ULN * Albumin ≥ 2.5 g/dl 10. Patients must have the following non-hematological laboratory values: * Serum potassium ≥ Lower Limit of Normal (LLN), * Total serum calcium \[corrected for serum albumin\] or ionized calcium ≥LLN, * Serum magnesium ≥ LLN * Serum phosphorus ≥ LLN * Normal thyroid function (TSH and free T4) (hypothyroidism correctable with supplements is allowed) 11. Baseline Multiple Uptake Gated Acquisition scan (MUGA) or echocardiogram (ECHO) must demonstrate Left Ventricular Ejection Fraction (LVEF) ≥ the lower limit of the institutional normal 12. Patients must be willing and able to undergo bone marrow aspirates as per protocol, with/without bone marrow biopsy according to their center's practice. The bone marrow aspirate /biopsy must be adequate to allow for comparison for the later efficacy response assessments. 13. Patients must have an M component at baseline above a minimum threshold of: 1g/dl (10g/L) for serum M component, or 200mg/24h urine M component.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Response Rate (Complete Response(CR) / Partial Response (PR)) | From Start of the Study up to 57 Weeks approximately. | The response (complete response (CR) / partial response (PR)) rate as per Bladé criteria was assessed by the investigator. Response to treatment was evaluated in participants with multiple myeloma (MM) who have received at least two prior lines of therapy and whose disease was refractory to the most recent line of therapy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Benefit Rate | From Start of the Study up to 57 Weeks approximately. | Clinical benefit rate is defined by the percentage of participants achieving either a confirmed tumor response or stable disease (SD) for at least 24 weeks. Response Criteria in Solid Tumors (RECIST) is a system for measuring tumor shrinkage or progression in terms of the longest dimensions of the tumor on imaging scans such as computerized tomography (CT). A partial response requires a decrease of 30% or more, Progression requires an increase of at least 20%, and Stable disease falls in between these two. All responses have a repeat assessment to confirm the response |
| Duration of Response | From Start of the Study up to 57 Weeks approximately. | Duration of response is defined as time between time to first documented response (CR/PR) and time to first documented disease progression or death. |
| Time to Response | From Start of the Study up to 57 Weeks approximately. | Time to response is defined as time between Day 1 cycle 1 and time to first documented response (CR/PR). |
| Progression Free Survival (PFS) | From Start of the Study up to 57 Weeks approximately. | Progressions free survival is defined as time between Day 1 cycle 1 and time to first documented disease progression or death. Disease progression will be determined as per response criteria. |
| Safety and Tolerability | From Start of the Study up to 57 Weeks approximately. | Adverse Event (AE) are defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. Serious adverse events are any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgment of investigators represent significant hazards. |
| Overall Response Rate | From Start of the Study up to 57 Weeks approximately. | Overall response rate is the proportion of patients with a best overall response of complete response (CR) or partial response (PR) according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria (Overall Response (OR) = CR + PR). Complete Response (CR): Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm Partial Response (PR): At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. |
| Maximum Plasma Concentration (Cmax) of Panobinostat | Pre-dose, 0.25, 1-2, and 3-4 hours post dose on Day 1 and Day 8 | Cmax is defined as the maximum observed drug concentration observed in plasma over all PK sample concentrations. It will be obtained from the Cmax parameter calculated by WinNonlin®. If there is no measurable concentration in the subject's PK profile, then Cmax will be missing for that subject. Cmax will be reported in units of ng/mL. |
| Area Under the Plasma Concentration (AUC0-24) of Panobinostat | Pre-dose, 0.25, 1-2, and 3-4 hours post dose on Day 1 and Day 8 | Area under the curve (AUC) is defined as the area under concentration-time curve as a measure of drug exposure. The area under the plasma concentration-time curve from time zero to 24 hours. |
| Last Observed Plasma Concentration (Clast) of Panobinostat | Pre-dose, 0.25, 1-2, and 3-4 hours post dose on Day 1 and Day 8 | Clast is defined as the Last observed (quantifiable) plasma concentration (Clast), in units of ng/mL. Blood samples were collected to assess Clast. |
| Time of Clast (Tlast) of Panobinostat | Pre-dose, 0.25, 1-2, and 3-4 hours post dose on Day 1 and Day 8 | Time of Clast (Tlast) will be obtained from the Tlast parameter calculated by WinNonlin®. If there is no measurable concentration in the subject's PK profile, then Tlast will be missing for that participants. Tlast will be reported in units of h. |
| Time to Peak Concentration (Tmax) of Panobinostat | Pre-dose, 0.25, 1-2, and 3-4 hours post dose on Day 1 and Day 8 | Tmax is defined as the time at which the Cmax occurs. It will be obtained from the Tmax parameter calculated by WinNonlin®. If there is no measurable Cmax in the subject's pharmacokinetic (PK) profile, then Tmax will be missing for that subject. Tmax will be reported in units of h. |
Countries
Germany, United States
Participant flow
Recruitment details
The study was conducted at 27 centers in 6 countries
Pre-assignment details
A total 38 participants were enrolled in the study, of which 38 discontinued the study.
Participants by arm
| Arm | Count |
|---|---|
| Panobinostat Participants received panobinostat 20 mg orally OD, three times a week on days: 1, 3 and 5, then 8, 10 and 12, then 15, 17 and 19 of each cycle, as part of a 3-week (21 days) treatment cycle. | 38 |
| Total | 38 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Abnormal laboratory value | 2 |
| Overall Study | Adverse Event | 5 |
| Overall Study | Death | 1 |
| Overall Study | Disease progression | 26 |
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Panobinostat |
|---|---|
| Age, Continuous | 60 years STANDARD_DEVIATION 6.58 |
| Race/Ethnicity, Customized Black | 5 Participants |
| Race/Ethnicity, Customized Caucasian | 31 Participants |
| Race/Ethnicity, Customized Other | 1 Participants |
| Race/Ethnicity, Customized Pacific islander | 1 Participants |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 7 / 38 |
| other Total, other adverse events | 37 / 38 |
| serious Total, serious adverse events | 17 / 38 |
Outcome results
Primary
Response Rate (Complete Response(CR) / Partial Response (PR))
The response (complete response (CR) / partial response (PR)) rate as per Bladé criteria was assessed by the investigator. Response to treatment was evaluated in participants with multiple myeloma (MM) who have received at least two prior lines of therapy and whose disease was refractory to the most recent line of therapy.
Time frame: From Start of the Study up to 57 Weeks approximately.
Population: The analysis was performed in Full Analysis Set (FAS) population was defined according to the intention-to-treat principle. This population included all participants enrolled into the study. Enrolled patients were those who had received at least one dose of study drug. The outcome measure was not achieved as the study was terminated due to insufficient clinical efficacy in the targeted participants population. Due to insufficient data, this outcome could not be measured.
Secondary
Area Under the Plasma Concentration (AUC0-24) of Panobinostat
Area under the curve (AUC) is defined as the area under concentration-time curve as a measure of drug exposure. The area under the plasma concentration-time curve from time zero to 24 hours.
Time frame: Pre-dose, 0.25, 1-2, and 3-4 hours post dose on Day 1 and Day 8
Population: The analysis was performed in PAS population, defined as all participants who provide at least one post-dose PK plasma sample. Here, number of participants analyzed refer to the number of participants evaluable for this outcome at specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Panobinostat | Area Under the Plasma Concentration (AUC0-24) of Panobinostat | Day 1 | 72.0 ng*hr/ml | Standard Deviation 36.1 |
| Panobinostat | Area Under the Plasma Concentration (AUC0-24) of Panobinostat | Day 8 | 81.6 ng*hr/ml | Standard Deviation 37.56 |
Secondary
Clinical Benefit Rate
Clinical benefit rate is defined by the percentage of participants achieving either a confirmed tumor response or stable disease (SD) for at least 24 weeks. Response Criteria in Solid Tumors (RECIST) is a system for measuring tumor shrinkage or progression in terms of the longest dimensions of the tumor on imaging scans such as computerized tomography (CT). A partial response requires a decrease of 30% or more, Progression requires an increase of at least 20%, and Stable disease falls in between these two. All responses have a repeat assessment to confirm the response
Time frame: From Start of the Study up to 57 Weeks approximately.
Population: The analysis was performed in FAS population was defined according to the intention-to-treat principle. This population included all participants enrolled into the study. Enrolled patients were those who had received at least one dose of study drug. The outcome measure was not achieved as the study was terminated due to insufficient clinical efficacy in the targeted participants population. Due to insufficient data, this outcome could not be measured.
Secondary
Duration of Response
Duration of response is defined as time between time to first documented response (CR/PR) and time to first documented disease progression or death.
Time frame: From Start of the Study up to 57 Weeks approximately.
Population: The analysis was performed in FAS population was defined according to the intention-to-treat principle. This population included all participants enrolled into the study. Enrolled patients were those who had received at least one dose of study drug. The outcome measure was not achieved as the study was terminated due to insufficient clinical efficacy in the targeted participants population. Due to insufficient data, this outcome could not be measured.
Secondary
Last Observed Plasma Concentration (Clast) of Panobinostat
Clast is defined as the Last observed (quantifiable) plasma concentration (Clast), in units of ng/mL. Blood samples were collected to assess Clast.
Time frame: Pre-dose, 0.25, 1-2, and 3-4 hours post dose on Day 1 and Day 8
Population: The analysis was performed in PAS population, defined as all participants who provide at least one post-dose PK plasma sample. Here, number of participants analyzed refer to the number of participants evaluable for this outcome at specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Panobinostat | Last Observed Plasma Concentration (Clast) of Panobinostat | Day 1 | 0.3 ng/mL | Standard Deviation 0.18 |
| Panobinostat | Last Observed Plasma Concentration (Clast) of Panobinostat | Day 8 | 1.1 ng/mL | Standard Deviation 1.13 |
Secondary
Maximum Plasma Concentration (Cmax) of Panobinostat
Cmax is defined as the maximum observed drug concentration observed in plasma over all PK sample concentrations. It will be obtained from the Cmax parameter calculated by WinNonlin®. If there is no measurable concentration in the subject's PK profile, then Cmax will be missing for that subject. Cmax will be reported in units of ng/mL.
Time frame: Pre-dose, 0.25, 1-2, and 3-4 hours post dose on Day 1 and Day 8
Population: The analysis was performed in PAS population, defined as all participants who provide at least one post-dose PK plasma sample. Here, number of participants analyzed refer to the number of participants evaluable for this outcome at specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Panobinostat | Maximum Plasma Concentration (Cmax) of Panobinostat | Day 1 | 7.6 ng/mL | Standard Deviation 5.52 |
| Panobinostat | Maximum Plasma Concentration (Cmax) of Panobinostat | Day 8 | 9.7 ng/mL | Standard Deviation 6.51 |
Secondary
Overall Response Rate
Overall response rate is the proportion of patients with a best overall response of complete response (CR) or partial response (PR) according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria (Overall Response (OR) = CR + PR). Complete Response (CR): Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm Partial Response (PR): At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
Time frame: From Start of the Study up to 57 Weeks approximately.
Population: The analysis was performed in FAS population was defined according to the intention-to-treat principle. This population included all participants enrolled into the study. Enrolled patients were those who had received at least one dose of study drug. The outcome measure was not achieved as the study was terminated due to insufficient clinical efficacy in the targeted participants population. Due to insufficient data, this outcome could not be measured.
Secondary
Progression Free Survival (PFS)
Progressions free survival is defined as time between Day 1 cycle 1 and time to first documented disease progression or death. Disease progression will be determined as per response criteria.
Time frame: From Start of the Study up to 57 Weeks approximately.
Population: The analysis was performed in FAS population was defined according to the intention-to-treat principle. This population included all participants enrolled into the study. Enrolled patients were those who had received at least one dose of study drug. The outcome measure was not achieved as the study was terminated due to insufficient clinical efficacy in the targeted participants population. Due to insufficient data, this outcome could not be measured.
Secondary
Safety and Tolerability
Adverse Event (AE) are defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. Serious adverse events are any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgment of investigators represent significant hazards.
Time frame: From Start of the Study up to 57 Weeks approximately.
Population: The analysis was performed on Safety population consisted of all participants who had received at least one dose of study medication and had one valid post-baseline assessment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Panobinostat | Safety and Tolerability | Participants with Adverse Events | 38 Participants |
| Panobinostat | Safety and Tolerability | Study-drug-related Serious Adverse Events | 3 Participants |
| Panobinostat | Safety and Tolerability | Deaths | 7 Participants |
| Panobinostat | Safety and Tolerability | On treatment deaths | 3 Participants |
| Panobinostat | Safety and Tolerability | Serious Adverse Events | 17 Participants |
| Panobinostat | Safety and Tolerability | Adverse Events Leading to discontinuation | 8 Participants |
Secondary
Time of Clast (Tlast) of Panobinostat
Time of Clast (Tlast) will be obtained from the Tlast parameter calculated by WinNonlin®. If there is no measurable concentration in the subject's PK profile, then Tlast will be missing for that participants. Tlast will be reported in units of h.
Time frame: Pre-dose, 0.25, 1-2, and 3-4 hours post dose on Day 1 and Day 8
Population: The analysis was performed in PAS population, defined as all participants who provide at least one post-dose PK plasma sample. Here, number of participants analyzed refer to the number of participants evaluable for this outcome at specified time point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Panobinostat | Time of Clast (Tlast) of Panobinostat | Day 1 | 47.8 Hours |
| Panobinostat | Time of Clast (Tlast) of Panobinostat | Day 8 | 24.3 Hours |
Secondary
Time to Peak Concentration (Tmax) of Panobinostat
Tmax is defined as the time at which the Cmax occurs. It will be obtained from the Tmax parameter calculated by WinNonlin®. If there is no measurable Cmax in the subject's pharmacokinetic (PK) profile, then Tmax will be missing for that subject. Tmax will be reported in units of h.
Time frame: Pre-dose, 0.25, 1-2, and 3-4 hours post dose on Day 1 and Day 8
Population: The analysis was performed in Pharmacokinetic Analysis (PAS) population, defined as all participants who provide at least one post-dose Pharmacokinetic (PK) plasma sample. Here, number of participants analyzed refer to the number of participants evaluable for this outcome at specified time point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Panobinostat | Time to Peak Concentration (Tmax) of Panobinostat | Day 1 | 1.7 Hours |
| Panobinostat | Time to Peak Concentration (Tmax) of Panobinostat | Day 8 | 1.2 Hours |
Secondary
Time to Response
Time to response is defined as time between Day 1 cycle 1 and time to first documented response (CR/PR).
Time frame: From Start of the Study up to 57 Weeks approximately.
Population: The analysis was performed in FAS population was defined according to the intention-to-treat principle. This population included all participants enrolled into the study. Enrolled patients were those who had received at least one dose of study drug. The outcome measure was not achieved as the study was terminated due to insufficient clinical efficacy in the targeted participants population. Due to insufficient data, this outcome could not be measured.