Multiple Myeloma
Conditions
Keywords
autologous hematopoietic cell transplant (HCT), autologous
Brief summary
The purpose of this study is to learn more about ways to prevent or delay relapse of multiple myeloma (MM). This study will determine the best dosing schedule of LBH589 maintenance therapy as well as the safety (side effects) and tolerability of LBH589 maintenance therapy after autologous hematopoietic cell transplant (HCT).
Interventions
DRUGPanobinostat
Maintenance therapy dosing as outlined in Cohorts A and B.
Sponsors
Novartis Pharmaceuticals
H. Lee Moffitt Cancer Center and Research Institute
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adult patients, age ≥ 18 years old * Ability to provide written informed consent obtained prior to participation in the study and any related procedures being performed * Histologically confirmed diagnosis of multiple myeloma * Meeting the Criteria for Symptomatic Multiple Myeloma (CRAB criteria) before the initiation of systemic chemotherapy * Received high-dose melphalan (≥ 140 mg/m\^2) followed by autologous HCT based on the institutional guidelines and within +45 and +180 after autologous HCT at the time of panobinostat maintenance initiation * Must have achieved at least partial response (PR) prior to autologous HCT and must not have progressive disease (PD) prior to the initiation of maintenance therapy * Must meet the following laboratory criteria (prior to the initiation of panobinostat maintenance): Absolute neutrophil count (ANC) ≥ 1 x 10\^9/L; Hemoglobin ≥ 8 g/dl; Platelets ≥ 50 x 10\^9/L (without transfusion support); Creatinine clearance ≥ 40 ml/min or serum creatinine ≤ 2.5 x upper limit of normal (ULN); aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN; Serum bilirubin ≤ 1.5 x ULN; Albumin \> 3.0 g/dl; Clinically euthyroid. Note: Participants are permitted to receive thyroid hormone supplements to treat underlying hypothyroidism. * Baseline (pre-HCT) multigated acquisition (MUGA) or echocardiogram (ECHO) must demonstrate left ventricular ejection fraction (LVEF) ≥ the limit of normal (LLN) of the institutional normal * Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2 or Karnofsky performance status ≥ 70% * Prior histone deacetylase (HDAC), deacetylase (DAC), HSP90 inhibitors or valproic acid for the treatment of cancer is allowed
Exclusion criteria
* Potential participants who have purely non-secretory multiple myeloma (i.e., the absence of a measurable protein in serum by electrophoresis and immunofixation and the absence of Bence-Jones protein in the urine defined by use of electrophoresis and immunofixation) * Prior allogeneic HCT * Prior solid organ transplant requiring immunosuppressive therapy * Potential participants who will need valproic acid for any medical condition during the study or within 5 days prior to first panobinostat treatment * Impaired cardiac function or clinically significant cardiac diseases * Diarrhea \> Common Terminology Criteria for Adverse Events (CTCAE) grade 2 * Other concurrent severe and/or uncontrolled medical conditions (e.g., uncontrolled diabetes or active or uncontrolled infection) including abnormal laboratory values, that could cause unacceptable safety risks or compromise compliance with the protocol * Using medications that have a relative risk of prolonging the QT interval or inducing torsade de pointes if treatment cannot be discontinued or switched to a different medication prior to starting study drug * Have received targeted agents within 2 weeks or within 5 half-lives of the agent and active metabolites (whichever is longer) and who have not recovered from side effects of those therapies. * Have received either immunotherapy within \< 8 weeks; chemotherapy within \< 4 weeks; or radiation therapy to \> 30% of marrow-bearing bone within \< 2 weeks prior to starting study treatment; or who have not yet recovered from side effects of such therapies * Have undergone major surgery ≤ 4 weeks prior to starting study drug or have not recovered from side effects of such therapy * Women who are pregnant or breast feeding or women of childbearing potential (WOCBP) not using an effective method of birth control. WOCBP must have a negative serum pregnancy test within 24 hours of receiving the first dose of study medication. * Male patients whose sexual partners are WOCBP not using effective birth control * A prior malignancy with in the last 5 years (except for basal or squamous cell carcinoma, or in situ cancer of the cervix) * Known positivity for human immunodeficiency virus (HIV) or hepatitis C; baseline testing for HIV and hepatitis C is not required * Any significant history of non-compliance to medical regimens or unwilling or unable to comply with the instructions given to him/her by the study staff
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Relative Dose Intensity (RDI) Per Cohort | Up to 2 years | Investigators will calculate RDI for each cohort. Relative dose intensity (RDI) represents the ratio of the amount of a drug actually delivered \[actual dose intensity (DI)\] to the amount planned (planned DI). The purpose of calculating RDI is to evaluate whether the planned DI of a chemotherapy treatment was actually achieved which may suggest the feasibility of planned treatment regimen. There are multitude of reports demonstrating a correlation between RDI and survival in cancer treatment. RDI = (total dose received by the patient = mg)/(planned full dose of drug = mg). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Complete Response Rate | Up to 5 years | Complete Response (CR) rate to panobinostat maintenance therapy after autologous HCT. CR: Negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas, and \< 5% plasma cells in bone marrow. |
| Progression Free Survival (PFS) | at 2 years | Progressive Disease (PD) according to Uniform Response Reporting Criteria for Multiple Myeloma by the International Myeloma Working Group (IMWG). Increase of 25% from lowest response value in any of the following: * Serum M- component (absolute increase must be ≥ 0.5 g/dL) * Urine M-component (absolute increase must be ≥ 200 mg/24 h) * Only in patients without measurable serum and urine M protein levels and without measurable disease by free light chain (FLC) levels, bone marrow plasma cell percentage (absolute percentage must be ≥ 10% ) * Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas * Development of hypercalcemia (corrected serum calcium \> 11.5 mg/dL) that can be attributed solely to the plasma cell proliferative disorder |
| Overall Survival (OS) | at 2 years | OS: The length of time from either the date of diagnosis or the start of treatment for a disease, such as cancer, that patients diagnosed with the disease are still alive. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort A: Maintenance Therapy Panobinostat (LBH589): 20 mg by mouth three (3) times per week, every other week, of a 28-day schedule.
Panobinostat: Maintenance therapy dosing as outlined in Cohorts A and B. | 15 |
| Cohort B: Maintenance Therapy Panobinostat (LBH589): 10 mg by mouth daily for seven (7) days, every other week, of a 28-day schedule.
Panobinostat: Maintenance therapy dosing as outlined in Cohorts A and B. | 15 |
| Total | 30 |
Baseline characteristics
| Characteristic | Cohort A: Maintenance Therapy | Cohort B: Maintenance Therapy | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 4 Participants | 7 Participants | 11 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants | 8 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 0 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants | 15 Participants | 27 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 13 Participants | 13 Participants | 26 Participants |
| Region of Enrollment United States | 15 participants | 15 participants | 30 participants |
| Sex: Female, Male Female | 6 Participants | 5 Participants | 11 Participants |
| Sex: Female, Male Male | 9 Participants | 10 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 15 |
| other Total, other adverse events | 10 / 15 | 11 / 15 |
| serious Total, serious adverse events | 2 / 15 | 3 / 15 |
Outcome results
Primary
Relative Dose Intensity (RDI) Per Cohort
Investigators will calculate RDI for each cohort. Relative dose intensity (RDI) represents the ratio of the amount of a drug actually delivered \[actual dose intensity (DI)\] to the amount planned (planned DI). The purpose of calculating RDI is to evaluate whether the planned DI of a chemotherapy treatment was actually achieved which may suggest the feasibility of planned treatment regimen. There are multitude of reports demonstrating a correlation between RDI and survival in cancer treatment. RDI = (total dose received by the patient = mg)/(planned full dose of drug = mg).
Time frame: Up to 2 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A: Maintenance Therapy | Relative Dose Intensity (RDI) Per Cohort | 97.9 percentage of dose |
| Cohort B: Maintenance Therapy | Relative Dose Intensity (RDI) Per Cohort | 89.6 percentage of dose |
Secondary
Complete Response Rate
Complete Response (CR) rate to panobinostat maintenance therapy after autologous HCT. CR: Negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas, and \< 5% plasma cells in bone marrow.
Time frame: Up to 5 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A: Maintenance Therapy | Complete Response Rate | 73.33 percentage |
| Cohort B: Maintenance Therapy | Complete Response Rate | 66.6 percentage |
Secondary
Overall Survival (OS)
OS: The length of time from either the date of diagnosis or the start of treatment for a disease, such as cancer, that patients diagnosed with the disease are still alive.
Time frame: at 2 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A: Maintenance Therapy | Overall Survival (OS) | 100 percentage of participants |
| Cohort B: Maintenance Therapy | Overall Survival (OS) | 100 percentage of participants |
Secondary
Progression Free Survival (PFS)
Progressive Disease (PD) according to Uniform Response Reporting Criteria for Multiple Myeloma by the International Myeloma Working Group (IMWG). Increase of 25% from lowest response value in any of the following: * Serum M- component (absolute increase must be ≥ 0.5 g/dL) * Urine M-component (absolute increase must be ≥ 200 mg/24 h) * Only in patients without measurable serum and urine M protein levels and without measurable disease by free light chain (FLC) levels, bone marrow plasma cell percentage (absolute percentage must be ≥ 10% ) * Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas * Development of hypercalcemia (corrected serum calcium \> 11.5 mg/dL) that can be attributed solely to the plasma cell proliferative disorder
Time frame: at 2 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A: Maintenance Therapy | Progression Free Survival (PFS) | 71.8 percentage of participants |
| Cohort B: Maintenance Therapy | Progression Free Survival (PFS) | 53.3 percentage of participants |