Multiple Myeloma in Relapse, Refractory Multiple Myeloma, Relapsed and Bortezomib Refractory Multiple Myeloma
Conditions
Keywords
Multiple Myeloma, Relapsed Multiple Myeloma, Refractory Multiple Myeloma
Brief summary
This study is designed to assess the effectiveness of the combination of Panobinostat plus Bortezomib and Dexamethasone in patients with relapsed and bortezomib refractory Multiple Myeloma.
Detailed description
This is a phase II, two stage, single arm, open label, multi-center study of oral PAN in combination with BTZ/Dex in patients with relapsed and refractory multiple myeloma, who are bortezomib-refractory and have received at least 2 prior lines of therapy. Patients must have been exposed to an iMID (lenalidomide or thalidomide) and progressed on or within 60 days of their last BTZ-containing line of therapy.
Interventions
DRUGpanobinostat
PAN 20 mg PO given TIW, weeks 1&2 of each 3-week cycle;• BTZ 1.3 mg/m2 IV push given BIW weeks 1&2 of each 3 week cycle (days 1,4,8 and 11);• Dex 20 mg PO given QIW, weeks 1&2 of each 3-week cycle (days 1,2,4,5,8,9,11 and 12)
DRUGbortezomib
DRUGdexamethasone
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. Patient has a previous diagnosis of multiple myeloma, based on IMWG 2003 definitions. All three of the following criteria must have been met: * Monoclonal immunoglobulin (M component) on electrophoresis, and on immunofixation on serum or on total 24 hour urine * Bone marrow (clonal) plasma cells ≥ 10% or biopsy proven plasmacytoma * Related organ or tissue impairment (CRAB symptoms: anemia, hypercalcemia, lytic bone lesions, renal insufficiency, hyperviscosity, amyloidosis or recurrent infections) 2. Patient must have relapsed and refractory MM and must require treatment for the relapsed disease 3. Patients must have received at least 2 prior lines of therapy which include an IMiD (thalidomide or lenalidomide) 4. Patient must be refractory to the last bortezomib containing line of therapy given in the relapsed and refractory setting defined as: * having progressed on or within 60 days of the last bortezomib-containing line of therapy 5. Patient has measurable disease on M protein at study screening defined by at least one of the following measurements as per thresholds clarified in IMWG 2003 disease definitions (Kyle, et al 2003): * Serum M-protein ≥ 1 g/dL (≥ 10 g/L) * Urine M-protein ≥ 200 mg/24 h 6. Patients treated with local radiotherapy with or without concomitant exposure to steroids for pain control or management of cord/nerve root compression, are eligible. Two weeks must have lapsed since last date of radiotherapy, which is recommended to be a limited field. Patients who require concurrent radiotherapy should have entry to the protocol deferred until the radiotherapy is completed and 2 weeks have passed since the last date of therapy 7. Patient's age is ≥ 18 years at time of signing the informed consent 8. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ≤ 2 9. Patient has the following laboratory values within 3 weeks before starting study drug (lab tests may be repeated, as clinically indicated, to obtain acceptable values before screen fail is concluded but supportive therapies are not to be administered within the week prior to screening tests for absolute neutrophil count or platelet counts) * Absolute neutrophil count (ANC) ≥ 1.0 x 109 /L * Platelet count ≥ 70 x 109 /L * Serum potassium, magnesium, phosphorus, within normal limits (WNL) for institution * Total calcium (corrected for serum albumin) or ionized calcium ≥ LLN, and not higher than CTCAE grade 1 in case of elevated value Note: Potassium, calcium, magnesium, and/or phosphorus supplements may be given to correct values that are \< LLN: * AST/SGOT and ALT/SGPT ≤ 2.5 x ULN * Serum total bilirubin ≤ 1.5 ULN (or ≤ 3.0 x ULN if patient has Gilbert syndrome) * Serum creatinine levels ≤ 2.5 x ULN, or calculated creatinine clearance ≥ 40 ml/min 10. Patient has provided written informed consent prior to any screening procedures 11. Patient is able to swallow capsules 12. Patient must be able to adhere to the study visit schedule and other protocol requirements 13. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test at within 7 days prior to start of study treatment
Exclusion criteria
1. Primary refractory disease (patients that never reached at least an MR for over 60 days under any prior therapy) 2. Patients who have a history of prior MM treatment with a DAC inhibitor including panobinostat 3. Patients who have had prior allogeneic stem cell transplantation and show evidence of active graft-versus-host disease that requires immunosuppressive therapy 4. Peripheral neuropathy ≥ CTCAE grade 2 5. Patients who will need valproic acid for any medical condition during the study or within 5 days prior to the first administration of study drug / treatment or who cannot be switch to safely to alternative anti-epileptic medication 6. Patients who have impaired cardiac function including any of the following: * Congenital long QT syndrome, complete left bundle branch block or use of a permanent cardiac pacemaker, history or presence of ventricular tachyarrhythmias, clinically significant resting bradycardia (\< 50 beats per minute). Right bundle branch block + left anterior hemiblock (bifascicular block) * QTcF \> 450 msec on screening ECG * Presence of unstable atrial fibrillation. Patients with stable atrial fibrillation are allowed in the study provided they do not meet other cardiac or prohibited drug
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (PR+nCR+CR) | after eight cycyles of treatment (24 weeks) | Overall response rate=(PR+nCR+CR) CR= \< 5% plasma cells in bone marrow. No confirmation on bone marrow plasma cell (additional assessment) is needed to document CR except patients with non-secretory myeloma where the bone marrow examination must be repeated after an interval of at least 6 weeks, Absence of M-protein in serum and urine by immunofixation,nCR same as CR without out Absence of M-protein in serum and urine by immunofixation,PR+ 50% reduction of serum M-protein and sofft tissue Plasmacytomas all for more than 6 weeks. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Responders to Treatment | after eight cycyles of treatment (24 weeks) | The primary endpoint for this phase II study of patients with bortezomib-refractory MM is response after a maximum of 8 cycles of therapy as defined by the modified EBMT criteria. |
| Time to Response (Greater Than or Equal to PR) Based on Investigator Assessment | after eight cycyles of treatment (24 weeks) | Time to response is defined as the time from the date of first administration of study treatment to the date of first documented evidence of CR or nCR or PR (whichever status is recorded first). Patients who do not have a response of PR or better by the data cut-off date are censored. |
| Progression-free Survival | 24 weeks | Progression-free survival (PFS) was defined as the time from the date of first study treatment to first occurrence of documented progressive disease /relapse or death. Time from randomization until disease progression or death by Kaplan-Meier estimates |
| Time to Progression | 24 weeks | Time from randomization until objective tumor progression; does not include deaths-- Kaplan-Meier estimates |
| Over All Survival | 24 weeks | Kaplan Meier estimates- median time to event |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Panobinostat + Bortezomib & Dexamethasone panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory multiple myeloma | 55 |
| Total | 55 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 11 |
| Overall Study | Death | 1 |
| Overall Study | Lack of Efficacy | 36 |
| Overall Study | New Cancer Therapy | 2 |
| Overall Study | Withdrawal by Subject | 5 |
Baseline characteristics
| Characteristic | Panobinostat + Bortezomib & Dexamethasone |
|---|---|
| Age, Continuous | 61.9 years STANDARD_DEVIATION 10.54 |
| Sex: Female, Male Female | 26 Participants |
| Sex: Female, Male Male | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 53 / 55 |
| serious Total, serious adverse events | 39 / 55 |
Outcome results
Primary
Overall Response Rate (PR+nCR+CR)
Overall response rate=(PR+nCR+CR) CR= \< 5% plasma cells in bone marrow. No confirmation on bone marrow plasma cell (additional assessment) is needed to document CR except patients with non-secretory myeloma where the bone marrow examination must be repeated after an interval of at least 6 weeks, Absence of M-protein in serum and urine by immunofixation,nCR same as CR without out Absence of M-protein in serum and urine by immunofixation,PR+ 50% reduction of serum M-protein and sofft tissue Plasmacytomas all for more than 6 weeks.
Time frame: after eight cycyles of treatment (24 weeks)
Population: Full Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Panobinostat + Bortezomib & Dexamethasone | Overall Response Rate (PR+nCR+CR) | 34.5 percentage of participants |
Secondary
Over All Survival
Kaplan Meier estimates- median time to event
Time frame: 24 weeks
Population: FAS
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Panobinostat + Bortezomib & Dexamethasone | Over All Survival | 559.0 Days |
Secondary
Progression-free Survival
Progression-free survival (PFS) was defined as the time from the date of first study treatment to first occurrence of documented progressive disease /relapse or death. Time from randomization until disease progression or death by Kaplan-Meier estimates
Time frame: 24 weeks
Population: Full Analysis Set (FAS)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Panobinostat + Bortezomib & Dexamethasone | Progression-free Survival | 164.0 days |
Secondary
Responders to Treatment
The primary endpoint for this phase II study of patients with bortezomib-refractory MM is response after a maximum of 8 cycles of therapy as defined by the modified EBMT criteria.
Time frame: after eight cycyles of treatment (24 weeks)
Population: Full Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Panobinostat + Bortezomib & Dexamethasone | Responders to Treatment | Complete Response (CR) | 0 participants |
| Panobinostat + Bortezomib & Dexamethasone | Responders to Treatment | near Complete Response(nCR) | 1 participants |
| Panobinostat + Bortezomib & Dexamethasone | Responders to Treatment | Partial Response (PR) | 18 participants |
| Panobinostat + Bortezomib & Dexamethasone | Responders to Treatment | Minimal Response (MR) | 10 participants |
| Panobinostat + Bortezomib & Dexamethasone | Responders to Treatment | No Change | 20 participants |
| Panobinostat + Bortezomib & Dexamethasone | Responders to Treatment | Pregressive Disease (PD) | 3 participants |
| Panobinostat + Bortezomib & Dexamethasone | Responders to Treatment | Unknown | 3 participants |
Secondary
Time to Progression
Time from randomization until objective tumor progression; does not include deaths-- Kaplan-Meier estimates
Time frame: 24 weeks
Population: FAS
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Panobinostat + Bortezomib & Dexamethasone | Time to Progression | 164.0 Days |
Secondary
Time to Response (Greater Than or Equal to PR) Based on Investigator Assessment
Time to response is defined as the time from the date of first administration of study treatment to the date of first documented evidence of CR or nCR or PR (whichever status is recorded first). Patients who do not have a response of PR or better by the data cut-off date are censored.
Time frame: after eight cycyles of treatment (24 weeks)
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Panobinostat + Bortezomib & Dexamethasone | Time to Response (Greater Than or Equal to PR) Based on Investigator Assessment | 51.8 Days | Standard Deviation 30.92 |