Study of Panobinostat in Combination With Bortezomib and Dexamethasone in Japanese Patients With Relapsed/Refractory Multiple Myeloma

Study Overview
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Brief Summary
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The purpose of this study was to evaluate the efficacy and safety of panobinostat in combination with bortezomib and dexamethasone in Japanese patients with relapsed/refractory multiple myeloma.

Official Title
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A Phase II, Multi-center, Single Arm, Open Label Study to Evaluate the Efficacy and Safety of Panobinostat in Combination With Bortezomib and Dexamethasone in Japanese Patients With Relapsed/Refractory Multiple Myeloma

Conditions
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Relapse/Refractory Multiple Myeloma

Intervention / Treatment
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* Drug: LBH589 (panobinostat)
* Drug: bortezomib
* Drug: dexamethasone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient had a previous diagnosis of multiple myeloma Patient required retreatment for multiple myeloma Patient had measurable M component in serum or urine at study screening Exclusion Criteria: Primary refractory disease (patients that never reached at least an minor response for over 60 days under any prior therapy) Patient who had been treated by bortezomib before, and did not reach at least a minor response under this therapy, or progressed under it or within 60 days of last dose Patient received prior treatment with DAC inhibitors including panobinostat Patient had impaired cardiac function, or a prolonged QTc interval at screening ECG

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LBH589 + bortezomib + dexamethasone<br>Participants were administered LBH589 (panobinostat)in combination with bortezomib and dexamethasone 2 weeks on/1 week off. | Drug: LBH589 (panobinostat)<br>* Panobinostat (PAN) capsules were supplied at dose strengths of 10 mg and 15 mg. and dosed at 20mg during treatment phase 1 (21 days) and treatment phase 2 (42 days)<br>Drug: bortezomib<br>* Bortezomib (BTZ) s.c: 1.3 mg/m2 was administered during both treatment phase 1 (21 days) & treatment phase 2 (42 days).<br>Drug: dexamethasone<br>* Dexamethasone (Dex): 20mg tablets taken during both treatment phase 1 (21 days & treatment phase 2 (42 days)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Near Complete Response (nCR)/ Complete Response (CR) Rate | nCR plus CR rate after 8 cycles of therapy as defined by the modified European Society for Bone and Marrow Transplantation (EBMT) criteria per investigator assessment as the proportion of participants with nCR or CR as their best overall response. | after 24 weeks (8 cycles; cycle = 21 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | PFS is defined as time from first dose of study treatment to progression or death due to any cause, based on modified European Society for Bone and Marrow Transplantation (EBMT) criteria per Investigator's assessment | duration of study up to approx. 4 years | 
| Overall Response Rate (ORR) | ORR is defined as the proportion of participants with CR, nCR or partial response (PR) based on modified EBMT criteria per investigator assessment | 24 weeks (8 cycles; cycle = 21 days) | 
| Overall Survival (OS) | OS is defined as time from first dose of study treatment to death | up to 30 days after end of study, approx. 4 years | 
| Minimal Response Rate (MRR) Per Investigator | MRR is based on modified EBMT criteria per investigator assessment | after 24 weeks (8 cycles; cycle = 21 days) | 
| Time to Response (TTR) Per Investigator | TTR is defined as the time from the date of first dose of study treatment to first documented response (PR or nCR or CR) per modified EBMT criteria as assessed by investigator | duration of study up to approx. 4 years | 
| Time to Progression/Relapse (TTP) Per Investigator | TTP is defined as the time from the date of the first dose of study treatment to the date of the first documented disease progression or relapse | duration of study up to approx. 4 years | 
| Duration of Response (DOR) Per Investigator | DOR is defined as the time from date of the first documented CR/nCR or PR to the date of the first documented progression or relapse or death due to MM | duration of study up to approx. 4 years | 
| Quality of Life (QoL) as Measured by FACT/GOG-Ntx Total Score | QoL as measured by Functional Assessment of Cancer Therapy/ Gynecology Oncology Group Neurotoxicity (FACT/GOG-NTX) scale calculated scores and changes from baseline were summarized by visit. The FACT/GOG-Ntx is a measure to assess neurotoxicity from systemic chemotherapy. The recall period for this measure is the past 7 days. FACT/GOG-Ntx Total Score: 0 - 152 (28 + 28 + 24 + 28 + 44 = 152). (FACT-G Physical Well-Being Score: 0 - 28, FACT-G Social/Family Well-Being Score: 0 - 28, FACT-G Emotional Well-Being Score: 0 - 24, FACT-G Functional Well-Being Score: 0 - 28, FACT/GOG-Ntx Neurotoxicity Subscale Score: 0 - 44). 4. The scales are combined. The higher the score, the better the QOL. | Baseline, Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, and 156 | 
| Composite PharmacoKinetics (PK) of Panobinostat and Bortezomib: AUClast, AUC0-24h, AUC0-48h, AUCinf | PK sample collection was performed in subjects who agreed to blood samplings for the PK assessments of PAN and BTZ. The order of administration of the 3 study treatment components was 1) PAN, 2) Dex, and 3) BTZ. | Predose, 0.5h, 1h, 2h, 3h, 4h 8h, 24h, 48h post dose | 
| Composite PharmacoKinetics (PK) of Panobinostat and Bortezomib: Cmax | Cmax: The maximum (peak) observed plasma concentration. PK sample collection was performed in subjects who agreed to blood samplings for the PK assessments of PAN and BTZ. The order of administration of the 3 study treatment components was 1) PAN, 2) Dex, and 3) BTZ. | Predose, 0.5h, 1h, 2h, 3h, 4h 8h, 24h, 48h post dose | 
| Composite PharmacoKinetics (PK) of Panobinostat and Bortezomib: Tmax | Tmax: The time to reach maximum (peak) plasma concentration. PK sample collection was performed in subjects who agreed to blood samplings for the PK assessments of PAN and BTZ. The order of administration of the 3 study treatment components was 1) PAN, 2) Dex, and 3) BTZ. | Predose, 0.5h, 1h, 2h, 3h, 4h 8h, 24h, 48h post dose | 
| Composite PharmacoKinetics (PK) of Panobinostat and Bortezomib: T1/2 | T1/2: The elimination half-life associated with the terminal slope (Lambda_z) of a semi logarithmic concentration-time curve | Predose, 0.5h, 1h, 2h, 3h, 4h 8h, 24h 48h post dose | 
| Composite PharmacoKinetics (PK) of Panobinostat and Bortezomib: Lambda_z | Lambda_z: The terminal elimination rate constant (h-1) | Predose, 0.5h, 1h, 2h, 3h, 4h 8h, 24h 48h post dose | 
| Composite PharmacoKinetics (PK) of Panobinostat and Bortezomib: CL/F | CL/F: The apparent total body clearance of drug from the plasma | Predose, 0.5h, 1h, 2h, 3h, 4h 8h, 24h 48h post dose | 
| Composite PharmacoKinetics (PK) of Panobinostat and Bortezomib: Vz/F | Vz/F: The apparent volume of distribution during terminal phase (associated with Lambda_z) | Predose, 0.5h, 1h, 2h, 3h, 4h 8h, 24h 48h post dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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LBH589, panobinostat, bortezomib, dexamethasone, Phase II, bortezomib and dexamethasone, Japanese patients, relapsed/refractory multiple myeloma, Panobinostat (PAN)