Panobinostat or Placebo With Bortezomib and Dexamethasone in Patients With Relapsed Multiple Myeloma

Study Overview
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Brief Summary
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Panobinostat (LBH589) is a highly potent pan-deacetylase inhibitor (pan-DACi), inclusive of HDAC6, which disrupts aggresome function, promotes accumulation of cytotoxic misfolded protein aggregates and triggers myeloma cell death. Combination of pan-DAC and protease inhibition by co-treatment with panobinostat (PAN) and bortezomib (BTZ) has demonstrated synergistic cytotoxicity in vitro and in vivo in pre-clinical experiments. Furthermore, clinical experience in advanced multiple myeloma (MM) patients treated by oral panobinostat and i.v bortezomib ± dexamethasone showed very encouraging results for efficacy and manageable toxicity profile. Given the medical need for improved treatment strategies for patients with previously treated and relapsed MM, the purpose of this prospective, multinational, randomized, double-blind, placebo-controlled, parallel group Phase III study is to compare the results in progression-free survival of 2 combination therapies, panobinostat with bortezomib and dexamethasone or placebo with bortezomib and dexamethasone, in patients with previously treated MM whose disease has recurred or progressed.

Official Title
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A Multicenter, Randomized, Double Blind, Placebo Controlled Phase III Study of Panobinostat in Combination With Bortezomib and Dexamethasone in Patients With Relapsed Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Panobinostat
* Drug: Bortezomib
* Drug: Dexamethasone
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient has a previous diagnosis of multiple myeloma. Patient requires retreatment for multiple myeloma Patient has measurable M component in serum or urine at study screening Exclusion Criteria: Patient who has progressed under all prior lines of anti MM therapy Patient who has 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 has shown intolerance to bortezomib or to dexamethasone or components of these drugs or has any contraindication to one or the other drug , following locally applicable prescribing information Patient received prior treatment with DAC inhibitors including panobinostat Patient has impaired cardiac function, or a prolonged QTc interval at screening ECG Patient taking medications with relative risk of prolonging the QT interval or inducing Torsade de pointes Female patient who is pregnant or breast feeding or with childbearing potential and not willing to use a double method of contraception up to 3 months after the end of study treatment. Male patient who is not willing to use a barrier method of contraception up to 3 months after the end of study treatment. Other protocol-defined inclusion/exclusion criteria may apply.

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Panobinostat + Bortezomib + Dexamethasone<br> | Drug: Panobinostat<br>* Panobinostat was administered 3x week ( 2 weeks on 1 week off)<br>* Other names: LBH589;Drug: Bortezomib<br>* Bortezomib was administered 2 x week ( 2weeks on 1 week off)<br>* Other names: (Velcade®);Drug: Dexamethasone<br>* Dexamethasone was adminstered on day of Bortezomib and the day after Bortezomib administration<br>|
| Placebo Comparator: Placebo + Bortezomib + Dexamethasone<br> | Drug: Bortezomib<br>* Bortezomib was administered 2 x week ( 2weeks on 1 week off)<br>* Other names: (Velcade®);Drug: Dexamethasone<br>* Dexamethasone was adminstered on day of Bortezomib and the day after Bortezomib administration<br>Drug: Placebo<br>* Placebo was administered 3x week ( 2 weeks on 1 week off)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival Events in Patients Treated With Panobinostat in Combination With Bortezomib and Dexamethasone vs. Patients Treated by Placebo in Combination With Bortezomib and Dexamethasone. |  | 45 months | 
| Progression Free Survival in Patients Treated With Panobinostat in Combination With Bortezomib and Dexamethasone vs. Patients Treated by Placebo in Combination With Bortezomib and Dexamethasone. |  | 45 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival in Patients Treated With Panobinostat in Combination With Bortezomib and Dexamethasone vs. Patients Treated by Placebo in Combination With Bortezomib and Dexamethasone | Number of OS events | 45 months | 
| Overall Survival in Patients Treated With Panobinostat in Combination With Bortezomib and Dexamethasone vs. Patients Treated by Placebo in Combination With Bortezomib and Dexamethasone | survival time in months | 45 months | 
| Overall Response Rate in Patients Treated With Panobinostat in Combination With Bortezomib and Dexamethasone vs. Patients Treated by Placebo in Combination With Bortezomib and Dexamethasone. | Best overall response based on mEBMT criteria per investigator assessment | 45 months | 
| Time to Response Per Investigator Assessment (mEBMT Criteria) of Response Patients Treated With Panobinostat in Combination With Bortezomib and Dexamethasone vs. Patients Treated by Placebo in Combination With Bortezomib and Dexamethasone. |  | 45 months | 
| Duration of Response Per Investigator Assessment (mEBMT Criteria) Patients Treated With Panobinostat in Combination With Bortezomib and Dexamethasone vs. Patients Treated by Placebo in Combination With Bortezomib and Dexamethasone. |  | 45 months | 
| Time to Progression/Relapse Per Investigator Assessment (mEBMT Criteria) Patients Treated With Panobinostat in Combination With Bortezomib and Dexamethasone vs. Patients Treated by Placebo in Combination With Bortezomib and Dexamethasone. |  | 45 months | 
| European Organization for Research and Treatment of Cancer Multiple Myeloma Module (EORTC) QLQ-MY20-Change From Baseline by Treatment Group | Higher values in the disease symptoms and side effects of treatment scores indicate worsening. Higher scores in the future perspective and body image scores indicate improvement. LS Means and SEM are estimated from the repeated measures model. Following factors and covariates are included in the repeated measurement model: time, treatment, treatment by time interaction, number of prior lines of anti-MM therapy (1/ 2 and 3), prior use of BTZ (Yes/ No), baseline score.Disease Symptom is the sum of 20 questions, total score ranges from 0 (best possible outcome) to 100 (worst possible outcome), All subscales of EORTC QLQ-MY20 have the same score range of 0 -100. Decrease in symptom scores from baseline indicate improvement in symptoms. | 12, 24 and 48 weeks | 
| European Organization for Research and Treatment of Cancer Multiple Myeloma Module (EORTC ) QLQ-C30 - Summary Statistics by Treatment Group | The EORTC QLQ-C30 measures functional dimensions (physical, role, emotional, cognitive, and social), three multi-item symptom scales (fatigue, nausea/vomiting, and pain), six single-item symptom scales (dyspnea, sleep disturbance, appetite loss, constipation, diarrhea and financial impact) and a global health status/QoL scale. Disease Symptom is the sum of 30 questions, total score ranges from 0 (best possible outcome) to 100 (worst possible outcome), All subscales of EORTC QLQ-C30 have the same score range of 0 -100. For global health status and other functional scales,an increase from baseline indicates improvement of QoL. Whereas for symptoms scales, fatigue, dyspnea, insomnia, appetite loss, constipation and diarrhea, decrease in scores from baseline indicate improvement in symptoms. | 12, 24 and 48 weeks | 
| Functional Assessment of Chronic Illness Therapy (FACIT) Measurement System : FACT/GOG-NTX-Change From Baseline by Treatment Group | Chronic Illness Therapy (FACIT) Measurement System and focuses on four general quality of life domains for physical well being, functional well-being, social/family well-being, and emotional well-being, and includes additional items to characterize treatment-related neurotoxicity. Higher subscales/total scores represent higher QOL. In the case of the neurotoxicity subscale, lower scores correspond to higher neurotoxicity. The recall period referenced in the questionnaire is the past 7 days.Ranges for FACT-G subscales are as follows:.PWB, scale 0 -28, , NtxS scale 0-44, FACT/GOG-Ntx trial outcome index scale is 0-100 and FACT-G scale is also scaled 0-100. An increase from baseline in these scores indicate improvement. | 12, 24 and 48 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Myeloma, DACi, Bortezomib, Combination, Panobinostat, LBH589D, relapsed, Velcade®, Combination,