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

Phase 3

Completed

Conditions: Multiple Myeloma

Interventions: Drug: Panobinostat
Drug: Bortezomib
Drug: Placebo
Drug: Dexamethasone

Registration Number: NCT01023308

Lead Sponsor: Novartis Pharmaceuticals

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 767

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo + Bortezomib + Dexamethasone	Placebo	-
Panobinostat + Bortezomib + Dexamethasone	Panobinostat	-
Panobinostat + Bortezomib + Dexamethasone	Bortezomib	-
Panobinostat + Bortezomib + Dexamethasone	Dexamethasone	-
Placebo + Bortezomib + Dexamethasone	Bortezomib	-
Placebo + Bortezomib + Dexamethasone	Dexamethasone	-

Primary Outcome Measures

Name	Time	Method
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
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

Secondary Outcome Measures

Name	Time	Method
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
Overall 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	survival time in 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.	45 months	Best overall response based on mEBMT criteria per investigator assessment
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-C30 - Summary Statistics by Treatment Group	12, 24 and 48 weeks	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.
European Organization for Research and Treatment of Cancer Multiple Myeloma Module (EORTC) QLQ-MY20-Change From Baseline by Treatment Group	12, 24 and 48 weeks	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.
Functional Assessment of Chronic Illness Therapy (FACIT) Measurement System : FACT/GOG-NTX-Change From Baseline by Treatment Group	12, 24 and 48 weeks	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.