Panobinostat/Bortezomib/Dexamethasone in Relapsed or Relapsed-and-refractory Multiple Myeloma

Study Overview
=================
Brief Summary
-----------------
NOTE: The study data was transferred to zr pharma& following the divestment of Panobinostat to pharma&. Prior to study completion under the sponsorship of Secura Bio, the study was initiated and conducted in part under the sponsorship of Novartis. The purpose of this study is to investigate the safety and efficacy of three different regimens of PAN (20 mg TIW, 20 mg BIW, and 10 mg TIW) in combination with s.c. BTZ and Dex and to provide exposure, safety and efficacy data to identify the optimal regimen of PAN in a randomized, 3-arm parallel design. This study will also assess the impact of administering s.c. BTZ (in combination with PAN and Dex) twice weekly for 4 cycles, and then weekly starting from Cycle 5 until disease progression in patients ≤ 75 years of age. Patients > 75 years of age will receive for the entire treatment period s.c. BTZ weekly (in combination with PAN and Dex) until disease progression. Patients will be treated until disease progression or until they discontinue earlier due to unacceptable toxicity or for other reasons. Patients who discontinued study treatment for reasons other than disease progression will be followed for efficacy every 6 weeks. All patients will be followed for survival until the last patient entering long-term follow-up has completed a 3-year survival follow-up or discontinued earlier.

Official Title
-----------------
A Multicenter, Randomized, Open-label Phase 2 Study Evaluating the Safety and Efficacy of Three Different Regimens of Oral Panobinostat in Combination With Subcutaneous Bortezomib and Oral Dexamethasone in Patients With Relapsed or Relapsed/Refractory Multiple Myeloma Who Have Been Previously Exposed to Immunomodulatory Agents

Conditions
-----------------
Multiple Myeloma

Intervention / Treatment
-----------------
* Drug: panobinostat capsules
* Drug: bortezomib injection
* Drug: dexamethasone tablets


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: multiple myeloma as per IMWG 2014 definition requiring treatment for relapsed or relapsed/refractory disease measurable disease based on central protein assessment 1 to 4 prior lines of therapy prior IMiD exposure acceptable lab values prior to randomization Exclusion Criteria: primary refractory myeloma refractory to bortezomib concomitant anti-cancer therapy (other than BTZ/Dex and bisphosphonates) prior treatment with DAC inhibitors clinically significant, uncontrolled heart disease and/or recent cardiac event (within 6 months prior to randomization) unresolved diarrhea ≥ CTCAE grade 2 or presence of medical condition associated with chronic diarrhea (such as irritable bowel syndrome, inflammatory bowel disease) Other protocol-defined inclusion/exclusion criteria may apply.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A - 20mg PAN TIW<br>20mg panobinostat three times a week, 2 weeks on/1 week of in combination with s.c. bortezomib and p.o. dexamethasone | Drug: panobinostat capsules<br>* 20mg, 10mg or 15mg (for dose reductions only)<br>* Other names: PAN, LBH589;Drug: bortezomib injection<br>* 1.3mg/m^2 sub-cutaneous administration; Cycle 1-4: 2 weeks on/1 week off twice a week for patients ≤ 75 years at time of screening; once a week for patient > 75 years Cycle 5+: once a week for all patients<br>* Other names: BTZ;Drug: dexamethasone tablets<br>* pre and 24h after BTZ administration; patients ≤ 75 years at time of screening: 20mg/dose patients > 75 years: 10mg/dose<br>* Other names: Dex;|
| Experimental: Arm B - 20mg PAN BIW<br>20mg panobinostat twice a week, 2 weeks on/1 week off in combination with s.c. bortezomib and p.o. dexamethasone | Drug: panobinostat capsules<br>* 20mg, 10mg or 15mg (for dose reductions only)<br>* Other names: PAN, LBH589;Drug: bortezomib injection<br>* 1.3mg/m^2 sub-cutaneous administration; Cycle 1-4: 2 weeks on/1 week off twice a week for patients ≤ 75 years at time of screening; once a week for patient > 75 years Cycle 5+: once a week for all patients<br>* Other names: BTZ;Drug: dexamethasone tablets<br>* pre and 24h after BTZ administration; patients ≤ 75 years at time of screening: 20mg/dose patients > 75 years: 10mg/dose<br>* Other names: Dex;|
| Experimental: Arm C - 10mg PAN TIW<br>10mg panobinostat three times a week 2 weeks on/1 week off in combination with s.c. bortezomib and p.o. dexamethasone | Drug: panobinostat capsules<br>* 20mg, 10mg or 15mg (for dose reductions only)<br>* Other names: PAN, LBH589;Drug: bortezomib injection<br>* 1.3mg/m^2 sub-cutaneous administration; Cycle 1-4: 2 weeks on/1 week off twice a week for patients ≤ 75 years at time of screening; once a week for patient > 75 years Cycle 5+: once a week for all patients<br>* Other names: BTZ;Drug: dexamethasone tablets<br>* pre and 24h after BTZ administration; patients ≤ 75 years at time of screening: 20mg/dose patients > 75 years: 10mg/dose<br>* Other names: Dex;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate (ORR) up to 8 cycles | assessed according to IMWG guidelines | up to 8 cycles per patient, approximately 30 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ORR throughout study |  | approximately 70 months | 
| individual immunophenotypic complete response (CR) rate |  | approximately 30 and 70 months | 
| Progression-free survival |  | approximately 30 and 70 months | 
| Maximum plasma concentration (Cmax) for panobinostat (PAN) and bortezomib (BTZ) |  | approximately 30 months | 
| Time to progression |  | approximately 30 and 70 months | 
| Time to response |  | approximately 30 and 70 months | 
| Duration of response (DOR) |  | approximately 30 and 70 months | 
| European Organization of Research and Treatment of Cancer Quality of Life core 30-item questionnaire scores over time compared | EORTC QLQ-C30 on-treatment and in post treatment follow-up | approximately 30 and 70 months | 
| individual stringent CR rate |  | approximately 30 and 70 months | 
| individual CR rate |  | approximately 30 and 70 months | 
| overall survival |  | approximately 30 and 70 months | 
| individual Very Good Partial Response rate |  | approximately 30 and 70 months | 
| Functional Assessment of Cancer Therapy / Gynecologic Oncology Group - Neurotoxicity scale scores over time | FACT/GOG-Ntx on-treatment | approximately 30 and 70 months | 
| Time to reach Cmax for PAN and BTZ |  | approximately 30 months | 
| Minimum observed plasma concentration (Cmin) for PAN and BTZ |  | approximately 30 months | 
| Observed plasma concentration 24 hours after single and multiple dose administration of PAN and BTZ |  | 24 hours after every dose, approximately 30 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
multiple myeloma, relapsed or relapsed/refractory, LBH589, panobinostat, bortezomib, dexamethasone