Panobinostat in Combination With Carfilzomib and Dexamethasone in Relapsed or Relapsed and Refractory Multiple Myeloma

Study Overview
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Brief Summary
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The purpose of this study is to investigate the anti-myeloma effect of panobinostat given at two different doses (10 mg and 20 mg oral) in combination with carfilzomib (20/56 mg/m2 i.v.) and low dose dexamethasone (20 mg oral) vs carfilzomib plus low-dose dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma. Safety and efficacy will be evaluated. Treatment will be administered in 4-week cycles until patients discontinue due to disease progression or unacceptable toxicity or for other reasons. Patients who discontinue the study treatment for reasons other than documented disease progression will be followed for disease assessments every 8 weeks until progression. All patients will be followed for survival until 3 years have passed from their entry into the study, or they have discontinued the follow up earlier.

Official Title
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A Randomized, Triple-arm, Controlled, Open-label, Multicenter Phase II Study Assessing Two Different Doses of Panobinostat in Combination With Carfilzomib and Dexamethasone in Relapsed or Relapsed and Refractory Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: panobinostat (capsules)
* Drug: carfilzomib (infusion)
* Drug: dexamethasone (tablets)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Previous diagnosis of MM based on IMWG definitions (Rajkumar, 2014) Prior treatment with 1 to 3 prior lines of therapy Relapsed or relapsed and refractory MM Measureable disease at screening based on central laboratory assessment ECOG Performance status ≤ 2 Acceptable lab values prior to starting study treatment Exclusion Criteria: Primary refractory myeloma Prior treatment with DAC inhibitors including panobinostat Prior treatment with carfilzomib Allogeneic stem cell transplant recipient with graft versus host disease (either active or requiring immunosuppression) Any concomitant anti-cancer therapy besides the study treatment (bisphosphonates are permitted only if commenced prior to the start of screening period) Intolerance to dexamethasone or contraindication to carfilzomib or dexamethasone Unresolved diarrhea ≥ CTCAE grade 2 or a 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
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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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: PAN (10mg) + CFZ + Dex<br>Panobinostat (PAN) 10mg orally, combined with carfilzomib (CFZ) 20/56 mg/m2 i.v. and dexamethasone (Dex) 20mg orally, in 4 week cycle | Drug: panobinostat (capsules)<br>* Panobinostat capsules, oral: 10mg, 15mg, 20mg dosing 3x a week, 1 week on / 1 week off, in a 4 week cycle (28 days). Treatment arm A: only capsules of 10mg will be used Treatment arm B: capsules of 10mg and 15mg are foreseen for dose reduction only.<br>* Other names: PAN, LBH589;Drug: carfilzomib (infusion)<br>* Carfilzomib infusion; 20 mg/m2 i.v. on C1D1 and C1D2; 56 mg/m2 i.v. on subsequent dosing days (2x a week; 3 weeks on/1 weeks off ); 4 week cycle (28 days)<br>* Other names: CFZ;Drug: dexamethasone (tablets)<br>* Dexamethasone tablets p.o. 20 mg on days of carfilzomib infusion (2x week) and on D22 and D23 of each 4 week cycle (28 days)<br>* Other names: Dex;|
| Experimental: Arm B: PAN (20mg) + CFZ + Dex<br>Panobinostat (PAN) 20mg orally, combined with carfilzomib (CFZ) 20/56 mg/m2 i.v. and dexamethasone (Dex) 20mg orally, in 4 week cycle | Drug: panobinostat (capsules)<br>* Panobinostat capsules, oral: 10mg, 15mg, 20mg dosing 3x a week, 1 week on / 1 week off, in a 4 week cycle (28 days). Treatment arm A: only capsules of 10mg will be used Treatment arm B: capsules of 10mg and 15mg are foreseen for dose reduction only.<br>* Other names: PAN, LBH589;Drug: carfilzomib (infusion)<br>* Carfilzomib infusion; 20 mg/m2 i.v. on C1D1 and C1D2; 56 mg/m2 i.v. on subsequent dosing days (2x a week; 3 weeks on/1 weeks off ); 4 week cycle (28 days)<br>* Other names: CFZ;Drug: dexamethasone (tablets)<br>* Dexamethasone tablets p.o. 20 mg on days of carfilzomib infusion (2x week) and on D22 and D23 of each 4 week cycle (28 days)<br>* Other names: Dex;|
| Active Comparator: Arm C: CFZ + Dex<br>Carfilzomib (CFZ) 20/56 mg/m2 i.v. and dexamethasone (Dex) 20mg orally, in 4 week cycle | Drug: carfilzomib (infusion)<br>* Carfilzomib infusion; 20 mg/m2 i.v. on C1D1 and C1D2; 56 mg/m2 i.v. on subsequent dosing days (2x a week; 3 weeks on/1 weeks off ); 4 week cycle (28 days)<br>* Other names: CFZ;Drug: dexamethasone (tablets)<br>* Dexamethasone tablets p.o. 20 mg on days of carfilzomib infusion (2x week) and on D22 and D23 of each 4 week cycle (28 days)<br>* Other names: Dex;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate (ORR) using investigator's response assessment | The primary endpoint if Overall Response Rate (ORR) using investigator response assessment according to IMWG criteria. The analysis of ORR will be performed after all randomized patients have completed 6 months of study treatment or discontinued treatment earlier. | All patients treated for 6 cycles (cycle=28 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Very Good Partial Response (VGPR) or better as best response using investigator response assessment based on International Myeloma Working Group (IMWG) criteria | Investigators' response assessment assessed on IMWG criteria will be used. The VGPR or better rate is defined as the proportion of patients with a confirmed VGPR or better response as their best overall response. | All patients treated for 6 cycles (cycle=28 days) | 
| Progression-free survival (PFS) using investigator's response assessment based on IMWG criteria | PFS is defined as the time from date of randomization to date of first documented disease progression or death (regardless of cause of death). | All patients treated for 6 cycles (cycle=28 days) | 
| Overall survival (OS) | OS is defined as the time from date of randomization to the date of death due to any cause. If a patient is not known to have died, survival will be censored at the date of last contact. | All patients treated for 6 cycles (cycle=28 days) | 
| Time to response (TTR) using investigator's response assessment based on IMWG criteria | TTR is the time between date of randomization to the date of first onset of partial response (PR) or better response. | All patients treated for 6 cycles (cycle=28 days) | 
| Duration of Response (DOR) using investigator's response assessment based on IMWG criteria | DOR is defined as the duration from the first documented onset of PR or better response the date of first documented disease progression or death due to multiple myeloma. DOR will use only the patients with PR or better as their best response. | All patients treated for 6 cycles (cycle = 28 days) | 
| Time to progression (TTP) using investigator's response assessment based on IMWG criteria | TTP is defined as the time from the date of randomization to the ate of the first documented disease progression or death due to multiple myeloma. | All patients treated for 6 cycles (cycle = 28 days) | 
| Time to reach Cmax for panobinostat (PAN) and carfilzomib (CFZ) | The maximum (peak) observed plasma concentration after single and multiple dose administration (ng/mL) of PAN and CFZ. | All patients treated for 6 cycles (cycle=28 days); | 
| Minimum observed plasma concentration (Cmin) for carfilzomib | The minimum (trough) observed plasma concentration after single and multiple dose administration (ng/mL) of PAN and CFZ. | All patients treated for 6 cycles (cycle=28 days) | 
| Concentration of panobinostat in blood plasma in 48 hrs after the dose. | The area under the concentration-time curve (AUC) from time zero to 48 hours (ng*h/mL) after the dose of PAN | All patients treated for 6 cycles (cycle = 28 days) | 
| Total carfilzomib exposure over time in blood plasma . | The AUC from time zero to infinity (ng*h/mL) for CFZ. | All patients treated for 6 cycles (cycle=28 days) | 
| Health related quality of life (HRQoL) change over time measured by EORTC questionnaire QLQ-C30 and QLQ-MY20 for disease symptoms | HRQoL questionnaires are patient reported outcomes, which provide functional assessment of cancer therapy. | All patients treated for 6 cycles (cycle=28 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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multiple myeloma, MM, relapsed, relapsed and refractory, panobinostat, LBH589, histone deacetylase inhibitor, carfilzomib, proteasome inhibitor