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Panobinostat in Combination With Carfilzomib and Dexamethasone in Relapsed or Relapsed and Refractory Multiple Myeloma (PANORAMA-5)

Primary Purpose

Multiple Myeloma

Status

Withdrawn

Phase

Phase 2

Locations

Study Type

Interventional

Intervention

panobinostat (capsules)

carfilzomib (infusion)

dexamethasone (tablets)

About this trial

This is an interventional treatment trial for Multiple Myeloma focused on measuring multiple myeloma, MM, relapsed, relapsed and refractory, panobinostat, LBH589, histone deacetylase inhibitor, carfilzomib, proteasome inhibitor

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Active Comparator

Arm Label

Arm A: PAN (10mg) + CFZ + Dex

Arm B: PAN (20mg) + CFZ + Dex

Arm C: CFZ + Dex

Arm Description

Panobinostat (PAN) 10mg orally, combined with carfilzomib (CFZ) 20/56 mg/m2 i.v. and dexamethasone (Dex) 20mg orally, in 4 week cycle

Panobinostat (PAN) 20mg orally, combined with carfilzomib (CFZ) 20/56 mg/m2 i.v. and dexamethasone (Dex) 20mg orally, in 4 week cycle

Carfilzomib (CFZ) 20/56 mg/m2 i.v. and dexamethasone (Dex) 20mg orally, in 4 week cycle

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

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).

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.

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.

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.

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.

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.

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.

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

Total carfilzomib exposure over time in blood plasma .

The AUC from time zero to infinity (ng*h/mL) for CFZ.

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.

Full Information

NCT ID

NCT02756663

First Posted

April 12, 2016

Last Updated

November 7, 2016

Sponsor

Novartis Pharmaceuticals

1. Study Identification

Unique Protocol Identification Number

NCT02756663

Brief Title

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

Acronym

PANORAMA-5

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

November 2016

Overall Recruitment Status

Withdrawn

Study Start Date

December 2016 (undefined)

Primary Completion Date

February 2021 (Anticipated)

Study Completion Date

February 2021 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Novartis Pharmaceuticals

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Multiple Myeloma

Keywords

multiple myeloma, MM, relapsed, relapsed and refractory, panobinostat, LBH589, histone deacetylase inhibitor, carfilzomib, proteasome inhibitor

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

0 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Arm A: PAN (10mg) + CFZ + Dex

Arm Type

Experimental

Arm Description

Panobinostat (PAN) 10mg orally, combined with carfilzomib (CFZ) 20/56 mg/m2 i.v. and dexamethasone (Dex) 20mg orally, in 4 week cycle

Arm Title

Arm B: PAN (20mg) + CFZ + Dex

Arm Type

Experimental

Arm Description

Panobinostat (PAN) 20mg orally, combined with carfilzomib (CFZ) 20/56 mg/m2 i.v. and dexamethasone (Dex) 20mg orally, in 4 week cycle

Arm Title

Arm C: CFZ + Dex

Arm Type

Active Comparator

Arm Description

Carfilzomib (CFZ) 20/56 mg/m2 i.v. and dexamethasone (Dex) 20mg orally, in 4 week cycle

Intervention Type

Drug

Intervention Name(s)

panobinostat (capsules)

Other Intervention Name(s)

PAN, LBH589

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

carfilzomib (infusion)

Other Intervention Name(s)

CFZ

Intervention Description

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)

Intervention Type

Drug

Intervention Name(s)

dexamethasone (tablets)

Other Intervention Name(s)

Dex

Intervention Description

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)

Primary Outcome Measure Information:

Title

Overall response rate (ORR) using investigator's response assessment

Description

Time Frame

All patients treated for 6 cycles (cycle=28 days)

Secondary Outcome Measure Information:

Title

Very Good Partial Response (VGPR) or better as best response using investigator response assessment based on International Myeloma Working Group (IMWG) criteria

Description

Time Frame

All patients treated for 6 cycles (cycle=28 days)

Title

Progression-free survival (PFS) using investigator's response assessment based on IMWG criteria

Description

PFS is defined as the time from date of randomization to date of first documented disease progression or death (regardless of cause of death).

Time Frame

All patients treated for 6 cycles (cycle=28 days)

Title

Overall survival (OS)

Description

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.

Time Frame

All patients treated for 6 cycles (cycle=28 days)

Title

Time to response (TTR) using investigator's response assessment based on IMWG criteria

Description

TTR is the time between date of randomization to the date of first onset of partial response (PR) or better response.

Time Frame

All patients treated for 6 cycles (cycle=28 days)

Title

Duration of Response (DOR) using investigator's response assessment based on IMWG criteria

Description

Time Frame

All patients treated for 6 cycles (cycle = 28 days)

Title

Time to progression (TTP) using investigator's response assessment based on IMWG criteria

Description

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.

Time Frame

All patients treated for 6 cycles (cycle = 28 days)

Title

Time to reach Cmax for panobinostat (PAN) and carfilzomib (CFZ)

Description

The maximum (peak) observed plasma concentration after single and multiple dose administration (ng/mL) of PAN and CFZ.

Time Frame

All patients treated for 6 cycles (cycle=28 days);

Title

Minimum observed plasma concentration (Cmin) for carfilzomib

Description

The minimum (trough) observed plasma concentration after single and multiple dose administration (ng/mL) of PAN and CFZ.

Time Frame

All patients treated for 6 cycles (cycle=28 days)

Title

Concentration of panobinostat in blood plasma in 48 hrs after the dose.

Description

The area under the concentration-time curve (AUC) from time zero to 48 hours (ng*h/mL) after the dose of PAN

Time Frame

All patients treated for 6 cycles (cycle = 28 days)

Title

Total carfilzomib exposure over time in blood plasma .

Description

The AUC from time zero to infinity (ng*h/mL) for CFZ.

Time Frame

All patients treated for 6 cycles (cycle=28 days)

Title

Health related quality of life (HRQoL) change over time measured by EORTC questionnaire QLQ-C30 and QLQ-MY20 for disease symptoms

Description

HRQoL questionnaires are patient reported outcomes, which provide functional assessment of cancer therapy.

Time Frame

All patients treated for 6 cycles (cycle=28 days)

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Novartis Pharmaceuticals

Organizational Affiliation

Novartis Pharmaceuticals

Official's Role

Study Director

12. IPD Sharing Statement

Learn more about this trial

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

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