Panobinostat/Bortezomib/Dexamethasone in Relapsed or Relapsed-and-refractory Multiple Myeloma (PANORAMA_3)

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

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 3 different regimens of panobinostat (20 milligrams [mg] thrice a week [TIW], 20 mg twice a week [BIW], and 10 mg TIW) in combination with subcutaneous bortezomib and dexamethasone and to provide exposure, safety and efficacy data to identify the optimal regimen of panobinostat in a randomized, 3-arm parallel design. This study will also assess the impact of administering subcutaneous bortezomib (in combination with panobinostat and dexamethasone) twice weekly for 4 cycles, and then weekly starting from Cycle 5 until disease progression in participants ≤ 75 years of age. Participants > 75 years of age will receive subcutaneous bortezomib weekly for the entire treatment period (in combination with panobinostat and dexamethasone) until disease progression.

Participants will be treated until disease progression or until they discontinue earlier due to unacceptable toxicity or for other reasons.

Participants who discontinued study treatment for reasons other than disease progression will be followed for efficacy every 6 weeks.

All participants will be followed for survival until the last participant entering long-term follow-up has completed a 3-year survival follow-up or discontinued earlier.

Study Overview

• Status: Completed
• Conditions: Multiple Myeloma
• Intervention / Treatment: Drug: Panobinostat Capsules; Drug: Bortezomib Injection; Drug: Dexamethasone tablets

• Study Type: Interventional
• Enrollment (Actual): 248
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • Victoria
    • Prahran, Victoria, Australia, 3181
      • Novartis Investigative Site
• Belgium
  • Hasselt, Belgium, 3500
    • Novartis Investigative Site
• Brazil
  • Sao Paulo, Brazil, 05403-000
    • Novartis Investigative Site
  • SP
    • Sao Paulo, SP, Brazil, 04537 081
      • Novartis Investigative Site
  • Sao Paulo
    • Barretos, Sao Paulo, Brazil, 14784 400
      • Novartis Investigative Site
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 1Z2
      • Novartis Investigative Site
  • Ontario
    • Kitchener, Ontario, Canada, N2G 1G3
      • Novartis Investigative Site
• Czechia
  • Praha, Czechia, 12808
    • Novartis Investigative Site
  • Czech Republic
    • Ostrava Poruba, Czech Republic, Czechia, 708 52
      • Novartis Investigative Site
• France
  • Avignon Cedex 9, France, 84902
    • Novartis Investigative Site
  • Grenoble, France, 38043
    • Novartis Investigative Site
  • La Roche sur Yon Cedex, France, 85295
    • Novartis Investigative Site
  • Lille, France, 59037
    • Novartis Investigative Site
  • Metz, France, 57000
    • Novartis Investigative Site
  • Nantes Cedex 1, France, 44093
    • Novartis Investigative Site
  • Paris, France, 75231
    • Novartis Investigative Site
  • Pessac, France, 33604
    • Novartis Investigative Site
  • Bayonne Cedex
    • Bayonne, Bayonne Cedex, France, 64109
      • Novartis Investigative Site
• Germany
  • Bad Saarow, Germany, 15526
    • Novartis Investigative Site
  • Bayreuth, Germany, 95445
    • Novartis Investigative Site
  • Darmstadt, Germany, 64287
    • Novartis Investigative Site
  • Dresden, Germany, 01307
    • Novartis Investigative Site
  • Halle Saale, Germany, 06120
    • Novartis Investigative Site
  • Hamburg, Germany, 22763
    • Novartis Investigative Site
  • Kiel, Germany, 24105
    • Novartis Investigative Site
  • Leipzig, Germany, 04103
    • Novartis Investigative Site
• Greece
  • Athens, Greece, 115 27
    • Novartis Investigative Site
  • Athens, Greece, 115 28
    • Novartis Investigative Site
  • Patras, Greece, 265 00
    • Novartis Investigative Site
• Hungary
  • Budapest, Hungary, 1097
    • Novartis Investigative Site
  • Kaposvar, Hungary, 7400
    • Novartis Investigative Site
  • Nyiregyhaza, Hungary, 4400
    • Novartis Investigative Site
  • HUN
    • Debrecen, HUN, Hungary, 4032
      • Novartis Investigative Site
• Italy
  • RM
    • Roma, RM, Italy, 00161
      • Novartis Investigative Site
  • RN
    • Rimini, RN, Italy, 47900
      • Novartis Investigative Site
• Korea, Republic of
  • Hwasun, Korea, Republic of, 58128
    • Novartis Investigative Site
  • Seoul, Korea, Republic of, 03080
    • Novartis Investigative Site
• Lebanon
  • Beirut, Lebanon
    • Novartis Investigative Site
  • Beirut, Lebanon, 166830
    • Novartis Investigative Site
  • Sidon, Lebanon, 652
    • Novartis Investigative Site
• Netherlands
  • Amsterdam, Netherlands, 1081 HV
    • VUmc, Hematology, PK2 BR012
  • Dordrecht, Netherlands, 3318 AT
    • Albert Schweitzer ziekenhuis, Hematology
• Norway
  • Oslo, Norway, NO 0450
    • Novartis Investigative Site
• Poland
  • Lublin, Poland, 20 090
    • Novartis Investigative Site
  • Torun, Poland, 87 100
    • Novartis Investigative Site
  • Warszawa, Poland, 02 776
    • Novartis Investigative Site
  • Warszawa, Poland, 02 106
    • Novartis Investigative Site
  • Wroclaw, Poland, 50 367
    • Novartis Investigative Site
• Portugal
  • Braga, Portugal, 4710243
    • Novartis Investigative Site
  • Porto, Portugal, 4200-072
    • Novartis Investigative Site
• Russian Federation
  • Saint Petersburg, Russian Federation, 191024
    • Novartis Investigative Site
  • Saratov, Russian Federation, 410012
    • Novartis Investigative Site
• Spain
  • Madrid, Spain, 28041
    • Novartis Investigative Site
  • Madrid, Spain, 28006
    • Novartis Investigative Site
  • Madrid, Spain, 28040
    • Novartis Investigative Site
  • Zaragoza, Spain, 50009
    • Novartis Investigative Site
  • Andalucia
    • Malaga, Andalucia, Spain, 29010
      • Novartis Investigative Site
  • Castilla Y Leon
    • Salamanca, Castilla Y Leon, Spain, 37007
      • Novartis Investigative Site
  • Catalunya
    • Barcelona, Catalunya, Spain, 08035
      • Novartis Investigative Site
    • Barcelona, Catalunya, Spain, 08036
      • Novartis Investigative Site
    • L'Hospitalet De Llobregat, Catalunya, Spain, 08907
      • Novartis Investigative Site
  • Santa Cruz De Tenerife
    • La Laguna, Santa Cruz De Tenerife, Spain, 38320
      • Novartis Investigative Site
• Sweden
  • Lulea, Sweden, SE 971 80
    • Novartis Investigative Site
  • Lund, Sweden, SE-221 85
    • Novartis Investigative Site
  • Uppsala, Sweden, SE-751 85
    • Novartis Investigative Site
• Thailand
  • Bangkok, Thailand, 10330
    • Novartis Investigative Site
  • Chiang Mai, Thailand, 50200
    • Novartis Investigative Site
  • Muang
    • Mueang Nonthaburi, Muang, Thailand, 40002
      • Novartis Investigative Site
• Turkey
  • Ankara, Turkey, 06100
    • Novartis Investigative Site
  • Istanbul, Turkey, 34899
    • Novartis Investigative Site
  • Izmir, Turkey, 35340
    • Novartis Investigative Site
• United States
  • Arkansas
    • Fayetteville, Arkansas, United States, 72703
      • Novartis Investigative Site
  • California
    • Los Angeles, California, United States, 90017
      • Novartis Investigative Site
  • Colorado
    • Fort Collins, Colorado, United States, 80528
      • Novartis Investigative Site
  • Florida
    • Gainesville, Florida, United States, 32608
      • Novartis Investigative Site
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Novartis Investigative Site
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • Novartis Investigative Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Novartis Investigative Site
  • New York
    • Lake Success, New York, United States, 11042
      • Novartis Investigative Site
  • West Virginia
    • Morgantown, West Virginia, United States, 26506
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• multiple myeloma per International Myeloma Working Group 2014 definition
• requiring treatment for relapsed or relapsed/refractory disease
• measurable disease based on central protein assessment
• received 1 to 4 prior lines of therapy
• prior immunomodulatory agent(s) exposure
• acceptable lab values prior to randomization

Exclusion Criteria:

• primary refractory myeloma
• refractory to bortezomib
• concomitant anti-cancer therapy (other than bortezomib/dexamethasone and bisphosphonates)
• prior treatment with pan-deacetylase inhibitors
• clinically significant, uncontrolled heart disease and/or recent cardiac event (within 6 months prior to randomization)
• unresolved diarrhea ≥ Common Terminology Criteria for adverse events grade 2 or presence of medical condition associated with chronic diarrhea (such as irritable bowel syndrome and inflammatory bowel disease)

Other protocol-defined inclusion/exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A - 20 mg Panobinostat TIW; 20 mg panobinostat TIW, 2 weeks on/1 week off in combination with subcutaneous bortezomib and per oral dexamethasone	Drug: Panobinostat Capsules; 20 mg, 10 mg or 15 mg (for dose reductions only); Other Names: Farydak; LBH589; PAN; Drug: Bortezomib Injection; 1.3 mg/square meter subcutaneous administration. Cycle 1-4: 2 weeks on/1 week off, BIW for participants ≤ 75 years at time of screening; once a week for participants > 75 years. Cycle 5+: once a week for all participants.; Other Names: Velcade; BTZ; Drug: Dexamethasone tablets; Pre and 24 hours after bortezomib administration. Participants ≤ 75 years at time of screening: 20 mg/dose participants; > 75 years: 10 mg/dose.; Other Names: Decadron; Dex
Experimental: Arm B - 20 mg Panobinostat BIW; 20 mg panobinostat BIW, 2 weeks on/1 week off in combination with subcutaneous bortezomib and per oral dexamethasone	Drug: Panobinostat Capsules; 20 mg, 10 mg or 15 mg (for dose reductions only); Other Names: Farydak; LBH589; PAN; Drug: Bortezomib Injection; 1.3 mg/square meter subcutaneous administration. Cycle 1-4: 2 weeks on/1 week off, BIW for participants ≤ 75 years at time of screening; once a week for participants > 75 years. Cycle 5+: once a week for all participants.; Other Names: Velcade; BTZ; Drug: Dexamethasone tablets; Pre and 24 hours after bortezomib administration. Participants ≤ 75 years at time of screening: 20 mg/dose participants; > 75 years: 10 mg/dose.; Other Names: Decadron; Dex
Experimental: Arm C - 10 mg Panobinostat TIW; 10 mg panobinostat TIW, 2 weeks on/1 week off in combination with subcutaneous bortezomib and per oral dexamethasone	Drug: Panobinostat Capsules; 20 mg, 10 mg or 15 mg (for dose reductions only); Other Names: Farydak; LBH589; PAN; Drug: Bortezomib Injection; 1.3 mg/square meter subcutaneous administration. Cycle 1-4: 2 weeks on/1 week off, BIW for participants ≤ 75 years at time of screening; once a week for participants > 75 years. Cycle 5+: once a week for all participants.; Other Names: Velcade; BTZ; Drug: Dexamethasone tablets; Pre and 24 hours after bortezomib administration. Participants ≤ 75 years at time of screening: 20 mg/dose participants; > 75 years: 10 mg/dose.; Other Names: Decadron; Dex

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate (ORR)	ORR is defined as the percentage of participants with a confirmed partial response (PR) or better (immunophenotypic complete response [iCR] or stringent complete response [sCR] or complete response [CR] or very good partial response [VGPR]) as their best overall response after completion of up to 8 cycles of assigned study regimen. Each cycle was 21 days long. Best overall response was the best post-baseline confirmed overall response observed in a given participant and was determined based on overall responses observed at all post-baseline response assessments, recorded from randomization until progressive disease (PD), death, start of new therapy, withdrawal of consent, or end of study, whatever came first. ORR was assessed blindly per independent review committee (IRC) according to International Myeloma Working Group (IMWG) criteria.	Up to 168 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ORR Throughout the Study	ORR is defined as the percentage of participants with a confirmed PR or better (iCR or sCR or CR or VGPR) as their best overall response throughout the entire study. Best overall response was the best post-baseline confirmed overall response observed in a given participant and was determined based on overall responses observed at all post-baseline response assessments, recorded from randomization until PD, death, start of new therapy, withdrawal of consent or end of study, whatever came first. ORR was assessed blindly per IRC according to IMWG criteria.	Up to 5.2 years
iCR Rate	iCR, based on IMWG criteria per blinded IRC assessment, is defined as: negative immunofixation of serum and urine; disappearance of any soft tissue plasmacytoma(s), in the case of any presence of soft tissue plasmacytoma(s) at baseline; less than 5% plasma cells in bone marrow; normal free light chain (FLC) ratio; absence of clonal plasma cells in bone marrow analyzed by immunohistochemistry or 2- to 4-color flow cytometry; absence of phenotypically aberrant plasma cells (clonal) in bone marrow (BM) with a minimum of 1 million total BM cells analyzed by multiparametric flow cytometry (>4 colors). Results reported as percentage of participants achieving iCR.	Up to 5.2 years
sCR Rate	sCR, based on IMWG criteria per blinded IRC assessment, is defined as: negative immunofixation of serum and urine; disappearance of any soft tissue plasmacytoma(s), in the case of any presence of soft tissue plasmacytoma(s) at baseline; less than 5% plasma cells in bone marrow; normal FLC ratio; absence of clonal plasma cells in bone marrow analyzed by immunohistochemistry or 2- to 4-color flow cytometry. Results reported as percentage of participants achieving sCR.	Up to 5.2 years
CR Rate	CR, based on IMWG criteria per blinded IRC assessment, is defined as: negative immunofixation of serum and urine; disappearance of any soft tissue plasmacytoma(s), in the case of any presence of soft tissue plasmacytoma(s) at baseline; less than 5% plasma cells in bone marrow; in case the only measurable disease at baseline is the serum FLC assessment, a normal FLC ratio of 0.26 to 1.65 is required additionally to qualify for CR. Results reported as percentage of participants achieving CR.	Up to 5.2 years
VGPR Rate	VGPR, based on IMWG criteria per blinded IRC assessment, is defined as: serum and/or urine M protein detectable by immunofixation but not on protein electrophoresis, or ≥90% reduction from baseline in serum) and urine M protein <100 milligrams/24 hours); in the case of the presence of any soft tissue plasmacytoma(s) at baseline, a reduction in the sum of the products of the cross-diameters by ≥50% from baseline is required; in case the only measurable disease in a participant at baseline is the serum FLC level (that is, no measurable disease in serum and urine PEP), a decrease of >90% in the difference between involved and uninvolved FLC levels from baseline is required. Results reported as percentage of participants achieving VGPR.	Up to 5.2 years
Progression-free Survival (PFS)	PFS, assessed based on IMWG criteria per blind IRC assessment, is defined as the time from date of randomization to date of first documented disease progression or death (regardless of cause of death).	Up to 5.2 years
Overall Survival (OS)	OS is defined as the time from date of randomization to the date of death due to any cause.	Up to 5.2 years
Maximum Plasma Concentration (Cmax): Panobinostat	Serial blood samples were collected for panobinostat Cmax analysis. Results are reported in nanograms/milliliter (ng/mL).	Cycle 1 Day 1 (Pre-dose, up to 8 hours post dose)
Cmax: Bortezomib	Serial blood samples were collected for bortezomib Cmax analysis. Results are reported in ng/mL.	Cycle 1 Day 1 (Pre-dose, up to 8 hours post dose)
Time to Reach Cmax (Tmax): Panobinostat	Serial blood samples were collected for panobinostat Tmax analysis. Results are reported in hours.	Cycle 1 Day 1 (Pre-dose, up to 8 hours post dose)
Tmax: Bortezomib	Serial blood samples were collected for bortezomib Tmax analysis. Results are reported in hours.	Cycle 1 Day 1 (Pre-dose, up to 8 hours post dose)
Exposure Response: Cmax for Panobinostat	The exposure-response relationship was assessed utilizing Cmax (Cycle 1 Day 1) for panobinostat versus the outcomes of ORR, grade 3/4 thrombocytopenia, and grade 3/4 diarrhea. Two statistical models were used: logistic regression models, in which these 3 outcomes were treated in a binary fashion according to their occurrence; Cox regression models, with the relevant outcomes being the time to occurrence of grade 3/4 thrombocytopenia and the time to occurrence of grade 3/4 diarrhea. Results are reported as model-based probability. An increase in the model-based probability indicates an increase in the occurrence of the outcomes (ORR, grade 3/4 thrombocytopenia, 3/4 diarrhea) with increasing values of Cmax (that is, with increasing dose of panobinostat).	Up to 5.2 Years
Change From Baseline in European Organization of Research and Treatment of Cancer (EORTC) Quality of Life Core 30-item Questionnaire (QLQ-C30) Global Health Status (GHS) Score	Health-related quality of life (HRQoL) was assessed by the EORTC QLQ-C30, which is frequently employed in clinical oncology trials and is recognized as reliable and valid. The EORTC QLQ-C30 measures functional dimensions (physical, role, emotional, cognitive, and social), 3 symptom items (fatigue, nausea/vomiting, and pain), 6 single items (dyspnea, sleep disturbance, appetite loss, constipation, diarrhea and financial impact), and a global health scale (GHS) and quality-of-life scale. For each domain and item, a linear transformation is applied to standardize the score between 0 and 100. Results are presented specifically for the GHS score. A higher GHS score indicates a higher HRQoL. Each cycle was 21 days long.	Cycle 15 Day 1, at approximately 295 days
Change From Baseline in the Functional Assessment of Cancer Therapy (FACT)/Gynecologic Oncology Group-Neurotoxicity (GOG-Ntx) Neurotoxicity Subscale Score	HRQoL was assessed by the FACT/GOG-Ntx, a 38-item questionnaire designed to assess general quality of life and severity and impact of neurotoxicity from systemic chemotherapy. It is frequently employed in clinical oncology trials and is recognized as a reliable and valid measure to assess symptoms associated with neurotoxicity. It focuses on 4 general quality of life domains for physical well-being, functional well-being, social/family well-being, and emotional well-being, and includes the neurotoxicity subscale domain to characterize treatment-related neurotoxicity. Results are presented specifically for the 11-item neurotoxicity subscale, which uses a 5-point rating scale (0=not at all; 1=a little bit; 2=somewhat; 3=quite a bit; 4=very much). Each item is scored from 0-4, with the severity of neurotoxicity measured as the sum of the 11 items, ranging from 0 to 44. Lower scores indicate lower neurotoxicity and higher HRQoL. Each cycle was 21 days long.	Cycle 15 Day 1, at approximately 295 days
Time to Progression (TTP)	TTP, based on IMWG criteria per blinded IRC assessment, is defined as the time from the date of randomization to the date of the first documented disease progression or death due to multiple myeloma.	Up to 5.2 years
Time to Response (TTR)	TTR, based on IMWG criteria per blinded IRC assessment, is the time between date of randomization to the date of first onset of PR or better response (iCR or sCR or CR or VGPR).	Up to 5.2 years
Duration of Response (DOR)	DOR, based on IMWG criteria per blinded IRC assessment, is defined as the duration from the first documented onset of PR or better (iCR or sCR or CR or VGPR) to the date of first documented disease progression or death due to multiple myeloma.	Up to 5.2 years

Collaborators and Investigators

• Sponsor: pharmaand GmbH
• Investigators: Study Director: SecuraBio, SecuraBio

Publications and helpful links

General Publications

• Laubach JP, Schjesvold F, Mariz M, Dimopoulos MA, Lech-Maranda E, Spicka I, Hungria VTM, Shelekhova T, Abdo A, Jacobasch L, Polprasert C, Hajek R, Illes A, Wrobel T, Sureda A, Beksac M, Goncalves IZ, Blade J, Rajkumar SV, Chari A, Lonial S, Spencer A, Maison-Blanche P, Moreau P, San-Miguel JF, Richardson PG. Efficacy and safety of oral panobinostat plus subcutaneous bortezomib and oral dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma (PANORAMA 3): an open-label, randomised, phase 2 study. Lancet Oncol. 2021 Jan;22(1):142-154. doi: 10.1016/S1470-2045(20)30680-X. Epub 2020 Dec 7.

Study record dates

Study Major Dates

• Study Start (Actual): April 27, 2016
• Primary Completion (Actual): October 18, 2019
• Study Completion (Actual): August 15, 2022

Study Registration Dates

• First Submitted: December 16, 2015
• First Submitted That Met QC Criteria: January 11, 2016
• First Posted (Estimated): January 13, 2016

Study Record Updates

• Last Update Posted (Actual): July 12, 2024
• Last Update Submitted That Met QC Criteria: July 10, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Keywords: bortezomib; dexamethasone; multiple myeloma; LBH589; panobinostat; relapsed or relapsed/refractory
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Multiple Myeloma; Neoplasms, Plasma Cell; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Histone Deacetylase Inhibitors; Dexamethasone; Bortezomib; Panobinostat
• Other Study ID Numbers: CLBH589D2222; 2015-001564-19 (EudraCT Number)

Plan for Individual participant data (IPD)

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No