Study of Panobinostat in Combination With Bortezomib and Dexamethasone in Japanese Patients With Relapsed/Refractory Multiple Myeloma

A Phase II, Multi-center, Single Arm, Open Label Study to Evaluate the Efficacy and Safety of Panobinostat in Combination With Bortezomib and Dexamethasone in Japanese Patients With Relapsed/Refractory Multiple Myeloma

The purpose of this study was to evaluate the efficacy and safety of panobinostat in combination with bortezomib and dexamethasone in Japanese patients with relapsed/refractory multiple myeloma.

Study Overview

• Status: Completed
• Conditions: Relapse/Refractory Multiple Myeloma
• Intervention / Treatment: Drug: LBH589 (panobinostat); Drug: bortezomib; Drug: dexamethasone

• Study Type: Interventional
• Enrollment (Actual): 31
• Phase: Phase 2

Contacts and Locations

Study Locations

• Japan
  • Aomori, Japan, 030 8553
    • Novartis Investigative Site
  • Niigata, Japan, 951-8566
    • Novartis Investigative Site
  • Tokushima, Japan, 770-8503
    • Novartis Investigative Site
  • Aichi
    • Nagoya-city, Aichi, Japan, 467-8602
      • Novartis Investigative Site
  • Chiba
    • Kashiwa-city, Chiba, Japan, 277-8567
      • Novartis Investigative Site
  • Ehime
    • Matsuyama-city, Ehime, Japan, 790-8524
      • Novartis Investigative Site
  • Fukuoka
    • Fukuoka city, Fukuoka, Japan, 812-8582
      • Novartis Investigative Site
  • Gifu
    • Ogaki-city, Gifu, Japan, 503-8502
      • Novartis Investigative Site
  • Gunma
    • Maebashi city, Gunma, Japan, 371 8511
      • Novartis Investigative Site
    • Shibukawa-city, Gunma, Japan, 377-0280
      • Novartis Investigative Site
  • Hyogo
    • Kobe-city, Hyogo, Japan, 650-0047
      • Novartis Investigative Site
  • Ibaraki
    • Higashiibaraki-gun, Ibaraki, Japan, 311-3193
      • Novartis Investigative Site
  • Kyoto
    • Kyoto-city, Kyoto, Japan, 602-8566
      • Novartis Investigative Site
  • Miyagi
    • Sendai-shi, Miyagi, Japan, 983 8520
      • Novartis Investigative Site
  • Okayama
    • Okayama city, Okayama, Japan, 701-1192
      • Novartis Investigative Site
  • Osaka
    • Suita city, Osaka, Japan, 565 0871
      • Novartis Investigative Site
  • Tokyo
    • Koto ku, Tokyo, Japan, 135 8550
      • Novartis Investigative Site
    • Shibuya, Tokyo, Japan, 150-8935
      • Novartis Investigative Site
    • Shinjuku ku, Tokyo, Japan, 162 8655
      • Novartis Investigative Site
    • Tachikawa, Tokyo, Japan, 190-0014
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Patient had a previous diagnosis of multiple myeloma
• Patient required retreatment for multiple myeloma
• Patient had measurable M component in serum or urine at study screening

Exclusion Criteria:

• Primary refractory disease (patients that never reached at least an minor response for over 60 days under any prior therapy)
• Patient who had 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 received prior treatment with DAC inhibitors including panobinostat
• Patient had impaired cardiac function, or a prolonged QTc interval at screening ECG

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: LBH589 + bortezomib + dexamethasone; Participants were administered LBH589 (panobinostat)in combination with bortezomib and dexamethasone 2 weeks on/1 week off.

Drug: LBH589 (panobinostat); Panobinostat (PAN) capsules were supplied at dose strengths of 10 mg and 15 mg. and dosed at 20mg during treatment phase 1 (21 days) and treatment phase 2 (42 days); Drug: bortezomib; Bortezomib (BTZ) s.c: 1.3 mg/m2 was administered during both treatment phase 1 (21 days) & treatment phase 2 (42 days).; Drug: dexamethasone; Dexamethasone (Dex): 20mg tablets taken during both treatment phase 1 (21 days & treatment phase 2 (42 days)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Near Complete Response (nCR)/ Complete Response (CR) Rate	nCR plus CR rate after 8 cycles of therapy as defined by the modified European Society for Bone and Marrow Transplantation (EBMT) criteria per investigator assessment as the proportion of participants with nCR or CR as their best overall response.	after 24 weeks (8 cycles; cycle = 21 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS)	PFS is defined as time from first dose of study treatment to progression or death due to any cause, based on modified European Society for Bone and Marrow Transplantation (EBMT) criteria per Investigator's assessment	duration of study up to approx. 4 years
Overall Response Rate (ORR)	ORR is defined as the proportion of participants with CR, nCR or partial response (PR) based on modified EBMT criteria per investigator assessment	24 weeks (8 cycles; cycle = 21 days)
Overall Survival (OS)	OS is defined as time from first dose of study treatment to death	up to 30 days after end of study, approx. 4 years
Minimal Response Rate (MRR) Per Investigator	MRR is based on modified EBMT criteria per investigator assessment	after 24 weeks (8 cycles; cycle = 21 days)
Time to Response (TTR) Per Investigator	TTR is defined as the time from the date of first dose of study treatment to first documented response (PR or nCR or CR) per modified EBMT criteria as assessed by investigator	duration of study up to approx. 4 years
Time to Progression/Relapse (TTP) Per Investigator	TTP is defined as the time from the date of the first dose of study treatment to the date of the first documented disease progression or relapse	duration of study up to approx. 4 years
Duration of Response (DOR) Per Investigator	DOR is defined as the time from date of the first documented CR/nCR or PR to the date of the first documented progression or relapse or death due to MM	duration of study up to approx. 4 years
Quality of Life (QoL) as Measured by FACT/GOG-Ntx Total Score	QoL as measured by Functional Assessment of Cancer Therapy/ Gynecology Oncology Group Neurotoxicity (FACT/GOG-NTX) scale calculated scores and changes from baseline were summarized by visit. The FACT/GOG-Ntx is a measure to assess neurotoxicity from systemic chemotherapy. The recall period for this measure is the past 7 days. FACT/GOG-Ntx Total Score: 0 - 152 (28 + 28 + 24 + 28 + 44 = 152). (FACT-G Physical Well-Being Score: 0 - 28, FACT-G Social/Family Well-Being Score: 0 - 28, FACT-G Emotional Well-Being Score: 0 - 24, FACT-G Functional Well-Being Score: 0 - 28, FACT/GOG-Ntx Neurotoxicity Subscale Score: 0 - 44). 4. The scales are combined. The higher the score, the better the QOL.	Baseline, Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, and 156
Composite PharmacoKinetics (PK) of Panobinostat and Bortezomib: AUClast, AUC0-24h, AUC0-48h, AUCinf	PK sample collection was performed in subjects who agreed to blood samplings for the PK assessments of PAN and BTZ. The order of administration of the 3 study treatment components was 1) PAN, 2) Dex, and 3) BTZ.	Predose, 0.5h, 1h, 2h, 3h, 4h 8h, 24h, 48h post dose
Composite PharmacoKinetics (PK) of Panobinostat and Bortezomib: Cmax	Cmax: The maximum (peak) observed plasma concentration. PK sample collection was performed in subjects who agreed to blood samplings for the PK assessments of PAN and BTZ. The order of administration of the 3 study treatment components was 1) PAN, 2) Dex, and 3) BTZ.	Predose, 0.5h, 1h, 2h, 3h, 4h 8h, 24h, 48h post dose
Composite PharmacoKinetics (PK) of Panobinostat and Bortezomib: Tmax	Tmax: The time to reach maximum (peak) plasma concentration. PK sample collection was performed in subjects who agreed to blood samplings for the PK assessments of PAN and BTZ. The order of administration of the 3 study treatment components was 1) PAN, 2) Dex, and 3) BTZ.	Predose, 0.5h, 1h, 2h, 3h, 4h 8h, 24h, 48h post dose
Composite PharmacoKinetics (PK) of Panobinostat and Bortezomib: T1/2	T1/2: The elimination half-life associated with the terminal slope (Lambda_z) of a semi logarithmic concentration-time curve	Predose, 0.5h, 1h, 2h, 3h, 4h 8h, 24h 48h post dose
Composite PharmacoKinetics (PK) of Panobinostat and Bortezomib: Lambda_z	Lambda_z: The terminal elimination rate constant (h-1)	Predose, 0.5h, 1h, 2h, 3h, 4h 8h, 24h 48h post dose
Composite PharmacoKinetics (PK) of Panobinostat and Bortezomib: CL/F	CL/F: The apparent total body clearance of drug from the plasma	Predose, 0.5h, 1h, 2h, 3h, 4h 8h, 24h 48h post dose
Composite PharmacoKinetics (PK) of Panobinostat and Bortezomib: Vz/F	Vz/F: The apparent volume of distribution during terminal phase (associated with Lambda_z)	Predose, 0.5h, 1h, 2h, 3h, 4h 8h, 24h 48h post dose

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Suzuki K, Sunami K, Matsumoto M, Maki A, Shimada F, Suzuki K, Shimizu K. Phase II, Multicenter, Single-Arm, Open-Label Study to Evaluate the Efficacy and Safety of Panobinostat in Combination with Bortezomib and Dexamethasone in Japanese Patients with Relapsed or Relapsed-and-Refractory Multiple Myeloma. Acta Haematol. 2021;144(3):264-274. doi: 10.1159/000508529. Epub 2020 Dec 4.

Study record dates

Study Major Dates

• Study Start (Actual): December 16, 2014
• Primary Completion (Actual): December 29, 2017
• Study Completion (Actual): December 25, 2018

Study Registration Dates

• First Submitted: October 24, 2014
• First Submitted That Met QC Criteria: November 10, 2014
• First Posted (Estimate): November 14, 2014

Study Record Updates

• Last Update Posted (Actual): November 18, 2019
• Last Update Submitted That Met QC Criteria: October 28, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Keywords: bortezomib; dexamethasone; Phase II; Japanese patients; LBH589; panobinostat; relapsed/refractory multiple myeloma; bortezomib and dexamethasone; Panobinostat (PAN)
• 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: CLBH589D1201

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

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