A Trial Evaluating Efficacy & Safety of RVD +/- Panobinostat in Transplant Eligible, Newly Diagnosed Multiple Myeloma (NDMM) (PANORAMA4)

A Randomized, Phase II Trial Evaluating the Efficacy and Safety of Lenalidomide, Bortezomib and Dexamethasone (RVD) With or Without Panobinostat in Transplant Eligible, Newly Diagnosed Multiple Myeloma

This was a multicenter, open-label, randomized phase II study which were to enroll 112 newly diagnosed symptomatic multiple myeloma patients in a 1:1 fashion. Patients were to enroll at approximately 20 centers in the United States.

Patients were to undergo stem cell mobilization with plerixafor plus Granulocyte Colony Stimulating Factor (G-CSF), according to investigator discretion, after 4 cycles of induction therapy. Study treatment interruption for stem cell collection were not to exceed 30 days. All patients were to receive one additional cycle of study treatment after stem cell collection and then proceed to autologous transplant using melphalan 200mg/m2(140mg/m2 for patients > 70 years), as conditioning.

After Autologus Stem Cell Transplant( ASCT), patients still on study were to initiate maintenance therapy within the 60-120 day period following ASCT, provided they have adequate blood count and clinical recovery. Patients in the RVD arm were to initiate maintenance therapy with lenalidomide alone, and patients in RVD-panobinostat arm were to receive lenalidomide + panobinostat maintenance. Lenalidomide were to be dosed orally at 10mg/day continuously in both arms, increasing to 15mg/day after the first 84 day cycle. Panobinostat were to be dosed at 10mg three times a week, every other week. Total planned duration of maintenance therapy were to be 3 years.

Patients were to remain on study treatment until they complete the maintenance phase, or until they experience disease progression, unacceptable toxicity, or at the discretion of the Investigator.

Study Overview

• Status: Terminated
• Conditions: Multiple Myeloma
• Intervention / Treatment: Drug: Revlimid; Drug: Velcade; Drug: dexamethasone; Drug: Farydak

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90095
      • David Geffen School of Medicine at UCLA UCLA
  • Florida
    • Pembroke Pines, Florida, United States, 33028
      • Memorial West Cancer Center Memorial Cancer Institute
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Northside Hospital Central Research Dept.
  • Nebraska
    • Omaha, Nebraska, United States, 68124
      • Oncology Hematology West Nebraska Cancer Specialists dbaNebraska Cancer Specialists
  • Texas
    • San Antonio, Texas, United States, 78234
      • Brooke Army Medical Center Hematology/Oncology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 74 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Key Inclusion Criteria:

• Patient newly diagnosed with multiple myeloma, based on following IMWG 2014 definition (Rajkumar et al 2014):
• Clonal bone marrow plasma cells ≥ 10% or biopsy-proven bony or extramedullary plasmacytoma and any one or more of the following myeloma defining events:
• Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder

• Any one or more of the following biomarkers of malignancy:

  1. Clonal bone marrow plasma cell percentage ≥ 60%
  2. Involved: uninvolved serum free light chain ratio ≥ 100
  3. >1 focal lesions on MRI studies
• Patient with measurable disease defined by at least 1 of the following conditions present at screening:
• Serum M-protein by Protein Electrophoresis (PEP) ≥ 1.0 g/dL (≥ 10 g/L).
• Urine M-protein by PEP ≥ 200 mg/24 hours. Involved serum free light chain level ≥ 10 mg/dL (≥ 100 mg/L), provided that the serum free light chain ratio is abnormal.
• Patient eligible for autologous stem cell transplantation based on the investigator's clinical judgment.
• Patient with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2
• Patient's age ≥ 18 and <75 years at time of signing the informed consent
• Patient provided written informed consent prior to any screening procedures
• Women of childbearing potential (WOCBP) with a negative serum pregnancy test at screening and a negative urine pregnancy test at baseline

Key Exclusion Criteria:

Patients eligible for this study must not meet any of the following criteria:

• Any concomitant anti-cancer therapy (other than bortezomib/lenalidomide/dexamethasone; bisphosphonates are permitted only if commenced prior to the start of screening period)
• Unresolved diarrhea ≥ CTCAE grade 2 or presence of medical condition associated with chronic diarrhea (such as irritable bowel syndrome, inflammatory bowel disease).
• Allogeneic stem cell transplant recipient presenting with graft versus host disease either active or requiring immunosuppression
• Patient shown intolerance to bortezomib or to dexamethasone or components of these drugs or has any contraindication to one or the other drug, following locally applicable prescribing information
• Patient with rade ≥ 2 peripheral neuropathy or grade 1 peripheral neuropathy with pain on clinical examination at screening
• Patient received prior treatment with DAC inhibitors including Panobinostat
• Patient needing valproic acid for any medical condition during the study or within 5 days prior to first administration of panobinostat/study treatment.
• Patient taking any anti-cancer therapy concomitantly (bisphosphonates are permitted only if commenced prior to the start of screening period)

• Patient who received:

  1. prior anti-myeloma chemotherapy or medication including Immunomodulator (IMiDs) and Dex ≤ 3 weeks prior to start of study.
  2. experimental therapy or biologic immunotherapy including monoclonal antibodies ≤ 4 weeks prior to start of study.
  3. prior radiation therapy ≤ 4 weeks or limited field radiotherapy ≤ 2 weeks prior start of study.
• Patient has not recovered from all therapy-related toxicities associated with above listed treatments to < grade 2 CTCAE.
• Patient undergone major surgery ≤ 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy to < grade 2 CTCAE
• Patients with evidence of mucosal or internal bleeding
• Clinically significant, uncontrolled heart disease and/or recent cardiac event (within 6 month prior to screening)
• Inability to determine the Fridericia's Correction Formula (QTc) F interval
• Patient with an impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of panobinostat (e.g. ulcerative disease, uncontrolled nausea, vomiting, malabsorption syndrome, obstruction, or stomach and/or small bowel resection)
• Sexually active males unless they use a condom during intercourse while taking the drug during treatment, and for 6 months after stopping treatment
• Pregnant or nursing (lactating) women.

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

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm 1 - RVD + Pan; Revlimid, Velcade, dexamethasone and Farydak	Drug: Revlimid; Revlimid was used with dexamethasone to treat patients with multiple myeloma; Other Names: lenalidomide; Drug: Velcade; Velcade was a proteasome inhibitor indicated for treatment of patients with multiple myeloma; Other Names: bortezomib; Drug: dexamethasone; Dexamethasone was a steroid used to treat patients with multiple myeloma.; Other Names: Decadron; Drug: Farydak; FARYDAK® (panobinostat) capsules was a prescription medicine used, in combination with bortezomib and dexamethasone, to treat adults with a type of cancer called multiple myeloma after at least 2 other types of treatment have been tried.; Other Names: panobinostat, LBH589
Active Comparator: Arm 2 - RVD; Revlimid, Velcade and Dexamethasone	Drug: Revlimid; Revlimid was used with dexamethasone to treat patients with multiple myeloma; Other Names: lenalidomide; Drug: Velcade; Velcade was a proteasome inhibitor indicated for treatment of patients with multiple myeloma; Other Names: bortezomib; Drug: dexamethasone; Dexamethasone was a steroid used to treat patients with multiple myeloma.; Other Names: Decadron

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Near Complete Response (nCR)/CR Rate of the Combination of Panobinostat With Bortezomib, Lenalidomide and Dexamethasone (P-RVD) vs RVD in Newly Diagnosed Multiple Myeloma Patients	84 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Minimal Residual Disease (MRD) Negativity (mCR) After 4 Cycles of Induction by Next Gen Sequencing	MRD negativity by Clonal Sequencing (ClonoSEQTM) assay (Adaptive Biotechnologies)	Month 3
Best Overall Response Rate (ORR) and MRD Negativity After ASCT and Maintenance	ORR (CR + PR) and MRD negativity after ASCT and maintenance	Month 3 up to end of study, approximately 3 years.
Depth of Response by International Myeloma Working Group (IMWG) Criteria	Rate of Very Good Partial Response (VGPR), Complete Response (CR) and Stringent Complete Response (sCR)	Day 22 up to end of study, approximately 3 years
Duration of Response		From measurable response to the date of first documented progression or date of death from any cause, whichever came first, assessed up to 3 years.
Overall Survival		3 years after the last patient is enrolled to the study
Progression Free Survival		3 years after the last patient is enrolled to the study

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): June 14, 2016
• Primary Completion (Actual): May 22, 2017
• Study Completion (Actual): May 22, 2017

Study Registration Dates

• First Submitted: March 9, 2016
• First Submitted That Met QC Criteria: March 25, 2016
• First Posted (Estimate): March 28, 2016

Study Record Updates

• Last Update Posted (Actual): July 24, 2018
• Last Update Submitted That Met QC Criteria: June 26, 2018
• Last Verified: June 1, 2018

More Information

Terms related to this study

• Keywords: transplant; multiple myeloma; LBH589; panobinostat; ASCT; farydak
• 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; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Histone Deacetylase Inhibitors; Dexamethasone; Lenalidomide; Bortezomib; Panobinostat
• Other Study ID Numbers: CLBH589DUS106

Plan for Individual participant data (IPD)

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

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