Panobinostat or Placebo With Bortezomib and Dexamethasone in Patients With Relapsed Multiple Myeloma (PANORAMA-1)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT01023308
First received: November 30, 2009
Last updated: September 21, 2015
Last verified: September 2015
  Purpose

Panobinostat (LBH589) is a highly potent pan-deacetylase inhibitor (pan-DACi), inclusive of HDAC6, which disrupts aggresome function, promotes accumulation of cytotoxic misfolded protein aggregates and triggers myeloma cell death. Combination of pan-DAC and protease inhibition by co-treatment with panobinostat (PAN) and bortezomib (BTZ) has demonstrated synergistic cytotoxicity in vitro and in vivo in pre-clinical experiments. Furthermore, clinical experience in advanced multiple myeloma (MM) patients treated by oral panobinostat and i.v bortezomib ± dexamethasone showed very encouraging results for efficacy and manageable toxicity profile.

Given the medical need for improved treatment strategies for patients with previously treated and relapsed MM, the purpose of this prospective, multinational, randomized, double-blind, placebo-controlled, parallel group Phase III study is to compare the results in progression-free survival of 2 combination therapies, panobinostat with bortezomib and dexamethasone or placebo with bortezomib and dexamethasone, in patients with previously treated MM whose disease has recurred or progressed.


Condition Intervention Phase
Multiple Myeloma
Drug: Panobinostat
Drug: Bortezomib
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: A Multicenter, Randomized, Double Blind, Placebo Controlled Phase III Study of Panobinostat in Combination With Bortezomib and Dexamethasone in Patients With Relapsed Multiple Myeloma

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Progression-free Survival Events in Patients Treated With Panobinostat in Combination With Bortezomib and Dexamethasone vs. Patients Treated by Placebo in Combination With Bortezomib and Dexamethasone. [ Time Frame: 45 months ] [ Designated as safety issue: No ]
  • Progression Free Survival in Patients Treated With Panobinostat in Combination With Bortezomib and Dexamethasone vs. Patients Treated by Placebo in Combination With Bortezomib and Dexamethasone. [ Time Frame: 45 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Overall Response Rate in Patients Treated With Panobinostat in Combination With Bortezomib and Dexamethasone vs. Patients Treated by Placebo in Combination With Bortezomib and Dexamethasone. [ Time Frame: 45 months ] [ Designated as safety issue: No ]

    Best overall response based on mEBMT criteria per investigator assessment:

    Stringent complete response (sCR): CR as defined below plus:

    Normal FLC ratio and Absence of clonal cells in bone marrow Complete response: Negative immunofixation on serum and urine and Disappearance of any soft tissue plasmacytomas and ≤5% plasma cells in bone marrow Very good partial reaponse:Serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein plus urine M-protein level <100 mg per 24 h Partial response: ≥50% reduction of serum M-protein ≥90% urine M-protein reduction or <200 mg/24 h ≥50% decrease in soft-tissue plasmacytomas Stable disease: Not meeting criteria for CR, VGPR, PR or progressive disease


  • Time to Response Per Investigator Assessment (mEBMT Criteria) of Response Patients Treated With Panobinostat in Combination With Bortezomib and Dexamethasone vs. Patients Treated by Placebo in Combination With Bortezomib and Dexamethasone. [ Time Frame: 45 months ] [ Designated as safety issue: No ]
  • Duration of Response Per Investigator Assessment (mEBMT Criteria) Patients Treated With Panobinostat in Combination With Bortezomib and Dexamethasone vs. Patients Treated by Placebo in Combination With Bortezomib and Dexamethasone. [ Time Frame: 45 months ] [ Designated as safety issue: No ]
  • Time to Progression/Relapse Per Investigator Assessment (mEBMT Criteria) Patients Treated With Panobinostat in Combination With Bortezomib and Dexamethasone vs. Patients Treated by Placebo in Combination With Bortezomib and Dexamethasone. [ Time Frame: 45 months ] [ Designated as safety issue: No ]

    EBMT criteria to assess myeloma response:

    • Complete Response (CR)-absence of serum and urine monoclonal paraprotein for 6 weeks, plus no increase in size or number of lytic bone lesions, plus other factors)
    • Partial Response (PR)-not all CR criteria, plus >=50% reduction in serum monoclonal paraprotein plus others
    • Minimal Response (MR)- 25-49% reduction in serum monoclonal paraprotein plus others
    • Stable Disease (SD)- not MR or progressive disease (PD)
    • Progressive Disease (PD)- reappearance of monoclonal paraprotein, lytic bone lesions, other
    • Not Evaluable (NE).

  • European Organization for Research and Treatment of Cancer Multiple Myeloma Module( EORTC QLQ-MY20) -Change From Baseline by Treatment Group [ Time Frame: 12, 24 and 48 weeks ] [ Designated as safety issue: No ]
    Higher values in the disease symptoms and side effects of treatment scores indicate worsening. Higher scores in the future perspective and body image scores indicate improvement. LS Means and SEM are estimated from the repeated measures model. Following factors and covariates are included in the repeated measurement model: time, treatment, treatment by time interaction, number of prior lines of anti-MM therapy (1/ 2 and 3), prior use of BTZ (Yes/ No), baseline score.Disease Symptom is the sum of 20 questions, total score ranges from 0 (best possible outcome) to 100 (worst possible outcome)", All subscales of EORTC QLQ-MY20 have the same score range of 0 -100. Decrease in symptom scores from baseline indicate improvement in symptoms.

  • European Organization for Research and Treatment of Cancer Quality of Life Questionaire : EORTC QLQ-C30 - Summary Statistics by Treatment Group [ Time Frame: 12, 24 and 48 weeks ] [ Designated as safety issue: No ]
    The EORTC QLQ-C30 measures functional dimensions (physical, role, emotional, cognitive, and social), three multi-item symptom scales (fatigue, nausea/vomiting, and pain), six single-item symptom scales (dyspnea, sleep disturbance, appetite loss, constipation, diarrhea and financial impact) and a global health status/QoL scale. Disease Symptom is the sum of 30 questions, total score ranges from 0 (best possible outcome) to 100 (worst possible outcome)", All subscales of EORTC QLQ-C30 have the same score range of 0 -100. For global health status and other functional scales, an increase from baseline indicates improvement of QoL. Whereas for symptoms scales, fatigue, dyspnea, insomnia, appetite loss, constipation and diarrhea, decrease in scores from baseline indicate improvement in symptoms.

  • FACT/GOG-NTX-Change From Baseline by Treatment Group [ Time Frame: 12, 24 and 48 weeks ] [ Designated as safety issue: No ]
    The FACT/GOG-NTX was developed from the Functional Assessment of Chronic Illness Therapy (FACIT) Measurement System and focuses on four general quality of life domains for physical well being, functional well-being, social/family well-being, and emotional well-being, and includes additional items to characterize treatment-related neurotoxicity. Higher subscales/total scores represent higher QOL. In the case of the neurotoxicity subscale, lower scores correspond to higher neurotoxicity. The recall period referenced in the questionnaire is the past 7 days.Ranges for FACT-G subscales are as follows:.PWB, SWB and FWB scale 0 -28, EWB scale 0-24, NtxS scale 0-44, FACT/GOG-Ntx trial outcome index scale is 0-100 and FACT-G scale is also scaled 0-100. An increase from baseline in these scores indicate improvement.


Enrollment: 768
Study Start Date: December 2009
Study Completion Date: July 2015
Primary Completion Date: March 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Panobinostat + Bortezomib + Dexamethasone
Panobinostat was given 20 mg hard gelatin capsules . Bortezomib was given at 1.3 mg/m2 as a 3 to 5 second bolus intravenous (IV)injection. Dexamethasone was given as an oral dose of 20 mg/day.
Drug: Panobinostat
Other Name: LBH589
Drug: Bortezomib
Placebo Comparator: Placebo + Bortezomib + Dexamethasone
Placebo was given as a hard gelatin capsule in the image of Panobinostat . Bortezomib was given at 1.3 mg/m2 as a 3 to 5 second bolus intravenous (IV) injection. Dexamethasone was given as an oral dose of 20 mg/day.
Drug: Bortezomib

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patient has a previous diagnosis of multiple myeloma.
  2. Patient requires retreatment for multiple myeloma
  3. Patient has measurable M component in serum or urine at study screening

Exclusion Criteria:

  1. Patient who has progressed under all prior lines of anti MM therapy
  2. Patient who has 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
  3. Patient has 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
  4. Patient received prior treatment with DAC inhibitors including panobinostat
  5. Patient has impaired cardiac function, or a prolonged QTc interval at screening ECG
  6. Patient taking medications with relative risk of prolonging the QT interval or inducing Torsade de pointes
  7. Female patient who is pregnant or breast feeding or with childbearing potential and not willing to use a double method of contraception up to 3 months after the end of study treatment. Male patient who is not willing to use a barrier method of contraception up to 3 months after the end of study treatment.

Other protocol-defined inclusion/exclusion criteria may apply.

  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT01023308

  Show 213 Study Locations
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

Additional Information:
No publications provided

Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT01023308     History of Changes
Other Study ID Numbers: CLBH589D2308  2009-015507-52 
Study First Received: November 30, 2009
Results First Received: March 23, 2015
Last Updated: September 21, 2015
Health Authority: United States: Food and Drug Administration

Keywords provided by Novartis:
Myeloma
DACi
Bortezomib
Combination,

Additional relevant MeSH terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Blood Protein Disorders
Cardiovascular Diseases
Hematologic Diseases
Hemorrhagic Disorders
Hemostatic Disorders
Immune System Diseases
Immunoproliferative Disorders
Lymphoproliferative Disorders
Neoplasms
Neoplasms by Histologic Type
Paraproteinemias
Vascular Diseases
BB 1101
Bortezomib
Dexamethasone
Dexamethasone 21-phosphate
Dexamethasone acetate
Panobinostat
Anti-Inflammatory Agents
Antiemetics
Antineoplastic Agents
Antineoplastic Agents, Hormonal
Autonomic Agents
Central Nervous System Agents
Enzyme Inhibitors
Gastrointestinal Agents
Glucocorticoids
Histone Deacetylase Inhibitors

ClinicalTrials.gov processed this record on February 04, 2016