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

• ClinicalTrials.gov Identifier: NCT01023308
• Recruitment Status: Completed
• First Posted: December 2, 2009
• Results First Posted: October 23, 2015
• Last Update Posted: March 17, 2020
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: November 30, 2009
• First Posted Date: December 2, 2009
• Results First Submitted Date: March 23, 2015
• Results First Posted Date: October 23, 2015
• Last Update Posted Date: March 17, 2020
• Actual Study Start Date: December 21, 2009
• Actual Primary Completion Date: July 30, 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 21, 2015)

• 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 ]
• 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 ]

• Original Primary Outcome Measures (submitted: December 1, 2009): To compare 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: 30 months ]

Current Secondary Outcome Measures (submitted: November 2, 2016)

• Overall 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 ]
  Number of OS events
• Overall 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 ]
  survival time in months
• 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 ]
  Best overall response based on mEBMT criteria per investigator assessment
• 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 ]
• 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 ]
• 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 ]
• 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 ]
  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 Multiple Myeloma Module (EORTC ) QLQ-C30 - Summary Statistics by Treatment Group [ Time Frame: 12, 24 and 48 weeks ]
  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.
• Functional Assessment of Chronic Illness Therapy (FACIT) Measurement System : FACT/GOG-NTX-Change From Baseline by Treatment Group [ Time Frame: 12, 24 and 48 weeks ]
  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, scale 0 -28, , 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.

Original Secondary Outcome Measures (submitted: December 1, 2009)

• To compare overall 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: 30 months ]
• To compare overall response rate of partial or better response in patients treated with panobinostat in combination with bortezomib and dexamethasone vs. patients treated by placebo in combination with bortezomib and dexamethasone. [ Time Frame: 30 months ]
• To compare time to response and duration 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: 30 months ]
• To assess safety of the combination therapy. [ Time Frame: 30 months ]
• To evaluate health-related quality of life and symptoms of multiple myeloma [ Time Frame: 30 months ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Panobinostat or Placebo With Bortezomib and Dexamethasone in Patients With Relapsed Multiple Myeloma
• 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

Brief Summary

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.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Multiple Myeloma

Intervention

• Drug: Panobinostat
  Panobinostat was administered 3x week ( 2 weeks on 1 week off)
  Other Name: LBH589
• Drug: Bortezomib
  Bortezomib was administered 2 x week ( 2weeks on 1 week off)
  Other Name: (Velcade®)
• Drug: Dexamethasone
  Dexamethasone was adminstered on day of Bortezomib and the day after Bortezomib administration
• Drug: Placebo
  Placebo was administered 3x week ( 2 weeks on 1 week off)

Study Arms

• Experimental: Panobinostat + Bortezomib + Dexamethasone
  Interventions:

  • Drug: Panobinostat
  • Drug: Bortezomib
  • Drug: Dexamethasone
• Placebo Comparator: Placebo + Bortezomib + Dexamethasone
  Interventions:

  • Drug: Bortezomib
  • Drug: Dexamethasone
  • Drug: Placebo

Publications *

• San-Miguel JF, Einsele H, Moreau P. The Role of Panobinostat Plus Bortezomib and Dexamethasone in Treating Relapsed or Relapsed and Refractory Multiple Myeloma: A European Perspective. Adv Ther. 2016 Nov;33(11):1896-1920. doi: 10.1007/s12325-016-0413-7. Epub 2016 Sep 27.
• San-Miguel JF, Hungria VT, Yoon SS, Beksac M, Dimopoulos MA, Elghandour A, Jedrzejczak WW, Gunther A, Nakorn TN, Siritanaratkul N, Schlossman RL, Hou J, Moreau P, Lonial S, Lee JH, Einsele H, Sopala M, Bengoudifa BR, Binlich F, Richardson PG. Overall survival of patients with relapsed multiple myeloma treated with panobinostat or placebo plus bortezomib and dexamethasone (the PANORAMA 1 trial): a randomised, placebo-controlled, phase 3 trial. Lancet Haematol. 2016 Nov;3(11):e506-e515. doi: 10.1016/S2352-3026(16)30147-8. Epub 2016 Oct 14.
• Richardson PG, Hungria VT, Yoon SS, Beksac M, Dimopoulos MA, Elghandour A, Jedrzejczak WW, Guenther A, Nakorn TN, Siritanaratkul N, Schlossman RL, Hou J, Moreau P, Lonial S, Lee JH, Einsele H, Sopala M, Bengoudifa BR, Corrado C, Binlich F, San-Miguel JF. Panobinostat plus bortezomib and dexamethasone in previously treated multiple myeloma: outcomes by prior treatment. Blood. 2016 Feb 11;127(6):713-21. doi: 10.1182/blood-2015-09-665018. Epub 2015 Dec 2. Erratum In: Blood. 2016 Jun 30;127(26):3460.
• San-Miguel JF, Hungria VT, Yoon SS, Beksac M, Dimopoulos MA, Elghandour A, Jedrzejczak WW, Gunther A, Nakorn TN, Siritanaratkul N, Corradini P, Chuncharunee S, Lee JJ, Schlossman RL, Shelekhova T, Yong K, Tan D, Numbenjapon T, Cavenagh JD, Hou J, LeBlanc R, Nahi H, Qiu L, Salwender H, Pulini S, Moreau P, Warzocha K, White D, Blade J, Chen W, de la Rubia J, Gimsing P, Lonial S, Kaufman JL, Ocio EM, Veskovski L, Sohn SK, Wang MC, Lee JH, Einsele H, Sopala M, Corrado C, Bengoudifa BR, Binlich F, Richardson PG. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1195-206. doi: 10.1016/S1470-2045(14)70440-1. Epub 2014 Sep 18. Erratum In: Lancet Oncol. 2015 Jan;16(1):e6.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 8, 2020): 767
• Original Estimated Enrollment (submitted: December 1, 2009): 676
• Actual Study Completion Date: July 30, 2015
• Actual Primary Completion Date: July 30, 2015 (Final data collection date for primary outcome measure)

Eligibility 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Austria, Belgium, Brazil, Canada, China, Czechia, Denmark, Egypt, Finland, France, Germany, Greece, Hong Kong, Israel, Italy, Japan, Korea, Republic of, Lebanon, Mexico, Netherlands, Norway, Poland, Russian Federation, Singapore, South Africa, Spain, Sweden, Taiwan, Thailand, Turkey, United Kingdom, United States
• Removed Location Countries: Czech Republic

Administrative Information

• NCT Number: NCT01023308
• Other Study ID Numbers: CLBH589D2308; 2009-015507-52 ( EudraCT Number )
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Original Responsible Party: external Affairs, Novartis Pharmaceuticals
• Current Study Sponsor: Novartis Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

• PRS Account: Novartis
• Verification Date: March 2020