A study of panobinostat in combination with bortezomib and dexamethasone in patients with relapsed multiple myeloma

• Register: EUCTR
• Last refreshed on: 29 August 2016
• Main ID: EUCTR2009-015507-52-SE
• Date of registration: 15/10/2009
• Prospective Registration: Yes
• Primary sponsor: Novartis Pharma Services AG
• Public title: A study of panobinostat in combination with bortezomib and dexamethasone in patients with relapsed multiple myeloma
• Scientific 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
• Date of first enrolment: 13/11/2009
• Target sample size: 762
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2009-015507-52
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: Single blind: Double blind: yes Parallel group: Cross over: Other: If controlled, specify comparator, Other Medicinial Product: Placebo: yes Other:
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Austria, Belgium, Czech Republic, Denmark, Finland, France, Germany, Greece, Italy, Netherlands, Poland, Spain, Sweden, United Kingdom

Key inclusion & exclusion criteria

Inclusion criteria:
1. Patient has a previous diagnosis of multiple myeloma, based on IMWG 2003 definitions. All three of the following criteria must have been met:
a. Monoclonal immunoglobulin (M component) on electrophoresis, and on immunofixation on serum or on total 24 hour urine
b. Bone marrow (clonal) plasma cells = 10% or biopsy proven plasmacytoma
c. Related organ or tissue impairment (CRAB symptoms: anemia, hypercalcemia, lytic bone lesions, renal insufficiency, hyperviscosity, amyloidosis or recurrent infections)
2. Patient with 1 to 3 prior lines of therapy who require retreatment of myeloma (cf IMWG 2003 ) for one of the 2 conditions below:
a. Relapsed, defined by disease that recurred in a patient that responded under a prior therapy, by reaching a MR or better, and had not progressed under this therapy nor up to 60 days of last dose of this therapy. Patients priorly treated by BTZ may be eligible.
b. Relapsed-and-refractory to a therapy, provided that meets both conditions:
- patient has relapsed to at least one prior line
- and patient was refractory to another line (except BTZ), by either not reaching a MR, or progressed while under this therapy, or within 60 days of its last dose
3. Patient has measurable disease on M protein at study screening defined by at least one of the following measurements as per thresholds clarified in IMWG 2003 disease definitions (Kyle, et al 2003):
• Serum M-protein = 1 g/dL (= 10 g/L)
• Urine M-protein = 200 mg/24 h
4. Patients treated with local radiotherapy with or without concomitant exposure to steroids for pain control or management of cord/nerve root compression, are eligible. Two weeks must have lapsed since last date of radiotherapy, which is recommended to be a limited field. Patients who require concurrent radiotherapy should have entry to the protocol deferred until the radiotherapy is completed and 2 weeks have passed since the last date of therapy
5. Patient’s age is = 18 years at time of signing the informed consent
6. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of = 2
7. Patient has the following laboratory values within 3 weeks before starting study drug (lab tests may be repeated, as clinically indicated, to obtain acceptable values before screen fail is concluded but supportive therapies are not to be administered within the week prior to screening tests for absolute neutrophil count or platelet counts)
a. Absolute neutrophil count (ANC) = 1.5 x 109 /L
b. Platelet count = 100 x 109 /L
c. Serum potassium, magnesium, phosphorus, within normal limits (WNL) for institution
d. Total calcium (corrected for serum albumin) or ionized calcium = LLN, and not higher than CTCAE grade 1 in case of elevated value
Note: Potassium, calcium, magnesium, and/or phosphorus supplements may be given to correct values that are < LLN:
e. AST/SGOT and ALT/SGPT = 2.5 x ULN
f. Serum total bilirubin = 1.5 ULN (or = 3.0 x ULN if patient has Gilbert syndrome)
g. Serum creatinine levels = 1.5 x ULN, or calculated creatinine clearance = 60 ml/min
8. Patient has provided written informed consent prior to any screening procedures
9. Patient is able to swallow capsules
10. Patient must be able to adhere to the study visit schedule and other protocol requirements
11. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test at within 7 days prior to start of study treatment

Are the trial subjects under 18? no
Number of subject
Exclusion criteria:
1. Patients who have progressed under all prior lines of anti MM therapy (primary refractory)
2. Patients who have been refractory to prior BTZ (ie. did not achieve at least a MR, or have progressed under it or within 60 days of last dose)
3. Allogeneic stem cell transplant recipient presenting with graft versus host disease either active or requiring immunosuppression
4. 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
5. Patient has grade = 2 peripheral neuropathy or grade 1 peripheral neuropathy with pain on clinical examination within 14 days before randomization
6. Patient received prior treatment with DAC inhibitors including panobinostat
7. Patient needing valproic acid for any medical condition during the study or within 5 days prior to first administration of panobinostat/study treatment
8. Patient taking any anti-cancer therapy concomitantly (bisphosphonates are permitted only if commenced prior to the start of screening period)
9. Patient has another primary malignancy < 3 years from first dose of study treatment
10. Patient who received:
a. prior anti-myeloma chemotherapy or medication including IMiDs and Dex = 3 weeks prior to start of study.
b. experimental therapy or biologic immunotherapy including monoclonal antibodies = 4 weeks prior to start of study.
c. prior radiation therapy = 4 weeks or limited field radiotherapy = 2 weeks prior start of study.
11. Patient has not recovered from all therapy-related toxicities associated with above listed treatments to < grade 2 CTCAE.
12. Patient has 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
13. Patients with evidence of mucosal or internal bleeding
14. Patient has unresolved diarrhea = CTCAE grade 2
15. Patient has impaired cardiac function, including any one of the following:
a. LVEF < LLN of institutional norm, as determined by ECHO or MUGA
b. obligate use of a permanent cardiac pacemaker
c. congenital long QT syndrome
d. history or presence of ventricular tachy-arrhythmias
e. resting bradycardia defined as < 50 beats per minute
f. QTcF > 450 msec on screening ECG
g. complete left bundle branch block (LBBB), bifascicular block
h. any clinically significant ST segment and/or T-wave abnormalities
i. presence of unstable atrial fibrillation (ventricular response rate > 100 bpm). Patients with stable atrial fibrillation can be enrolled provided they do not meet other cardiac exclusion criteria.
j. myocardial infarction or unstable angina pectoris = 6 months prior to starting study drug
k. symptomatic congestive heart failure (New York Heart Association class III-IV)
l. other clinically significant heart disease and vascular disease (e.g. uncontrolled hypertension)
16. Patient taking medications with relative risk of prolonging the QT interval or inducing Torsade de pointes, if such treatment cannot be discontinued or switched to a different medication prior to starting study drug
17. Patient has 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)
18. Patient has any other concurrent severe and

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Multiple Myeloma (MM), relapsed or relapsed-and-refractory
MedDRA version: 14.1 Level: PT Classification code 10028228 Term: Multiple myeloma System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Therapeutic area: Diseases [C] - Cancer [C04]

Intervention(s)

Product Name: panobinostat
Product Code: LBH589
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Panobinostat
CAS Number: 404950-80-7
Current Sponsor code: LBH589
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 5-
Pharmaceutical form of the placebo: Capsule, hard
Route of administration of the placebo: Oral use

Product Name: panobinostat
Product Code: LBH589
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Panobinostat
CAS Number: 404950-80-7
Current Sponsor code: LBH589
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 20-
Pharmaceutical form of the placebo: Capsule, hard
Route of administration of the placebo: Oral use

Trade Name: Velcade
Product Name: Velcade
Pharmaceutical Form: Powder for solution for injection
INN or Proposed INN: Bortezomib
CAS Number: 179324-69-7
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 1-

Trade Name: Fortecortin
Product Name: Fortecortin
Pharmaceutical Form: Tablet
INN or Proposed INN: Dexamethasone
CAS Number: 50-02-2
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 0.5-

Trade Name: Fortecortin
Product Name: Fortecortin
Pharmaceutical Form: Tablet
INN or Proposed INN: Dexamethasone
CAS Number: 50-02-2
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 2-

Trade Name: Fortecortin
Product Name: Fortecortin
Pharmaceutical Form: Tablet
INN or Proposed INN: Dexamethasone
CAS Number: 50-02-2
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 4-

Trade Name: Fortecortin
Product Name: Fortecortin
Pharmaceutical Form: Tablet
INN or Proposed INN: Dexamethasone
CAS Number: 50-02-2
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 8-

Product Name: panobinostat
Product Code: LBH589
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Panobinostat
CAS Number: 404950-80-7
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Primary Outcome(s)

Secondary Objective: Key Secondary
• To compare OS (overall survival)
Other Secondary
• To compare ORR (overall response rate) comprising CR, nCR and PR
• To compare nCR plus CR rate (near complete response plus + complete response)
• To compare MRR (minor response rate)
• To compare TTR (time to response)
• To compare TTP (time to progression)
• To assess duration of response (DOR; from first occurring PR or better)
• To assess safety of the combination therapy
• To assess health-related quality of life and symptoms of multiple myeloma

Main Objective: To compare progression-free survival (PFS), in patients treated with PAN in combination with BTZ/Dex vs. patients treated with placebo in combination with BTZ/Dex

Timepoint(s) of evaluation of this end point: Every three weeks during treatment and then every 6 weeks after end of treatment

Primary end point(s): PFS i.e PD for patients not in CR or relapse for patients in CR (per investigator assessment based on modified EBMT criteria) or death from any cause

Secondary Outcome(s)

Secondary end point(s): 1. OS
2. ORR (comprising CR, nCR, and PR)
3. nCR+CR
4. MRR
5. TTR
6. DOR
7. TTP
8. HRQoL and multiple myeloma symptoms as measured by: EORTC QLQ-C30, EORTC QLQ-MY20, and FACT/GOG-NTX

Timepoint(s) of evaluation of this end point: 1. to 7.:every 3 weeks during treatment and then every 6 weeks after end of treatment
8.: at screening, day 1 of each cycle and study evaluation completion

Secondary ID(s)

CLBH589D2308

Source(s) of Monetary Support

Novartis Pharma Service AG