Safety Study of LBH589 When Given in Combination With Bortezomib in Adult Patients With Multiple Myeloma

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT00532389
First received: September 18, 2007
Last updated: March 11, 2014
Last verified: March 2014
  Purpose

This study comprises of a dose-escalation and dose expansion phase and will determine the maximum tolerated dose of oral Panobinostat on a continuous schedule in adult in combination with bortezomib. Safety, tolerability, PK and PD profile of the combined treatments will be assessed as secondary objectives. Dose expansion phase will explore in a non continuous Panobinostat schedule with bortezomib and dexamethasone, safety and tolerability and PK profile of Panobinostat and Bortezomib with and without Dexamethasone


Condition Intervention Phase
Multiple Myeloma
Drug: LBH589
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase Ib, Multi-center, Open-label, Dose-escalation Study of Oral LBH589 When Administered in Combination With Bortezomib in Adult Patients With Multiple Myeloma

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • To determine the MTD of panobinostat with bortezomib [ Time Frame: throughout the study ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • The safety and tolerability of the study continuous Panobinostat treatment in dose escalation phase and non continuous schedule of panobinostat in dose expansion phase [ Time Frame: throughtout the study ] [ Designated as safety issue: Yes ]
  • To characterize the PK profile of bortezomib; the PK profile of panobinostat with and without bortezomib; the PK profile of bortezomib and panobinostat with and without dexamethasone [ Time Frame: cycle 1 & cycle 2 ] [ Designated as safety issue: Yes ]
  • To assess the preliminary efficacy of the study treatment [ Time Frame: throughout the study ] [ Designated as safety issue: No ]

Enrollment: 62
Study Start Date: October 2007
Study Completion Date: October 2013
Primary Completion Date: October 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Panobinostat (LBH589) Drug: LBH589

  Eligibility

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

Inclusion criteria:

  1. Patients must have a diagnosis of active multiple myeloma according to the International Myeloma Working Group criteria (IMWG., 2003), and be deemed by the investigator as requiring treatment.
  2. Patients must have received at least one prior line of therapy and includes patients whose disease has relapsed as well as relapsed-refractory MM . (Durie et. al., 2006). One prior line of therapy may consist of induction followed by autologous stem cell transplantation.
  3. Patients must be suitable (according to their local product information and applicable health authority recommendations) for treatment with BTZ. Note: patients previously treated with BTZ are eligible to participate in the trial.
  4. Patients enrolled to dose expansion phase must have measurable M component at entry according to the IMWG Criteria (Durie et al, 2006) including at least one of the following:

    • Serum M-protein by sPEP ≥ 1 g/dL (> 10g/l)
    • For patients with IgA M-protein whose sPEP is not providing sufficiently precise quantification due to confounded migration of M-protein with serum beta globulins, a quantification by nephelometry / turbidometry is permitted and must show serum M-protein ≥ 1 g/dL
    • Urine M-protein by uPEP ≥ 200 mg/24 h
    • Serum FLC assay: Involved FLC level ≥ 100 mg/L, provided serum FLC ratio is abnormal. (abnormal if FLC ratio is <0.26 or >1.65 )
  5. Adults ≥ 18 years old
  6. ECOG Performance Status ≤ 2
  7. Life expectancy > 12 weeks
  8. Patients must have the following laboratory values:

    • ANC ≥ 1.5 x 109/L
    • Platelets ≥ 100x 109/L
    • Calculated CrCl ≥ 30 mL/min (MDRD Formula)
    • AST and ALT ≤ 2.5 x ULN
    • Serum bilirubin ≤ 1.5 x ULN
    • Serum potassium, magnesium, phosphorous, within normal limits (WNL) for institution
    • Total calcium (corrected for serum albumin) or ionized calcium equal to lower normal limits for institution or greater (≥ LLN) but not higher than CTCAE grade 1
    • Note: Potassium, calcium, magnesium, and/or phosphorous supplements may be given to correct values that are < LLN.
  9. Baseline MUGA or ECHO must demonstrate LVEF ≥ the lower limit of the institutional normal
  10. All patients (dose-escalation and dose-expansion patients) must be willing to undergo a mandatory bone marrow aspirate sampling at baseline (for cytology) and another later in the study if the patient eventually goes on to experience a CR or PR. For patients who join the study at the dose-expansion phase, they must also give consent to have an extra volume of sample taken for exploratory biomarker testing. Potential dose-expansion phase patients who do not consent for this biomarker sample collection will not be eligible to participate in the trial (Note: One extra bone aspirate sample at C2D1 is optional as per the protocol).
  11. Able to sign informed consent and to comply with the protocol
  12. Patient is able to swallow capsules

Exclusion criteria:

  1. Prior exposure to a HDAC inhibitor compound used in the treatment of MM
  2. Patients with Refractory MM (i.e. patients refractory to all prior therapies) who under all prior previous lines of therapy have :

    • either never reached a response better than SD
    • or whose disease progressed from any best response while still under therapy
    • or whose disease progressed within 60 days of last dose of therapy
  3. Patients who have had prior allogeneic stem cell transplantation and show evidence of active graft-versus-host disease or of graft-versus-host disease that requires immunosuppressive therapy.
  4. Patient has grade 1 peripheral neuropathy with pain or grade ≥ 2 peripheral neuropathy on clinical examination within 14 days before first study treatment
  5. Impaired cardiac function or clinically significant cardiac diseases, including any one of the following:

    • Patients with congenital long QT syndrome
    • History or presence of sustained ventricular tachyarrhythmia. (Patients with a history of atrial arrhythmia are eligible but should be discussed with the Sponsor prior to enrollment)
    • Any history of ventricular fibrillation or torsade de pointes
    • Bradycardia defined as HR< 50 bpm. Patients with pacemakers are eligible if HR ≥ 50 bpm.
    • Screening ECG with a QTc > 450 msec
    • Right bundle branch block + left anterior hemiblock (bifascicular block)
    • Patients with myocardial infarction or unstable angina ≤ 6 months prior to starting study drug
    • Other clinically significant heart disease (e.g., CHF NY Heart Association class III or IV , uncontrolled hypertension, history of labile hypertension, or history of poor compliance with an antihypertensive regimen)
  6. Impairment of GI function or GI disease that may significantly alter the absorption of PAN
  7. Patient has unresolved diarrhea ≥ CTCAE grade 2
  8. Other concurrent severe and/or uncontrolled medical conditions (e.g., uncontrolled diabetes, active or uncontrolled infection, acute diffuse pulmonary disease, pericardial disease, uncontrolled thyroid dysfunction ) including abnormal laboratory values, that could cause unacceptable safety risks or compromise compliance with the protocol
  9. Patients using medications that have a relative risk of prolonging the QT interval or inducing torsade de pointes if treatment cannot be discontinued or switched to a different medication prior to starting study drug
  10. Patients who need valproic acid for any medical condition during the study or within 5 days prior to the first PAN treatment.
  11. Patients who have received targeted agents within 2 weeks or within 5 half-lives of the agent and active metabolites (which ever is longer) and who have not recovered from side effects of those therapies.
  12. Patients who have received either immunotherapy within ≤ 8 weeks; chemotherapy within ≤ 4 weeks; or radiation therapy to > 30% of marrow-bearing bone within ≤ 2 weeks prior to starting study treatment; or who have not yet recovered from side effects of such therapies.
  13. Patients who have received steroids (e.g. Dex) ≤ 2 weeks prior to starting study treatment or who have not recovered from side effects of such therapy. Concomitant therapy medications that include corticosteroids are allowed if patients receive < 10 mg of prednisone or equivalent as indicated for other medical conditions, or up to 100 mg of hydrocortisone as pre-medication for administration of certain medications or blood products while enrolled in this study.
  14. Patients who have undergone major surgery ≤ 4 weeks prior to starting study drug or who have not recovered from side effects of such therapy
  15. Women who are pregnant or breast feeding or women of childbearing potential (WOCBP)not willing to use a double method of contraception during the study and for 3 months after treatment. One of these methods of contraception must be a barrier method. WOCBP are defined as women who have not undergone a hysterectomy or who have not been naturally postmenopausal for at least 12 consecutive months (i.e., who has had menses any time in the preceding 12 consecutive months). Women of childbearing potential must have a negative serum pregnancy test within 7 days of the first administration of oral PAN
  16. Male patients whose sexual partners are WOCBP not using a double method of contraception during the study and for 3 months after treatment. One of these methods of contraception must be a condom
  17. Patients with a prior malignancy with in the last 3 years (except for basal or squamous cell carcinoma, or in situ cancer of the cervix)
  18. Patients with any significant history of non-compliance to medical regimens or unwilling or unable to comply with the instructions given to him/her by the study staff.
  19. Patients who have shown intolerance to BTZ or to Dex or components of these drugs or has any contraindication to one or the other drug, following locally applicable prescribing information

Other protocol defined inclusion/exclusion criteria may apply

  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00532389

Locations
United States, Florida
Innovative Medical Research of South Florida Dept.ofInnovativeMedResearch
Miami Shores, Florida, United States, 33138
United States, Massachusetts
Dana Farber Cancer Institute Clinical Research Coordinator
Boston, Massachusetts, United States, 02115
United States, New Jersey
Hackensack University Medical Center Multiple Myeloma Division
Hackensack, New Jersey, United States, 07601
United States, Washington
Swedish Medical Center Dept.ofSwedishMedicalCtr.
Seattle, Washington, United States
Australia, Australian Capital Territory
Novartis Investigative Site
Canberra, Australian Capital Territory, Australia, 2606
Canada, British Columbia
Novartis Investigative Site
Vancouver, British Columbia, Canada, V5Z 1M9
Canada, Quebec
Novartis Investigative Site
Montreal, Quebec, Canada, H1T 2M4
Germany
Novartis Investigative Site
Berlin, Germany, 10117
Novartis Investigative Site
Kiel, Germany, 24105
Novartis Investigative Site
Leipzig, Germany, 04103
Novartis Investigative Site
München, Germany, 80336
Novartis Investigative Site
Wuerzburg, Germany, 97070
Italy
Novartis Investigative Site
Bologna, BO, Italy, 40138
Novartis Investigative Site
Torino, TO, Italy, 10126
Spain
Novartis Investigative Site
Salamanca, Castilla y Leon, Spain, 37007
Novartis Investigative Site
Barcelona, Catalunya, Spain, 08036
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: NCT00532389     History of Changes
Other Study ID Numbers: CLBH589B2207, 2006-006638-16
Study First Received: September 18, 2007
Last Updated: March 11, 2014
Health Authority: United States: Food and Drug Administration
Australia: Department of Health and Ageing Therapeutic Goods Administration
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Italy: National Institute of Health
Spain: Spanish Agency of Medicines

Keywords provided by Novartis:
Myeloma
Multiple Myeloma
Bortezomib
LBH589
Combination

Additional relevant MeSH terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Bortezomib
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on April 21, 2014