Efficacy and Safety of LBH589B in Adult Patients With Multiple Myeloma
Condition: Multiple Myeloma
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell
Intervention: LBH589
Intervention MeSH terms: Panobinostat
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 38.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Multiple myeloma; adults; LBH589; refractory

Summary:

      This study will evaluate the efficacy and safety of LBH589B in adult patients with multiple
      myeloma who have received at least two prior therapies and are refractory to their last
      therapy. Patients must have received in prior therapy either bortezomib or lenalidomide
    

Eligibility criteria:

        Inclusion criteria:

          1. Adults ≥ 18 years old

          2. Subjects must have signed the consent form before undergoing any study specific
             screening procedures and before participation in this study. The subject must be fully
             informed by the investigator of the nature and potential risks of participation in
             this study.

          3. Patients must have had a diagnosis of symptomatic multiple myeloma (from IMWG see
             (Kyle et al,2003) meeting all three of the following criteria:

               -  Monoclonal immunoglobulin (spike on electrophoresis, or band on immunofixation)
                  on serum or on 24 hour urine.

               -  Bone marrow (clonal) plasma cells or plasmacytoma

               -  Related organ or tissue impairment (anemia, hypercalcemia, lytic bone lesions,
                  renal insufficiency, hyperviscosity or recurrent infections) (The Kyle et al 2003
                  definition of symptomatic Myeloma has been adapted based on the new exclusion
                  criteria defined in protocol amendment 1)

          4. Subjects must have received at least two prior lines of therapy and be refractory to
             the most recent line of therapy according to the following definitions: Refractory to
             most recent line of therapy Defined by disease progression during treatment or within
             60 - 100 days after the completion of the most recent line of therapy. This includes
             the development of disease progression during maintenance or consolidation therapy
             with high dose glucocorticoids, or any other specific MM therapy Sixty days is counted
             from the point in time when the first response assessment is performed after
             completion of the last line of therapy. At a maximum, disease progression should be
             documented within 100 days after the last day of the last dose of any anti-MM therapy,
             including if last regimen of the most recent line of therapy was Autologous Stem Cell
             Transplant (ASCT). Stable disease patients also part of the IMWG definition are not
             eligible for this trial. At study screening, Progressive Disease (PD) will be assessed
             by comparing screening values or symptoms in reference to the baseline (values or
             symptoms) of their last line of therapy. Should a patient have experienced an initial
             response on their last line of therapy, PD should be assessed in reference to the
             lowest values of the initial confirmed response Minimal Response(MR) / Partial
             Response (PR) / Complete Response (CR).

             Disease progression is defined by having one or more of the following:

               -  >25% increase in the level of serum monoclonal paraprotein, which must also be an
                  absolute increase of at least 5 g/L and confirmed on a repeat investigation.

               -  >25% increase in 24-hour urinary light chain excretion, which must also be an
                  absolute increase of at least 200 mg/24 h and confirmed on a repeat
                  investigation.

               -  >25% increase in plasma cells in a bone marrow aspirate or on bone marrow biopsy,
                  which must also be an absolute increase of at least 10%

               -  Definite increase in the size of existing lytic bone lesions or soft tissue
                  plasmacytomas.

               -  Development of new bone lesions or soft tissue plasmacytomas (not including
                  compression fracture).

               -  Development of hypercalcemia (corrected serum calcium > 11.5 mg/dL or 2.8 mmol/L
                  not attributable to any other cause).

          5. Subjects must have previously been treated with bortezomib and at least one of the
             following: lenalidomide or thalidomide

          6. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤ 2

          7. Patients must have the following hematological laboratory values:

               -  Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L (or ≥1.0 x 109/L if the neutropenia
                  is clinically related to progressive myeloma with bone marrow infiltration of >
                  50% involvement

               -  Hemoglobin ≥ 8.0 g/dl

               -  Platelets ≥ 75.0 x 109/L (or ≥ 50.0 x 109/L x if the thrombocytopenia is
                  clinically related to progressive myeloma with bone marrow infiltration > 50%
                  involvement

          8. Patients must have the following renal function as shown by :

               -  Calculated Creatinine Clearance (CrCL) > 30ml/min (Cockcroft and Gault formula)

          9. Patients must have adequate liver function as shown by:

               -  Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤ 2.5 x Upper
                  limit of normal (ULN)

               -  Serum bilirubin ≤ 1.5 x ULN

               -  Albumin ≥ 2.5 g/dl

         10. Patients must have the following non-hematological laboratory values:

               -  Serum potassium ≥ Lower Limit of Normal (LLN),

               -  Total serum calcium [corrected for serum albumin] or ionized calcium ≥LLN,

               -  Serum magnesium ≥ LLN

               -  Serum phosphorus ≥ LLN

               -  Normal thyroid function (TSH and free T4) (hypothyroidism correctable with
                  supplements is allowed)

         11. Baseline Multiple Uptake Gated Acquisition scan (MUGA) or echocardiogram (ECHO) must
             demonstrate Left Ventricular Ejection Fraction (LVEF) ≥ the lower limit of the
             institutional normal

         12. Patients must be willing and able to undergo bone marrow aspirates as per protocol,
             with/without bone marrow biopsy according to their center's practice. The bone marrow
             aspirate /biopsy must be adequate to allow for comparison for the later efficacy
             response assessments.

         13. Patients must have an M component at baseline above a minimum threshold of: 1g/dl
             (10g/L) for serum M component, or 200mg/24h urine M component.

        Exclusion criteria:

          1. Prior therapy with an Histone Deacetylase (HDAC) inhibitor for the treatment of
             Multiple Myeloma (MM)

          2. Patients with non-secretory MM

          3. Patients who have received allogenic stem cell transplantation < 12 months prior to
             study

          4. Patients who have had prior allogenic stem cell transplantation and show evidence of
             active graft versus-host disease that requires immunosuppressive therapy

          5. Patients with amyloidosis

          6. Patients with peripheral neuropathy > grade 2

          7. 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 Heart Rate (HR)< 50 bpm. Patients with pacemakers are
                  eligible if HR ≥ 50 bpm.

               -  Screening Electrocardiogram (ECG) with a corrected QT interval (QTc) > 450 msec

               -  Right bundle branch block + left anterior hemi-block (bi-fascicular block)

               -  Patients with myocardial infarction or unstable angina ≤ 6 months prior to
                  starting study drug

          8. Other clinically significant heart disease (e.g., Congestive Heart Failure (CHF NY)
             Heart Association class III or IV, uncontrolled hypertension, or history of poor
             compliance with an antihypertensive regimen)

          9. Impairment of GI function or GI disease that may significantly alter the absorption of
             LBH589

         10. Patients with unresolved diarrhea > CTCAE grade 1.

         11. Other concurrent severe and/or uncontrolled medical conditions that could cause
             unacceptable safety risks or compromise compliance with the protocol

         12. Patients using medications that have a relative risk of prolonging the QT interval or
             inducing torsades de pointes if the medications cannot be discontinued or switched to
             a different medication prior to starting study drug

         13. Concomitant use of CYP3A4 inhibitors

         14. Patients with an active bleeding diathesis or on any treatment with therapeutic doses
             of sodium warfarin (Coumadin®) or any other anti-vitamin K drug. Low doses of
             Coumadin® (e.g., ≤ 2 mg/day), or low doses of any other anti-vitamin K drug, for line
             patency is allowable

         15. Patients who have received chemotherapy, radiation therapy or any investigational
             drugs, bortezomib or other immunomodulatory therapy (e.g., thalidomide, lenalidomide)
             or immunotherapy ≤ 3 weeks prior to starting study drug or who have not recovered from
             side effects of such therapy

         16. Patients who have received high-dose corticosteroids as the only component of their
             most recent line of therapy

         17. Patients who have received steroids (e.g., dexamethasone) ≤ 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 subjects
             receive < 20 mg of prednisone or equivalent as indicated for other medical conditions
             (and not as maintenance or an anticancer therapy for MM), or up to 100 mg of
             hydrocortisone as premedication for a administration of certain medications or blood
             products, while enrolled in this study.

         18. Patients whose clinical condition would need valproic acid therapy during study or ≤ 5
             days prior to starting drug

         19. Patients who have undergone major surgery ≤ 4 weeks prior to starting study drug or
             who have not recovered from side effects of such therapy

         20. 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
             LBH589

         21. 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

         22. Patients with a current second malignancy or a prior malignancy within the last 5
             years except adequately treated basal cell or squamous cell skin cancer or in situ
             cervical cancer

         23. Patients with any significant history of non compliance to medical regimens or
             unwilling or unable to comply with the protocol or unable to grant reliable informed
             consent.