Phase II, Single-Center, Oral Panobinostat in Combination With Lenalidomide and Dexamethasone in Multiple Myeloma (MM)
Condition: Multiple Myeloma
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell
Intervention: Panobinostat; Lenalidomide; Dexamethasone
Intervention description: Each cycle is 28 days. Panobinostat will be given 20 mg: Days 1,3,5,15,17,19.; Each cycle is 28 days. Lenalidomide will be given 25 mg: Days 1-21.; Each cycle is 28 days. Dexamethasone will be given for patients 75 years old and younger a dose of 40 mg on Days 1, 8 and 15. Dexamethasone will be given for patients older than 75 years old, 20 mg on Days 1, 8 and 15.
Intervention MeSH terms: Dexamethasone; Lenalidomide; Panobinostat
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 32.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Panobinostat; Lenalidomide; Dexamethasone

Summary:

      The purpose of this clinical research study is to find out the effects of a drug called
      panobinostat (LBH589) when given to people like you with multiple myeloma in combination with
      the drugs lenalidomide and dexamethasone. The safety of this combination of drugs will also
      be studied. Your physical state, changes in the state of your multiple myeloma, and
      laboratory findings taken while on-study will help us decide if panobinostat combined with
      dexamethasone and lenalidomide is safe and effective.

      This goal of this study therefore is to determine the activity of the combination of
      panobinostat thrice weekly every other week, lenalidomide, and weekly dexamethasone in a
      similar group of subjects. The doses of lenalidomide and dexamethasone will be that which is
      approved by the FDA for multiple myeloma and you will take each drug at a specific frequency
      over a 4 week (28 day) period. This period is called a "study cycle".
    

Eligibility criteria:

        Inclusion Criteria:

          1. Patients must have a history of symptomatic multiple myeloma according to the
             International Myeloma Working Group criteria (IMWG, 2003), as defined as the following
             three criteria:

               1. Clonal plasma cells >10% on bone marrow biopsy

               2. A monoclonal protein (paraprotein) in either serum or urine(except in cases of
                  non-secretory myeloma)

               3. Evidence of end-organ damage felt related to the plasma cell disorder (related
                  organ or tissue impairment, ROTI, commonly referred to by the acronym "CRAB"):

                    -  Hypercalcemia serum Ca ≥ 11.5 mg/dL or

                    -  Renal insufficiency attributable to myeloma. Serum creatinine > 2mg/dL

                    -  Anemia: Normochromic, normocytic with a hemoglobin value > 2g/dL below the
                       lower limit of normal or a hemoglobin <10 g/dL

                    -  Bone lesions (lytic lesions, severe osteopenia or pathologic fractures

          2. Patients must have received at least one prior line of therapy. For example; One prior
             line of therapy may consist of all predetermined components of induction followed by
             autologous stem cell transplantation and maintenance.

          3. Patient has relapsed or relapsed/refractory MM.

               1. Relapsed is defined as the development of disease progression following the
                  achievement of stable disease (SD) or better to the most recent anti-MM regimen.

               2. Refractory is defined as experiencing less than a partial response (PR) to or
                  progressive disease (PD) within 6 months after completion of the most recent
                  anti-MM regimen.

          4. Patients must currently have measureable disease, as defined as:

               1. a. Serum M protein ≥ 1.0 g/dl (≥ 10 mg/l)

               2. Urine M protein ≥ 200 mg/24h

               3. Serum free light chain assay: involved FLC level ≥ 10mg/dl (≥ 100 mg/l) provided
                  serum FLC ratio is abnormal

               4. If no monoclonal protein is detected (non-secretory disease), then > 30%
                  monoclonal bone marrow plasma cells.

          5. Patients must be suitable (according to their local product information) for treatment
             or re-treatment with lenalidomide & dexamethasone. Note: patients previously treated
             with lenalidomide & dexamethasone are eligible to participate in the trial.

          6. Male or female adults ≥ 18 years old

          7. ECOG Performance Status ≤ 2

          8. Life expectancy > 12 weeks

          9. Patients must have the following laboratory values:

               1. ANC ≥ 1.5 x 109/L for patients in whom < 50% of bone marrow nucleated cells are
                  plasma cells; or an ANC > 1.0 x 109/Lfor patients in whom > 50% of bone marrow
                  nucleated cells are plasma cells.

               2. Hemoglobin ≥ 9 g/dl

               3. Platelets ≥ 75x 109/L for patients in whom < 50% of bone marrow nucleated cells
                  are plasma cells; or > 50 x 109/L for patients in whom > 50% of bone marrow
                  nucleated cells are plasma cells.

               4. Calculated CrCl ≥ 50 mL/min (MDRD Formula)

               5. Hepatic:

               6. AST and ALT ≤ 2.5 x ULN,

               7. Serum bilirubin ≤ 1.5 x ULN

               8. Electrolytes:

               9. Serum potassium ≥ LLN,

              10. Total serum calcium [corrected for serum albumin] or ionized calcium ≥LLN

              11. Serum magnesium ≥ LLN

              12. Serum phosphorus ≥ LLN

              13. Normal thyroid function (TSH and free T4) (Clinically euthyroid patients are
                  acceptable).

         10. Able to sign informed consent and to comply with the protocol

        Exclusion criteria

          1. Patients who will need valproic acid for any medical condition during the study or
             within 5 days prior to first panobinostat treatment

          2. Impaired cardiac function or clinically significant cardiac diseases, including any
             one of the following:

               1. History or presence of sustained ventricular tachyarrhythmia. (Patients with a
                  history of atrial arrhythmia are eligible but should be discussed with Novartis
                  prior to enrollment)

               2. Any history of ventricular fibrillation or torsade de pointes

               3. Bradycardia defined as HR< 50 bpm. Patients with pacemakers are eligible if
                  resting HR ≥ 50 bpm.

               4. Screening ECG with a QTc > 450 msec

               5. Right bundle branch block + left anterior hemiblock (bifascicular block)

               6. Patients with myocardial infarction or unstable angina ≤ 6 months prior to
                  starting study drug

               7. 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)

          3. Impairment of GI function or GI disease that may significantly alter the absorption of
             panobinostat

          4. Patients with diarrhea > CTCAE grade 2

          5. Other concurrent severe and/or uncontrolled medical conditions (e.g., uncontrolled
             diabetes or active or uncontrolled infection) including abnormal laboratory values,
             that could cause unacceptable safety risks or compromise compliance with the protocol

          6. 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

          7. Patients who have received targeted agents within 2 weeks or within 5 half-lives of
             the agent and active metabolites (whichever is longer) and who have not recovered from
             side effects of those therapies.

          8. 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.

          9. Subject has received a cumulative dose of corticosteroids more than the equivalent of
             ≥ 140 mg of prednisone within the 2-week period before Cycle 1 Day 1.

         10. Patients who have undergone major surgery ≤ 4 weeks prior to starting study drug or
             who have not recovered from side effects of such therapy

         11. Women who are pregnant or breast feeding or women of childbearing potential (WOCBP)
             not using an effective method of birth control. WOCBP are defined as sexually mature
             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 24hrs of receiving the first dose of study
             medication.

         12. Male patients whose sexual partners are WOCBP not using effective birth control

         13. Patients with a prior malignancy with in the last 5 years (except for basal or
             squamous cell carcinoma, or in situ cancer of the cervix)

         14. Patients with known positivity for human immunodeficiency virus (HIV) ) or hepatitis
             C; baseline testing for HIV and hepatitis C is not required

         15. 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.

         16. Patients with a history of Deep Vein Thrombosis or thromboembolism within < 6 months
             prior to starting study treatment

         17. Patients for whom prophylactic anticoagulation therapy (eg. 325mg aspirin PO daily or
             warfarin (Coumadin®) 1-2 mg/day, or any other coumarin-derivative anticoagulants) is
             not an option.

         18. Patients who have received allogeneic stem cell transplantation < 12 months prior to
             entering the study

         19. Patients who have had prior allogeneic stem cell transplantation and show evidence of
             active graft-versus-host disease that requires immunosuppressive therapy.

         20. All patients must agree to follow the requirements for lenalidomide counseling,
             pregnancy testing and birth control. For women of childbearing potential (WOCBP) this
             includes pregnancy testing prior to prescribing lenalidomide and to either commit to
             continued abstinence from heterosexual intercourse or begin acceptable methods of
             birth control for 28 days prior to prescribing lenalidomide, during therapy and for 28
             days after the last dose of lenalidomide. WOCBP must also agree to ongoing pregnancy
             testing. Men must agree to use a latex condom during sexual contact with a WOCBP even
             if they have had a successful vasectomy and must agree not to donate semen during
             study drug therapy and for a period of time after therapy. All patients must abstain
             from donating blood, agree not to share lenalidomide with others and be counseled
             about the risks of lenalidomide. See Appendix 2 requirements including the definition
             of WOCBP.