Phase II, Single-Center, Oral Panobinostat in Combination With Lenalidomide and Dexamethasone in Multiple Myeloma (MM)

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".

The study drug, panobinostat, is made by Novartis Pharmaceuticals Corporation. Panobinostat has not yet been approved by the Food and Drug Administration (FDA) and thus is considered an experimental drug in this research study. Panobinostat is not available to you "on the market" (available for you to buy). It is only available in clinical trials for patients like you with your medical condition. Panobinostat is a drug that may slow down the growth of multiple myeloma or kill multiple myeloma cells by blocking certain enzymes (proteins produced by cells). Panobinostat has shown effects against cancers such as multiple myeloma in laboratory studies and in studies using animals; however, it is not known if this medicine will show the same activity in humans. As of 31st December 2009, a total of 1116 patients have already received treatment with panobinostat.

Unlike panobinostat, lenalidomide (Revlimid©) and dexamethasone are approved by the FDA and are already available for purchase on the US market. Clinical trials have shown that lenalidomide, especially taken with dexamethasone, produces positive clinical responses with manageable side effects when given to subjects with multiple myeloma.

In this study, subjects will take panobinostat capsules, lenalidomide, and dexamethasone all orally. The purpose of this combination is to interfere with the cancerous cells in multiple and different ways as each of these drugs acts differently on cancer cells. By combining the drugs and giving them at the same time, it might be possible to slow the progression of your disease, rather than if study drugs were given separately. Researchers have combined laboratory studies on animals with this drug combination and the combined effect has been shown to be worthwhile to justify clinical trials in humans.

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.