Melphalan and Panobinostat (LBH589) for the Treatment of Patients With Recurrent Multiple Myeloma

OBJECTIVES:

Primary

• To establish the maximum tolerated dose (MTD) and determine the dose-limiting toxicities (DLT) of panobinostat in combination with melphalan in patients with relapsed or refractory multiple myeloma. (Phase I)
• To determine the dose of this regimen to be used in the Phase II portion of the study. (Phase I)
• To determine the efficacy as evidenced by the response rate (combined complete response, very good partial response, partial response, and minimal response) in patients treated with this regimen. (Phase II)

Secondary

• To obtain preliminary evidence of efficacy of the combination of LBH589 and melphalan for patients with relapsed or refractory multiple myeloma. (Phase I)
• To determine the safety and tolerability of this regimen in these patients. (Phase II)
• To determine time to disease progression, time to response, and duration of response in patients treated with this regimen. (Phase II)
• To determine progression-free survival and overall survival of patients treated with this regimen. (Phase II)

OUTLINE: This is a multicenter, phase I, dose-escalation study followed by a phase II study.

Patients receive oral panobinostat once daily on days 1, 3, 5, 8, 10, and 12 and oral melphalan once daily on days 1, 3 and 5. Treatment repeats every 28 days for up to 8 courses in the absence of disease progression or unacceptable toxicity.

Inclusion criteria

• Diagnosis of multiple myeloma, based on the following criteria:

• Major criteria

• Plasmacytomas on tissue biopsy (1)
• Bone marrow plasmacytosis (> 30% plasma cells) (2)
• Monoclonal immunoglobulin (Ig) spike on serum electrophoresis, IgG > 3.5 g/dL or IgA > 2.0 g/dL, and kappa or lambda light chain excretion > 1 g/day on 24-hour urine protein electrophoresis (3)
• Minor Criteria

• Bone marrow plasmacytosis (10-30% plasma cells) (a)
• Monoclonal immunoglobulin present but of lesser magnitude than given under major criteria (b)
• Lytic bone lesions ©)
• Normal IgM < 50 mg/dL, IgA < 100 mg/dL, or IgG < 600 mg/dL (d)
• Meets any of the following sets of multiple myeloma diagnostic criteria:

• Any two of the major criteria
• Major criterion 1 plus minor criterion b, c, or d
• Major criterion 3 plus minor criterion a or c
• Minor criteria a, b, and c, OR a, b, and d
• Measurable disease, defined as a monoclonal immunoglobulin spike on serum electrophoresis of ≥ 1 g/dL and/or urine monoclonal immunoglobulin spike of ≥ 200 mg/24 hours, or evidence of lytic bone disease
• Must have received ≥ 1 prior treatment regimen OR refractory to most recent chemotherapy

• Relapsed following stabilization or response to standard first-line chemotherapy (e.g., vincristine, doxorubicin hydrochloride, and prednisone or melphalan and prednisone) or first-line high-dose chemotherapy
• Refractory (i.e., failure to achieve at least complete or partial response or stable disease) to most recent chemotherapy, whether or not containing systemic corticosteroids
• Prior treatment with ≤ 4 days of a total of 400 mg of prednisone (or an equivalent potency of another steroid) for myeloma is not considered a regimen
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
• Life expectancy > 3 months
• Platelet count ≥ 75 x 10^9/L (≥ 50 x 10^9/L if bone marrow is extensively infiltrated)
• Absolute neutrophil count ≥ 1.5 x 10^9/L (≥ 1.0 x 10^9/L if bone marrow is extensively infiltrated)
• Aspartate transaminase (AST) and Alanine transaminase (ALT) ≤ 2.5 times upper limit of normal (ULN)
• Serum bilirubin ≤ 1.5 times ULN
• Creatinine clearance ≥ 30 mL/min; creatinine > 10 mL/min and < 30 mL/min due to significant myelomatous involvement of the kidneys allowed with medical director approval
• Serum potassium ≥ lower limit of normal (LLN)
• Serum magnesium ≥ LLN
• Serum phosphorus ≥ LLN
• Prior localized radiotherapy

Exclusion criteria

• Plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes (POEMS syndrome)
• Plasma cell leukemia
• Pregnant or nursing females; fertile patients must use effective contraception
• Peripheral neuropathy > grade 2
• Impaired cardiac function or clinically significant cardiac disease (including congenital long QT syndrome, history or presence of sustained ventricular tachyarrhythmia; history of ventricular fibrillation or Torsade de Pointes; bradycardia, defined as heart rate (HR) < 50 beats per minute (bpm) [pacemaker allowed provided HR ≥ 50 bpm]; corrected QT interval > 450 msec on screening ECG; left ventricular ejection fraction below normal on screening ECHO or multigated acquisition (MUGA) scan; right bundle branch block with left anterior hemiblock (bifascicular block); myocardial infarction or unstable angina within the past 6 months; New York Heart Association class III-IV congestive heart failure; uncontrolled hypertension; history of labile hypertension; history of poor compliance with an antihypertensive regimen)
• Impaired gastrointestinal (GI) function or GI disease that may significantly alter the absorption of panobinostat
• Prior malignancy within the past 5 years except basal cell or squamous cell carcinoma or carcinoma in situ of the cervix
• Other concurrent severe and/or uncontrolled medical or psychiatric conditions (e.g., uncontrolled diabetes or active or uncontrolled infection), including abnormal laboratory values that could cause unacceptable safety risks or compromise protocol compliance
• Known positivity for HIV or hepatitis B or C
• Severe hypercalcemia (i.e., serum calcium ≥ 14 mg/dL)
• Significant history of non-compliance to medical regimens or unwillingness or inability to comply with instructions given by the study staff
• Concurrent medication that risk prolonging the QT interval or inducing Torsades de Pointes
• Prior panobinostat
• Received chemotherapy, bortezomib, thalidomide, lenalidomide or arsenic trioxide within 3 wks of enrollment (with the exception of nitrosoureas within 6 wks of enrollment)
• Received corticosteroids (>10 mg/day prednisone or equivalent) within three weeks before enrollment.
• Received immunotherapy within < 8 weeks; antibody 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.