Melphalan and Panobinostat in Treating 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.

DISEASE CHARACTERISTICS:

- 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 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

- Nonmeasurable disease (i.e., patients with nonsecretory or oligosecretory
multiple myeloma) not allowed

- 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

- No plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy,
monoclonal protein, and skin changes (POEMS syndrome)

- No plasma cell leukemia

PATIENT CHARACTERISTICS:

- 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)

- AST and 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

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- No peripheral neuropathy > grade 2

- No impaired cardiac function or clinically significant cardiac disease, including any
1 of the following:

- 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

- QTc > 450 msec on screening ECG

- LVEF below normal on screening ECHO or MUGA scan

- Right bundle branch block with left anterior hemiblock (bifascicular block)

- Myocardial infarction or unstable angina within the past 6 months

- Other clinically significant heart disease, including any of the following:

- NYHA class III-IV congestive heart failure

- Uncontrolled hypertension

- History of labile hypertension

- History of poor compliance with an antihypertensive regimen

- No impairment of gastrointestinal (GI) function or GI disease that may significantly
alter the absorption of panobinostat

- No prior malignancy within the past 5 years except basal cell or squamous cell
carcinoma or carcinoma in situ of the cervix

- No 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

- No known positivity for HIV or hepatitis B or C

- No severe hypercalcemia (i.e., serum calcium ≥ 14 mg/dL)

- No significant history of non-compliance to medical regimens or unwillingness or
inability to comply with instructions given by the study staff

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- Recovered from all prior therapy

- Prior localized radiotherapy allowed

- At least 3 weeks since prior chemotherapy (≥ 6 weeks for nitrosoureas)

- At least 3 weeks since prior corticosteroids (> 10 mg/day prednisone or equivalent)

- More than 4 weeks since prior major surgery

- Recent kyphoplasty allowed at investigator's discretion

- More than 8 weeks since prior immunotherapy

- More than 4 weeks since prior antibody therapy

- More than 2 weeks since prior radiotherapy to > 30% of marrow-bearing bone

- No prior panobinostat

- No concurrent medication that risk prolonging the QT interval or inducing Torsades de
Pointes