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

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as melphalan, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Panobinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving melphalan together with panobinostat may kill more cancer cells. PURPOSE: This phase I/II trial is studying the side effects and best dose of melphalan when given together with panobinostat in treating patients with recurrent multiple myeloma.

Detailed Description
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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.

Official Title
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A Phase I/II Study of Oral Melphalan Combined With LBH589 for Patients With Relapsed or Refractory Multiple Myeloma (MM)

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Melphalan
* Drug: Panobinostat


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Melphalan and Panobinostat<br>Schedule A: 10mg/daily of LBH589 PO on days 1, 3 and 5 of weeks 1-4 of a 28-day cycle and melphalan PO at 0.05 mg/kg on days 1-5 of week 1. Toxicity led to the following changes in dose and schedule Schedule B1: 10mg/daily of LBH589 PO on days 1, 3 and 5 of weeks 1-4 and 0.05 mg/kg melphalan PO on days 1, 3 and 5 of week 1. Schedule B2: 20mg/daily of LBH589 PO on days 1, 3 and 5 of weeks 1-4 and 0.05 mg/kg melphalan POon days 1, 3 and 5 of week 1. Schedule C: 20mg/daily of LBH589 PO on days 1, 3 and 5 of weeks 1 and 2 and 0.05 mg/kg melphalan PO on days 1, 3 and 5 of week 1 Schedule D1: 15 mg/daily LBH589 PO and 0.05 mg/kg melphalan PO on days 1, 3 and 5 of week 1. Schedule D2: 15 mg/daily LBH589 PO and 0.10 mg/kg melphalan PO on days 1, 3 and 5 of week 1. Schedule D3: 20 mg/daily LBH589 PO and 0.05 mg/kg melphalan PO on days 1, 3 and 5 of week 1. | Drug: Melphalan<br>* Same as above<br>* Other names: Phenylalanine mustard, Alkeran;Drug: Panobinostat<br> <br> * Other names: LBH589;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) | Phase 1: to determine the MTD of panobinostat (LBH589) in combination with melphalan to be used in the Phase 2 portion of the study | 12 months | 
| MTD | Phase 1: to determine MTD of melphalan in combination with panobinostat to be used in the Phase 2 portion of the study | 12 months | 
| Overall Response Rate (ORR) and Clinical Benefit Rate (CBR) [ORR= Complete Response (CR) + Very Good Partial Response (VGPR) + Partial Response (PR)]; CBR=ORR + Minimal Response (MR)] Following Treatment With Panobinostat and Melphalan | Responses were evaluated according to criteria modified from those developed by Blade et al., 1998 The reference point for evaluating response improvement is the baseline. This baseline reference point is also valid when a patient has already achieved a response and transitions through into a better response grade. | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response |  | First evidence of PR or better (for overall response) and MR or better (for clinical benefit response) to start of disease progression or death | 
| Time to Progression |  | Time from the start of treatment to progressive disease | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage I multiple myeloma, stage II multiple myeloma, stage III multiple myeloma, refractory multiple myeloma