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

NCT00743288 | Completed Phase 1 Results

• 3 other identifiers: CDR0000612441ONCOTHER-CLBH589BUS15TLBH
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 4

Brief Summary

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.

Conditions

Multiple Myeloma

Keywords

stage I multiple myeloma; stage II multiple myeloma; stage III multiple myeloma; refractory multiple myeloma

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (2)

• 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

Study Arms (1)

Melphalan and Panobinostat

EXPERIMENTAL

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; Drug: Panobinostat

Interventions

Melphalan DRUG

Same as above

Also known as: Phenylalanine mustard, Alkeran

Melphalan and Panobinostat

Panobinostat DRUG

Also known as: LBH589

Melphalan and Panobinostat

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Oncotherapeutics: lead
• Novartis: collaborator

Study Sites (4)

Comprehensive Blood and Cancer Center

Bakersfield, California, 93309-0633, United States

Location

James R. Berenson MD, Incorporated

West Hollywood, California, 90069, United States

Location

Rocky Mountain Cancer Centers - Denver Midtown

Denver, Colorado, 80218, United States

Location

Center for Cancer and Blood Disorders

Bethesda, Maryland, 20817, United States

Location

Related Publications (1)

• Berenson JR, Hilger JD, Yellin O, Boccia RV, Matous J, Dressler K, Ghazal HH, Jamshed S, Kingsley EC, Harb WA, Noga SJ, Nassir Y, Swift RA, Vescio R. A phase 1/2 study of oral panobinostat combined with melphalan for patients with relapsed or refractory multiple myeloma. Ann Hematol. 2014 Jan;93(1):89-98. doi: 10.1007/s00277-013-1910-2. Epub 2013 Oct 18.

  PMID: 24135804 RESULT

MeSH Terms

Conditions

Multiple Myeloma

Interventions

Melphalan; Panobinostat

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phenylalanine; Amino Acids, Aromatic; Amino Acids, Cyclic; Amino Acids; Amino Acids, Peptides, and Proteins; Hydroxamic Acids; Hydroxylamines; Amines; Hydroxy Acids; Carboxylic Acids; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Director, Clinical Operations
• Organization: Oncotherapeutics

lthulin@oncotherapeutics.com

323-623-1200

Study Officials

• James R. Berenson, MD

  Oncotherapeutics

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 27, 2008
• First Posted: August 28, 2008
• Study Start: July 1, 2008
• Primary Completion: November 1, 2012
• Study Completion: December 1, 2012
• Last Updated: May 8, 2014
• Results First Posted: April 25, 2014

Record last verified: 2014-04

Locations

US (4)