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Efficacy of Panobinostat in Patients With Relapsed and Bortezomib-refractory Multiple Myeloma (MACS1271)

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ClinicalTrials.gov Identifier: NCT01083602
Recruitment Status : Completed
First Posted : March 10, 2010
Results First Posted : March 27, 2015
Last Update Posted : December 21, 2017
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Brief Summary:
This study is designed to assess the effectiveness of the combination of Panobinostat plus Bortezomib and Dexamethasone in patients with relapsed and bortezomib refractory Multiple Myeloma.

Condition or disease Intervention/treatment Phase
Relapsed and Bortezomib Refractory Multiple Myeloma Refractory Multiple Myeloma Multiple Myeloma in Relapse Drug: panobinostat Drug: bortezomib Drug: dexamethasone Phase 2

Detailed Description:
This is a phase II, two stage, single arm, open label, multi-center study of oral PAN in combination with BTZ/Dex in patients with relapsed and refractory multiple myeloma, who are bortezomib-refractory and have received at least 2 prior lines of therapy. Patients must have been exposed to an iMID (lenalidomide or thalidomide) and progressed on or within 60 days of their last BTZ-containing line of therapy.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 55 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II, Multi-center, Single Arm, Open Label Study of Panobinostat in Combination With Bortezomib and Dexamethasone in Patients With Relapsed and Bortezomib-refractory Multiple Myeloma
Study Start Date : June 2010
Actual Primary Completion Date : February 2014
Actual Study Completion Date : February 2014

Arm Intervention/treatment
Experimental: panobinostat + bortezomib & dexamethasone
panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory multiple myeloma
Drug: panobinostat
PAN 20 mg PO given TIW, weeks 1&2 of each 3-week cycle;• BTZ 1.3 mg/m2 IV push given BIW weeks 1&2 of each 3 week cycle (days 1,4,8 and 11);• Dex 20 mg PO given QIW, weeks 1&2 of each 3-week cycle (days 1,2,4,5,8,9,11 and 12)
Other Names:
  • LBH589
  • PAN

Drug: bortezomib
Other Name: BTZ

Drug: dexamethasone
Other Name: DEX

Primary Outcome Measures :
  1. Overall Response Rate (PR+nCR+CR) [ Time Frame: after eight cycyles of treatment (24 weeks) ]
    Overall response rate=(PR+nCR+CR) CR= < 5% plasma cells in bone marrow. No confirmation on bone marrow plasma cell (additional assessment) is needed to document CR except patients with non-secretory myeloma where the bone marrow examination must be repeated after an interval of at least 6 weeks, Absence of M-protein in serum and urine by immunofixation,nCR same as CR without out Absence of M-protein in serum and urine by immunofixation,PR+ 50% reduction of serum M-protein and sofft tissue Plasmacytomas all for more than 6 weeks.

Secondary Outcome Measures :
  1. Responders to Treatment [ Time Frame: after eight cycyles of treatment (24 weeks) ]
    The primary endpoint for this phase II study of patients with bortezomib-refractory MM is response after a maximum of 8 cycles of therapy as defined by the modified EBMT criteria.

  2. Time to Response (Greater Than or Equal to PR) Based on Investigator Assessment [ Time Frame: after eight cycyles of treatment (24 weeks) ]
    Time to response is defined as the time from the date of first administration of study treatment to the date of first documented evidence of CR or nCR or PR (whichever status is recorded first). Patients who do not have a response of PR or better by the data cut-off date are censored.

  3. Progression-free Survival [ Time Frame: 24 weeks ]
    Progression-free survival (PFS) was defined as the time from the date of first study treatment to first occurrence of documented progressive disease /relapse or death. Time from randomization until disease progression or death by Kaplan-Meier estimates

  4. Time to Progression [ Time Frame: 24 weeks ]
    Time from randomization until objective tumor progression; does not include deaths-- Kaplan-Meier estimates

  5. Over All Survival [ Time Frame: 24 weeks ]
    Kaplan Meier estimates- median time to event

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Patient has a previous diagnosis of multiple myeloma, based on IMWG 2003 definitions. All three of the following criteria must have been met:

    • Monoclonal immunoglobulin (M component) on electrophoresis, and on immunofixation on serum or on total 24 hour urine
    • Bone marrow (clonal) plasma cells ≥ 10% or biopsy proven plasmacytoma
    • Related organ or tissue impairment (CRAB symptoms: anemia, hypercalcemia, lytic bone lesions, renal insufficiency, hyperviscosity, amyloidosis or recurrent infections)
  2. Patient must have relapsed and refractory MM and must require treatment for the relapsed disease
  3. Patients must have received at least 2 prior lines of therapy which include an IMiD (thalidomide or lenalidomide)
  4. Patient must be refractory to the last bortezomib containing line of therapy given in the relapsed and refractory setting defined as:

    • having progressed on or within 60 days of the last bortezomib-containing line of therapy
  5. Patient has measurable disease on M protein at study screening defined by at least one of the following measurements as per thresholds clarified in IMWG 2003 disease definitions (Kyle, et al 2003):

    • Serum M-protein ≥ 1 g/dL (≥ 10 g/L)
    • Urine M-protein ≥ 200 mg/24 h
  6. Patients treated with local radiotherapy with or without concomitant exposure to steroids for pain control or management of cord/nerve root compression, are eligible. Two weeks must have lapsed since last date of radiotherapy, which is recommended to be a limited field. Patients who require concurrent radiotherapy should have entry to the protocol deferred until the radiotherapy is completed and 2 weeks have passed since the last date of therapy
  7. Patient's age is ≥ 18 years at time of signing the informed consent
  8. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ≤ 2
  9. Patient has the following laboratory values within 3 weeks before starting study drug (lab tests may be repeated, as clinically indicated, to obtain acceptable values before screen fail is concluded but supportive therapies are not to be administered within the week prior to screening tests for absolute neutrophil count or platelet counts)

    • Absolute neutrophil count (ANC) ≥ 1.0 x 109 /L
    • Platelet count ≥ 70 x 109 /L
    • Serum potassium, magnesium, phosphorus, within normal limits (WNL) for institution
    • Total calcium (corrected for serum albumin) or ionized calcium ≥ LLN, and not higher than CTCAE grade 1 in case of elevated value

    Note: Potassium, calcium, magnesium, and/or phosphorus supplements may be given to correct values that are < LLN:

    • AST/SGOT and ALT/SGPT ≤ 2.5 x ULN
    • Serum total bilirubin ≤ 1.5 ULN (or ≤ 3.0 x ULN if patient has Gilbert syndrome)
    • Serum creatinine levels ≤ 2.5 x ULN, or calculated creatinine clearance ≥ 40 ml/min
  10. Patient has provided written informed consent prior to any screening procedures
  11. Patient is able to swallow capsules
  12. Patient must be able to adhere to the study visit schedule and other protocol requirements
  13. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test at within 7 days prior to start of study treatment

Exclusion Criteria:

  1. Primary refractory disease (patients that never reached at least an MR for over 60 days under any prior therapy)
  2. Patients who have a history of prior MM treatment with a DAC inhibitor including panobinostat
  3. Patients who have had prior allogeneic stem cell transplantation and show evidence of active graft-versus-host disease that requires immunosuppressive therapy
  4. Peripheral neuropathy ≥ CTCAE grade 2
  5. Patients who will need valproic acid for any medical condition during the study or within 5 days prior to the first administration of study drug / treatment or who cannot be switch to safely to alternative anti-epileptic medication
  6. Patients who have impaired cardiac function including any of the following:

    • Congenital long QT syndrome, complete left bundle branch block or use of a permanent cardiac pacemaker, history or presence of ventricular tachyarrhythmias, clinically significant resting bradycardia (< 50 beats per minute). Right bundle branch block + left anterior hemiblock (bifascicular block)
    • QTcF > 450 msec on screening ECG
    • Presence of unstable atrial fibrillation. Patients with stable atrial fibrillation are allowed in the study provided they do not meet other cardiac or prohibited drug exclusion criteria
    • Previous history of angina pectoris or acute MI within 6 months
    • Congestive heart failure (New York Heart Association functional classification III-IV)
    • Patient has any other clinically significant cardiovascular disease (e.g. uncontrolled hypertension)
  7. Patient has an impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of panobinostat (e.g., ulcerative disease, uncontrolled nausea, vomiting, malabsorption syndrome, obstruction, or significant small bowel resection)
  8. Patient has unresolved diarrhea ≥ CTCAE grade 2
  9. Patients who have any other concurrent severe and/or uncontrolled medical condition(s) including, but not limited to: uncontrolled diabetes mellitus, active or uncontrolled infection, chronic obstructive or chronic restrictive pulmonary disease (e.g. dyspnea at rest from any cause), symptomatic thyroid dysfunction, significant bleeding tendency, that could cause unacceptable safety risks or compromise compliance with the protocol
  10. Patients who are using medications that have a known relative risk of prolonging the QT interval or of inducing Torsade de Pointes, where such treatment cannot be discontinued or switched to a different medication prior to starting study drug
  11. Women who are pregnant or breast feeding
  12. Patients with evidence of another malignancy not in remission or history of such a malignancy within the last 5 years (except for treated basal or squamous cell carcinoma, or in situ cancer of the cervix)
  13. Patients who have received prior to starting study treatment either radiation therapy to > 30% of marrow-bearing bone within 4 weeks; myelotoxic chemotherapy within 4 weeks; or immunotherapy within 8 weeks; or who have not yet recovered from side effects of such therapies
  14. 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
  15. Use of chemo-, biologic or immunologic therapy and/or other investigational agents while the patient is on study treatment.
  16. Patient taking any anti-cancer therapy concomitantly (bisphosphonates are permitted only if commenced prior to the start of screening period)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01083602

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United States, California
University of California at Los Angeles
Los Angeles, California, United States, 90095
Stanford University Medical Center Division of Hematology
Stanford, California, United States, 94305-5826
United States, Florida
H. Lee Moffitt Cancer Center & Research Institute
Tampa, Florida, United States, 33612
United States, Georgia
Emory University School of Medicine/Winship Cancer Institute Dept. of Winship Cancer Inst.
Atlanta, Georgia, United States, 30322
Georgia Regents University MedCollege of GA Cancer Ctr 2
Augusta, Georgia, United States, 30912
United States, Illinois
Hematology/Oncology of the North Shore Orchard Healthcare Res. Inc.
Skokie, Illinois, United States, 60076
United States, Massachusetts
Dana Farber Cancer Institute
Boston, Massachusetts, United States, 02115
United States, New Jersey
Somerset Hematology Oncology Associates Somerset Hema Oncol Assoc (2)
Somerset, New Jersey, United States, 08873
United States, New York
Montefiore Medical Center
Bronx, New York, United States, 10467
United States, North Carolina
Duke University Medical Center Dept. of DUMC (4)
Durham, North Carolina, United States, 27710
United States, Tennessee
Vanderbilt University Medical Center, Clinical Trials Center Vanderbilt UMC
Nashville, Tennessee, United States, 37212
United States, Texas
MD Anderson Cancer Center/University of Texas MD Anderson CC
Houston, Texas, United States, 77030
United States, Wisconsin
Medical College of Wisconsin
Milwaukee, Wisconsin, United States, 53226
Sponsors and Collaborators
Novartis Pharmaceuticals
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
Principal Investigator: Steven Young, M.D. Somerset Hematology Oncology
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01083602    
Other Study ID Numbers: CLBH589DUS71
First Posted: March 10, 2010    Key Record Dates
Results First Posted: March 27, 2015
Last Update Posted: December 21, 2017
Last Verified: November 2017
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
Multiple Myeloma
Relapsed Multiple Myeloma
Refractory Multiple Myeloma
Additional relevant MeSH terms:
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Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Anti-Inflammatory Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Histone Deacetylase Inhibitors
Enzyme Inhibitors