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LBH589 Alone or in Combination With Erythropoietin Stimulating Agents (ESA) in Patients With Low or Int-1 Risk Myelodysplastic Syndromes (MDS) (GEPARD)

This study has been terminated.
(The study was terminated due to lack of efficacy of single agent LBH589 in the 4 month open label core phase and due to enrollment difficulties.)
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT01034657
First received: December 16, 2009
Last updated: November 30, 2016
Last verified: November 2016
  Purpose
This study assessed the efficacy and safety of LBH589 as single agent and in combination with ESA in red blood cell transfusion-dependent Low and Int-1 MDS patients being either refractory to ESA or with a low probability of response. The study had a non-randomized core phase followed by a randomized phase.

Condition Intervention Phase
Myelodysplastic Syndrome (MDS)
Drug: LBH589
Drug: Epoetin Alfa
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A One Year, Open Label, Multicenter Trial of LBH589 Alone or in Combination With ESA in Red Blood Cell Transfusion-dependent LOW and INT-1 MDS Patients Being Either Refractory to ESA or With a Low Probability of Response - the GErman PAnobinostat Low Risk MDS Trial - GEPARD Study

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Percentage of Participants With Hematological Response of the Erythropoetic System (HI-E) - Core Phase [ Time Frame: 16 weeks ]
    HI-E was assessed according to the modified international working group (IWG) criteria for HI. Erythroid response (pretreatment, <11 g/dL): Hgb increase by ≥ 1.5 g/dL, relevant reduction of units of RBC transfusions by an absolute number of at least 4 RBC transfusions/8 wk compared with the pretreatment transfusion number in the previous 8 wk, and only RBC transfusions given for a Hgb of ≤ 9.0 g/dL pretreatment were counted in the RBC transfusion response evaluation; Platelet response (pretreatment, < 100 x 109/L): absolute increase of ≥ 30 x 109/L for participants starting with > 20 x 109/L and platelets Increase from < 20 x 109/L to > 20 x 109/L and by at least 100%; Neutrophil response (pretreatment, < 1.0 x 109/L): at least 100% increase and an absolute increase > 0.5 x 109/L; Progression or relapse after HI: At least 1 of the following: At least 50% decrement from maximum response levels in granulocytes or platelets, reduction in Hgb by ≥1.5 g/dL, or transfusion dependence.


Secondary Outcome Measures:
  • Percentage of Participants With HI-E - Randomized Phase [ Time Frame: 32 weeks, 52 weeks ]
    HI-E was assessed according to the modified international working group (IWG) criteria for HI. Erythroid response (pretreatment, <11 g/dL): Hgb increase by ≥ 1.5 g/dL, relevant reduction of units of RBC transfusions by an absolute number of at least 4 RBC transfusions/8 wk compared with the pretreatment transfusion number in the previous 8 wk, and only RBC transfusions given for a Hgb of ≤ 9.0 g/dL pretreatment were counted in the RBC transfusion response evaluation; Platelet response (pretreatment, < 100 x 109/L): absolute increase of ≥ 30 x 109/L for participants starting with > 20 x 109/L and platelets Increase from < 20 x 109/L to > 20 x 109/L and by at least 100%; Neutrophil response (pretreatment, < 1.0 x 109/L): at least 100% increase and an absolute increase > 0.5 x 109/L; Progression or relapse after HI: At least 1 of the following: At least 50% decrement from maximum response levels in granulocytes or platelets, reduction in Hgb by ≥1.5 g/dL, or transfusion dependence.

  • Percentage of Participants With Objective Response During Core Phase [ Time Frame: 16 weeks ]
    Objective response (complete remission (CR) + partial remission (PR) and HI-platelet (HI-P) response + HI-neutrophil (HI-N) response) was assessed according to the modified IWG criteria: CR bone marrow with 5% myeloblasts with normal maturation of al cell lines (persistent dysplasia is noted) and peripheral blood with Hgb >= 11 g/dL platelets >=100 X 10^9/L, neutrophils >= 1.0 x 10^9/L and blasts 0%. PR = All CR if abnormal before treatment except bone marrow blasts decreased by>=50% over pretreatment but still >5% (ellularity and morphology not relevant). HI-P (pretreatment, < 100 x 109/L) = absolute increase of ≥ 30 x 109/L for participants starting with > 20 x 109/L and platelets Increase from < 20 x 109/L to > 20 x 109/L and by at least 100%; HI-N (pretreatment, < 1.0 x 109/L) = at least 100% increase and an absolute increase > 0.5 x 10^9/L.

  • Percentage of Participants With Objective Response During the Randomized Phase [ Time Frame: 32 weeks, 48 weeks ]
    Objective response (complete remission (CR) + partial remission (PR) and HI-platelet (HI-P) response + HI-neutrophil (HI-N) response) was assessed according to the modified IWG criteria: CR bone marrow with 5% myeloblasts with normal maturation of al cell lines (persistent dysplasia is noted) and peripheral blood with Hgb >= 11 g/dL platelets >=100 X 10^9/L, neutrophils >= 1.0 x 10^9/L and blasts 0%. PR = All CR if abnormal before treatment except bone marrow blasts decreased by>=50% over pretreatment but still >5% (ellularity and morphology not relevant). HI-P (pretreatment, < 100 x 109/L) = absolute increase of ≥ 30 x 109/L for participants starting with > 20 x 109/L and platelets Increase from < 20 x 109/L to > 20 x 109/L and by at least 100%; HI-N (pretreatment, < 1.0 x 109/L) = at least 100% increase and an absolute increase > 0.5 x 10^9/L.

  • Frequency Distribution of IPSS Score Status - Core Phase [ Time Frame: baseline ]
    The IPSS score values were calculated based on the results of bone marrow analysis. A score value of 0 has bone marrow blast <5%, karyotype of normal, sole: -Y, del 5Q, del 20q and cytopenias (lineages affected) of 0 to 1. Score value of 0.5 has 5-10 bone marrow blasts, karyotype of Others and cytopenias of 2 to 3. A score value of 1.0 has complex >= 3 chromosomal abnormalities and/or chromosome 7 anomalies. A score of 1.5 has 11-20 bone marrow blasts and a score of 2.0 has 21-30 bone marrow blasts. The prognostic score is determined by the sum of the single scoring values. The risk groups are determined as follows: Low = 0 points (5.7 years of median survival); intermediate -1 (INT-1) = 0.5-1.0 points (3.5 years of median survival); INT-2 = 1.5-2.0 points (1.2 years of median survival); and high >=2.5 points (6 months of median survival).

  • Frequency Distribution of IPSS Score Status - Randomized Phase [ Time Frame: 52 weeks ]
    The IPSS score values were calculated based on the results of bone marrow analysis. A score value of 0 has bone marrow blast <5%, karyotype of normal, sole: -Y, del 5Q, del 20q and cytopenias (lineages affected) of 0 to 1. Score value of 0.5 has 5-10 bone marrow blasts, karyotype of Others and cytopenias of 2 to 3. A score value of 1.0 has complex >= 3 chromosomal abnormalities and/or chromosome 7 anomalies. A score of 1.5 has 11-20 bone marrow blasts and a score of 2.0 has 21-30 bone marrow blasts. The prognostic score is determined by the sum of the single scoring values. The risk groups are determined as follows: Low = 0 points (5.7 years of median survival); intermediate -1 (INT-1) = 0.5-1.0 points (3.5 years of median survival); INT-2 = 1.5-2.0 points (1.2 years of median survival); and high >=2.5 points (6 months of median survival).

  • Mean Single Scoring Values of the IPSS - Core Phase [ Time Frame: baseline ]
    The IPSS score values were calculated based on the results of bone marrow analysis. A score value of 0 has bone marrow blast <5%, karyotype of normal, sole: -Y, del 5Q, del 20q and cytopenias (lineages affected) of 0 to 1. Score value of 0.5 has 5-10 bone marrow blasts, karyotype of Others and cytopenias of 2 to 3. A score value of 1.0 has complex >= 3 chromosomal abnormalities and/or chromosome 7 anomalies. A score of 1.5 has 11-20 bone marrow blasts and a score of 2.0 has 21-30 bone marrow blasts. The prognostic score is determined by the sum of the single scoring values. The risk groups are determined as follows: Low = 0 points (5.7 years of median survival); intermediate -1 (INT-1) = 0.5-1.0 points (3.5 years of median survival); INT-2 = 1.5-2.0 points (1.2 years of median survival); and high >=2.5 points (6 months of median survival).

  • Mean Single Scoring Values of the IPSS - Randomized Phase [ Time Frame: 52 weeks ]
    The IPSS score values were calculated based on the results of bone marrow analysis. A score value of 0 has bone marrow blast <5%, karyotype of normal, sole: -Y, del 5Q, del 20q and cytopenias (lineages affected) of 0 to 1. Score value of 0.5 has 5-10 bone marrow blasts, karyotype of Others and cytopenias of 2 to 3. A score value of 1.0 has complex >= 3 chromosomal abnormalities and/or chromosome 7 anomalies. A score of 1.5 has 11-20 bone marrow blasts and a score of 2.0 has 21-30 bone marrow blasts. The prognostic score is determined by the sum of the single scoring values. The risk groups are determined as follows: Low = 0 points (5.7 years of median survival); intermediate -1 (INT-1) = 0.5-1.0 points (3.5 years of median survival); INT-2 = 1.5-2.0 points (1.2 years of median survival); and high >=2.5 points (6 months of median survival).

  • Overall Survival (OS) - Overall Period [ Time Frame: 48 weeks ]
    OS was defined as the time from start of treatment to death from any cause.

  • Time to Response - Overall Period [ Time Frame: 52 weeks ]
    Time to response was defined as the time from start of treatment to the first documented response (complete [CR] or partial [PR]) according to modified IWG criteria for HI.

  • Event-free Survival (EFS) - Overall Period [ Time Frame: 52 weeks ]
    EFS was defined as the time from start of treatment to failure or death from any cause.

  • Progression-free Survival (PFS) - Overall Period [ Time Frame: 52 weeks ]
    PFS was defined as the time from start of treatment to disease progression or death from MDS.

  • Disease-free Survival (DFS) - Overall Period [ Time Frame: 52 weeks ]
    DFS was defined as the time from start of treatment to the time to relapse.

  • Time to Cause-specific Death - Overall Period [ Time Frame: 52 weeks ]
    Time to cause-specific death was defined as the time from start of treatment to death related to MDS.


Enrollment: 34
Study Start Date: November 2009
Study Completion Date: August 2012
Primary Completion Date: August 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: LBH589
During the core phase, all participants received oral LBH589 40 mg (30 mg after a protocol amendment) for 4 months. During the randomization phase, participants with hematological improvement of the erythropoetic system (HI-E) and participants with stable disease, who were randomized to single agent LBH589, continued on single agent LBH589 40mg/30mg for an additional 4 months.
Drug: LBH589
LBH589 was supplied at dose strengths of 5 mg or 20 mg hard gelatin capsules.
Other Name: Panobinostat
Experimental: LBH589 + Epoetin Alfa
During the randomized phase, participants randomized to LBH589 + Epoetin Alfa (ESA) received oral LBH589 40mg/30mg + ESA 30000 international units (IU)/week injected subcutaneously for 4 months.
Drug: LBH589
LBH589 was supplied at dose strengths of 5 mg or 20 mg hard gelatin capsules.
Other Name: Panobinostat
Drug: Epoetin Alfa
Epoetin alfa was supplied as 10000 IU/1 mL in a ready-to-use syringe.
Other Name: ESA, HEXAL®

  Eligibility

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

Key Inclusion Criteria:

  • Patients with a lower risk MDS (LOW or INT-1 according to IPSS)
  • Red blood cell transfusion dependency of at least 4 Units/8 weeks.
  • Not responding to Erythropoietin stimulating agents (ESA) or having a low chance to do so
  • Age-adjusted normal cardiac, kidney, liver function

Key Exclusion Criteria:

  • Concomitant use of ESA
  • Concomitant use of any other investigational drug
  • Other malignancy that is not in remission for at least 1 year
  • Platelet Count < 75 x 109/L
  • Impaired cardiac function or clinically significant cardiac diseases
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01034657

Locations
Germany
Novartis Investigative Site
Mannheim, Baden-Württemberg, Germany, 68305
Novartis Investigative Site
Berlin, Germany, 12203
Novartis Investigative Site
Bonn, Germany, 53105
Novartis Investigative Site
Dresden, Germany, 01307
Novartis Investigative Site
Duesseldorf, Germany, 40225
Novartis Investigative Site
Duisburg, Germany, 47166
Novartis Investigative Site
Frankfurt, Germany, 60590
Novartis Investigative Site
Goettingen, Germany, 37075
Novartis Investigative Site
Hannover, Germany, 30625
Novartis Investigative Site
Leipzig, Germany, 04103
Novartis Investigative Site
Muenchen, Germany, 81675
Novartis Investigative Site
Ulm, Germany, 89081
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01034657     History of Changes
Other Study ID Numbers: CLBH589BDE04  EudraCT 2009-010403-84  2009-010403-84 
Study First Received: December 16, 2009
Results First Received: August 25, 2016
Last Updated: November 30, 2016

Keywords provided by Novartis:
MDS
bone marrow
anemia
cytopenia
transfusion dependance
EPO
ESA
erythropoietin
LBH589
Myelodysplastic Syndromes
hematopoietic improvement
IPSS Low
IPSS Int-1
HI-E
HDAC Inhibitor
HDAC-I
DAC-I
Deacetylase-Inhibitor
Histone Deacetylase-Inhibitor
red blood cell transfusions

Additional relevant MeSH terms:
Syndrome
Myelodysplastic Syndromes
Preleukemia
Disease
Pathologic Processes
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Neoplasms
Histone Deacetylase Inhibitors
Panobinostat
Epoetin Alfa
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Hematinics

ClinicalTrials.gov processed this record on February 17, 2017