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

Myelodysplastic Syndrome (MDS) Clinical Trial

— GEPARD  

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01034657
• Other study ID #: CLBH589BDE04
• Secondary ID: EudraCT 2009-010
• Status: Terminated
• Phase: Phase 2
• First received: December 16, 2009
• Last updated: August 8, 2017
• Start date: November 2009
• Est. completion date: August 2012

Study information

• Verified date: August 2017
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 34
• Est. completion date: August 2012
• Est. primary completion date: August 2012
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Myelodysplastic Syndrome (MDS)
• Myelodysplastic Syndromes
• Preleukemia
• Syndrome

Intervention

Drug:
• LBH589
LBH589 was supplied at dose strengths of 5 mg or 20 mg hard gelatin capsules.
• Epoetin Alfa
Epoetin alfa was supplied as 10000 IU/1 mL in a ready-to-use syringe.

Locations

Country	Name	City	State
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Bonn
Germany	Novartis Investigative Site	Dresden
Germany	Novartis Investigative Site	Duesseldorf
Germany	Novartis Investigative Site	Duisburg
Germany	Novartis Investigative Site	Frankfurt
Germany	Novartis Investigative Site	Goettingen
Germany	Novartis Investigative Site	Hannover
Germany	Novartis Investigative Site	Leipzig
Germany	Novartis Investigative Site	Mannheim	Baden-Württemberg
Germany	Novartis Investigative Site	Muenchen
Germany	Novartis Investigative Site	Ulm

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants With Hematological Response of the Erythropoetic System (HI-E) - Core Phase	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.	16 weeks
Secondary	Percentage of Participants With HI-E - Randomized Phase	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.	32 weeks, 52 weeks
Secondary	Percentage of Participants With Objective Response During Core Phase	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.	16 weeks
Secondary	Percentage of Participants With Objective Response During the Randomized Phase	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.	32 weeks, 48 weeks
Secondary	Frequency Distribution of IPSS Score Status - Core Phase	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).	baseline
Secondary	Frequency Distribution of IPSS Score Status - Randomized Phase	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).	52 weeks
Secondary	Mean Single Scoring Values of the IPSS - Core Phase	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).	baseline
Secondary	Mean Single Scoring Values of the IPSS - Randomized Phase	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).	52 weeks
Secondary	Overall Survival (OS) - Overall Period	OS was defined as the time from start of treatment to death from any cause.	48 weeks
Secondary	Time to Response - Overall Period	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.	52 weeks
Secondary	Event-free Survival (EFS) - Overall Period	EFS was defined as the time from start of treatment to failure or death from any cause.	52 weeks
Secondary	Progression-free Survival (PFS) - Overall Period	PFS was defined as the time from start of treatment to disease progression or death from MDS.	52 weeks
Secondary	Disease-free Survival (DFS) - Overall Period	DFS was defined as the time from start of treatment to the time to relapse.	52 weeks
Secondary	Time to Cause-specific Death - Overall Period	Time to cause-specific death was defined as the time from start of treatment to death related to MDS.	52 weeks

External Links

•   Results for CLBH589BDE04 from the Novartis Clinical Trial Results Website