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Epoetin Alfa

Panobinostat

Histone Deacetylase Inhibitors

Enzyme Inhibitors

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.

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.

LBH589 was supplied at dose strengths of 5 mg or 20 mg hard gelatin capsules.

LBH589

Epoetin alfa was supplied as 10000 IU/1 mL in a ready-to-use syringe.

Novartis Pharmaceuticals

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.

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

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

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.

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.

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).

OS was defined as the time from start of treatment to death from any cause.

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.

EFS was defined as the time from start of treatment to failure or death from any cause.

PFS was defined as the time from start of treatment to disease progression or death from MDS.

DFS was defined as the time from start of treatment to the time to relapse.

Time to cause-specific death was defined as the time from start of treatment to death related to MDS.

LBH589 - Core Phase

LBH589 - Randomized Phase

LBH589 + ESA - Randomized Phase

Participant, who was eligible for randomization, was not randomized. The participant had stable disease and should have been randomized, but in error, was considered a responder and therefore continued on single agent LBH589.

Not Randomized

Age, Continuous

Sex: Female, Male

Study Director

Participants from the core phase, who had valid response data, were analyzed.

Percentage of Participants With Hematological Response of the Erythropoetic System (HI-E) - Core Phase

32 weeks (n=5,1,1)

52 weeks (n=4,3,1)

LBH589 + Epoetin Alfa

Participants from the randomized phase, who had valid response data, were analyzed.

Percentage of Participants With HI-E - Randomized Phase

Participants from the core phase, who had valid data, were analyzed.

Percentage of Participants With Objective Response During Core Phase

Week 32 ( n=5,1,1)

Week 48 (n=6,5,1)

Participants from the randomized phase, who had valid data, were analyzed.

Percentage of Participants With Objective Response During the Randomized Phase

Baseline (core phase), Low

Baseline (core phase),, INT-1

Baseline (core phase),, INT-2

Baseline (core phase), High

All participants from the core phase were analyzed.

Frequency Distribution of IPSS Score Status - Core Phase

Week 52 (randomized phase), Low

Week 52 (randomized phase), , INT-1

Week 52 (randomized phase), INT-2

Week 52 (randomized phase), HIgh

Only participants from the randomized phase, who had values at week 52, were included in the analysis.

Frequency Distribution of IPSS Score Status - Randomized Phase

Mean Single Scoring Values of the IPSS - Core Phase

Participants from the randomized phase, who had values at week 52, were included in the analysis.

Mean Single Scoring Values of the IPSS - Randomized Phase

Overall Survival (OS) - Overall Period

Time to response could not be evaluated because there was no response.

Time to Response - Overall Period

Event-free survival could not be evaluated because there was no response, no progression or no disease-free period.

Event-free Survival (EFS) - Overall Period

PFS could not be evaluated because there was no progression.

Progression-free Survival (PFS) - Overall Period

DFS could not be evaluated because there was no disease-free period.

Disease-free Survival (DFS) - Overall Period

Time to cause-specific death could not be evaluated because there was no cause-specific death.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
LBH589 Alone or in Combination With Erythropoietin Stimulating Agents (ESA) in Patients With Low or Int-1 Risk Myelodysplastic Syndromes (MDS)	NCT01034657	Myelodysplastic...	LBH589 Epoetin Alfa	18 Years -	Novartis
LBH589 Alone or in Combination With Erythropoietin Stimulating Agents (ESA) in Patients With Low or Int-1 Risk Myelodysplastic Syndromes (MDS)	NCT01034657	Myelodysplastic...	LBH589 Epoetin Alfa	18 Years -	Novartis

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