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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
34
LBH589 was supplied at dose strengths of 5 mg or 20 mg hard gelatin capsules.
Epoetin alfa was supplied as 10000 IU/1 mL in a ready-to-use syringe.
Novartis Investigative Site
Mannheim, Baden-Wurttemberg, Germany
Novartis Investigative Site
Berlin, Germany
Novartis Investigative Site
Bonn, Germany
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.
Time frame: 16 weeks
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.
Time frame: 32 weeks, 52 weeks
Percentage of Participants With Objective Response During Core Phase
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Novartis Investigative Site
Dresden, Germany
Novartis Investigative Site
Duisburg, Germany
Novartis Investigative Site
Düsseldorf, Germany
Novartis Investigative Site
Frankfurt, Germany
Novartis Investigative Site
Göttingen, Germany
Novartis Investigative Site
Hanover, Germany
Novartis Investigative Site
Leipzig, Germany
...and 2 more locations
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.
Time frame: 16 weeks
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.
Time frame: 32 weeks, 48 weeks
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).
Time frame: baseline
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).
Time frame: 52 weeks
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).
Time frame: baseline
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).
Time frame: 52 weeks
Overall Survival (OS) - Overall Period
OS was defined as the time from start of treatment to death from any cause.
Time frame: 48 weeks
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.
Time frame: 52 weeks
Event-free Survival (EFS) - Overall Period
EFS was defined as the time from start of treatment to failure or death from any cause.
Time frame: 52 weeks
Progression-free Survival (PFS) - Overall Period
PFS was defined as the time from start of treatment to disease progression or death from MDS.
Time frame: 52 weeks
Disease-free Survival (DFS) - Overall Period
DFS was defined as the time from start of treatment to the time to relapse.
Time frame: 52 weeks
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.
Time frame: 52 weeks