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NCT02631070: MEDALIST

A Study of Luspatercept (ACE-536) to Treat Anemia Due to Very Low, Low, or Intermediate Risk Myelodysplastic Syndromes

Completed Phase 3 Results posted Last updated 17 December 2021
What this trial tests

Phase 3 trial testing Luspatercept in Myelodysplastic Syndromes in 229 participants. Completed in 26 November 2020.

Timeline
9 February 2016
Primary endpoint
18 June 2019
26 November 2020

Quick facts

Lead sponsorCelgene
PhasePhase 3
StatusCompleted
Study typeINTERVENTIONAL
Allocationrandomized
Designparallel
Maskingquadruple
Primary purposetreatment
Enrollment229
Start date9 February 2016
Primary completion18 June 2019
Estimated completion26 November 2020
Sites74 locations across France, Italy, Netherlands, Belgium, Sweden, United Kingdom, Germany, Canada

Drugs / interventions tested

Conditions studied

Sponsor

Celgene — full company profile →

Who can join

18 and older, any sex, with Myelodysplastic Syndromes. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Percentage Of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 8 Weeks From Week 1 to Week 24 Primary · From Week 1 through Week 24 of study treatment

RBC-TI response was defined as the absence of any Red Blood Cells (RBC) transfusion during any consecutive 56-day (8-week) period (ie, Days 1 to 56, Days 2 to 57, Days 3 to 58, etc.) during the first 24 weeks of study treatment. Participants had to have at least 56 days (≥ 8 weeks) of transfusion independence prior to (and including) the Week 24 cut-off date to qualify as a responder. Participants who failed to achieve RBC-TI at least 56 days prior to or on the cut-off date were counted as non-responders.

GroupValue95% CI
Luspatercept37.9130.20 – 46.10
Placebo13.166.49 – 22.87
Percentage of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 12 Weeks From Week 1 to Week 24 Secondary · From Week 1 through Week 24 of study treatment

RBC-TI Response was defined as the absence of any Red Blood Cells (RBC) transfusion during any consecutive 84-day (12-week) period (ie, Days 1 to 84, Days 2 to 85, Days 3 to 86, etc.) during the first 24 weeks of treatment.

GroupValue95% CI
Luspatercept28.1021.14 – 35.93
Placebo7.892.95 – 16.40
Percentage of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 12 Weeks From Week 1 to Week 48 Secondary · From Week 1 through Week 48 of study treatment

RBC-TI Response was defined as the absence of any Red Blood Cells (RBC) transfusion during any consecutive 84-day (12-week) period (ie, Days 1 to 84, Days 2 to 85, Days 3 to 86, etc.) during the first 48 weeks of treatment.

GroupValue95% CI
Luspatercept33.3325.93 – 41.40
Placebo11.845.56 – 21.29
Percentage of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 8 Weeks From Week 1 Through Week 48 Secondary · From Week 1 through Week 48 of study treatment

RBC-TI response was defined as the absence of any Red Blood Cells (RBC) transfusion during any consecutive 56-day (8-week) period (ie, Days 1 to 56, Days 2 to 57, Days 3 to 58, etc.) during Week 1 through Week 48. Participants had to have at least 56 days (≥ 8 weeks) of transfusion independence prior to (and including) the Week 48 cut-off date to qualify as a responder. Participants who failed to achieve RBC-TI at least 56 days prior to Week 48 were counted as non-responders.

GroupValue95% CI
Luspatercept45.1037.05 – 53.34
Placebo15.798.43 – 25.96
Change From Baseline in RBC Units Transfused Over Fixed 16-Week Period Secondary · At Baseline (16 weeks prior to first dose of study treatment) and Weeks 9 to 24 or Weeks 33 to 48

Mean change in total number of Red Blood Cells (RBC) units transfused over a fixed 16-week period (Week 9-24 or Week 33-48) from the total number of RBC units transfused in the 16 weeks immediately on or prior to first dose of study treatment.

Weeks 9 to 24
GroupValue95% CI
Luspatercept-3.0± 5.17
Placebo0.4± 4.25
Weeks 33 to 48
GroupValue95% CI
Luspatercept-4.9± 4.22
Placebo-3.9± 7.14
Percentage of Participants Who Achieved a Modified Hematologic Erythroid Response (mHI-E) Over Any Consecutive 56-Day Period Secondary · Week 1 through 24 or Week 1 Through Week 48

A modified HI-E response was defined as the percentage of participants meeting the modified HI-E per the International Working Group (IWG) sustained over 56-day consecutive period during the Treatment period. For participants with a baseline RBC transfusion burden of ≥ 4 units/8 weeks, a mHI-E was defined as a reduction in RBC transfusion of at least 4 units/8 weeks; for participants with baseline RBC transfusion burden of \<4 units/8 weeks, mHI-E, was defined as a mean increase in hemoglobin of ≥ 1.5 g/dL for 8 weeks in the absence of RBC transfusions.

Week 1 Through Week 24
GroupValue95% CI
Luspatercept52.944.72 – 61.05
Placebo11.85.56 – 21.29
Week 1 Through Week 48
GroupValue95% CI
Luspatercept58.850.59 – 66.71
Placebo17.19.43 – 27.47
Percentage of Participants Who Achieved a Mean Hemoglobin (Hgb) Increase of at Least 1.0 g/dL Over Any Consecutive 56-Day Period in Absence of Red Blood Cells (RBC) Transfusions Secondary · Week 1 though Week 24 and Week 1 through 48

A mean hgb increase of ≥ 1.0 g/dL was analyzed as the percentage of participants with a hgb increase ≥ 1.0 g/dL compared with baseline (after applying the 14/3 day rule) that was sustained over any consecutive 56-day (8-week) period in the absence of RBC transfusions during the treatment period. (Week 1 through Week 24 and Week 1 through Week 48).

Week 1 Through Week 24
GroupValue95% CI
Luspatercept35.327.75 – 43.42
Placebo7.92.95 – 16.40
Week 1 Through Week 48
GroupValue95% CI
Luspatercept41.233.29 – 49.41
Placebo10.54.66 – 19.69
Duration of Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 Through Week 24 Secondary · From start of study treatment to 16 weeks after last dose, up to approximately 93 weeks

Duration of RBC-TI was defined as the longest duration of response for participants who achieved RBC-TI of ≥ 8 weeks during the treatment period Week 1 through Week 24. Participants who maintained RBC-TI through the end of the treatment period were censored at the date of IP discontinuation or death, whichever occurred first. Median was estimated from unstratified Kaplan Meier method.

GroupValue95% CI
Luspatercept30.620.6 – 40.6
Placebo13.69.1 – 54.9
Duration of Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 Through Week 48 Secondary · From start of study treatment to 16 weeks after last dose, up to approximately 93 weeks

Duration of RBC-TI was defined as the longest duration of response for participants who achieved RBC-TI of ≥ 8 weeks during the treatment period Week 1 through Week 48. Participants who maintained RBC-TI through the end of the treatment period were censored at the date of IP discontinuation or death, whichever occurred first. Median was estimated from unstratified Kaplan Meier method.

GroupValue95% CI
Luspatercept30.620.6 – 50.9
Placebo18.610.9 – NA
Mean Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Quality of Life Score Secondary · Baseline and Cycle 3, Day 1 (C3 D1), C5 D1, C7 D1, Week 25, every other cycle during extension phase (C1 D1, C3 D1, C5 D1, etc. up to C59 D1) and end of treatment. Each cycle is composed of 21 days.

The EORTC questionnaire is a validated health-related quality of life (HRQoL) measure applicable to participants with any cancer diagnosis. Version 3.0 of the questionnaire was used in the study. It is composed of 30 items that address 15 domains, including one global health status, functional domains, and symptom domains. Domain scores are transformed to a 0 to 100 scale, where higher scores on the global quality of life score indicate better function. As such, a positive change from Baseline score indicates an improvement in quality of life.

Cycle 3 Day 1 (C3 D1)
GroupValue95% CI
Luspatercept-4.1± 21.01
Placebo0.1± 15.95
C5 D1
GroupValue95% CI
Luspatercept-2.4± 20.73
Placebo2.2± 17.13
C7 D1
GroupValue95% CI
Luspatercept-2.1± 23.04
Placebo-0.6± 18.63
Week 25
GroupValue95% CI
Luspatercept-1.8± 21.75
Placebo0.2± 18.88
Extension Phase C1 D1
GroupValue95% CI
Luspatercept0.0± 25.32
Placebo6.3± 14.60
Extension Phase C3 D1
GroupValue95% CI
Luspatercept2.0± 19.68
Placebo-3.9± 26.86
Extension Phase C5 D1
GroupValue95% CI
Luspatercept0.8± 18.40
Placebo0.6± 20.04
Extension Phase C7 D1
GroupValue95% CI
Luspatercept-0.5± 20.03
Placebo3.8± 20.87
Percentage of Participants Who Achieved a Hematologic Improvement in Neutrophil Response (HI-N) Over Any Consecutive 56-day Period Secondary · Week 1 through Week 24 or Week 1 Through Week 48 of study treatment

Percentage of participants who achieved a hematologic improvement in neutrophil response (HI-N) per IWG criteria sustained over any consecutive 56-day (8-week) period, during the treatment period (Week 1 to Week 24 and Week 1 to Week 48) HI-N was defined as at least a 100% increase and an absolute increase \> 0.5 X 10\^9/L.

Week 1 Through Week 24
GroupValue95% CI
Luspatercept13.31.66 – 40.46
Placebo00.00 – 30.85
Week 1 Through Week 48
GroupValue95% CI
Luspatercept20.04.33 – 48.09
Placebo10.00.25 – 44.50
Percentage of Participants Who Achieved a Hematologic Improvement in Platelet Response (HI-P) Over Any Consecutive 56-day Period Secondary · Week 1 through Week 24 or Week 1 Through Week 48 of study treatment

Percentage of participants who achieved a hematologic improvement platelet response (HI-P) was defined as the percentage of participants meeting the HI-P criteria per the IWG sustained over any consecutive 56-day (8-week) period (Week 1 to Week 24 and Week 1 to Week 48) during the treatment period. HI - P reponse was defined as: * Absolute increase of ≥ 30 X 10\^9/L in platelets for participants starting with \> 20 X 10\^9/L platelets * Increase in platelets from \< 20 X 10\^9/L to \> 20 X 10\^9/L and by at least 100%

Week 1 Through Week 24
GroupValue95% CI
Luspatercept50.015.70 – 84.30
Placebo33.34.33 – 77.72
Week 1 Through Week 48
GroupValue95% CI
Luspatercept62.524.49 – 91.48
Placebo33.34.33 – 77.72

Adverse events — posted to ClinicalTrials.gov

Time frame: All-cause mortality was assessed from first dose to study completion (up to approximately 57 months). SAEs and Other AEs were assessed from first dose to 100 days following last dose (up to approximately 91 weeks). Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Luspatercept
Serious: 66/153 (43%)
Deaths: 45/153
Placebo
Serious: 23/76 (30%)
Deaths: 24/76

Serious adverse events (132 terms)

ReactionSystemLuspaterceptPlacebo
PneumoniaInfections and infestations
FallInjury, poisoning and procedural complications
Femur fractureInjury, poisoning and procedural complications
SepsisInfections and infestations
Urinary tract infectionInfections and infestations
Refractory anaemia with an excess of blastsNeoplasms benign, malignant and unspecified (incl cysts and polyps)
AnaemiaBlood and lymphatic system disorders
Angina pectorisCardiac disorders
PyrexiaGeneral disorders
Hip fractureInjury, poisoning and procedural complications
Back painMusculoskeletal and connective tissue disorders
Basal cell carcinomaNeoplasms benign, malignant and unspecified (incl cysts and polyps)
Squamous cell carcinoma of skinNeoplasms benign, malignant and unspecified (incl cysts and polyps)
Transformation to acute myeloid leukaemiaNeoplasms benign, malignant and unspecified (incl cysts and polyps)
SyncopeNervous system disorders
Atrial fibrillationCardiac disorders
Atrioventricular blockCardiac disorders
Cardiac failureCardiac disorders
BronchitisInfections and infestations
Lower respiratory tract infectionInfections and infestations
Humerus fractureInjury, poisoning and procedural complications
Myelodysplastic syndromeNeoplasms benign, malignant and unspecified (incl cysts and polyps)
Cerebral haemorrhageNervous system disorders
Acute kidney injuryRenal and urinary disorders
DyspnoeaRespiratory, thoracic and mediastinal disorders
Other adverse events (49 terms — click to expand)

ReactionSystemLuspaterceptPlacebo
FatigueGeneral disorders
DiarrhoeaGastrointestinal disorders
AstheniaGeneral disorders
Oedema peripheralGeneral disorders
NauseaGastrointestinal disorders
DizzinessNervous system disorders
CoughRespiratory, thoracic and mediastinal disorders
Back painMusculoskeletal and connective tissue disorders
DyspnoeaRespiratory, thoracic and mediastinal disorders
HeadacheNervous system disorders
FallInjury, poisoning and procedural complications
ConstipationGastrointestinal disorders
Urinary tract infectionInfections and infestations
PyrexiaGeneral disorders
BronchitisInfections and infestations
Upper respiratory tract infectionInfections and infestations
NasopharyngitisInfections and infestations
HypertensionVascular disorders
AnaemiaBlood and lymphatic system disorders
VomitingGastrointestinal disorders
Decreased appetiteMetabolism and nutrition disorders
ArthralgiaMusculoskeletal and connective tissue disorders
MyalgiaMusculoskeletal and connective tissue disorders
InsomniaPsychiatric disorders
VertigoEar and labyrinth disorders
HyperglycaemiaMetabolism and nutrition disorders
HyperuricaemiaMetabolism and nutrition disorders
EpistaxisRespiratory, thoracic and mediastinal disorders
PalpitationsCardiac disorders
Abdominal painGastrointestinal disorders
Abdominal pain upperGastrointestinal disorders
InfluenzaInfections and infestations
PruritusSkin and subcutaneous tissue disorders
Aspartate aminotransferase increasedInvestigations
HyperkalaemiaMetabolism and nutrition disorders
SyncopeNervous system disorders
Influenza like illnessGeneral disorders
Alanine aminotransferase increasedInvestigations
Weight decreasedInvestigations
Iron overloadMetabolism and nutrition disorders

Most-reported serious reactions: Pneumonia, Fall, Femur fracture, Sepsis, Urinary tract infection, Refractory anaemia with an excess of blasts, Anaemia, Angina pectoris.

Data from ClinicalTrials.gov NCT02631070 adverse events section.

Sponsor's own description

The study will be conducted in compliance with the International Council on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good Clinical Practice (GCP) and applicable regulatory requirements. This is a Phase 3, double-blind, randomized, placebo-controlled, multicenter study to determine the efficacy and safety of luspatercept (ACE-536) versus placebo in participants with anemia due to the Revised International Prognostic Scoring System (IPSS-R) very low, low, or intermediate MDS with ring sideroblasts who require red blood cell (RBC) transfusions.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Luspatercept in Patients with Lower-Risk Myelodysplastic Syndromes.
    Fenaux P, Platzbecker U, Mufti GJ, Garcia-Manero G, et al · · 2020 · cited 384× · PMID 31914241 · DOI 10.1056/nejmoa1908892
  2. Novel therapies emerging in oncology to target the TGF-β pathway.
    Kim BG, Malek E, Choi SH, Ignatz-Hoover JJ, et al · · 2021 · cited 336× · PMID 33823905 · DOI 10.1186/s13045-021-01053-x
  3. TGF-β signaling in the tumor metabolic microenvironment and targeted therapies.
    Shi X, Yang J, Deng S, Xu H, et al · · 2022 · cited 188× · PMID 36115986 · DOI 10.1186/s13045-022-01349-6
  4. TGF-beta signal transduction: biology, function and therapy for diseases.
    Tie Y, Tang F, Peng D, Zhang Y, et al · · 2022 · cited 97× · PMID 36534225 · DOI 10.1186/s43556-022-00109-9
  5. Myelodysplastic syndromes current treatment algorithm 2018.
    Steensma DP. · · 2018 · cited 91× · PMID 29795386 · DOI 10.1038/s41408-018-0085-4
  6. Sotatercept, a novel transforming growth factor β ligand trap, improves anemia in β-thalassemia: a phase II, open-label, dose-finding study.
    Cappellini MD, Porter J, Origa R, Forni GL, et al · · 2019 · cited 62× · PMID 30337358 · DOI 10.3324/haematol.2018.198887
  7. The role of TGFβ in hematopoiesis and myeloid disorders.
    Bataller A, Montalban-Bravo G, Soltysiak KA, Garcia-Manero G. · · 2019 · cited 57× · PMID 30816330 · DOI 10.1038/s41375-019-0420-1
  8. Myelofibrosis-Related Anemia: Current and Emerging Therapeutic Strategies.
    Naymagon L, Mascarenhas J. · · 2017 · cited 54× · PMID 31723730 · DOI 10.1097/hs9.0000000000000001

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Other trials of Luspatercept

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