Clinical Trials /

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

NCT02631070

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 subjects with anemia due to IPSS-R very low, low, or intermediate MDS with ring sideroblasts who require RBC transfusions.

Related Conditions:
  • Myelodysplastic Syndromes
Recruiting Status:

Active, not recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title:A Study of Luspatercept (ACE-536) to Treat Anemia Due to Very Low, Low, or Intermediate Risk Myelodysplastic Syndromes
  • Official Title:A PHASE 3, DOUBLE-BLIND, RANDOMIZED STUDY TO COMPARE THE EFFICACY AND SAFETY OF LUSPATERCEPT (ACE-536) VERSUS PLACEBO FOR THE TREATMENT OF ANEMIA DUE TO IPSS-R VERY LOW, LOW, OR INTERMEDIATE RISK MYELODYSPLASTIC SYNDROMES IN SUBJECTS WITH RING SIDEROBLASTS WHO REQUIRE RED BLOOD CELL TRANFUSIONS

Clinical Trial IDs

  • ORG STUDY ID: ACE-536-MDS-001
  • NCT ID: NCT02631070

Trial Conditions

  • Myelodysplastic Syndromes

Trial Interventions

DrugSynonymsArms
LuspaterceptACE-536Experimental Arm - Luspatercept (ACE-536)

Trial Purpose

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 subjects with anemia due to International Prognostic Scoring System-Revised (IPSS-R) very low, low, or intermediate Myelodysplastic syndrome (MDS) with ring sideroblasts (≥ 15%) who require Red blood cell (RBC) transfusions.

Detailed Description

Anemia is considered to be one of the most prevalent cytopenias in patients who have myelodysplastic syndromes, an umbrella term used to describe disorders relating to the ineffective production of red blood cells, white blood cells, and/or platelets. Ranging in severity from mild (asymptomatic) to severe, anemia can result in patients requiring regular red blood cell (RBC) transfusions, which can lead to further complications from iron overload. The goal of this study is to assess the safety and efficacy of luspatercept versus placebo in anemic patients who are categorized as International Prognostic Scoring System-Revised (IPSS-R) very low, low, or intermediate risk Myelodysplastic syndrome (MDS), have ring sideroblasts present, and require constant RBC transfusions. The design of the study will allow a period of initial randomization of patients into either the luspatercept or placebo arm, followed by a double-blind treatment period, and then an MDS disease assessment visit. For those patients that are determined to be experiencing clinical benefit as judged from the study Investigator by this disease assessment visit, they will be permitted to enter the double-blind Extension Phase of the study. Once patients are discontinued from study treatment, they will enter a post treatment follow-up period.

Trial Arms

NameTypeDescriptionInterventions
Experimental Arm - Luspatercept (ACE-536)ExperimentalStarting dose of 1.0 mg/kg subcutaneous injection every 3 weeks
  • Luspatercept
    Control Arm: PlaceboPlacebo ComparatorSubcutaneous injection every 3 weeks

      Eligibility Criteria

      Inclusion Criteria:

      Subjects must satisfy the following criteria to be enrolled in the study:

      1. Subject is ≥ 18 years of age the time of signing the informed consent form (ICF).

      2. Subject has a diagnosis of Myelodysplastic syndrome (MDS) (according to WHO 2008) that meets International Prognostic Scoring System-Revised (IPSS-R) classification of very low, low, or intermediate risk disease and has

      - Ring sideroblasts ≥ 15% of erythroid precursors in the bone marrow

      - Fewer than 5% blasts in the bone marrow

      3. Subjects requiring red blood cell transfusions ≥ 2 units in an 8-week period

      4. Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2

      5. Subjects who are refractory/intolerant/ineligible to prior ESA treatment, defined as:

      - Refractory to prior Erythropoiesis- stimulating agents(ESA) treatment: documentation of non-response or response that is no longer maintained to prior ESA-containing regimen, either as single agent or combination (eg, with G-CSF); ESA regimen must have been either recombinant human erythropoietin (rHu EPO) ≥ 40,000 IU/wk for at least 8 doses or equivalent OR darbepoetin alpha ≥ 500 μg Q3W for at least 4 doses or equivalent

      - Intolerant to prior ESA treatment: documentation of discontinuation of prior ESA-containing regimen, either as single agent or combination (eg, with G-CSF), at any time after introduction due to intolerance or an adverse event

      - ESA ineligible: low chance of response to ESA base on endogenous serum erythropoietin level > 200 U/L for subjects not previously treated with ESAs

      Exclusion Criteria:

      - The presence of any of the following will exclude a subject from enrollment:

      1. Prior therapy with disease modifying agents (eg, immune-modulatory drug [IMiDs such as lenalidomide], hypomethylating agents, or immunosuppressive therapy [IST]) or experimental agents for underlying Myelodysplastic syndrome (MDS) disease

      2. Previously treated with either luspatercept (ACE-536) or sotatercept (ACE-011)

      3. MDS associated with del 5q cytogenetic abnormality

      4. Secondary MDS, ie, MDS that is known to have arisen as the result of chemical injury or treatment with chemotherapy and/or radiation for other diseases.

      5. Known clinically significant anemia due to iron, vitamin B12, or folate deficiencies, or autoimmune or hereditary hemolytic anemia, or gastrointestinal bleeding

      - iron deficiency to be determined by a bone marrow aspirate stain for iron, calculated transferrin saturation (iron/total iron binding capacity) ≤ 20%, or serum ferritin ≤ 15 μg/L 6. Prior allogeneic or autologous stem cell transplant 7. Known history of diagnosis of Acute myeloid leukemia (AML) 8. Use of any of the following within 5 weeks prior to randomization:

      - anticancer cytotoxic chemotherapeutic agent or treatment

      - corticosteroid, except for subjects on a stable or decreasing dose for ≥ 1 week prior to randomization for medical conditions other than MDS

      - iron-chelating agents, except for subjects on a stable or decreasing dose for at least 8 weeks prior to randomization

      - other red blood cell (RBC) hematopoietic growth factors (eg, Interleukin-3) 15. Prior history of malignancies, other than MDS, unless the subject has been free of the disease for ≥ 5 years. However, subjects with the following history/concurrent conditions are allowed:

      - Basal or squamous cell carcinoma of the skin

      - Carcinoma in situ of the cervix

      - Carcinoma in situ of the breast

      - Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, metastasis [TNM] clinical staging system) 16. Major surgery within 8 weeks prior to randomization. Subjects must have completely recovered from any previous surgery prior to randomization

      Maximum Eligible Age:N/A
      Minimum Eligible Age:18 Years
      Eligible Gender:Both
      Healthy Volunteers:No

      Primary Outcome Measures

      Measure:Red Blood Cell Transfusion Independence (RBC-TI) ≥ 8 weeks
      Time Frame:Week 1 through week 24
      Safety Issue:No
      Description:Proportion of subjects who are red blood cell (RBC) transfusion free over any consecutive 56-day period within week 1 through week 24

      Secondary Outcome Measures

      Measure:Red Blood Cell Transfusion Independence (RBC-TI) ≥ 12 weeks
      Time Frame:Up to approximately 48 weeks
      Safety Issue:No
      Description:Proportion of subjects who are Red blood cell (RBC) transfusion free over any consecutive 84-day period within week 1 through 24 and week 1 through 48
      Measure:Red Blood Cell Transfusion Independence (RBC-TI) ≥ 8 weeks
      Time Frame:Up to approximately 48 weeks
      Safety Issue:No
      Description:Proportion of subjects who are Red blood cell (RBC) transfusion free over any consecutive 56-day period within week 1 through week 48
      Measure:Reduction in red blood cell (RBC) units transfused over 16 weeks
      Time Frame:Up to approximately 48 weeks
      Safety Issue:No
      Description:Mean change in total Red blood cell (RBC) units transfused over a fixed 16-week period within week 8 trough 24 and week 32 through 48
      Measure:Proportion of subjects achieving Modified hematologic improvement - erythroid (mHI-E) per International Working Group (IWG) over any consecutive 56 days
      Time Frame:Up to approximately 48 weeks
      Safety Issue:No
      Description:Proportion of subjects achieving modified Hematological improvement-erythroid (HI-E) over any consecutive 56-day period during the treatment period
      Measure:Mean hemoglobin increase ≥ 1.0 g/dL
      Time Frame:Up to approximately 48 weeks
      Safety Issue:No
      Description:Proportion of subjects achieving hemoglobin (Hgb) increase from baseline ≥ 1.0 g/dL over any consecutive 56-day period in absence of Red blood cell (RBC) transfusions
      Measure:Duration of Red Blood Cell Transfusion Independence (RBC-TI)
      Time Frame:Up to approximately 3.5 years
      Safety Issue:No
      Description:Maximum duration of red blood cell (RBC) transfusion independence for subjects who achieve RBC TI ≥ 8 weeks
      Measure:Change in EORTC QLQ-C30 score
      Time Frame:Up to approximately 3.5 years
      Safety Issue:No
      Description:Change in EORTC QLQ-C30 scores per scheduled visits
      Measure:Hematologic improvement - neutrophils (HI-N) per International Working Group (IWG)
      Time Frame:Up to approximately 48 weeks
      Safety Issue:No
      Description:Proportion of subjects achieving HI-N over any consecutive 56-day period
      Measure:Mean decrease in serum ferritin
      Time Frame:Up to approximately 48 weeks
      Safety Issue:No
      Description:Change in serum ferritin over scheduled assessments
      Measure:Mean decrease in iron chelation therapy (ICT) use
      Time Frame:Up to approximately 48 weeks
      Safety Issue:No
      Description:The change in daily dose for each subject is calculated as the difference of post-baseline mean daily dose and baseline mean daily dose. Analysis of covariance (ANCOVA) will be used to compare the treatment difference between groups, with the stratification factors and baseline ICT value as covariates.
      Measure:Time to red blood cell transfusion independence (RBC-TI)
      Time Frame:Up to approximately 48 weeks
      Safety Issue:No
      Description:Time between randomization and the date onset of TI is first observed (ie, Day 1 of 56 days without any RBC transfusions).
      Measure:Number of subjects progressing to acute myeloid leukemia (AML)
      Time Frame:Up to approximately 3 years
      Safety Issue:No
      Description:Assessments/measurements that were collected in different units of measure will be aggregated and presented by standard units for the study.
      Measure:Time to progression to acute myeloid leukemia (AML)
      Time Frame:Up to approximately 3 years
      Safety Issue:No
      Description:Is defined as the time between randomization and first diagnosis of AML as per WHO classification of ≥ 20% blasts in peripheral blood or bone marrow.
      Measure:Overall survival (OS)
      Time Frame:Up to approximately 3.5 years
      Safety Issue:No
      Description:Overall survival is defined as the time from date of randomization to death due to any cause
      Measure:Adverse Events (AEs)
      Time Frame:Up to approximately 3.5 years
      Safety Issue:Yes
      Description:Type, frequency, severity of AEs and relationship of AEs to luspatercept/placebo
      Measure:Frequency of anti-drug antibodies (ADA)
      Time Frame:Up to approximately 3.5 years
      Safety Issue:No
      Description:Will be collected for assessment of anti-drug antibodies (ADA) against luspatercept in serum in all subjects
      Measure:Pharmacokinetics - AUC
      Time Frame:Up to approximately 1 year
      Safety Issue:No
      Description:Area under the plasma concentration-time curve
      Measure:Pharmacokinetics ‐ Cmax
      Time Frame:Up to approximately 1 year
      Safety Issue:No
      Description:Maximum observed concentration in plasma

      Trial Keywords

      • Luspatercept
      • Transfusion dependent
      • Lower risk
      • Low risk
      • Myelodysplastic Syndromes
      • ESA refractory
      • ESA intolerant
      • ESA ineligible
      • ACE-536
      • Anemia
      • Ring Sideroblasts
      • Require Red Blood Cell Transfusions
      • MEDALIST
      • MDS
      • IPSS-R very low/IPSS-R low/IPSS-R intermediate