A Study of Luspatercept (ACE-536) to Treat Anemia Due to Very Low, Low, or Intermediate Risk Myelodysplastic Syndromes
Condition: Myelodysplastic Syndromes
MeSH terms: Preleukemia; Anemia; Myelodysplastic Syndromes; Syndrome
Intervention: Luspatercept; Placebo
Intervention MeSH terms: Luspatercept
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 229.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
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

Summary:

      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.
    

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. Documented diagnosis of MDS according to World Health Organization (WHO)/French
             American British (FAB) classification that meets IPSS R classification of very low,
             low, or intermediate risk disease, and:

        Ring sideroblast ≥ 15% of erythroid precursors in bone marrow or ≥ 5% (but < 15%) if SF3B1
        mutation is present.

          -  < 5% blasts in bone marrow

          -  Peripheral blood white blood cell (WBC) count < 13,000/µL 3. Requires red blood cell
             RBC transfusions 4. Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2 5.
             Subjects who are refractory/intolerant/ineligible to prior erythropoietin-stimulating
             agents (ESA) treatment, defined as:

          -  Refractory to prior - erythropoietin stimulating agents 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 granulocyte colony stimulating factor
             (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 for underlying 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 serum ferritin less than or equal to 15 ug/L and
             additional testing if clinically indicated (eg, calculated transferrin saturation
             [iron/total iron binding capacity less than or equal to 20%] or bone marrow aspirate
             stain for iron).

          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 RBC hematopoietic growth factors (eg, Interleukin-3)

               -  investigational drug or device, or approved therapy for investigational use. If
                  the half-life of the previous investigational product is known, use within 5
                  times the half-life prior to randomization or within 5 weeks, whichever is longer
                  is excluded.

          9. Prior history of malignancies, other than MDS, unless the subject has been free of the
             disease (including completion of any active or adjuvant treatment for prior
             malignancy) 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)

         10. Major surgery within 8 weeks prior to randomization. Subjects must have completely
             recovered from any previous surgery prior to randomization