Clinical Trial 23208

• Overview

  Study Title:

  A Phase 3, Open-label, Randomized Study to Compare the Efficacy and Safety of Luspatercept (ACE-536) vs Epoetin Alfa for the Treatment of Anemia Due to Revised International Prognostic Scoring System (IPSS-R) Very Low, Low, or Intermediate-Risk Myelodysplastic Syndrome (MDS) in Erythropoietin-stimulating Agent (ESA)-naive Participants who are Non-Transfusion Dependent (NTD): The "ELEMENT-MDS" Trial

  Objective:

  Primary Objectives: Secondary Objectives:

• Treatments

  Therapies:

  Therapy (NOS)

  Medications:

  ACE-536 (Luspatercept); Epoetin Alfa (erythropoietin); Luspatercept ()

• Inclusion Criteria

  Key Inclusion Criteria:
  • Participants, or according to local regulations (see Appendix 13 for country and region specific requirements), their legally acceptable representative (LAR; refer to Appendix 2) must have signed and dated an Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written informed consent form in accordance with regulatory, local, and institutional guidelines. This must be obtained before performing any protocol related procedures that are not part of normal patient care.
  • Participant has documented diagnosis of MDS according to WHO 201672 (Appendix 5) that meets IPSS-R classification37 (Appendix 6) of very low, low, or intermediate-risk disease, (intermediate-risk of ≤ 3.5 IPSS-R score) confirmed via bone marrow aspirate and: > Participant has a baseline endogenous serum erythropoietin (sEPO) level of ≤ 500 U/L.
  • Participant must be transfusion independent, according to IWG 201871 criteria (Appendix 15) as documented by the following criteria: Received no RBC transfusions within the 16 weeks prior to randomization. Note: RBC transfusions of 1 to 2 units within the 16 weeks prior to enrollment are allowed, provided those 1-2 RBC transfusion units are administered for an acute event/illness (ie, surgical procedure, bleeding, infection) or presence of comorbidity (including cardiovascular, pulmonary, cerebrovascular), and not for the treatment of low hemoglobin (with or without symptoms) alone.
  • Participant has a baseline Hb concentration prior to randomization of ≤ 9.5 g/dL. The baseline Hb will be calculated using the mean of the two lowest available Hb measurements within 16 weeks prior to randomization and must include at least one central lab Hb reading done within the screening period (no more than 35 days before randomization). Note: the two Hb measurements must have been performed at least seven days apart. Hb levels less than 21 days following RBC transfusion should not be used. Split samples for local assessments are not required.
  • Participant has symptom(s) of anemia. Participant records a severity score of “moderate” or greater on at least 1 PGI-S item of fatigue, weakness, shortness of breath, or dizziness performed during the screening period.
  • Participant has an Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2.
  • Participant is erythropoiesis-stimulating agent naive. Participants may be randomized at the investigator’s discretion if the participant received no more than 2 prior doses of epoetin alfa, epoetin alfa biosimilar, or darbepoetin alfa, with the last dose at least 8 weeks prior to randomization.
  • Participant must be ≥ 18 years of age (or local age of consent) at the time of signing the informed consent.
  • Investigators shall counsel individuals of childbearing potential (IOCBP) (as defined in Appendix 4) and male participants who are sexually active with IOCBP, on the importance of pregnancy prevention, the implications of an unexpected pregnancy, and the potential of fetal toxicity occurring due to transmission of study intervention, present in seminal fluid, to a developing fetus, even if the participant has undergone a successful vasectomy or if the partner is pregnant.
  • The investigator shall evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention.
  • Other inclusion criteria may apply.

• Exclusion Criteria

  Key Exclusion Criteria:
  • Participant with MDS associated with del(5q) cytogenetic abnormality or MDS unclassifiable (MDS-U) according to WHO 2016 classification.
  • Participant with the following subtypes of myelodysplastic/myeloproliferative neoplasms (MDS/MPN) according to WHO 2016 classification72: chronic myelomonocytic leukemia; atypical chronic myeloid leukemia, BCR-ABL1 negative; juvenile myelomonocytic leukemia; or MDS/MPN unclassifiable. Note that MDS/MPN-RS-T is not an exclusion.
  • Participant with known clinically significant anemia due to iron, vitamin B12, or folate deficiencies, or autoimmune or hereditary hemolytic anemia (including severe G6PD deficiency, pyruvate kinase deficiency, hemoglobinopathy such as sickle cell disease, etc), or hypothyroidism, or any type of known clinically significant bleeding or sequestration, or drug-induced anemia (eg, mycophenolate).
  • Participant with known history of diagnosis of AML.
  • Persistent hypertension with systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg or both, during the screening period despite adequate treatment, or with a history of hypertensive crisis or hypertensive encephalopathy.
  • Participant with prior history of malignancies other than MDS, unless the participant has been free of the disease for ≥ 5 years. However, participants with the following history/concurrent conditions are allowed: i) Basal or squamous cell carcinoma of the skin. ii) Carcinoma in situ of the cervix. iii) Carcinoma in situ of the breast. iv) Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, metastasis clinical staging system.
  • Participant with major surgery within 8 weeks prior to randomization. Participants must have completely recovered from any previous surgery prior to randomization.
  • Participant with history of cerebrovascular accident (including ischemic, embolic, and hemorrhagic cerebrovascular accident), transient ischemic attack, deep venous thrombosis (including proximal and distal), pulmonary or arterial embolism, arterial thrombosis, or other venous thrombosis within 6 months prior to randomization. Note: prior superficial thrombophlebitis is not an exclusion criterion.
  • Participant with new-onset seizures or poorly controlled seizures within 12 weeks prior to randomization.
  • Participant with the following cardiac conditions within 6 months prior to randomization: myocardial infarction, uncontrolled angina, acute decompensated cardiac failure or New York Heart Association Class III-IV heart failure, or uncontrolled cardiac arrhythmia as determined by the investigator. Participants with a known ejection fraction of ˂ 35%, confirmed by a local echocardiogram or multi-gated acquisition scan performed within 6 months prior to randomization.
  • Participant with uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment).
  • Participant with known human immunodeficiency virus (HIV), known evidence of active infectious hepatitis B, and/or known evidence of active hepatitis C. Local laboratory testing confirming HIV, hepatitis B, and hepatitis C status should not have been performed beyond 5 weeks (35 days) prior to the date of ICF signature.
  • Participant with a history of pure red cell aplasia and/or antibody against erythropoietin.
  • Other exclusion criteria may apply.

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