study to evaluate the safety and efficacy of luspatercept (ace-536) in participants with beta-thalassemia (a536-04/mk-6143-002)

Conditions: B-Thalassemia

Summary: the purpose of this study is to evaluate the efficacy, safety, and pharmacokinetics, of ascending doses of luspatercept in participants with β-thalassemia. the primary objective of this study is to evaluate erythroid response, defined as: 1. a hemoglobin increase of ≥ 1.5 g/dl from baseline for ≥ 14 days (in the absence of red blood cell \[rbc\] transfusions) in non-transfusion dependent participants, or 2. a ≥ 20% reduction in rbc transfusion burden compared to pretreatment in transfusion dependent participants.


Eligibility criteria:
key inclusion criteria: * men or women ≥18 years of age * for the dose escalation phase of the study: documented diagnosis of β-thalassemia intermedia (transfusion dependent participants must not have begun regular transfusions at age \<4.0 years). for the expansion cohort: documented diagnosis of β-thalassemia (including β-thalassemia major or β-thalassemia intermedia) * prior splenectomy or spleen size \<18 cm in the longest diameter by abdominal ultrasound (dose escalation cohorts only) * anemia, defined as: (1) mean hemoglobin concentration \<10.0 g/dl of 2 measurements (one performed within one day prior to cycle 1 day 1 and the other performed during the screening period \[day -28 to day -1\]) in non-transfusion dependent participants, defined as having received \< 4 units of rbcs within 8 weeks prior to cycle 1 day 1, or (2) transfusion dependent participants, defined as requiring ≥ 4 units of rbcs every 8 weeks (confirmed over 6 months prior to cycle 1 day 1) * aspartate aminotransferase (ast) or alanine aminotransferase (alt) \<3 x upper limit of normal (uln) * serum creatinine ≤1.5 x uln * adequate pregnancy avoidance measures * participants are able to adhere to the study visit schedule, understand, and comply with all protocol requirements * understand and able to provide written informed consent key exclusion criteria: * any clinically significant pulmonary (including pulmonary hypertension), cardiovascular, endocrine, neurologic, hepatic, gastrointestinal, infectious, immunological (including clinically significant allo- or auto-immunization) or genitourinary disease considered by the investigator as not adequately controlled prior to cycle 1 day 1 * folate deficiency * symptomatic splenomegaly * known positive for human immunodeficiency virus (hiv), active infectious hepatitis b virus (hbv) or active infectious hepatitis c virus (hcv) * known history of thromboembolic events ≥grade 3 according to the national cancer institute-common terminology criteria for adverse events (nci-ctcae) version 4.0 (current active minor version) * ejection fraction \<50% by echocardiogram, multi-gated acquisition scan (muga), or cardiac magnetic resonance imaging (mri) * uncontrolled hypertension defined as systolic blood pressure (bp) ≥150 mm hg or diastolic bp ≥95 mm hg * heart failure class 3 or higher (new york heart association \[nyha\]) * qtc \>450 msec on screening electrocardiogram (ecg) * platelet count \ 1,000 x10\^9/l * proteinuria ≥grade 2 * any active infection requiring parenteral antibiotic therapy within 28 days prior to cycle 1 day 1 or oral antibiotics within 14 days of cycle 1 day 1 * treatment with another investigational drug or device, or approved therapy for investigational use ≤28 days prior to cycle 1 day 1, or if the half-life of the previous investigational product is known, within 5 times the half-life prior to cycle 1 day 1, whichever is longer * transfusion event within 7 days prior to cycle 1 day 1 * participants receiving or planning to receive hydroxyurea treatment. participants must not have had hydroxyurea within 90 days of cycle 1 day 1 * splenectomy within 56 days prior to cycle 1 day 1 * major surgery (except splenectomy) within 28 days prior to cycle 1 day 1. participants must have completely recovered from any previous surgery prior to cycle 1 day 1 * iron chelation therapy initiated within 56 days prior to cycle 1 day 1 * cytotoxic agents, systemic corticosteroids, immunosuppressants, or anticoagulant therapy such as warfarin or heparin within 28 days prior to cycle 1 day 1 (prophylactic aspirin up to 100 mg/day is permitted) * pregnant or lactating women * history of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the investigational drug * prior treatment with sotatercept (ace-011) or luspatercept (ace-536)