Clinical trial NCT01749540: Study to Evaluate the Safety and Efficacy of Luspatercept (ACE-536) in Participants With Beta-thalassemia (A536-04/MK-6143-002)
Official title: A Phase 2, Open-Label, Ascending Dose Study to Evaluate the Effects of ACE-536 in Patients With β-Thalassemia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: B-Thalassemia
Lead sponsor: Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA
Sponsor class: INDUSTRY
First posted: 2012-12-13
Enrollment: 64
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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 \<100 x10\^9/L or \>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)

Primary outcomes:
measure: Percentage of Non-transfusion Dependent (NTD) Participants With a Hemoglobin Increase of ≥1.5 g/dL From Baseline for ≥14 Days
timeFrame: Up to approximately 20 weeks
measure: Percentage of Transfusion Dependent (TD) Participants With a ≥20% Reduction in Red Blood Cell (RBC) Transfusion Burden From Baseline During a Rolling 12-week Interval
timeFrame: Any 12-week interval during the study (up to approximately 20 weeks)
Secondary outcomes:
measure: Number of Participants Who Experienced an Adverse Event (AE)
timeFrame: Up to approximately 20 weeks
measure: Number of Participants Who Experienced a Serious Adverse Event (SAE)
timeFrame: Up to approximately 20 weeks
measure: Number of Participants Who Experienced an Adverse Event (AE) of Grade 3 or Greater
timeFrame: Up to approximately 20 weeks
measure: Number of Participants Who Discontinued Study Treatment Due To an Adverse Event (AE)
timeFrame: Up to approximately 12 weeks
measure: Number of Participants Who Experienced a Dose-Limiting Toxicity (DLT)
timeFrame: Up to 28 days
measure: Percentage of Non-transfusion Dependent (NTD) Participants With a Hemoglobin Increase of ≥1.0 g/dL From Baseline During a Rolling 8-week Interval
timeFrame: Any 8-week interval during the study (up to approximately 20 Weeks)
measure: Percentage of Non-transfusion Dependent (NTD) Participants With a Hemoglobin Increase of ≥1.5 g/dL From Baseline During a Rolling 8-week Interval
timeFrame: Any 8-week interval during the study (up to approximately 20 Weeks)
measure: Percentage of Non-transfusion Dependent (NTD) Participants With a Hemoglobin Increase of ≥1.0 g/dL From Baseline During a Rolling 12-week Interval
timeFrame: Any 12-week interval during the study (up to approximately 20 Weeks)
measure: Percentage of Non-transfusion Dependent (NTD) Participants With a Hemoglobin Increase of ≥1.5 g/dL From Baseline During a Rolling 12-week Interval
timeFrame: Any 12-week interval during the study (up to approximately 20 Weeks)
measure: Percentage of Transfusion Dependent (TD) Participants With a ≥50% Reduction in Red Blood Cell (RBC) Transfusion Burden From Baseline During a Rolling 8-week Interval
timeFrame: Any 8-week interval during the study (up to approximately 20 weeks)
measure: Percentage of Transfusion Dependent (TD) Participants With a ≥50% Reduction in Red Blood Cell (RBC) Transfusion Burden From Baseline During a Rolling 12-week Interval
timeFrame: Any 12-week interval during the study (up to approximately 20 weeks)
measure: Percentage of Transfusion Dependent (TD) Participants Who Maintained Red Blood Cell (RBC) Transfusion Independence For ≥8 Weeks
timeFrame: Any 8-week interval during the study (up to approximately 20 weeks)
measure: Time To Erythroid Response for Non-transfusion Dependent (NTD) Participants Who Achieved a Hemoglobin Increase ≥1.0 g/dL During a Rolling 12-week Interval by Pooled Dose Groups
timeFrame: Any 12-week interval during the study (up to approximately 20 weeks)
measure: Time To Erythroid Response for Transfusion Dependent (TD) Participants Who Achieved a Transfusion Burden Reduction of ≥50% During a Rolling 12-week Interval
timeFrame: Any 12-week interval during the study (up to approximately 20 weeks)
measure: Duration of Erythroid Response for Non-transfusion Dependent (NTD) Participants Who Achieved a Hemoglobin Increase ≥1.0 g/dL During a Rolling 12-week Interval
timeFrame: Any 12-week interval during the study (up to approximately 20 weeks)
measure: Duration of Erythroid Response for Transfusion Dependent (TD) Participants Who Achieved a Transfusion Burden Reduction of ≥50% During a Rolling 12-week Interval
timeFrame: Any 12-week interval during the study (up to approximately 20 weeks)
measure: Percent Change From Baseline to End of Treatment in Mean Bone-specific Alkaline Phosphatase (BSAP)
timeFrame: Baseline (prior to first dose of study drug) and End of Treatment (up to Day 113)
measure: Percent Change From Baseline to End of Treatment in Mean C-telopeptide of Type I Collagen (CTX)
timeFrame: Baseline (prior to first dose of study drug) and End of Treatment (up to Day 113)
measure: Percent Change From Baseline to End of Treatment in Serum Iron
timeFrame: Baseline (prior to first dose of study drug) and End of Treatment (up to Day 113)
measure: Percent Change From Baseline to End of Treatment in Total Iron Binding Capacity (TIBC)
timeFrame: Baseline (prior to first dose of study drug) and End of Treatment (up to Day 113)
measure: Percent Change From Baseline to End of Treatment in Transferrin
timeFrame: Baseline (prior to first dose of study drug) and End of Treatment (up to Day 113)
measure: Percent Change From Baseline to End of Treatment in Soluble Transferrin Receptor
timeFrame: Baseline (prior to first dose of study drug) and End of Treatment (up to Day 113)
measure: Percent Change From Baseline to End of Treatment in Ferritin
timeFrame: Baseline (prior to first dose of study drug) and End of Treatment (up to Day 113)
measure: Percent Change From Baseline to Day 113 in Serum Non-transferrin Bound Iron (NTBI)
timeFrame: Baseline (prior to first dose of study drug) and Day 113
measure: Percent Change From Baseline to Day 113 in Calculated Transferrin Saturation
timeFrame: Baseline (prior to first dose of study drug) and Day 113
measure: Percent Change From Baseline to End of Treatment in Hepcidin
timeFrame: Baseline (prior to first dose of study drug) and End of Treatment (up to Day 113)
measure: Percent Change From Baseline to End of Treatment in Reticulocytes
timeFrame: Baseline (prior to first dose of study drug) and End of Treatment (up to Day 113)
measure: Percent Change From Baseline to End of Treatment in Erythropoietin
timeFrame: Baseline (prior to first dose of study drug) and End of Treatment (up to Day 113)
measure: Percent Change From Baseline to End of Treatment in Nucleated Red Blood Cell (nRBC) Count
timeFrame: Baseline (prior to first dose of study drug) and End of Treatment (up to Day 113)
measure: Percent Change From Baseline to End of Treatment in Hemoglobin A (Hb A)
timeFrame: Baseline (prior to first dose of study drug) and End of Treatment (up to Day 113)
measure: Percent Change From Baseline to End of Treatment in Hemoglobin A2 (Hb A2)
timeFrame: Baseline (prior to first dose of study drug) and End of Treatment (up to Day 113)
measure: Percent Change From Baseline to End of Treatment in Hemoglobin C (Hb C)
timeFrame: Baseline (prior to first dose of study drug) and End of Treatment (up to Day 113)
measure: Percent Change From Baseline to End of Treatment in Hemoglobin D (Hb D)
timeFrame: Baseline (prior to first dose of study drug) and End of Treatment (up to Day 113)
measure: Percent Change From Baseline to End of Treatment in Hemoglobin F (Hb F)
timeFrame: Baseline (prior to first dose of study drug) and End of Treatment (up to Day 113)
measure: Percent Change From Baseline to End of Treatment in Hemoglobin S (Hb S)
timeFrame: Baseline (prior to first dose of study drug) and End of Treatment (up to Day 113)
measure: Percent Change From Baseline to End of Treatment in Alpha Globin Gene
timeFrame: Baseline (prior to first dose of study drug) and End of Treatment (up to Day 113)
measure: Percent Change From Baseline to End of Treatment in Beta Globin Gene
timeFrame: Baseline (prior to first dose of study drug) and End of Treatment (up to Day 113)
measure: Percent Change From Baseline to End of Treatment in Gamma Globin Gene
timeFrame: Baseline (prior to first dose of study drug) and End of Treatment (up to Day 113)
measure: Percent Change From Baseline to End of Treatment in Haptoglobin
timeFrame: Baseline (prior to first dose of study drug) and End of Treatment (up to Day 113)
measure: Percent Change From Baseline to End of Treatment in Indirect Bilirubin
timeFrame: Baseline (prior to first dose of study drug) and End of Treatment (up to Day 113)
measure: Percent Change From Baseline to End of Treatment in Lactate Dehydrogenase (LDH)
timeFrame: Baseline (prior to first dose of study drug) and End of Treatment (up to Day 113)
measure: Change From Baseline to End of Treatment in Liver Iron Concentration (LIC) For Non-transfusion Dependent (NTD) Participants With Baseline LIC <3 mg/g Dry Weight
timeFrame: Baseline (prior to first dose of study drug) and End of Treatment (up to Day 113)
measure: Change From Baseline to End of Treatment in Liver Iron Concentration (LIC) For Non-transfusion Dependent (NTD) Participants With Baseline LIC ≥3 mg/g Dry Weight
timeFrame: Baseline (prior to first dose of study drug) and End of Treatment (up to Day 113)
measure: Percentage of Non-transfusion Dependent (NTD) Participants With Baseline Liver Iron Concentration (LIC) of ≥3 mg/g Dry Weight Who Have Demonstrated an LIC Response at End of Treatment
timeFrame: End of Treatment (up to Day 113)
measure: Percentage of Non-transfusion Dependent (NTD) Participants With Baseline Liver Iron Concentration (LIC) of ≥3 mg/g Dry Weight, Who Have Used Iron Chelation Therapy (ICT), and Who Have Demonstrated an LIC Response at End of Treatment
timeFrame: End of Treatment (up to Day 113)
measure: Percentage of Non-transfusion Dependent (NTD) Participants With Baseline Liver Iron Concentration (LIC) of ≥3 mg/g Dry Weight, Who Have Not Used Iron Chelation Therapy (ICT), and Who Have Demonstrated an LIC Response at End of Treatment
timeFrame: End of Treatment (up to Day 113)
measure: Change From Baseline to End of Treatment in Liver Iron Concentration (LIC) For Transfusion Dependent (TD) Participants With Baseline LIC <3 mg/g Dry Weight
timeFrame: Baseline (prior to first dose of study drug) and End of Treatment (up to Day 113)
measure: Change From Baseline to End of Treatment in Liver Iron Concentration (LIC) For Transfusion Dependent (TD) Participants With Baseline LIC ≥3 mg/g Dry Weight
timeFrame: Baseline (prior to first dose of study drug) and End of Treatment (up to Day 113)
measure: Percentage of Transfusion Dependent (TD) Participants With Baseline Liver Iron Concentration (LIC) of ≥3 mg/g Dry Weight Who Have Demonstrated an LIC Response at End of Treatment
timeFrame: End of Treatment (up to Day 113)
measure: Percentage of Transfusion Dependent (TD) Participants With Baseline Liver Iron Concentration (LIC) of ≥3 mg/g Dry Weight, Who Have Used Iron Chelation Therapy (ICT), and Who Have Demonstrated an LIC Response at End of Treatment
timeFrame: End of Treatment (up to Day 113)
measure: Percentage of Transfusion Dependent (TD) Participants With Baseline Liver Iron Concentration (LIC) of ≥3 mg/g Dry Weight, Who Have Not Used Iron Chelation Therapy (ICT), and Who Have Demonstrated an LIC Response at End of Treatment
timeFrame: End of Treatment (up to Day 113)
measure: Maximum Concentration (Cmax) of Luspatercept
timeFrame: Cycle 1 (21-day cycle): Days 1, 8, 11, and 15; Cycle 2 (21-day cycle): Day 1
measure: Time to Maximum Concentration (Tmax) of Luspatercept
timeFrame: Cycle 1 (21-day cycle): Days 1, 8, 11, and 15; Cycle 2 (21-day cycle): Day 1
measure: Area Under the Concentration Time Curve of Luspatercept From Time Zero to Day 21 (AUC0-21)
timeFrame: Cycle 1: Days 1, 8, 11, and 15; Day 22 (Cycle 2 Day 1). Cycles 1 and 2 are 21-day cycles
measure: Terminal Elimination Half Life (t½) of Luspatercept
timeFrame: Cycle 1 (21-day cycle): Days 1, 8, 11, and 15; Cycle 2 (21-day cycle): Days 1 and 8; Cycles 4 and 5 (21-day cycles): Days 1, 8, and 15; study follow-up on Days 113, 141, and 169
measure: Apparent Terminal Rate Constant (Lambda z) of Luspatercept
timeFrame: Cycle 1 (21-day cycle): Days 1, 8, 11, and 15; Cycle 2 (21-day cycle): Days 1 and 8; Cycles 4 and 5 (21-day cycles): Days 1, 8, and 15; study follow-up on Days 113, 141, and 169
Other outcomes:
Locations:
city: Athens
country: Greece
facility: Laiko General Hospital, Ampelokipi
city: Brindisi
country: Italy
facility: Ospedale "A. Perriino" U.O Ematologia
city: Catania
country: Italy
facility: ARNAS Garibaldi - P.O. Garibaldi Centro
city: Ferrara
country: Italy
facility: A.O.U. Arcispedale S. Anna
city: Modena
country: Italy
facility: CEMEF Medicina 2
city: Napoli
country: Italy
facility: A.O.U. Seconda Università degli Studi di Napoli
city: Napoli
country: Italy
facility: AORN A. Cardarelli
city: Orbassano
country: Italy
facility: A.O.U. San Luigi Gonzaga
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Cappellini MD, Taher AT. The use of luspatercept for thalassemia in adults. Blood Adv. 2021 Jan 12;5(1):326-333. doi: 10.1182/bloodadvances.2020002725.
citation: Piga A, Perrotta S, Gamberini MR, Voskaridou E, Melpignano A, Filosa A, Caruso V, Pietrangelo A, Longo F, Tartaglione I, Borgna-Pignatti C, Zhang X, Laadem A, Sherman ML, Attie KM. Luspatercept improves hemoglobin levels and blood transfusion requirements in a study of patients with beta-thalassemia. Blood. 2019 Mar 21;133(12):1279-1289. doi: 10.1182/blood-2018-10-879247. Epub 2019 Jan 7.