Study to Evaluate the Safety and Efficacy of Luspatercept (ACE-536) in Participants With Beta-thalassemia (A536-04/MK-6143-002)

NCT01749540 | Completed Phase 2 Results

• 3 other identifiers: A536-04MK-6143-0022012-002499-15
• Study Type: interventional
• Target: 64
• Locations: 2 countries
• Sites: 8

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. 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. 2.a ≥ 20% reduction in RBC transfusion burden compared to pretreatment in transfusion dependent participants.

Conditions

B-Thalassemia

Outcome Measures

Primary Outcomes (2)

• Percentage of Non-transfusion Dependent (NTD) Participants With a Hemoglobin Increase of ≥1.5 g/dL From Baseline for ≥14 Days

  An erythroid response in NTD participants was defined as a mean hemoglobin increase of ≥1.5 g/dL from baseline for ≥14 days in the absence of blood transfusion. Baseline hemoglobin for NTD participants was the average of two or more measurements performed during the screening period. Hemoglobin measurements within 2 weeks following red blood cell (RBC) transfusion or 56 days after the last dose were excluded from analysis. NTD participants were participants who had received \<4 units of RBCs within 8 weeks prior to the first dose of study drug. The percentage of participants with a hemoglobin increase of ≥1.5 g/dL from baseline for ≥14 days is presented.

  Up to approximately 20 weeks

• 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

  Transfusion burden for TD participants was defined as the ratio of RBC transfusion units (or milliliters) transfused during a 12-week interval divided by the duration of that interval compared to the ratio of RBC transfusion units 12 weeks prior to the start of treatment (baseline). The interval during the pretreatment period was defined as the 12 weeks prior to the first dose of study drug. An interval during the treatment plus follow-up period was defined as any 12-week interval after the first dose of study drug. TD participants were participants who had received ≥4 units of RBCs every 8 weeks (confirmed over 6 months prior to the first dose of study drug). The percentage of participants with a ≥20% reduction in RBC transfusion burden from baseline is presented.

  Any 12-week interval during the study (up to approximately 20 weeks)

Secondary Outcomes (56)

• Number of Participants Who Experienced an Adverse Event (AE)

  Up to approximately 20 weeks

• Number of Participants Who Experienced a Serious Adverse Event (SAE)

  Up to approximately 20 weeks

• Number of Participants Who Experienced an Adverse Event (AE) of Grade 3 or Greater

  Up to approximately 20 weeks

• Number of Participants Who Discontinued Study Treatment Due To an Adverse Event (AE)

  Up to approximately 12 weeks

• Number of Participants Who Experienced a Dose-Limiting Toxicity (DLT)

  Up to 28 days

Study Arms (7)

Luspatercept 0.2 mg/kg

EXPERIMENTAL

Participants receive luspatercept 0.2 mg/kg as a subcutaneous (SC) injection every 3 weeks (Q3W) on Day 1 of each cycle for up to 5 cycles (each cycle length = 21 days).

Drug: luspatercept

Luspatercept 0.4 mg/kg

EXPERIMENTAL

Participants receive luspatercept 0.4 mg/kg as an SC injection Q3W on Day 1 of each cycle for up to 5 cycles (each cycle length = 21 days).

Drug: luspatercept

Luspatercept 0.6 mg/kg

EXPERIMENTAL

Participants receive luspatercept 0.6 mg/kg as an SC injection Q3W on Day 1 of each cycle for up to 5 cycles (each cycle length = 21 days).

Drug: luspatercept

Luspatercept 0.8 mg/kg

EXPERIMENTAL

Participants receive luspatercept 0.8 mg/kg as an SC injection Q3W on Day 1 of each cycle for up to 5 cycles (each cycle length = 21 days).

Drug: luspatercept

Luspatercept 1.0 mg/kg

EXPERIMENTAL

Participants receive luspatercept 1.0 mg/kg as an SC injection Q3W on Day 1 of each cycle for up to 5 cycles (each cycle length = 21 days).

Drug: luspatercept

Luspatercept 1.25 mg/kg

EXPERIMENTAL

Participants receive luspatercept 1.25 mg/kg as an SC injection Q3W on Day 1 of each cycle for up to 5 cycles (each cycle length = 21 days).

Drug: luspatercept

Expansion Cohort

EXPERIMENTAL

Participants receive an initial dose of luspatercept 0.8 mg/kg as an SC injection on Day 1 of Cycle 1 (Cycle length = 21 days). For each subsequent cycle (up to 5 cycles), the dose was titrated up to a maximum dose of 1.25 mg/kg based on the safety review team (SRT) recommendations.

Drug: luspatercept

Interventions

luspatercept DRUG

subcutaneous injection

Also known as: ACE-536, MK-6143

Expansion Cohort; Luspatercept 0.2 mg/kg; Luspatercept 0.4 mg/kg; Luspatercept 0.6 mg/kg; Luspatercept 0.8 mg/kg; Luspatercept 1.0 mg/kg; Luspatercept 1.25 mg/kg

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA: lead

Study Sites (8)

Laiko General Hospital, Ampelokipi

Athens, Greece

Location

Ospedale "A. Perriino" U.O Ematologia

Brindisi, Italy

Location

ARNAS Garibaldi - P.O. Garibaldi Centro

Catania, Italy

Location

A.O.U. Arcispedale S. Anna

Ferrara, Italy

Location

CEMEF Medicina 2

Modena, Italy

Location

A.O.U. Seconda Università degli Studi di Napoli

Napoli, Italy

Location

AORN A. Cardarelli

Napoli, Italy

Location

A.O.U. San Luigi Gonzaga

Orbassano, Italy

Location

Related Publications (3)

• Piga A, Longo F, Gamberini MR, Voskaridou E, Ricchi P, Caruso V, Pietrangelo A, Zhang X, Shetty JK, Attie KM, Tartaglione I. Long-term safety and erythroid response with luspatercept treatment in patients with beta-thalassemia. Ther Adv Hematol. 2022 Dec 5;13:20406207221134404. doi: 10.1177/20406207221134404. eCollection 2022.

  PMID: 36505885 DERIVED

• 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.

  PMID: 33570654 DERIVED

• 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.

  PMID: 30617198 DERIVED

MeSH Terms

Conditions

beta-Thalassemia

Interventions

luspatercept

Condition Hierarchy (Ancestors)

Thalassemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme LLC

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 10, 2012
• First Posted: December 13, 2012
• Study Start: February 28, 2013
• Primary Completion: November 11, 2015
• Study Completion: November 11, 2015
• Last Updated: July 18, 2024
• Results First Posted: July 18, 2024

Record last verified: 2024-02

Locations

GR (1); IT (7)