A Phase 3, Open -label, Randomized Study to Compare the Efficacy and Safety of Luspatercept (ACE-536) versus Epoetin Alfa for the Treatment of Anemia Due to IPSS-R Very Low, Low or Intermediate Risk Myelodysplastic Syndromes (MDS) in ESA Naïve Subjects Who Require Red Blood Cell Transfusions.
- Trial ID
- 2022-501485-22-00
- Protocol
- ACE-536-MDS-002
- Sponsor
- Celgene Corp.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of luspatercept in achieving red blood cell transfusion independence (RBC-TI) for 12 weeks, with a concurrent mean hemoglobin increase of at least 1.5 g/dL, compared to epoetin alfa. This is specifically for the treatment of anemia due to very low, low, or intermediate risk **myelodysplastic syndromes** (MDS) in subjects who are naive to erythropoiesis-stimulating agents (ESA) and require red blood cell transfusions. The clinical relevance of this objective lies in potentially reducing the need for transfusions and improving hemoglobin levels, which can significantly impact the quality of life and overall management of patients with MDS.
Secondary objectives include:
- Assessing the safety and efficacy of luspatercept compared to epoetin alfa.
- Evaluating health-related quality of life (HRQoL) and anemia outcome measures using the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30) and the Functional Assessment of Cancer Therapy - Anemia (FACT-An) questionnaire for subjects treated with luspatercept compared to epoetin alfa.
- Evaluating pharmacokinetics for luspatercept in MDS subjects.
Participants
The clinical trial involves a total of **162 participants** diagnosed with **myelodysplastic syndrome (MDS)**, specifically those classified as very low, low, or intermediate risk according to the International Prognostic Scoring System - Revised (IPSS-R). The study population includes both male and female subjects, aged 18 years and older, who are erythropoiesis-stimulating agent (ESA) naïve and require red blood cell (RBC) transfusions. Participants were selected based on their documented diagnosis of MDS, an endogenous serum erythropoietin level of less than 500 U/L, and a transfusion requirement of 2 to 6 units of packed RBCs over 8 weeks. The trial includes individuals with an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. Lifestyle considerations such as diet and physical activity are not specified, but participants must adhere to study visit schedules and protocol requirements. The trial population includes vulnerable subjects, and both male and female participants of childbearing potential must comply with specific contraceptive measures during and after the study. The study aims to evaluate the efficacy of luspatercept in achieving red blood cell transfusion independence compared to epoetin alfa in this specific patient population.
Plans and Procedures
The clinical trial is designed as a **randomized**, open-label study to evaluate the efficacy and safety of **luspatercept** compared to **epoetin alfa** in treating anemia due to very low, low, or intermediate risk **myelodysplastic syndromes (MDS)** in subjects who have not previously received erythropoiesis-stimulating agents (ESA) and require red blood cell transfusions. The trial aims to assess the proportion of subjects achieving red blood cell transfusion independence for any 12-week period with a concurrent mean hemoglobin increase of at least 1.5 g/dL compared to baseline. The study is expected to run from September 3, 2018, to September 28, 2027, with a maximum treatment period of 24 months for each participant.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis of MDS, and transfusion requirements. Following randomization, participants will receive either luspatercept or epoetin alfa via **subcutaneous** injection. Regular follow-up visits will be scheduled to monitor efficacy and safety outcomes, including hemoglobin levels, transfusion requirements, and adverse events. The end-of-study visit will conclude the participant's involvement, assessing long-term outcomes and any remaining safety concerns.
The expected length of participant involvement is up to 24 months, with conditions for early termination including withdrawal of consent, significant protocol deviations, or adverse events that compromise participant safety. The trial will adhere to rigorous methodological standards to ensure the reliability and validity of the findings, contributing valuable insights into the management of anemia in MDS patients.
Treatment
The clinical trial involves the administration of **Epoetin Alfa**, marketed under the name EPREX, which is provided in three different concentrations: 10,000 IU/mL, 4,000 IU/mL, and 40,000 IU/mL. Each formulation is presented as a solution for injection in a pre-filled syringe. The pharmaceutical form is a solution for injection, and the route of administration is subcutaneous use. The maximum daily dose for Epoetin Alfa is 80,000 IU, with a total maximum dose of 1,920,000 IU over a treatment period of up to 24 weeks. The administration frequency is determined based on the clinical protocol, and participant compliance is monitored throughout the study. Epoetin Alfa is used as a comparator in this trial.
The experimental medication in this trial is **Luspatercept**, marketed as Reblozyl, available in two dosages: 25 mg and 75 mg, both in the form of powder for solution for injection. The pharmaceutical form is a solution for injection, and the administration route is subcutaneous. The maximum daily dose of Luspatercept is 1.75 mg/kg, with a total maximum dose of 14 mg/kg over a 24-week treatment period. Luspatercept is designated as an orphan drug and is the test product in this study. The dosing schedule is aligned with the study protocol, and compliance is closely monitored to ensure adherence to the treatment regimen.
No additional non-experimental treatments, such as standard-of-care therapy or placebo, are specified in this trial. The study aims to compare the efficacy and safety of Luspatercept versus Epoetin Alfa in treating anemia due to very low, low, or intermediate risk myelodysplastic syndromes in erythropoiesis-stimulating agent-naïve subjects requiring red blood cell transfusions. The trial is conducted under strict compliance monitoring to ensure accurate data collection and participant safety.
Efficacy
The efficacy of the investigational product in this clinical trial will be assessed primarily by evaluating the proportion of subjects who achieve **red blood cell transfusion independence (RBC-TI)** for any 12-week period, with a concurrent mean hemoglobin increase of at least 1.5 g/dL compared to baseline. This primary endpoint is designed to measure the effectiveness of luspatercept compared to epoetin alfa in treating anemia due to very low, low, or intermediate risk myelodysplastic syndromes (MDS) in erythropoiesis-stimulating agent (ESA) naïve subjects who require RBC transfusions.
Secondary endpoints include a variety of measures to further assess efficacy. These include the proportion of subjects who are RBC transfusion-free from Week 1 through Week 24, mean hemoglobin change over the 24-week period compared to baseline, and the proportion of subjects achieving hematologic improvement-erythroid (HI-E) over any consecutive 56-day period. Additional secondary endpoints involve the time from the first dose to the first onset of achieving HI-E, the maximum duration of RBC transfusion independence for subjects who achieve RBC-TI for at least 84 days, and the total number of RBC units transfused during treatment.
Other secondary endpoints will evaluate the time from the first dose to the first transfusion on treatment, the proportion of subjects who are RBC transfusion-free over consecutive 56-day and 24-week periods, and the evaluation of quality of life measures such as the EORTC QLQ-C30 score and FACT-An. The study will also assess the type, frequency, and severity of adverse events (AEs) and their relationship to luspatercept or epoetin alfa, as well as the pharmacokinetic (PK) model describing luspatercept exposure and variability, and the exposure-response relationship for selected efficacy and safety endpoints.
Additional analyses will include the frequency of antidrug antibodies and their effects on efficacy, safety, or PK, the number and percentage of subjects progressing to acute myeloid leukemia (AML), and the time to AML progression. Biomarker evaluations will be conducted to potentially impact luspatercept efficacy, predict response or relapse, and provide further prognostic classification of MDS subtypes. The study will also describe healthcare resource use associated with the investigational product and assess treatment satisfaction.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Subject is ≥ 18 years of age the time of signing the informed consent form (ICF). 2. Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted. 3. Subject is willing and able to adhere to the study visit schedule and other protocol requirements. 4. Subject has a documented diagnosis of MDS according to WHO 2016 classification that meets IPSS R classification of very low, low, or intermediate risk disease, and < 5% blasts in bone marrow. 5. Subject has an endogenous serum erythropoietin (sEPO) level of < 500 U/L. 6. Subject requires RBC transfusions, as documented by the following criteria: • A transfusion requirement of 2 to 6 pRBCs units/8 weeks confirmed for a minimum of 8 weeks immediately preceding randomization. Hemoglobin levels at the time of or within 7 days prior to administration of a RBC transfusion must have been ≤ 9.0 g/dL (5.6 mmol/L) with symptoms of anemia (or ≤ 7 g/dL [4.3 mmol/L] in the absence of symptoms) in order for the transfusion to be counted towards meeting eligibility criteria. Red blood cell transfusions administered when Hgb levels were > 9.0 g/dL (or > 7 g/dL in the absence of symptoms) and/or RBC transfusions administered for elective surgery, infections or bleeding events will not qualify as a required transfusion for the purpose of meeting eligibility criteria or stratification. The hemoglobin level after the last RBC transfusion prior to randomization must be < 11.0 g/dL (6.8 mmol/L) (centrally or locally analyzed).
- Subject has Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2. 8. Females of childbearing potential (FCBP), defined as a sexually mature woman who: 1) has achieved menarche at some point, 2) not undergone a hysterectomy or bilateral oophorectomy or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy or amenorrhea due to other medical reasons does not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months), must: •Have two negative pregnancy tests as verified by the investigator prior to starting study therapy (unless the screening pregnancy test was done within 72 hours of W1D1). She must agree to ongoing pregnancy testing during the course of the study, and after end of study treatment. •Either commit to true abstinence from heterosexual contact (which must be reviewed on a monthly basis and source documented), or agree to use, and be able to comply with, highly effective contraception without interruption, 5 weeks prior to starting investigational product, during the study therapy (including dose interruptions), and for 12 weeks after discontinuation of study therapy. 9. Male subjects must: •Practice true abstinence (which must be reviewed prior to each IP administration or on a monthly basis [eg, in the event of dose delays]) or agree to use a condom (latex or non-latex, but not made out of natural [animal] membrane) during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for at least 12 weeks following investigational product discontinuation, even if he has undergone a successful vasectomy.
Exclusion Criteria
- Subject with the any of the following prior treatments: •Erythropoiesis-stimulating agents (ESAs) Subjects may be randomized at the investigator's discretion contingent on the fact that the subject received no more than 2 doses of epoetin alfa (prior treatment with darbepoetin not acceptable for entry into the study). The last dose of epoetin alfa must be ≥ 8 weeks from the date of randomization. A blood sample to determine the endogenous sEPO level (central laboratory) for stratification must be taken within 5 days of randomization unless a prior screening sample analyzed by the central laboratory demonstrated an endogenous sEPO level ≤ 500 U/L •Granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF), within 8 weeks prior to randomization, unless given for treatment of febrile neutropenia •Disease modifying agents (eg, immune-modulatory drug [IMiDs such as lenalidomide] Except if the subject received ≤ 1 week of treatment with a disease modifying agent ≥ 8 weeks from randomization, at the investigator's discretion. •Hypomethylating agents Subjects may be randomized at the investigator's discretion contingent that the subject received no more than 2 doses of HMA. The last dose must be ≥ 8 weeks from the date of randomization. •Luspatercept (ACE-536) or sotatercept (ACE-011) •Immunosuppressive therapy for MDS •Hematopoietic cell transplant
- Subject with MDS associated with del(5q) cytogenetic abnormality or MDS unclassifiable (MDS-U) according to WHO 2016 classification.
- Subject with myelodysplastic/myeloproliferative neoplasms (MDS/MPN) according to WHO 2016 classification (ie, Chronic myelomonocytic leukemia (CMML), Atypical chronic myeloid leukemia (aCML), BCR-ABL12, Juvenile myelomonocytic leukemia (JMML), MDS/MPN unclassifiable.
- Subject with 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.
- Subject with known clinically significant anemia due to iron, vitamin B12, or folate deficiencies, or autoimmune or hereditary hemolytic anemia, or hypothyroidism, or any type of known clinically significant bleeding or sequestration. Subject with drug induced anemia (eg, mycophenolate). •Iron deficiency to be determined by serum ferritin < 100 µg/L and additional testing if clinically indicated (eg, calculated transferrin saturation [iron/total iron binding capacity ≤ 20%] or bone marrow aspirate stain for iron).
- Subject with known history of diagnosis of AML.
- Subject receiving any of the following treatment within 8 weeks prior to randomization: •Anticancer cytotoxic chemotherapeutic agent or treatment •Systemic 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) •Androgens, unless to treat hypogonadism •Hydroxyurea •Oral retinoids (except for topical retinoids) •Arsenic trioxide •Interferon and interleukins •Investigational drug or device, or approved therapy for investigational use (if 5 times the half-life of the previous investigational drug exceeds 8 weeks, then the time of exclusion should be extended up to 5 times the half-life of the investigational drug)
- Subject with uncontrolled hypertension, defined as repeated elevations of systolic blood pressure (SBP) of ≥ 150 mmHg and/or diastolic blood pressure (DBP) ≥ 100 mmHg despite adequate treatment.
- Subject with any of the following laboratory abnormalities: •Absolute neutrophil count (ANC) < 500/μL (0.5 x 10^9/L) •Platelet count < 50,000/μL (50 x 10^9/L) •Estimated glomerular filtration rate (eGFR) < 40 mL/min/1.73 m2 (Appendix F) •Serum aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT) or alanine aminotransferase/serum glutamic pyruvic transaminase (ALT/SGPT) ≥ 3.0 x upper limit of normal (ULN) •Total bilirubin ≥ 2.0 x ULN. Higher levels are acceptable if these can be attributed to active red blood cell precursor destruction within the bone marrow (ie, ineffective erythropoiesis) or in the presence of known history of Gilbert Syndrome.
- Subject with prior history of malignancies, other than MDS, unless the subject has been free of the disease for ≥ 5 years (see details in the Protocol).
- Subject has history of active SARS-CoV-2 infection within 4 weeks prior to screening, unless the subject has adequately recovered from COVID symptoms and related complications as per investigator's discretion and following a discussion with the Medical Monitor. Use of a live COVID-19 vaccine is prohibited within 4 weeks prior to randomization. Further exclusion criteria are noted in the Protocol.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 03 Sept 2018 | 1 |
 Belgium | Not Recruiting | 03 Sept 2018 | 10 |
 Czechia | Not Recruiting | 03 Sept 2018 | 11 |
 France | Not Recruiting | 03 Sept 2018 | 27 |
 Germany | Not Recruiting | 03 Sept 2018 | 12 |
 Greece | Not Recruiting | 03 Sept 2018 | 7 |
 Hungary | Not Recruiting | 03 Sept 2018 | 3 |
 Italy | Not Recruiting | 03 Sept 2018 | 42 |
 Lithuania | Not Recruiting | 03 Sept 2018 | 12 |
 The Netherlands | Not Recruiting | 03 Sept 2018 | — |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
EPREX 10,000 IU/mL solution for injection in pre-filled syringe. | Comparator | SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE | SUBCUTANEOUS USE | 80000 | 24 | PRD560978 |
Reblozyl 75 mg powder for solution for injection | Test | POWDER FOR SOLUTION FOR INJECTION | SUBCUTANEOUS USE | 1.75 | 24 | PRD9757717 |
Reblozyl 25 mg powder for solution for injection | Test | POWDER FOR SOLUTION FOR INJECTION | SUBCUTANEOUS | 1.75 | 24 | PRD9757762 |
EPREX 40,000 IU/mL solution for injection in pre-filled syringe. | Comparator | SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE | SUBCUTANEOUS USE | 80000 | 24 | PRD560972 |
EPREX 4,000 IU/mL solution for injection in pre-filled syringe. | Comparator | SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE | SUBCUTANEOUS USE | 80000 | 24 | PRD560977 |