Evaluation of Luspatercept Efficacy and Safety in Patients with Lower-Risk Myelodysplastic Syndromes with Ring Sideroblasts Requiring Red Blood Cell Transfusions
- Trial ID
- 2024-515069-33-00
- Protocol
- LUSPLUS
- Sponsor
- GWT-Tud GmbH
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **red blood cell transfusion independence (RBC-TI)** rate of luspatercept for the treatment of anemia in patients with lower-risk myelodysplastic syndromes with ring sideroblasts (MDS-RS) who require RBC transfusions. This is clinically relevant as achieving RBC-TI can significantly improve the quality of life and reduce the burden of transfusion-related complications in these patients.
Secondary objectives include:
- Determining response rates in MDS-RS patients who have failed prior therapy with lenalidomide or hypomethylating agents, according to IWG 2018 criteria.
- Assessing RBC-TI and response rates based on IWG 2006 criteria.
- Evaluating the effect of luspatercept on time to RBC-TI, duration of RBC-TI, increase in hemoglobin, neutrophils, and platelets, as well as a decrease in serum ferritin and iron chelation therapy use.
- Investigating the safety and tolerability of the luspatercept dosing regimen applied in this study.
- Comparing Quality of Life (QoL) using patient-reported outcome and performance outcome measures before and during luspatercept treatment.
Participants
The clinical trial involves a total of **15 participants** diagnosed with anemia due to very low-, low-, or intermediate-risk **myelodysplastic syndromes (MDS)** with ring sideroblasts, as defined by the International Prognostic Scoring System-Revised (IPSS-R). The study population includes both male and female subjects aged 18 years and older. Participants were selected based on their requirement for red blood cell (RBC) transfusions and their refractory, intolerant, or ineligible status to prior erythropoiesis-stimulating agents (ESA) treatment. The trial includes individuals who are able to adhere to the study visit schedule and protocol requirements. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. Lifestyle considerations such as diet and physical activity are not specified. The trial population includes vulnerable subjects, and both genders are represented. Key inclusion criteria include documented diagnosis of MDS with specific bone marrow and peripheral blood characteristics, and a history of RBC transfusion requirements. The trial does not specify any particular lifestyle modifications or restrictions for participants.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy and safety of **luspatercept** in patients with lower-risk myelodysplastic syndrome with ring sideroblasts (MDS-RS) who require red blood cell (RBC) transfusions. This is a phase IIIb, open-label, single-arm study. The primary objective is to assess the RBC transfusion independence (RBC-TI) rate from Week 1 through Week 24, according to the International Working Group (IWG) 2018 modified criteria. Secondary endpoints include RBC-TI rates through Week 52, median time to RBC-TI, and changes in RBC units transfused over specified periods.
The trial is expected to last until March 31, 2025, with an estimated recruitment start date of August 2, 2021. Participants will be involved in the study for a maximum treatment period of 24 weeks. The study includes several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor treatment response and safety, and an end-of-study visit to assess final outcomes. Participants must be 18 years or older, have documented MDS with specific criteria, and meet transfusion requirements. Conditions for early termination include non-compliance with the study protocol or adverse events that necessitate discontinuation of treatment.
Participants will receive **luspatercept** via subcutaneous injection, with a maximum daily dose of 1.75 mg/kg. The study will monitor safety measures, including the type, frequency, and severity of adverse events. The trial will also evaluate hematologic improvements and overall survival. The study is not low-intervention and is categorized as a phase III trial. Participants must adhere to the study visit schedule and protocol requirements, and specific criteria must be met for inclusion, such as prior treatment history and transfusion needs. The trial aims to provide valuable data on the effectiveness of **luspatercept** in managing anemia in MDS-RS patients.
Treatment
The clinical trial involves the administration of **luspatercept**, marketed under the name Reblozyl, which is provided in two dosages: 25 mg and 75 mg. Both formulations are presented as a **powder for solution for injection**. The active substance, luspatercept, is a recombinant fusion protein consisting of a modified form of the extracellular domain of human activin receptor IIB linked to the human IgG1 Fc domain. This protein is classified under the ATC code B03XA06. The pharmaceutical form for both dosages is a solution for injection, and the route of administration is subcutaneous use. The maximum daily and total dose is 1.75 mg/kg, with a treatment period extending up to 24 weeks. The product is specifically labeled for the study and is not a pediatric formulation. The trial is designed to evaluate the efficacy and safety of luspatercept in patients with lower-risk myelodysplastic syndromes (MDS) with a ring sideroblastic phenotype, focusing on achieving red blood cell transfusion independence.
No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are utilized in this study. The trial is structured as an open-label, single-arm study, and participant compliance is monitored through regular assessments of red blood cell transfusion independence, as per the International Working Group (IWG) 2018 criteria. The study is conducted under the sponsorship of Bristol-Myers Squibb Pharma EEIG, with the product holding marketing authorization in the EU under the numbers EU/1/20/1452/001 and EU/1/20/1452/002 for the 25 mg and 75 mg dosages, respectively.
Efficacy
The efficacy of **luspatercept** in the clinical trial will be assessed primarily by evaluating the red blood cell transfusion independence (RBC-TI) rate according to the International Working Group (IWG) 2018 modified criteria from Week 1 through Week 24. Secondary efficacy endpoints include the RBC-TI rate according to IWG 2006 criteria from Week 1 through Week 24 and through Week 52, median time to RBC-TI, and median duration of RBC-TI over the same periods. Additionally, changes in the number of RBC units transfused over fixed 16-week periods, the proportion of subjects achieving a mean hemoglobin increase of ≥ 1.0 g/dL over ≥ 8 weeks, and various hematologic improvements per IWG 2006 criteria will be measured.
Further secondary endpoints involve the mean change in serum ferritin and mean daily dose of iron chelation therapy (ICT) from Week 9 through 24 and Week 37 through 52 compared to baseline. The proportion of subjects with progression to acute myeloid leukemia (AML), overall survival (OS), and safety measures such as the type, frequency, and severity of adverse events (AEs) related to luspatercept will also be evaluated. Patient-reported outcomes (PRO) via the EORTC QLQ-C30 and performance outcomes (PerfO) via the "Timed Up and Go test" (TUG) will be assessed from baseline to Week 52 and to the end of treatment (EOT).
Inclusion and Exclusion Criteria
Inclusion Criteria
- Subject is 18 years of age or older at the time of signing the informed consent form (ICF)
- Subject is able to understand and voluntarily sign the ICF prior to any study-related assessments/procedures being conducted
- Subject has documented diagnosis of MDS according to WHO classification that meets IPSS-R classification[3] of very low-, low-, or intermediate-risk disease, and the following: • Ring sideroblasts (RS) ≥ 15% of erythroid precursors in bone marrow or ≥ 5% if SF3B1 mutation is present • Less than 5% blasts in bone marrow • Peripheral blood white blood cell (WBC) count < 13,000/μL
- Subject must be one of the following: • Refractory to prior ESA treatment: Documentation of non-response or response that was no longer maintained to prior ESA-containing regimen, either as a single agent or in combination (e.g., with granulocyte colony-stimulating factor [G-CSF]). The ESA regimen must be either: Recombinant human erythropoietin ≥ 40,000 IU/week for at least 8 weeks (=doses) or equivalent; or Darbepoetin-α ≥ 500 µg q3w for at least 4 doses or equivalent • Intolerant to prior ESA treatment: Documentation of discontinuation of prior ESA containing regimen, either as a single agent or in combination (e.g., with G-CSF), at any time after introduction due to intolerance or an adverse event (AE) • ESA ineligible: Low chance of response to ESA based on endogenous serum erythropoietin (EPO) level > 200 U/L for subjects not previously treated with ESAs • Refractory to- /relapsed after prior HMA treatment : Treatment failure/relapse after at least six (azacitidine) or four (decitabine) 4 week treatment cycles except for del(5q) MDS • Refractory to- /relapsed after prior lenalidomide treatment except for del(5q) MDS
- If previously treated with ESAs or G-CSF/granulocyte-macrophage colony-stimulating factor (GM-CSF), both agents must be discontinued ≥ 4 weeks prior to the date of starting treatment with the Investigational medicinal Product (IMP) in this study
- Required RBC transfusions, as documented by the following criteria: • Average transfusion requirement of ≥ 2 units/8 weeks of packed RBCs confirmed for a minimum period of 16 weeks immediately preceding start of treatment with IMP • Hemoglobin (Hb) levels at the time of or within 7 days prior to administration of an RBC transfusion must be ≤ 10.0 g/dL in order for the transfusion to be counted towards meeting eligibility criteria. RBC transfusions administered when Hb levels are > 10 g/dL and/or RBC transfusions administered for elective surgery do not qualify as a required transfusion for the purpose of meeting eligibility criteria • No consecutive 56-day period that is RBC transfusion-free during the 16 weeks immediately prior to starting treatment with IMP • Hb history of at least five Hb measurements that spans at least 100 days prior to the start of treatment with IMP
- Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2
- A female of childbearing potential (FCBP) for this study is defined as a sexually mature woman who: (1) has not undergone a hysterectomy or bilateral oophorectomy; or (2) is not naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., had menses at any time in the preceding 24 consecutive months). An FCBP participating in the study must: • Have 2 negative pregnancy tests as verified by the investigator prior to starting IMP (unless the screening pregnancy test is done within 72 hours of Cycle 1 Day 1). She must agree to ongoing pregnancy testing during the course of the study and after end of treatment (EOT). • If sexually active, agree to use, and be able to comply with, highly effective contraception** without interruption, 5 weeks prior to starting IMP, during treatment with IMP (including dose interruptions), and for 12 weeks after discontinuation of IMP. ** Highly effective contraception is defined in this protocol as the following (information also appears in the ICF): Hormonal contraception (e.g. birth control pills, injection, implant, transdermal patch, vaginal ring), intrauterine device, tubal ligation, or a partner with a vasectomy
- Male subjects must agree to use a condom, defined as a male latex condom or nonlatex condom NOT made out of natural (animal) membrane (e.g., polyurethane), during sexual contact with a pregnant female or an FCBP while participating in the study, during dose interruptions, and for at least 12 weeks following IMP discontinuation, even if he has undergone a successful vasectomy
- Subject is willing and able to adhere to the study visit schedule and other protocol requirements
Exclusion Criteria
- Prior therapy with disease modifying agents other than HMA or LEN for underlying MDS disease
- Estimated glomerular filtration rate or creatinine clearance < 40 mL/min
- Previously treated with either luspatercept or sotatercept
- Secondary MDS, i.e., MDS that is known to have arisen as the result of chemical injury or treatment with chemotherapy and/or radiation for other diseases
- Known clinically significant anemia due to iron, vitamin B12, or folate deficiencies, or autoimmune or hereditary hemolytic anemia, or gastrointestinal bleeding • Iron deficiency to be determined by local laboratory via serum ferritin ≤ 15 µg/L and additional testing if clinically indicated (e.g., calculated transferrin saturation [iron/total iron binding capacity ≤ 20%] or bone marrow aspirate stain for iron)
- Prior allogeneic or autologous stem cell transplant
- Known history of diagnosis of acute myeloid leukemia (AML)
- Use of any of the following within 5 weeks prior to the first dose of the IMP in this study: • Anticancer cytotoxic chemotherapeutic agent or treatment • Corticosteroid, except for subjects on a stable or decreasing dose for ≥ 1 week prior to the first dose of IMP for medical conditions other than MDS • ICT, except for subjects on a stable or decreasing dose for at least 8 weeks prior to the first dose of IMP • Other RBC hematopoietic growth factors (e.g., interleukin [IL]-3) • Investigational drug or device, or approved therapy for investigational use. If the half life of the previous study drug is known, the use of it within 5 times the half life prior to the first dose of IMP or within 5 weeks, whichever is longer, is excluded
- Uncontrolled hypertension, defined as repeated elevations of diastolic blood pressure (DBP) ≥ 100 mmHg despite adequate treatment
- Platelet count < 30,000/μL (30 × 109/L)
- Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) or alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) ≥ 3.0 × upper limit of normal (ULN)
- Total bilirubin ≥ 2.0 × ULN • Higher levels are acceptable if these can be attributed to active RBC precursor destruction within the bone marrow (i.e., ineffective erythropoiesis) or in the presence of known history of Gilbert Syndrome • Subjects are excluded if there is evidence of autoimmune hemolytic anemia manifested as a corrected reticulocyte count of > 2% with either a positive Coombs test or over 50% indirect bilirubin
- Prior history of malignancies, other than MDS, unless the subject is free of the disease (including completion of any active or adjuvant treatment for prior malignancy) for ≥ 5 years. However, subjects with the following history/concurrent conditions are allowed: • Basal or squamous cell carcinoma of the skin • Carcinoma in situ of the cervix • Carcinoma in situ of the breast • Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, metastasis clinical staging system)
- Major surgery within 8 weeks prior to the first dose of IMP. Subjects must be completely recovered from any previous surgery prior to the first dose of IMP
- History of stroke, deep venous thrombosis, pulmonary or arterial embolism within 6 months prior to the first dose of IMP
- Pregnant or breast-feeding females
- Myocardial infarction, uncontrolled angina, uncontrolled heart failure, or uncontrolled cardiac arrhythmia as determined by the investigator within 6 months prior to the first dose of IMP. Subjects with a known ejection fraction of ˂ 35%, confirmed by a local echocardiography or multigated acquisition scan (MUGA) performed within 6 months prior to the first dose of IMP, are excluded
- 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), known human immunodeficiency virus (HIV), known evidence of active infectious hepatitis B, and/or known evidence of active hepatitis C
- History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the IMP
- Subject is in custody by order of an authority or a court of law
- Participation in another interventional clinical study within the last 3 months prior to signing the ICF or simultaneous participation in other clinical studies, except if the patient is not or no longer under treatment in the other trial (i.e. follow-up phase)
- Close affiliation with the investigator (e.g., a close relative) or persons working at the study site
- Subject is an employee of the sponsor or involved Contract research Organization (CRO)
- Criteria which in the opinion of the investigator preclude participation for scientific reasons, for reasons of compliance, or for reasons of the subject’s safety
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 02 Aug 2021 | 2 |
 Germany | Not Recruiting | 02 Aug 2021 | 9 |
 Spain | Not Recruiting | 02 Aug 2021 | 37 |
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 |
|---|---|---|---|---|---|---|
Reblozyl 75 mg powder for solution for injection | Test | POWDER FOR SOLUTION FOR INJECTION | SUBCUTANEOUS USE | 1.75 | 24 | PRD9257437 |
Reblozyl 25 mg powder for solution for injection | Test | POWDER FOR SOLUTION FOR INJECTION | SUBCUTANEOUS USE | 1.75 | 24 | PRD9257430 |