Efficacy of Luspatercept in ESA-naive LR-MDS Patients With or Without Ring Sideroblasts Who do Not Require Transfusions

Study Overview
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Brief Summary
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Anemia in patients with very low, low or intermediate risk myelodysplastic syndromes (MDS), that are non-transfusion dependent

Detailed Description
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Patients with very low, low or intermediate risk myelodysplastic syndromes (MDS) presenting with anemia, transfusion independence (NTD) and naive towards ESA treatment

Official Title
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A Phase II, Open-label, Single Arm Study to Evaluate the Efficacy of Luspatercept in Erythropoiesis-stimulating Agent Naive Lower-risk MDS Patients With or Without Ring Sideroblasts Who do Not Require RBC Transfusions

Conditions
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Myelodysplastic Syndromes, Anemia

Intervention / Treatment
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* Drug: Luspatercept Injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of myelodysplastic syndrome (MDS) according to WHO classification Very low-, low-, or intermediate-risk disease MDS with up to 3.5 according to revised International Prognostic Scoring System (IPSS-R) Less than 5% blasts in bone marrow Peripheral blood white blood cell (WBC) count < 13,000/μL sEPO levels ≤ 500 mU/mL Non-transfusion dependence (NTD) according to IWG 2018 criteria Symptomatic anemia Age > 18 years Written informed consent Exclusion Criteria: Patient does not accept bone marrow sampling during screening and during treatment Patient does not accept regular peripheral blood sampling for screening and during treatment. Patient does not accept subcutaneous application of LUS every three weeks Prior treatment for anemia associated with MDS (i.e. ESA, luspatercept), except previously treated with G-CSF/granulocyte-macrophage colony-stimulating factor (GM-CSF), both agents must be discontinued at least 4 weeks before registration Secondary MDS, i.e. MDS arising 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. Prior allogeneic or autologous stem cell transplant Prior history of AML 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. Major surgery within 8 weeks prior to registration. Uncontrolled hypertension, defined as repeated elevations of systolic blood pressure ≥160 mmHg or of diastolic blood pressure (DBP) ≥ 100 mmHg despite adequate treatment Platelet count < 30,000/μL (30 × 10^9/L) Estimated glomerular filtration rate or creatinine clearance < 40 mL/min Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) ≥ 3.0 × upper limit of normal (ULN) Alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) ≥ 3.0 × ULN Total bilirubin ≥ 2.0 × ULN Eastern Cooperative Oncology Group (ECOG) performance status > 2 Stroke, deep venous thrombosis, pulmonary or arterial embolism within 6 months prior to registration Myocardial infarction, uncontrolled angina, uncontrolled heart failure, or uncontrolled cardiac arrhythmia within 6 months prior to registration. Subjects with a known ejection fraction of ˂ 35%, confirmed by a local echocardiography or multigated acquisition scan (MUGA) performed within 6 months prior to registration, 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 has any significant medical condition, laboratory abnormality, psychiatric illness, or is considered vulnerable by local regulations (e.g., imprisoned or institutionalized) that would prevent the subject from participating in the study. Subject has any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she participates in the study Subject has any condition or concomitant medication that confounds the ability to interpret data from the study. Use of any of the following within five weeks prior to registration are prohibited: Anticancer cytotoxic chemotherapeutic agent or treatment, Corticosteroid, except for subjects on a stable or decreasing dose for ≥ 1 week prior to inclusion for medical conditions other than MDS, Iron chelation therapy, except for subjects on a stable or decreasing dose for at least 8 weeks prior to registration, Other RBC hematopoietic growth factors (e.g. interleukin [IL]-3) Pregnant or breastfeeding females Positive pregnancy test in women of childbearing potential. Female subjects of childbearing potential unwilling to use a highly effective method of contraception for the course of the study through 90 days after the last dose of study medication. Male subjects with procreative capacity not willing to use a highly effective method of contraception, starting with the first dose of study therapy through 90 days after the last dose of study therapy. Participation in other interventional trials. Patients under legal supervision or guardianship.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Luspatercept<br>Single-arm design: All patients are treated with 1.75 mg Luspatercept per kg body weight subcutaneously on day 1 of each 21 day cycle for up to 24 weeks and in case of response for up to 1.5 years. | Drug: Luspatercept Injection<br>* All formally included patients will receive 1.75 mg/kg luspatercept administered subcutaneously every three weeks (on day 1 of each 21-day cycle) for a duration of 24 weeks. Responders at the response assessment (according to HI-E) in week 25 will be further treated with 1.75 mg/kg luspatercept until loss of response for an expected maximum of 18 months.<br>* Other names: LUS;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Erythroid response (HI-E) | To evaluate the proportion of patients who have an erythroid response (HI-E) according to the modified IWG 2018 criteria separately for four different clinical situations (cohorts) distinguished by two factors: Serum erythropoietin (sEPO) level AND Ring sideroblast (RS) status | At the end of cycle 8 (each cycle is 21 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HI-E response (erythroid response) duration | To evaluate HI-E response from the first day of response until loss of response. | From the date of treatment start until date of documented loss of response, assessed up to 18 months.] | 
| Time to HI-E (erythroid response) | To evaluate the time between start of treatment and first day of response. | From the date of treatment start until first day of response, assessed up to end of cycle 8 (each cycle is 21 days) | 
| Neutrophil (HI-N) responses | Neutrophil (HI-N) responses according to IWG 2018 criteria | At the end of cycle 8 (each cycle is 21 days) | 
| Platelet (HI-P) responses | Platelet (HI-P) responses according to IWG 2018 criteria | At the end of cycle 8 (each cycle is 21 days) | 
| Safety of luspatercept (toxicities and adverse events) | Assessments will include characterization of toxicities; characterization of AEs including type, incidence, severity, seriousness, and relationship to treatment | From the date of treatment start until the end of study, assessed up to 48 months | 
| Impact of treatment assessed by using the validated European Organisation for Research and Treatment of Cancer Core Quality of Life questionnaire (EORTC QLQ-C30) | To assess patient-reported quality of life during luspatercept treatment: 30 questions assessing the quality of life of oncology patients across 10 subscales will be analyzed. All subscales have a score range from 0 to 100 points. Function subscales: a higher score represents a higher quality of life. Symptoms subscales: higher score represents higher level of symptoms/problems, i.e., represents lower quality of life. | From the date of treatment start until the end of study, assessed up to 48 months. | 
| Impact of luspatercept on quality of life by using the validated Quality of Life in Myelodysplasia Scale (QUALMS) | QoL assessment using the QUALMS questionnaire up to end of treatment: 38-item assessment tool for patients with Myelodysplastic Syndromes (MDS) QUALMS scores ranged from 24 to 99, with higher scores for better outcome | From the date of treatment start until the end of study, assessed up to 48 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Anemia, MDS, Ring sideroblast, Low risk, non-transfusion dependence (NTD)