Lower-risk myelodysplastic syndrome with ring-sideroblastic phenotype (MDS-RS) MedDRA version: 21.0 Level: LLT Classification code 10028534 Term: Myelodysplastic syndrome NOS System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 20.0 Level: LLT Classification code 10068361 Term: MDS System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 20.0 Level: LLT Classification code 1
Conditions
Interventions
Trade Name: Reblozyl® 25 mg
Product Code: ACE-536
Pharmaceutical Form: Lyophilisate for solution for injection
INN or Proposed INN: LUSPATERCEPT
CAS Number: 1373715-00-4
Current Sponsor code: ACE-536
Sponsors
GWT-TUD GmbH
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Principal inclusion criteria 1. Subject is 18 years of age or older at the time of signing the informed consent form (ICF) 2. Subject is able to understand and voluntarily sign the ICF prior to any study-related assessments/procedures being conducted 3. Subject has documented diagnosis of MDS according to WHO classification that meets IPSS-R classification[4] 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 200 U/L for subjects not previously treated with ESAs • Refractory to- /relapsed after prior HMA treatment1: 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 treatment1 except for del(5q) MDS 5. 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 6. 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 7. Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2 8. 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 ongoin
Exclusion criteria
Exclusion criteria: Principal exclusion criteria 1. Prior therapy with disease modifying agents other than HMA or LEN for underlying MDS disease 2. Previously treated with either luspatercept or sotatercept 3. 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 4. 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) 5. Prior allogeneic or autologous stem cell transplant 6. Known history of diagnosis of acute myeloid leukemia (AML) 7. 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 8. Uncontrolled hypertension, defined as repeated elevations of diastolic blood pressure (DBP) = 100 mmHg despite adequate treatment 9. Platelet count 2% with either a positive Coombs test or over 50% indirect bilirubin 13. 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) 14. 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 15. History of stroke, deep venous thrombosis, pulmonary or arterial embolism within 6 months prior to the first dose of IMP 16. Pregnant or breast-feeding females 17. Myocardial infarction, uncontrolled angina, uncontrolled heart failure, or uncontrolled cardiac arrhythmia as determined by the investigator with
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective of the study is to evaluate red blood cell transfusion independence (RBC-TI) rate of luspatercept for the treatment of anemia due to International Prognostic Scoring System-Revised (IPSS-R) very low-, low-, or intermediate-risk MDS in subjects with ring sideroblasts (RS) who require RBC transfusions (according to IWG 2018 criteria);Secondary Objective: • To determine response rates in MDS-RS failing prior therapy with either lenalidomide (LEN) or hypomethylating agents (HMA) according to IWG 2018 criteria (max. 10 patients) • To determine RBC-TI and response rates according to IWG 2006 criteria • To evaluate the effect of luspatercept on: time to RBC-TI, duration of RBC-TI, increase in hemoglobin (Hb), neutrophils and platelets, decrease in serum ferritin and in iron chelation therapy (ICT) use • To investigate safety and tolerability of the luspatercept dosing regimen applied in this study • To investigate and compare Quality of Life (QoL) by patient-reported outcome (PRO) and performance outcome (PerfO) measures before and during luspatercept treatment;Primary end point(s): RBC-TI rate according to IWG 2018 modified criteria ;Timepoint(s) of evaluation of this end point: from Week 1 through Week 24 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • RBC-TI rate according to IWG 2006 criteria from Week 1 through Week 24 and through Week 52 • Median time to RBC-TI (Week 1 through Week 24 and through Week 52) • Median duration of RBC-TI (Week 1 through Week 24 and through Week 52) • Change in RBC units transfused over a fixed 16-weeks period (Week 9 through Week 24 and Week 37 through Week 52) compared to the 16-week period prior to screening • Proportion of subjects achieving mean Hb increase = 1.0 g/dL over = 8 weeks (Week 1 through Week 24 and through Week 52) • Proportion of subjects achieving modified hematologic improvement - erythroids (mHI-E) per IWG 2006 criteria (Week 1 through Week 24 and through Week 52) • Proportion of subjects achieving hematologic improvement - neutrophils (HI-N) per IWG 2006 criteria[2] (Week 1 through Week 24 and through Week 52) • Proportion of subjects achieving hematologic improvement - platelets (HI-P) per IWG 2006 criteria (Week 1 through Week 24 and through Week 52) • Mean change in serum ferritin from Week 9 through 24 and Week 37 through Week 52 compared to baseline • Mean change in mean daily dose of ICT from Week 9 through 24 and Week 37 through Week 52 compared to baseline • Proportion of subjects with progression to AML • Overall survival (OS) • Safety measures: type, frequency, severity of adverse events (AEs) and relationship to luspatercept, dose reductions and dose delays • Mean change in PRO (via EORTC QLQ-C30) and PerfO (via “Timed Up and Go test” [TUG]) from baseline (Week 1) to Week 52 and to End of Treatment (EOT).;Timepoint(s) of evaluation of this end point: as mentioned above in 5.2 | — |
Countries
Austria, Germany, Spain, Switzerland
Contacts
Public ContactMartin Puttrich
GWT-TUD GmbH
Outcome results
None listed