LUSPATERCEPT for Myelodysplastic syndrome (MDS) - lower-risk|Myelodysplastic syndrome with ring sideroblasts (MDS-RS)

Inclusion criteria

• {"criterion_text":"- Subject is 18 years of age or older at the time of signing the informed consent form (ICF)"}
• {"criterion_text":"- Subject is willing and able to adhere to the study visit schedule and other protocol requirements"}
• {"criterion_text":"- Subject is able to understand and voluntarily sign the ICF prior to any study-related assessments/procedures being conducted"}
• {"criterion_text":"- 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: •\tRing sideroblasts (RS) ≥ 15% of erythroid precursors in bone marrow or ≥ 5% if SF3B1 mutation is present •\tLess than 5% blasts in bone marrow •\tPeripheral blood white blood cell (WBC) count < 13,000/μL"}
• {"criterion_text":"- Subject must be one of the following: •\tRefractory to prior ESA treatment: Documentation of non-response or response that was no longer maintained to prior ESA-containing regimen, either as a single agent or in combination (e.g., with granulocyte colony-stimulating factor [G-CSF]).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: \tRecombinant human erythropoietin ≥ 40,000 IU/week for at least 8 weeks (=doses) or equivalent; or \tDarbepoetin-α ≥ 500 µg q3w for at least 4 doses or equivalent •\tIntolerant 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) •\tESA ineligible: Low chance of response to ESA based on endogenous serum erythropoietin (EPO) level > 200 U/L for subjects not previously treated with ESAs •\tRefractory 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 •\tRefractory to- /relapsed after prior lenalidomide treatment except for del(5q) MDS"}
• {"criterion_text":"- 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"}
• {"criterion_text":"- Required RBC transfusions, as documented by the following criteria: •\tAverage 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 •\tHemoglobin (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 •\tNo 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"}
• {"criterion_text":"- Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2"}
• {"criterion_text":"- 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: •\tHave 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). •\tIf 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. **\tHighly 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"}
• {"criterion_text":"- 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"}

Exclusion criteria

• {"criterion_text":"- Prior therapy with disease modifying agents other than HMA or LEN for underlying MDS disease"}
• {"criterion_text":"- Platelet count < 30,000/μL (30 × 109/L)"}
• {"criterion_text":"- Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) or alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) ≥ 3.0 × upper limit of normal (ULN)"}
• {"criterion_text":"- Total bilirubin ≥ 2.0 × ULN •\tHigher 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 •\tSubjects 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"}
• {"criterion_text":"- 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: •\tBasal or squamous cell carcinoma of the skin •\tCarcinoma in situ of the cervix •\tCarcinoma in situ of the breast •\tIncidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, metastasis clinical staging system)"}
• {"criterion_text":"- 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"}
• {"criterion_text":"- History of stroke, deep venous thrombosis, pulmonary or arterial embolism within 6 months prior to the first dose of IMP"}
• {"criterion_text":"- Pregnant or breast-feeding females"}
• {"criterion_text":"- 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"}
• {"criterion_text":"- 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"}
• {"criterion_text":"- History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the IMP"}
• {"criterion_text":"- Estimated glomerular filtration rate or creatinine clearance < 40 mL/min"}
• {"criterion_text":"- Subject is in custody by order of an authority or a court of law"}
• {"criterion_text":"- 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)"}
• {"criterion_text":"- Close affiliation with the investigator (e.g., a close relative) or persons working at the study site"}
• {"criterion_text":"- Subject is an employee of the sponsor or involved Contract research Organization (CRO)"}
• {"criterion_text":"- 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"}
• {"criterion_text":"- Previously treated with either luspatercept or sotatercept"}
• {"criterion_text":"- 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"}
• {"criterion_text":"- Known clinically significant anemia due to iron, vitamin B12, or folate deficiencies, or autoimmune or hereditary hemolytic anemia, or gastrointestinal bleeding •\tIron 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)"}
• {"criterion_text":"- Prior allogeneic or autologous stem cell transplant"}
• {"criterion_text":"- Known history of diagnosis of acute myeloid leukemia (AML)"}
• {"criterion_text":"- Use of any of the following within 5 weeks prior to the first dose of the IMP in this study: •\tAnticancer cytotoxic chemotherapeutic agent or treatment •\tCorticosteroid, 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 •\tICT, except for subjects on a stable or decreasing dose for at least 8 weeks prior to the first dose of IMP •\tOther RBC hematopoietic growth factors (e.g., interleukin [IL]-3) •\tInvestigational 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"}
• {"criterion_text":"- Uncontrolled hypertension, defined as repeated elevations of diastolic blood pressure (DBP) ≥ 100 mmHg despite adequate treatment"}

Primary endpoints

• {"endpoint_text":"- RBC-TI rate according to IWG 2018 modified criteria[1] from Week 1 through Week 24","definition_or_measurement_approach":"RBC-TI (red blood cell transfusion independence) rate measured per IWG 2018 modified criteria during Week 1 through Week 24"}

Secondary endpoints

• {"endpoint_text":"- RBC-TI rate according to IWG 2006 criteria from Week 1 through Week 24 and through Week 52","definition_or_measurement_approach":"RBC-TI rate measured per IWG 2006 criteria assessed from Week 1 through Week 24 and through Week 52"}
• {"endpoint_text":"- Median time to RBC-TI (Week 1 through Week 24 and through Week 52)","definition_or_measurement_approach":"Median time to achieve RBC-TI evaluated during Week 1 through Week 24 and through Week 52"}
• {"endpoint_text":"- Median duration of RBC-TI (Week 1 through Week 24 and through Week 52)","definition_or_measurement_approach":"Median duration (length) of RBC transfusion independence measured Week 1 through Week 24 and through Week 52"}
• {"endpoint_text":"- 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","definition_or_measurement_approach":"Change in number of RBC units transfused over specified 16-week windows compared to pre-screening 16-week period"}
• {"endpoint_text":"- Proportion of subjects achieving mean Hb increase ≥ 1.0 g/dL over ≥ 8 weeks (Week 1 through Week 24 and through Week 52)","definition_or_measurement_approach":"Proportion achieving mean hemoglobin increase ≥1.0 g/dL sustained for ≥8 weeks during specified windows"}
• {"endpoint_text":"- Proportion of subjects achieving modified hematologic improvement - erythroids (mHI-E) per IWG 2006 criteria (Week 1 through Week 24 and through Week 52)","definition_or_measurement_approach":"Proportion meeting mHI-E as defined by IWG 2006 during specified windows"}
• {"endpoint_text":"- Proportion of subjects achieving hematologic improvement - neutrophils (HI-N) per IWG 2006 criteria (Week 1 through Week 24 and through Week 52)","definition_or_measurement_approach":"Proportion meeting HI-N as per IWG 2006 criteria during specified windows"}
• {"endpoint_text":"- Proportion of subjects achieving hematologic improvement - platelets (HI-P) per IWG 2006 criteria (Week 1 through Week 24 and through Week 52)","definition_or_measurement_approach":"Proportion meeting HI-P as per IWG 2006 during specified windows"}
• {"endpoint_text":"- Mean change in serum ferritin from Week 9 through 24 and Week 37 through Week 52 compared to baseline","definition_or_measurement_approach":"Mean change in serum ferritin measured in the stated time windows versus baseline"}
• {"endpoint_text":"- Mean change in mean daily dose of ICT from Week 9 through 24 and Week 37 through Week 52 compared to baseline","definition_or_measurement_approach":"Mean change in daily dose of iron chelation therapy measured in specified windows versus baseline"}
• {"endpoint_text":"- Proportion of subjects with progression to AML","definition_or_measurement_approach":"Proportion of subjects who progress to acute myeloid leukemia (AML) during follow-up"}
• {"endpoint_text":"- Overall survival (OS)","definition_or_measurement_approach":"Overall survival measured from baseline to death from any cause"}
• {"endpoint_text":"- Safety measures: type, frequency, severity of adverse events (AEs) and relationship to luspatercept, dose reductions and dose delays","definition_or_measurement_approach":"Standard safety assessment: collection and classification of AEs, seriousness, severity, relationship to IMP, and recording of dose modifications"}
• {"endpoint_text":"- 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)","definition_or_measurement_approach":"Change from baseline in patient-reported outcomes (EORTC QLQ-C30) and performance outcome (TUG) at Week 52 and EOT"}

Austria

Earliest CTIS Part Ii Submission Date

21-10-2024

Latest Decision Or Authorization Date

05-11-2024

Processing Time Days

15

Number Of Sites

2

Number Of Participants

2

Germany

Earliest CTIS Part Ii Submission Date

21-10-2024

Latest Decision Or Authorization Date

30-10-2024

Processing Time Days

9

Number Of Sites

2

Number Of Participants

9

Spain

Earliest CTIS Part Ii Submission Date

21-10-2024

Latest Decision Or Authorization Date

29-10-2024

Processing Time Days

8

Number Of Sites

9

Number Of Participants

37

Primary sponsor

Full Name

GWT-Tud GmbH

Organisation Type

Pharmaceutical company

Country Of Registered Address

Germany

Third parties

• {"country":"Germany","full_name":"Marien Hospital Duesseldorf GmbH","duties_or_roles":"","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Germany","full_name":"Universitaetsklinikum Leipzig AöR","duties_or_roles":"Biobanking and translational program","organisation_type":"Educational Institution"}