Studie zur Untersuchung der Wirksamkeit und Sicherheit von Luspatercept bei Patient*innen mit Niedrigrisiko MDS und ring-sideroblastischem Phänotyp (MDS-RS)

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
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 50-

Trade Name: Reblozyl? 75 mg
Product Code: ACE-536
Pharmaceutical Form: Lyophilisate for solution for injection
INN or Proposed INN: LUSPATERCEPT
Current Sponsor code: ACE-536
Other descriptive name: 1373715-00-4
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 50-

Gender:
Female: yes
Male: yes

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 < 13,000/?L

4. 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 Refractory to prior ESA treatment: Documentation of non-response or response that was no longer maintained to prior ESA-containing regimen, either as a single agent or in combination (e.g. with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-a = 500 ?g 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 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:
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 ?g/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 < 30,000/?L (30 ? 10^9/L)

10. Estimated glomerular filtration rate or creatinine clearance < 40 mL/min

11. Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) or alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) = 3.0 ? upper limit of normal
(ULN)

12. 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

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