Assessment of Effectiveness and Safety of Luspatercept in Patients Suffering From Lower-risk Myelodysplastic Syndrome.

A Phase IIIb, Open-label, Single Arm Study to Evaluate the Efficacy and Safety of Luspatercept in Patients With Lower-risk MDS and Ring-sideroblastic Phenotype (MDS-RS)

A phase IIIb, open-label, single arm study to evaluate the efficacy and safety of luspatercept in patients with lower-risk MDS and ring-sideroblastic phenotype (MDS-RS)

This is a phase IIIb, single arm, multicenter study to further explore the efficacy and safety of luspatercept in subjects with anemia due to IPSS-R very low-, low-, or intermediate-risk MDS with RS who require RBC transfusions. The study will consist of a screening period, a treatment period (primary phase and extension phase), and a posttreatment follow-up period.

The study will involve study sites in Germany, France, Austria and Switzerland. It is planned to include 70 patients to receive treatment with luspatercept to end up with 64 evaluable subjects.

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[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

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   • Refractory to prior ESA treatment: Documentation of non-response or response that was no longer maintained to prior ESA-containing regimen, either as a single agent or in combination (e.g. with granulocyte colony-stimulating factor [G-CSF]).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-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 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 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

9. 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

10. Subject is willing and able to adhere to the study visit schedule and other protocol requirements

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 < 30,000/μL (30 × 109/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 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

18. 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

19. History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the IMP

20. Subject is in custody by order of an authority or a court of law

21. Participation in another interventional clinical study within the last 3 months prior to signing the ICF or simultaneous participation in other clinical studies

22. Close affiliation with the investigator (e.g. a close relative) or persons working at the study site

23. Subject is an employee of the sponsor or involved Contract research Organization (CRO)

24. 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