| Eligibility |
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was no longer maintained to prior ESA-containing regimen, either as a single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-a = 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
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