| Eligibility |
Inclusion Criteria:
Subjects must satisfy the following criteria to be enrolled in the study:
1. Subject is = 20 years of age the time of signing the informed consent form (ICF)
2. Subject must understand and voluntarily sign an ICF prior to any study-related
assessments/procedures being conducted.
3. Subject is willing and able to adhere to the study visit schedule and other protocol
requirements.
4. Subject has a documented diagnosis of MDS according to WHO 2016 classification that
meets IPSS-R classification of very low, low, or intermediate risk disease, and:
• < 5% blasts in bone marrow
5. Subject has symptomatic anemia with mean Hgb concentration < 10.0 g/dL from 2
measurements (one performed within 1 day prior to W1D1 and the other performed 7 to 35
days prior to W1D1) that does not require RBC transfusion. If more than one
measurement exists in the period of 7 to 35 days prior to W1D1, the most recent value
will be used.
6. Subject must be TI, as documented by the following criteria:
• No RBC transfusion administered within 16 weeks prior to W1D1 (except transfusions
due to blood loss or infection that occurred between 16 and 8 weeks prior to W1D1)
7. Subject has Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2
8. Females of childbearing potential (FCBP), defined as a sexually mature woman who:
1) has achieved menarche at some point, 2) not undergone a hysterectomy or bilateral
oophorectomy, or 3) has not been naturally postmenopausal (amenorrhea following cancer
therapy or amenorrhea due to other medical reasons does not rule out childbearing
potential) for at least 24 consecutive months (ie, has had menses at any time in the
preceding 24 consecutive months), must:
- Have two negative pregnancy tests as verified by the investigator prior to starting
study therapy (unless the screening pregnancy test was done within 72 hours of W1D1).
She must agree to ongoing pregnancy testing during the course of the study, and after
end of study treatment. This applies even if the subject practices true abstinence1
from heterosexual contact.
- Either commit to true abstinence from heterosexual contact (which must be reviewed on
a monthly basis and source documented) or agree to use, and be able to comply with,
highly effective contraception without interruption, 5 weeks prior to starting
investigational product, during the study therapy (including dose interruptions), and
for 12 weeks after discontinuation of study therapy.
- If breastfeeding, agree to stop breastfeeding prior to the participation in the study
and not to resume breastfeeding after treatment discontinuation.
9. Male subjects must:
- Practice true abstinence2 (which must be reviewed prior to each IP administration or
on a monthly basis [eg, in the event of dose delays]) or agree to use a condom (latex
or non-latex, but not made out of natural [animal] membrane) during sexual contact
with a pregnant female or a female of childbearing potential while participating in
the study, during dose interruptions and for at least 12 weeks following
investigational product discontinuation, even if he has undergone a successful
vasectomy.
Exclusion Criteria:
The presence of any of the following will exclude a subject from enrollment:
1. Subject with the any of the following prior treatments for underlying disease:
- Disease modifying agents (eg, immune-modulatory drug [IMiDs such as
lenalidomide])
- Except if the subject received = 1 week of treatment with a disease modifying
agent = 8 weeks from W1D1, at the investigator's discretion.
- Hypomethylating agents
- Subjects may be enrolled at the investigator's discretion contingent that the
subject received no more than 2 injections of HMA. The last dose must be = 8
weeks from the date of W1D1.
- Luspatercept (ACE-536) or sotatercept (ACE-011)
- Allogeneic and/or autologous hematopoietic cell transplant
2. Subject with myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN)
according to WHO 2016 classification (ie, chronic myelomonocytic leukemia (CMML),
atypical chronic myeloid leukemia (aCML), BCR-ABL12, juvenile myelomonocytic leukemia
(JMML), MDS/MPN unclassifiable.
3. Subject with secondary MDS, ie, MDS that is known to have arisen as the result of
chemical injury or treatment with chemotherapy and/or radiation for other diseases.
4. Subject with known clinically significant anemia due to iron, vitamin B12, or folate
deficiencies, or autoimmune or hereditary hemolytic anemia, or hypothyroidism, or any
type of known clinically significant bleeding or sequestration. Subject with drug
induced anemia (eg, mycophenolate).
• Iron deficiency to be determined by serum ferritin < 100 µg/L and additional testing
if clinically indicated (eg, calculated transferrin saturation [iron/total iron
binding capacity = 20%] or bone marrow aspirate stain for iron).
5. Subject with known history of diagnosis of AML
6. Subject receiving any of the following treatment within 8 weeks prior to W1D1:
- Anticancer cytotoxic chemotherapeutic agent or treatment
- ESAs
- Granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage
colonystimulating factor (GM-CSF), unless given for treatment of febrile
neutropenia
- Immunosuppressive therapy for MDS
- Systemic corticosteroid, except for subjects on a stable or decreasing dose for =
1 week prior to W1D1 for medical conditions other than MDS
- Other RBC hematopoietic growth factors (eg, Interleukin-3)
- Androgens, unless to treat hypogonadism
- Hydroxyurea, anagrelide
- Oral retinoids
- Arsenic trioxide
- Interferon and interleukins
- Investigational drug or device, or approved therapy for investigational use (if 5
times the half-life of the previous investigational drug exceeds 8 weeks, then
the time of exclusion should be extended up to 5 times the half-life of the
investigational drug)
7. Subject with uncontrolled hypertension, defined as repeated elevations of systolic
blood pressure (SBP) of = 150 mmHg and/or diastolic blood pressure (DBP) = 100 mmHg
despite adequate treatment, or with a history of hypertensive crisis or hypertensive
encephalopathy.
8. Subject with any of the following laboratory abnormalities:
- Absolute neutrophil count (ANC) < 500/µL (0.5 x 10^9/L)
- Platelet count < 30,000/µL (30 x 10^9/L) (Exclude subjects that may be at risk of
bleeding regardless of platelet counts. This includes [but is not limited to]
subjects currently using aspirin or heparin, immediately after surgery, or easily
causes bleeding such as nasal bleeding or subcutaneous bleeding or previous
episode of major bleeding where the cause was not effectively treated.)
- Estimated glomerular filtration rate (eGFR) < 40 mL/min/1.73 m^2 (via the
4-variable modification of diet in renal disease [MDRD] formula, Appendix G)
- Serum aspartate aminotransferase/serum glutamic oxaloacetic transaminase
(AST/SGOT) or alanine aminotransferase/serum glutamic pyruvic transaminase
(ALT/SGPT) = 3.0 x upper limit of normal (ULN)
- Total bilirubin = 2.0 x ULN. - Higher levels are acceptable if these can be
attributed to active red blood cell precursor destruction within the bone marrow
(ie, ineffective erythropoiesis) or in the presence of known history of Gilbert
Syndrome.
9. Subject with prior history of malignancies, other than MDS, unless the subject has
been free of the disease for = 5 years. However, subjects with the following
history/concurrent conditions are allowed if considered as curatively treated:
- 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 [TNM] clinical staging system)
10. Subject with major surgery within 8 weeks prior to W1D1. Subjects must have completely
recovered from any previous surgery prior to W1D1
11. Subject with history of cerebrovascular accident (including ischemic, embolic, and
hemorrhagic cerebrovascular accident), transient ischemic attack, deep venous
thrombosis (DVT; including proximal and distal), pulmonary or arterial embolism,
arterial thrombosis or other venous thrombosis within 6 months prior to W1D1 Note:
prior superficial thrombophlebitis is not an exclusion criterion.
12. Subject with the following cardiac conditions within 6 months prior to W1D1:
myocardial infarction, uncontrolled angina, acute decompensated cardiac failure or New
York Heart Association (NYHA) Class III-IV heart failure, or uncontrolled cardiac
arrhythmia as determined by the investigator. Subjects with a known ejection fraction
?35%, confirmed by a local echocardiogram (ECHO) or multi-gated acquisition (MUGA)
scan performed within 6 months prior to W1D1.
13. Subject with 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).
14. Subject with known human immunodeficiency virus (HIV), known evidence of active
infectious hepatitis B, and/or known evidence of active Hepatitis C. Local laboratory
testing confirming HIV, hepatitis B, and hepatitis C status should not have been
performed beyond 4 weeks prior to the date of ICF signature.
15. Subject with history of severe allergic or anaphylactic reactions or hypersensitivity
to recombinant proteins or excipients in luspatercept (see current IB).
16. Pregnant or breastfeeding females.
17. Subject has any significant medical condition, laboratory abnormality, psychiatric
illness, or is considered vulnerable by local regulations (eg, imprisoned or
institutionalized) that would prevent the subject from participating in the study.
18. Subject has any condition including the presence of laboratory abnormalities, which
places the subject at unacceptable risk if he/she were to participate in the study.
19. Subject has any condition or receives concomitant medication that confounds the
ability to interpret data from the study.
20. Subject has history of active SARS-CoV-2 infection within 4 weeks prior to screening,
unless the subject has adequately recovered from COVID-19 symptoms and related
complications as per investigator's discretion and following a discussion with the
Medical Monitor. Use of a live COVID-19 vaccine is prohibited within 4 weeks prior to
W1D1.
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