Efficacy and Safety Study of Luspatercept (ACE-536) Versus Epoetin Alfa for the Treatment of Anemia Due to IPSS-R Very Low, Low or Intermediate Risk Myelodysplastic Syndromes (MDS) in ESA Naïve Subjects Who Require Red Blood Cell Transfusions

Conditions:Blood Cancer, Blood Cancer, Anemia
Therapuetic Areas:Hematology, Oncology
Age Range:18 - Any
Start Date:January 2, 2019
End Date:December 29, 2025
Contact:Associate Director Clinical Trial Disclosure

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A Phase 3, Open-label, Randomized Study to Compare the Efficacy and Safety of Luspatercept (ACE-536) Versus Epoetin Alpha for the Treatment of Anemia Due to IPSS-R Very Low, Low or Intermediate Risk Due to Myelodysplastic Syndrome (MDS) ESA in Native Subjects Who Require Red Blood Cell Transfusions

The study will be conducted in compliance with the International Council for Harmonisation
(ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good
Clinical Practice (GCP) and applicable regulatory requirements.

This is an interventional active-controlled, open-label, randomized Phase 3 study to compare
the efficacy and safety of luspatercept (ACE-536) versus epoetin alfa for the treatment of
anemia due to IPSS-R very low, low or intermediate risk MDS in ESA naïve subjects who require
RBC transfusions.

The study is divided into the Screening Period, a Treatment Period and a Post-Treatment
Follow-up Period.

Anemia is considered to be one of the most prevalent cytopenias in patients who have
myelodysplastic syndromes, an umbrella term used to describe disorders relating to the
ineffective production of red blood cells, white blood cells, and/or platelets. Ranging in
severity from mild (asymptomatic) to severe, anemia can result in patients requiring regular
red blood cell (RBC) transfusions, which can lead to further complications from iron
overload. The goal of this study is to assess the safety and efficacy of luspatercept versus
epoetin alfa in anemic patients who are categorized as International Prognostic Scoring
System-Revised (IPSS-R) very low, low, or intermediate risk Myelodysplastic syndrome (MDS),
are ESA naïve, and require constant RBC transfusions. The design of the study will allow a
period of initial randomization of patients into either the luspatercept or epoetin alfa arm,
followed by an open-label treatment period. In both treatment arms, best supportive care
(BSC) may be used in combination with study treatment when clinically indicated per
investigator. Best supportive care includes, but is not limited to, treatment with
transfusions, antibiotic, antiviral and/or antifungal therapy, and nutritional support as
needed. Best supportive care for this study excludes the use of ESAs outside of the study
treatment. Patients should receive treatment up to a minimum of 24 weeks after which an MDS
Disease assessment visit is scheduled to assess the response to treatment. Patients who are
determined to be experiencing clinical benefit may continue treatment. Continued clinical
benefit will be re-assessed every 24 weeks. Once patients are discontinued from study
treatment, they will enter a post treatment follow-up period.

Inclusion Criteria:

Subjects must satisfy the following criteria to be randomized in the study:

1. Subject is ≥ 18 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

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 an endogenous serum erythropoietin (sEPO) level of < 500 U/L.

6. Subject requires RBC transfusions, as documented by the following criteria:

• Average transfusion requirement of 2 - 6 units/8 weeks of pRBCs confirmed for a
minimum of 8 weeks immediately preceding randomization.

- Hemoglobin levels at the time of or within 7 days prior to administration of a
RBC transfusion must have been ≤ 9.0 g/dL with symptoms of anemia (or ≤ 7 g/dL in
the absence of symptoms) in order for the transfusion to be counted towards
meeting eligibility criteria. Red blood cell transfusions administered when Hgb
levels were > 9.0 g/dL (or > 7 g/dL in the absence of symptoms) and/or RBC
transfusions administered for elective surgery, infections or bleeding events
will not qualify as a required transfusion for the purpose of meeting eligibility
criteria or stratification.

- The hemoglobin level after the last RBC transfusion prior to randomization must
be < 11.0 g/dL (centrally or locally analyzed).

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 not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally
postmenopausal (amenorrhea following cancer therapy 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.

- If sexually active, 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. 9. Male subjects must:

- Practice true abstinence (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 randomization (with the
randomization date defined as the date in which the subject is randomized in IRT):

1. Subject with the any of the following prior treatments:

- Erythropoiesis-stimulating agents (ESAs)

- Granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage
colony-stimulating factor (GM-CSF), unless given for treatment of febrile

- 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 randomization, at the investigator's

- Hypomethylating agents

- Subjects may be randomized at the investigator's discretion contingent that
the subject received no more than 2 doses of HMA. The last dose must be ≥ 8
weeks from the date of randomization.

- Luspatercept (ACE-536) or sotatercept (ACE-011)

- Immunosuppressive therapy for MDS

- Hematopoietic cell transplant

2. Subject with MDS associated with del(5q) cytogenetic abnormality or MDS unclassifiable
(MDS-U) according to WHO 2016 classification.

3. Subject with myelodysplastic/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
with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T), MDS/MPN unclassifiable.

4. 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.

5. 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).

6. Subject with known history of diagnosis of AML.

7. Subject receiving any of the following treatment within 8 weeks prior to

- Anticancer cytotoxic chemotherapeutic agent or treatment

- Systemic corticosteroid, except for subjects on a stable or decreasing dose for ≥
1 week prior to randomization for medical conditions other than MDS

- Iron-chelating agents, except for subjects on a stable or decreasing dose for at
least 8 weeks prior to randomization

- Other RBC hematopoietic growth factors (eg, Interleukin-3)

- Androgens, unless to treat hypogonadism

- Hydroxyurea

- Oral retinoids (except for topical 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)

8. 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.

9. Subject with any of the following laboratory abnormalities:

- Absolute neutrophil count (ANC) < 500/μL (0.5 x 109/L)

- Platelet count < 50,000/μL (50 x 109/L)

- Estimated glomerular filtration rate (eGFR) < 40 mL/min/1.73 m2 (via the
4-variable modification of diet in renal disease [MDRD] formula)

- 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.

10. 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:

- 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)

11. Subject with major surgery within 8 weeks prior to randomization. Subjects must have
completely recovered from any previous surgery prior to randomization.

12. 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 randomization
Note: prior superficial thrombophlebitis is not an exclusion criterion.

13. New-onset seizures or poorly controlled seizures within 12 weeks prior to

14. Subject with the following cardiac conditions within 6 months prior to randomization:
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 randomization.

15. 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).

16. Subject with known human immunodeficiency virus (HIV), known evidence of active
infectious Hepatitis B, and/or known evidence of active Hepatitis C.

17. Subject with history of severe allergic or anaphylactic reactions or hypersensitivity
to recombinant proteins or excipients in luspatercept (see Investigator's Brochure).

18. Subject with known hypersensitivity to the active substance or to any of the
excipients in epoetin alfa.

19. Subjects with history of pure red cell aplasia (PRCA) and/or antibody against

20. Pregnant or breastfeeding females.

21. 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.

22. 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.

23. Subject has any condition or receives concomitant medication that confounds the
ability to interpret data from the study.
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