A Phase 3, Open-label, Randomized 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 Myelodysplastic Syndromes (MDS) in ESA Naive Subjects Who Require Red Blood Cell Transfusions

JRCT ID: jRCT2080224135

Registered date:06/11/2018

Basic Information

• Recruitment status: completed

Health condition(s) or Problem(s) studied

Anemia due to a IPSS-R very low, low, or intermediate risk MDS
according to the WHO 2016 classification and a bone marrow blast count of < 5%, who are ESA naive with endogenous sEPO levels of < 500 U/L and who require
RBC transfusions (ie, 2 to 6 units/8 weeks of pRBCs confirmed for a minimum of 8 weeks
immediately preceding randomization).

• Date of first enrollment: 02/09/2019
• Target sample size: 15
• Countries of recruitment: Japan,Asia except Japan,North America,Europe,Oceania
• Study type: Interventional

Intervention(s)

Administer luspatercept subcutaneously every 3 weeks (21 days). The starting dose is 1.0 mg/kg and the dose may be increased to1.33 mg/kg, 1.75 mg/kg. The dose is adjusted in the range from 0.45 to 1.75 mg/kg depending on a hemoglobin level and the occurrence of adverse events.

Administer epoetin alfa subcutaneously every week (7 days). The starting dose is 450 IU/kg (maximum total starting dose is
40,000 IU) and the dose may be increased to787.5 IU/kg, 1,050 IU/kg (maximum total dose is 80,000 IU). The dose is adjusted in the range from 337.5 IU/kg to 1,050 IU/kg depending on a hemoglobin level and the occurrence of adverse events.

Outcome(s)

Primary Outcome

efficacy
RBC transfusion independence (RBC-TI) for 12 weeks [84 days] with an associated concurrent mean hemoglobin increase >= 1.5 g/dL (From Week 1 to Week 24)

Secondary Outcome

safety
efficacy
exploratory
pharmacokinetics
pharmacogenomics
-RBC transfusion independence (RBC-TI) for 24 weeks (From Week 1 to Week 24)
-Mean hemoglobin change over 24 weeks (From Week 1 to Week 24)
-Hematologic improvement - erythroid response (HI-E) per IWG (Cheson, 2006) (From Week 1 to Week 24)
-Time to HI-E (From Week 1 to Week 24)
-RBC-TI for >= 12 weeks (84 days) (From Week 1 to Week 24)
etc.

other

Key inclusion & exclusion criteria

• Age minimum: >= 18age old
• Age maximum: Not applicable
• Gender: Both

Include criteria

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
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 an endogenous serum erythropoietin level of < 500 U/L.
6) Subject requires RBC transfusions, as documented by the following criteria:
- A transfusion requirement of 2 to 6 pRBCs units/8 weeks 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 (5.6 mmol/L) with symptoms of anemia (or
<= 7 g/dL [4.3 mmol/L] 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 (6.8 mmol/L) (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 achieved menarche at some point, 2) not undergone a hysterectomy or bilateral
oophorectomy or 3) has not been naturallypostmenopausal (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)Refer to Section 6.1.14 for additional details. She must agree to ongoing pregnancy
testing during the course of the study, and after end of study treatment.
-Either commit to true abstinence1 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 2 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 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.

Exclude criteria

1) Subject with the any of the following prior treatments:
- Erythropoiesis-stimulating agents (ESAs)
-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 discretion.
-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 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 ug/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 randomization:
-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, or with a history of hypertensive crisis or hypertensive encephalopathy.
9) Subject with any of the following laboratory abnormalities:
-Absolute neutrophil count (ANC) < 500/uL (0.5 x 109/L)
-Platelet count < 50,000/uL (50 x 109/L)
-Estimated glomerular filtration rate (eGFR) < 40 mL/min/1.73 m2 (APPENDIX F)
-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] clinicalstaging 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 randomization.
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. 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.
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) Subject with history of pure red cell aplasia (PRCA) and/or antibody against erythropoietin.
20) Female subject who is pregnant or breastfeeding.
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.
24) Subject has history of active SARS-CoV-2 infection within 4 weeks prior to screening,
unless the subject has adequately recovered from COVID 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
randomization.

Related Information

• Primary Sponsor: Bristol-Myers Squibb
• Secondary ID(s): NCT03682536,JapicCTI-184196