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 Naïve Subjects who require Red Blood Cell Transfusions.
- Conditions
- anemia10002086
- Registration Number
- NL-OMON52493
- Lead Sponsor
- Celgene Corporation
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Completed
- Sex
- Not specified
- Target Recruitment
- 15
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 (sEPO) level of < 500 U/L., 6. Subject
requires RBC transfusions, as documented by the following criteria:, •
Transfusion requirement of 2 - 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 not
undergone a hysterectomy or bilateral oophorectomy or 2) 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., •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.
1.Subject with the any of the following prior treatments:, •Erythropoiesis-
stimulating agents (ESAs)
Subjects may be randomized at the investigator*s discretion contingent on the
fact that the subject received no more than 2 doses of epoetin alfa (prior
treatment with darbepoetin not acceptable for entry into the study). The last
dose of epoetin alfa must be >= 8 weeks from the date of randomization. A blood
sample to determine the endogenous sEPO level (central laboratory) for
stratification must be taken within 5 days of randomization unless a prior
screening sample analyzed by the central laboratory demonstrated an endogenous
sEPO level <= 500 U/L.
•Granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage
colony-stimulating factor (GM-CSF), unless given for treatment of febrile
neutropenia
•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 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 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 investigatio
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>The primary efficacy analysis will be the comparison of the response rates in<br /><br>the two treatment arms in the intent-to-treat (ITT) population. The primary<br /><br>efficacy endpoint is defined as the absence of any RBC transfusion of >= 12<br /><br>weeks with a mean hemoglobin increase<br /><br>>= 1.5 g/dL during the same time period over the first 24 weeks from baseline<br /><br>(Week 1 through Week 24) during the Treatment Period.</p><br>
- Secondary Outcome Measures
Name Time Method <p>- RBC transfusion independence (RBC-TI) for 24 weeks<br /><br>- Mean hemoglobin change over 24 weeks<br /><br>- Hematologic improvement - erythroid response (HI-E) per IWG<br /><br>- Time to HI-E<br /><br>- RBC-TI for >= 12 weeks (84 days)<br /><br>- Duration of RBC-TI >= 12 weeks (84 days)<br /><br>- Time from first dose to fist onset of transfusion independence >= 84 days<br /><br>- Time from first dose to first transfusion on treatment<br /><br>- RBC transfusion burden on treatment<br /><br>- RBC-TI for >= 56 days (8 weeks)<br /><br>- Proportion of subjects who are RBC-Transfusion free for a consecutive 24-week<br /><br>period in the first 48 weeks from first dose<br /><br>- Health-related quality-of-life<br /><br>- Safety<br /><br>- A population PK model and Exposure-response relationship<br /><br>- Antidrug antibodies<br /><br>- Progression to AML<br /><br>- Overall survival</p><br>