This study has been transitioned to CTIS with ID 2022-501485-22-00 check the CTIS register for the current data. Primary objective:• To evaluate the efficacy of luspatercept on RBC transfusion independence (RBC-TI for 12 weeks [84 days] with an…
ID
Source
Brief title
Condition
- Anaemias nonhaemolytic and marrow depression
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary efficacy analysis will be the comparison of the response rates in
the two treatment arms in the intent-to-treat (ITT) population. The primary
efficacy endpoint is defined as the absence of any RBC transfusion of >= 12
weeks with a mean hemoglobin increase
>= 1.5 g/dL during the same time period over the first 24 weeks from baseline
(Week 1 through Week 24) during the Treatment Period.
Secondary outcome
- RBC transfusion independence (RBC-TI) for 24 weeks
- Mean hemoglobin change over 24 weeks
- Hematologic improvement - erythroid response (HI-E) per IWG
- Time to HI-E
- RBC-TI for >= 12 weeks (84 days)
- Duration of RBC-TI >= 12 weeks (84 days)
- Time from first dose to fist onset of transfusion independence >= 84 days
- Time from first dose to first transfusion on treatment
- RBC transfusion burden on treatment
- RBC-TI for >= 56 days (8 weeks)
- Proportion of subjects who are RBC-Transfusion free for a consecutive 24-week
period in the first 48 weeks from first dose
- Health-related quality-of-life
- Safety
- A population PK model and Exposure-response relationship
- Antidrug antibodies
- Progression to AML
- Overall survival
Background summary
Luspatercept (ACE-536), an erythroid maturation agent, is a recombinant fusion
protein consisting of a modified form of the extracellular domain (ECD) of the
human activin receptor type IIB (ActRIIB) linked to the Fc portion of human
immunoglobulin G1 (IgG1-Fc). Luspatercept acts on endogenous inhibitors of
late-stage erythropoiesis (eg, growth differentiation factor 11, GDF11) to
increase release of mature erythrocytes into circulation. Nonclinical data
have demonstrated that luspatercept binds to negative regulators governing
late-stage erythroid development to inhibit their action, thereby promoting the
maturation of erythrocytes in the bone marrow. These findings suggest that
luspatercept may represent a novel therapeutic approach to anemia, particularly
in diseases in which ineffective erythropoiesis is a contributing factor, as in
β thalassemia and MDS.
Study objective
This study has been transitioned to CTIS with ID 2022-501485-22-00 check the CTIS register for the current data.
Primary objective:
• To evaluate the efficacy of luspatercept on RBC transfusion independence
(RBC-TI for 12 weeks [84 days] with an associated concurrent mean hemoglobin
increase >= 1.5 g/dL) compared with 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.
Secondary objectives:
• To assess the safety and efficacy of luspatercept compared to epoetin alfa
• To assess health-related quality-of-life (HRQoL) and anemia outcome measures
(ie, European Organization for Research and Treatment of Cancer Quality of Life
Questionnaire [EORTC QLQ-C30] and the Functional Assessment of Cancer Therapy -
Anemia [FACT-An] questionnaire) for subjects treated with luspatercept compared
to epoetin alfa.
• To evaluate pharmacokinetics for luspatercept in MDS subjects.
Study design
ACE-536-MDS-002 is a Phase 3, multicenter, randomized, open label, active
controlled study. The primary objective of the study is to evaluate RBC-TI in
the two treatment arms, luspatercept compared with 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 a Screening Period, a Treatment Period and a
Post-Treatment Follow-up Period.
Screening Period:
Subject screening procedures are to take place within 35 days prior to
randomization (after the subject has given written informed consent). During
the Screening Period, the subject will undergo safety and other assessments to
determine eligibility for the randomized study.
Central review of bone marrow aspirate smear, peripheral blood smear and
cytogenetics will be used to confirm MDS diagnosis according to the World
Health Organization (WHO) 2016 classification (Arber, 2016) and to determine
the baseline IPSS-R risk classification (Greenberg, 2012). A bone marrow
biopsy will be collected only when adequate aspirate is not attainable.
Transfusion history must be available for at least 16 weeks immediately
preceding and including the date of randomization.
Randomization:
Eligible subjects will be randomized by a central randomization procedure using
integrated response technology (IRT) at a 1:1 ratio to either the luspatercept
or the epoetin alfa arm. Randomization will be stratified based on RBC
transfusion burden at baseline, ring sideroblast status (RS) at baseline and
endogenous serum erythropoietin level (sEPO) at baseline.
Treatment Period:
The first dose of investigational product (IP) should be administered within 3
days of randomization at the latest.
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.
Subjects should receive IP through to a minimum of the 24-Week MDS Disease
Assessment Visit scheduled for Day 169, unless the subject experiences
unacceptable toxicities, withdraws consent, or meets any other treatment
discontinuation criteria.
The MDS Disease Assessment (Section 6.4.2) on Day 169 (and every 24 weeks
thereafter [ie, Day 337, Day 505, etc.]) consists of the investigator*s
assessment of clinical benefit from IP and status of underlying disease. For
subjects to remain on treatment beyond this timepoint both of the following
criteria must be confirmed in each subject:
• Evidence of clinical benefit defined as a transfusion reduction of >= 2 pRBC
units/8 weeks compared to the baseline (for any consecutive 8-week period
within the 12 weeks immediately preceding Day 169 and every 24 weeks thereafter
[ie, Day 337, Day 505, etc.]).
• Absence of disease progression per International Working Group (IWG) criteria
for altering natural history of MDS (Cheson, 2006) based on central
morphological assessment of bone marrow, peripheral blood and cytogenetics
results.
Based on the outcome of these assessments, subjects will either be discontinued
from treatment with IP, undergo End of Treatment (EOT) visit evaluations and
enter the Post-Treatment Follow-up Period or continue open-label treatment with
their assigned IP as long as the above criteria continue to be met or until the
subject experiences unacceptable toxicities, withdraws consent, or meets any
other discontinuation criteria.
Post-Treatment Follow-up Period:
All subjects who have received at least one dose of IP should undergo EOT and
42-Day Follow-up evaluations.
This includes (but is not limited to) the collection of adverse events (AEs),
concomitant drugs and RBC-transfusion data (until 8 weeks after last dose of IP
or the EOT Visit, whichever occurs later).
In addition, subjects will continue to be followed for 5 years from the first
dose of IP or 3 years from the last dose (whichever occurs later), for
monitoring for other malignancies/pre-malignances and progression to AML along
with data collection of subsequent MDS therapies, and overall survival unless
the subject withdraws consent from the study, dies or is lost to follow-up. For
that purpose, subjects will be followed after treatment every 12 weeks for 3
years from the date of last dose of IP and every 6 months thereafter, if
applicable.
An antidrug antibodies (ADA) sample(s) may be required in the Post-Treatment
Follow-up Period for subjects assigned to the luspatercept arm, who terminate
the Treatment Period with less than 1-year of ADA monitoring if a subject is
ADA positive at the time of treatment discontinuation.
Intervention
Eligible subjects will be randomized by a central randomization procedure using
integrated response technology (IRT) at a 1:1 ratio to one of the below
treatment arms:
• Experimental Arm: luspatercept (ACE-536): starting dose of 1.0 mg/kg
subcutaneous injection every 3 weeks (21 days; Q3W). Dose levels can be
increased in a stepwise manner beyond the starting dose to 1.33 mg/kg, and up
to a maximum of 1.75 mg/kg (with a maximum total dose of 168 mg).
• Control Arm: epoetin alfa (EPREX® or PROCRIT®): starting dose of 450 IU/kg
(maximum total starting dose is 40,000 IU) subcutaneous injection once every
week (7 days; QW). Dose levels can be increased in a stepwise manner beyond
the starting dose to 787.5 IU/kg, and up to a maximum of 1,050 IU/kg (with a
maximum total dose of 80,000 IU). Individual epoetin alfa doses according to
body weight will be rounded: up to the next 2,000 IU dose level for Starting
Dose Level and Dose Level - 1; and up to the next 4,000 IU for Dose Level +1
and Dose Level +2 for doses exceeding a calculated dosing of 56,000 IU
according to body weight.
Crossover between the treatment arms is not permitted during the Study
Treatment Period.
Study burden and risks
ECG
bonemarrow aspirate/biopsy
venapuntion
Questionnaires
Physical examination
Urine analysis
There may be risks or side effects of the study treatments.
Risks and side effects of Epoetin alfa:
Very common (>= 10%) reported side effects in subjects: These may affect more
than 1 in 10 people.
• Diarrhoea
• Feeling sick in your stomach
• Vomiting
• Fever
• Respiratory tract congestion, such as stuffy nose and sore throat, has been
reported in patients with kidney disease not yet on dialysis.
Common (>= 1% and < 10%) reported side effects in subjects: These may affect up
to 1 in 10 people
• Increased blood pressure (headaches, particularly sudden, stabbing
migraine-like headaches, feeling confused or having fits may be signs of a
sudden increase in blood pressure. This requires urgent treatment. Raised
blood pressure may require treatment with drugs [or adjustment to any drugs you
already take for high blood pressure]).
• Blood clots (including deep vein thrombosis and embolism) that may require
urgent treatment. You may have chest pain, breathlessness, and painful swelling
and redness, usually in the leg as symptoms.
• Cough
• Skin rashes, which may result from an allergic reaction.
• Bone or muscle pain
• Flu-like symptoms (such as headache, aches and pains in the joints, feeling
of weakness, chills, tiredness and dizziness. These may be more common at the
start of treatment.)
• Redness, burning and pain at the site of injection
• Swelling of the ankles, feet or fingers
• Arm or leg pain
Uncommon (>= 0.1% and < 1%) reported side effects in subjects: These may affect
up to 1 in 100 people
• High levels of blood potassium which can cause abnormal heart rhythm (this is
a very common side effect in patients on dialysis).
• Fits
• Nose or airway congestion
• Allergic reaction
• Hives
Rare (>= 0.01% and < 0.1%) reported side effects in subjects: These may affect
up to 1 in 1,000 people
• Symptoms of pure red cell aplasia (PRCA). PRCA causes sudden and severe
anemia. The symptoms are unusual tiredness, feeling dizzy, breathlessness. PRCA
has been very rarely reported mostly in patients with kidney disease after
months to years of treatment with epoetin alfa and other products that
stimulate red blood cell production.
• An increase in levels of platelets, particularly when starting treatment.
• Severe allergic reaction that may include a swollen face, lips, mouth, tongue
or throat; difficulty swallowing or breathing; and itchy rash (hives).
• Problem with the blood that may cause pain, dark colored urine or increased
sensitivity of the skin to sunlight (porphyria)
The needle cover of EPREX®/ERYPO® pre-filled syringes contains latex rubber
which may cause severe allergic reactions in people who are sensitive to latex.
Severe allergic reactions are rare side effects and may include: swollen face,
lips, mouth, tongue, or throat; difficulty swallowing or breathing; and itch
rash (hives).
Serious skin rashes including Stevens-Johnson syndrome and toxic epidermal
necrolysis have been reported in association with epoetin treatment. These can
appear as reddish target-like macules or circular patches often with central
blisters on the trunk, skin peeling, ulcers of mouth, throat, nose, genitals
and eyes and can be preceded by fever and flu-like symptoms.
Epoetin alfa is also a red blood cell growth factor and in some circumstances
the cancer may grow faster.
Risks and side effects of Luspatercept:
Very commonly (occurring in at least 1 out of 10 people) side effects:
- Diarrhoea;
- Nausea;
- Asthenia;
- Fatigue;
- Influenza-like illness;
- Bronchitis;
- Influenza;
- Upper respiratory tract infection;
- Urinary tract infection;
- Arthralgia;
- Bone pain;
- Back pain;
- Dizziness;
- Headache;
- Insomnia;
- Cough;
- Dyspnoea
- Hypertension;
- Prehypertension.
Less commonly (occurring in at least 5 out of 100 people but less than 1 out of
10 people) side effects:
- Extramedullary hematopoiesis;
- Vertigo, Vertigo Positional;
- Injection site reactions;
- Hypersensitivity;
- Traumatic fracture;
- Hyperuricaemia;
- Migraine;
- Syncope, Presyncope;
- Epistaxis.
In other adult luspatercept studies treating B-Thal (not treating MDS or MF),
blood clots occurred in the veins or arteries.
Patients with B-Thal are at increased risk of developing masses (extramedullary
hematopoietic masses) in the body. In the B-Thal BEYOND study, subjects with
non-transfusion dependent B-Thal taking luspatercept (about 6 out of 100
subjects) had more of these masses than those taking placebo (about 2 out of
100 subjects). Extramedullary hematopoietic masses have also been observed in
transfusion-dependent B-Thal patients taking luspatercept long-term. In some
patients (about 2 out of 100) these masses caused compression of the spine.
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Listed location countries
Age
Inclusion 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 (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.
Exclusion criteria
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 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 10^9/L)
•Platelet count < 50,000/µL (50 x 10^9/L)
•Estimated glomerular filtration rate (eGFR) < 40 mL/min/1.73 m2 (refer to
formula in appendix F of the protocol)
•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
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. Subjects with history of pure red cell aplasia (PRCA) and/or antibody
against erythropoietin.
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.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2022-501485-22-00 |
| EudraCT | EUCTR2017-003190-34-NL |
| ClinicalTrials.gov | NCT03682536;U1111-1218-1810 |
| CCMO | NL66370.028.18 |