A Phase 3, Double-Blind, Randomized Study To Compare The Efficacy And Safety Of Luspatercept (ACE-536) Versus Placebo For The Treatment Of Anemia Due To IPSS-R Very Low, Low, Or Intermediate Risk Myelodysplastic Syndromes In Subjects With Ring Syderoblasts Who Require Red Blood Cell Transfusions
- Conditions
- anemia10002086
- Registration Number
- NL-OMON47664
- Lead Sponsor
- Celgene Corporation
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Completed
- Sex
- Not specified
- Target Recruitment
- 12
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. Documented diagnosis of MDS according to WHO 2008 classification (Appendix
B) that meets IPSS-R classification (Greenberg, 2012; Appendix D) of very low,
low, or intermediate risk disease, and: Ring sideroblast * 15% of erythroid
precursors in bone marrow, and < 5% blasts in bone marrow
4. Refractory or intolerant to, or ineligible for, prior ESA treatment, as
defined by any one of the following:
- Refractory to prior ESA treatment - documentation of non-response or
response that is no longer maintained to prior ESA-containing regimen, either
as single agent or combination (eg, with G-CSF); ESA regimen must have been
either:
a) recombinant human erythropoietin (rHu EPO) * 40,000 IU/wk for at least 8
doses or equivalent;
OR
b) darbepoetin alpha * 500 *g Q3W for at least 4 doses or equivalent;
- Intolerant to prior ESA treatment - documentation of discontinuation of prior
ESAcontaining regimen, either as single agent or combination (eg, with G-CSF),
at any time after introduction due to intolerance or an adverse event
- ESA ineligible - Low chance of response to ESA based on endogenous serum
erythropoietin level > 200 U/L for subjects not previously treated with ESAs
5. If previously treated with ESAs or granulocyte colony-stimulating factor
(G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), both agents
must have been discontinued * 4 weeks prior to date of randomization.
6. Requires RBC transfusions, as documented by the following criteria:
- average transfusion requirement of * 2 units/8 weeks of pRBCs confirmed for a
minimum of 16 weeks immediately preceding randomization.
- no consecutive 56-day period that was RBC transfusion-free during the 16
weeks immediately preceding randomization
7. 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:
a) 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 C1D1). She must agree to ongoing pregnancy testing during the course
of the study, and after end of study treatment.
b) If sexually active, agree to use, and be able to comply with, 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 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 followin
1. Prior therapy with disease modifying agents or experimental agents for
underlying MDS disease
2. Previously treated with either luspatercept (ACE-536) or sotatercept
(ACE-011)
3. MDS associated with del 5q cytogenetic abnormality
4. 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. Known clinically significant anemia due to iron, vitamin B12, or folate
deficiencies, or autoimmune or hereditary hemolytic anemia, or gastrointestinal
bleeding
6. Prior allogeneic or autologous stem cell transplant
7. Known history of diagnosis of AML
8. Use of any of the following within 5 weeks prior to randomization:
- Anticancer cytotoxic chemotherapeutic agent or treatment
- 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)
9. Uncontrolled hypertension, defined as repeated elevations of diastolic blood
pressure (DBP) * 100 mmHg despite adequate treatment.
10. Absolute neutrophil count (ANC) < 500/*L (0.5 x 10^9/L)
11. Platelet count < 50,000/*L (50 x 10^9/L)
12. Estimated glomerular filtration rate (eGFR) or creatinine clearance < 40
mL/min
13. 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)
14. 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).
- Subjects are excluded if there is evidence of autoimmune hemolytic anemia
manifested as a corrected reticulocyte count of > 2% with either a positive
Coombs* test or over 50% indirect bilirubin
15. 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)
16. Major surgery within 8 weeks prior to randomization. Subjects must have
completely recovered from any previous surgery prior to randomization
17. History of stroke, deep venous thrombosis (DVT), pulmonary or arterial
embolism within 6 months prior to randomization
18. Pregnant or breastfeeding females
19. Myocardial infarction, uncontrolled angina, uncontrolled heart failure, or
uncontrolled cardiac arrhythmia as determined by the investigator within 6
months prior to randomization
20. 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), known
Human Immunodeficiency Virus (HIV), active Hepatitis B Virus (HBV) infection,
and/or Hepatitis C (HCV) infection.
21. History of
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>The primary efficacy endpoint of transfusion independent response is defined as<br /><br>the absence of any RBC transfusion during any consecutive 56 day period during<br /><br>the Primary Phase of the Treatment Period. </p><br>
- Secondary Outcome Measures
Name Time Method <p>The key secondary endpoint is the proportion of subjects achieving RBC-TI with<br /><br>duration * 12 weeks.</p><br>