Myelodysplastic syndrome (MDS) MedDRA version: 20.0 Level: LLT Classification code 10068361 Term: MDS System Organ Class: 100000004864
Conditions
Sponsors
Celgene Corporation
Eligibility
Sex/Gender
All
Inclusion criteria
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 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 =65 years) yes F.1.3.1 Number of subjects for this age range 247
Exclusion criteria
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), within 8 weeks prior to randomization, 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the efficacy of luspatercept on red blood cell 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 very low, low, or intermediate risk myelodysplastic syndromes (MDS) according to the International Prognostic Scoring System -Revised IPSS-R) in erythropoiesis stimulating agent (ESA) naïve subjects who require RBC transfusions. ;Secondary Objective: • 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, the 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 population pharmacokinetics and exposure-response relationships for luspatercept in MDS subjects;Primary end point(s): Proportion of subjects who are RBC transfusion-free for any 12-week period associated with a concurrent mean hemoglobin increase = 1.5 g/dL compared to baseline;Timepoint(s) of evaluation of this end point: Week 1 through Week 24 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. Proportion of subjects who are RBC transfusion-free from Week 1 through Week 24 2. Mean hemoglobin change over the 24-week period of Week 1 through Week 24 compared to baseline 3. Proportion of subjects achieving HI-E over any consecutive 56-day period 4. Time from first dose to first onset of achieving HI-E 5. Proportion of subjects who are RBC transfusion-free over a consecutive 84-day period 6. Maximum duration of RBC transfusion independence for subjects who achieve RBC-TI = 84 days 7. Time from first dose to first onset of transfusion independence = 84 days 8. Time from first dose to first transfusion on treatment 9. Total number of RBC units transfused on treatment 10. Proportion of subjects who are RBC transfusion-free over a consecutive 56-day period 11. Proportion of subjects who are RBC transfusion-free for a consecutive 24-week period in the first 48 weeks from first dose 12. Evaluation of EORTC QLQ-C30 score and FACT-An 13. Type, frequency, severity of AEs and relationship of AEs to luspatercept/epoetin alfa 14. A Population PK model that describes the PK exposure data of luspatercept and associated variability. Exposure-response relationship for selected endpoints of efficacy and safety 15. Frequency of antidrug antibodies and effects on efficacy, or safety, or PK 16. Number and percentage of subjects progressing to AML; time to AML progression 17. Time from date of randomization to death due to any cause 18. Evaluation of biomarkers that may potentially impact luspatercept efficacy, predict response or relapse, help to better understand MOA and/or provide further prognostic classification of MDS subtypes. Molecular markers (eg, SF3B1) include evaluation of MDSassociated gene mutations and their impact on drug efficacy, clinical response or relapse, drug MOA and prognostication of MDS. 19. Evaluation of healthcare resource use (eg, hospitalization) associated with investigational product (IP) during study | — |
Countries
Australia, Austria, Belgium, Canada, Czechia, France, Germany, Israel, Italy, Japan, Korea, Republic of, Lithuania, Netherlands, Poland, Portugal, Russian Federation, Spain, Sweden, Switzerland, Taiwan, Turkey, Ukraine, United Kingdom, United States
Contacts
Public ContactClinicalTrialDisclosure
Celgene Corporation
Outcome results
None listed