Subjects with ring sideroblasts who require regular Red Blood Cell (RBC) Transfusions due to anemia due to Myelodysplastic Syndromes (MDS) MedDRA version: 20.0 Level: LLT Classification code 10002272 Term: Anemia System Organ Class: 100000004851
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. 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 or = 5% (but 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. - Hemoglobin levels at the time of or within 7 days prior to administration of a RBC transfusion must have been = 10.0 g/dL in order for the transfusion to be counted towards meeting eligibility criteria. Red blood cell transfusions administered when Hgb levels were > 10.0 g/dL and/or RBC transfusions administered for elective surgery will not qualify as a required transfusion for the purpose of meeting eligibility criteria. - 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. This applies even if the subject practices true abstinence from heterosexual contact. b) If sexually active, agree to use, and be able to comply with, highly effective contraception without interruption, 5 weeks prior to starting investigational produ
Exclusion criteria
Exclusion criteria: 1. Prior therapy with disease modifying agents for underlying MDS disease a) subjects who previously received hypomethylating agents (HMA) or lenalidomide may be enrolled at the investigator's discretion contingent that the subject received no more than 2 doses of HMA or no more than 1 calendar week of treatment with lenalidomide The last dose must be = 5 weeks from the date of randomization 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) - investigational drug or device, or approved therapy for investigational use. If the half-life of the previous investigational product is known, use within 5 times the halflife prior to randomization or within 5 weeks, whichever is longer is excluded 9. Uncontrolled hypertension, defined as repeated elevations of diastolic blood pressure (DBP) = 100 mmHg despite adequate treatment 10. Absolute neutrophil count (ANC) 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 (including completion of any active or adjuvant treatment for prior malignancy) 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,
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate RBC transfusion independence (RBC-TI) of luspatercept compared with placebo for the treatment of anemia due to IPSS-R very low, low, or intermediate risk MDS in subjects with ring sideroblasts (= 15%) who require RBC transfusions;Primary end point(s): Red Blood Cell Transfusion Independence (RBC-TI) = 8 weeks - Proportion of subjects who are RBC transfusion free over any consecutive 56-day period;Timepoint(s) of evaluation of this end point: Week 1 through Week 24;Secondary Objective: 1. To assess the safety and tolerability of luspatercept compared with placebo 2. To evaluate the effect of luspatercept on reduction in RBC transfusions, increase in hemoglobin, duration of RBC-TI, improvement in health-related quality of life (HRQoL) (ie, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire [EORTC QLQ-C30]), increase in neutrophils, increase in platelets, decrease in serum ferritin, decrease in iron chelation therapy use, and time to RBC-TI compared with placebo 3. To evaluate population pharmacokinetics and exposure-response relationships for luspatercept in MDS subjects | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Key secondary endpoint 1. RBC-TI = 12 weeks - Proportion of subjects who are RBC transfusion free over any consecutive 84-day period 2. RBC-TI = 8 weeks - Proportion of subjects who are RBC transfusion free over any consecutive 56-day period 3. Reduction in RBC units transfused over 16 weeks - Mean change in total RBC units transfused over a fixed 16-week period 4. Modified hematologic improvement - erythroid (mHI-E) per IWG - Proportion of subjects achieving modified HI-E over any consecutive 56-day period 5. Mean hemoglobin increase = 1.0 g/dL - Proportion of subjects achieving hemoglobin (Hgb) increase from baseline = 1.0 g/dL over any consecutive 56-day period in absence of RBC transfusions 6. Duration of RBC-TI - Maximum duration of RBC transfusion independence for subjects who achieve RBC TI = 8 weeks 7. Health-related quality of life (HRQoL) - Change in EORTC QLQC30 score 8. Hematologic improvement - platelets (HI-P) per IWG; hematologic improvement-neutrophils (HI-N) per IWG - Proportion of subjects achieving HI-N / HI-P over any consecutive 56-day period 9. Mean decrease in serum ferritin - Change in serum ferritin 10. Mean decrease in iron chelation therapy (ICT) use - Change in mean daily dose of ICT 11. Time to RBC-TI - Time from first dose to first onset of transfusion independence = 8 weeks 12. Progression to AML - Number and percentage of subjects progressing to AML; time to AML progression 13. Overall survival - Time from date of randomization to death due to any cause 14. Safety - Type, frequency, severity of AEs and relationship of AEs to luspatercept/placebo 15. A population PK model - A Population PK model that describes the PK exposure data of luspatercept and associated variability. 16. Exposure-response relationship for the primary efficacy endpoint, AEs of interest, and selected secondary endpoints. 17. Anti-drug antibodies (ADA) - Frequency of anti-drug antibodies and effects on efficacy, or safety | — |
Countries
Belgium, Canada, France, Germany, Israel, Italy, Netherlands, Russian Federation, Spain, Sweden, Turkey, United Kingdom, United States
Contacts
Public ContactClinicalTrialDisclosure
Celgene Corporation
Outcome results
None listed