Subjects with Red Blood Cell Transfusion-Dependent Anemia and Thrombocytopenia due to IPSS Lower-Risk Myelodysplastic Syndromes MedDRA version: 15.0 Level: LLT Classification code 10068361 Term: MDS System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Sponsors
Celgene Corporation
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Age = 18 years at the time of signing the informed consent document 2. Have a documented diagnosis of MDS according to WHO 2008 classification 3. Be RBC transfusion-dependent as defined by: - Average transfusion requirement of = 2 units** per 28 days of RBCs confirmed for a minimum of 84 days immediately preceding randomization *Hemoglobin levels at the time of or within 7 days prior to administration of an RBC transfusion must have been = 9.0 g/dL in order for the transfusion to be counted towards RBC transfusion-dependent status. Red blood cell transfusions administered when Hgb levels were > 9.0 g/dL and/or RBC transfusions administered for elective surgery will not qualify as a required transfusion for the purpose of providing evidence of RBC transfusion-dependent status * No consecutive 42 days that are RBC-transfusion-free during the 84 days immediately preceding randomization 4. Have thrombocytopenia as defined by two platelet counts that are = 50 x 109/L and = 21 days apart. The second confirmatory platelet count must be obtained = 14 days prior to randomization - If additional platelet counts were obtained during the interim period, these must also have been = 50 x 109/L. Platelet counts > 50 x 109/L within the interim period are acceptable only if directly associated with a platelet transfusion administered within 7 days prior to the date of the platelet count 5. Have an ECOG performance status of 0, 1, or 2 6. Females of childbearing potential (FCBP) may participate, providing they meet the following conditions: - Agree to use at least two effective contraceptive methods (oral, injectable, or implantable hormonal contraceptive; tubal ligation; intra-uterine device; barrier contraceptive with spermicide; or vasectomized partner) throughout the study, and for 3 months following the last dose of study drug; and - Have a negative serum or urine pregnancy test (investigator’s discretion; sensitivity of at least 25 mIU/mL) at screening; and - Have a negative serum or urine pregnancy test (investigator’s discretion) within 72 hours prior to starting study therapy in the treatment phase (note that the screening serum pregnancy test can be used as the test prior to starting study therapy in the treatment phase if it is performed within the 72-hour timeframe) 7. Male subjects with a female partner of childbearing potential must agree to the use of at least two physician-approved contraceptive methods throughout the course of the study and should avoid fathering a child during the course of the study and for 3 months following the last dose of study drug Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 86 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 300
Exclusion criteria
Exclusion criteria: 1. IPSS higher-risk (INT-2 or High risk) MDS 2. 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 3. Hypoplastic MDS or other subtype with eligibility for treatment with immunotherapy 4. CMML, atypical chronic myeloid leukemia (CML) and unclassifiable myeloproliferative disease (MPD) 5. Prior treatment with any of the following: - Azacitidine (any formulation), decitabine or other hypomethylating agent - Lenalidomide 6. Prior allogeneic or autologous stem cell transplant 7. History of inflammatory bowel disease (eg, Crohn’s disease, ulcerative colitis), celiac disease (ie, sprue), prior gastrectomy or upper bowel removal, or any other gastrointestinal disorder or defect that would interfere with the absorption, distribution, metabolism or excretion of the study drug and/or predispose the subject to an increased risk of gastrointestinal toxicity 8. Thrombocytopenia secondary to other possible causes, including medication(s), congenital disorder(s), immune disorder(s) (eg, idiopathic thrombocytopenic purpura [ITP]), or microvascular disorder(s) (eg, disseminated intravascular coagulation, hemolytic uremic syndrome, thrombotic thrombocytopenic purpura) 9. Use of any of the following within 28 days prior to randomization: - cytotoxic, chemotherapeutic, targeted or investigational agents/therapies - thrombopoiesis-stimulating agents (TSAs; eg, Romiplostim, Eltrombopag, Interleukin-11) - ESAs and other RBC hematopoietic growth factors (eg, Interleukin-3) - hydroxyurea 10. Ongoing adverse events from previous treatment, regardless of the time period 11. Concurrent use of any of the following: - iron-chelating agents, except for subjects on a stable dose for at least 8 weeks (56 days) prior to randomization - corticosteroid, except for subjects on a stable or decreasing dose for = 1 week prior to randomization for medical conditions other than MDS 12. Prior history of malignancies, other than MDS, unless the subject has been free of the disease for = 3 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) 13. Significant active cardiac disease within the previous 6 months, including: - New York Heart Association (NYHA) class IV congestive heart failure; - Unstable angina or angina requiring surgical or medical intervention; and/or - Myocardial infarction 14. 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) 15. Known Human Immunodeficiency Virus (HIV) or Hepatitis C (HCV) infection, or evidence of active Hepatitis B Virus (HBV) infection 16. Abnormal coagulation parameters (PT > 15 seconds, PTT > 40 seconds, and/or INR > 1.5) 17. Any of the following laboratory abnormalities: - Serum AST/SGOT or ALT/SGPT > 2.5 x upper limit of normal (ULN) - Serum bilirubin > 1.5 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate RBC transfusion independence in the 2 treatment arms (oral azacitidine plus best supportive care versus placebo plus best supportive care) in subjects with RBC transfusion-dependent anemia and thrombocytopenia (platelet count = 50 x 109/L) due to IPSS lower-risk MDS.;Secondary Objective: To evaluate in both treatment arms: - overall survival (OS); - hematologic improvement-platelet response (HI-P); - duration of RBC transfusion independence and time to RBC transfusion independence; - progression to acute myeloid leukemia (AML), and time to AML progression; - hematologic improvement-erythroid response (HI-E); - platelet-transfusion independence, duration of platelet transfusion independence, and time to platelet transfusion independence; - hematologic response; - clinically significant bleeding events; - safety; - health-related quality-of-life (HRQoL); and - healthcare resource utilization.;Primary end point(s): The proportion of subjects in the overall population achieving RBC transfusion independence with duration = 84 days (12 weeks).;Timepoint(s) of evaluation of this end point: After all patients have either completed 12 months treatment or discontinued | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): - OS; - HI-P (IWG 2006 criteria); - Duration of RBC transfusion independence; - Time to RBC transfusion independence; - Proportion of subjects progressing to AML and time to AML progression; - HI-E (IWG 2006 criteria); - Proportion of platelet transfusion-dependent subjects at baseline achieving platelet transfusion independence with duration = 56 days (8 weeks); - Duration of platelet transfusion-independence; - Time to platelet transfusion independence; - Hematologic response (IWG 2006 criteria); - Proportion of subjects experiencing clinically significant bleeding events; - Safety (type, frequency, severity of AEs and relationship of AEs to oral azacitidine/placebo; monitoring for progression to AML and second primary malignancy); - HRQoL utilizing the Functional Assessment of Cancer Therapy-Anemia (FACT-An) and EuroQoL Group EQ-5D-3L instruments; and - Measures of healthcare resource utilization. Exploratory: -Correlative analyses to assess the relationship between azacitidine exposure and pharmacodynamic (eg, safety, efficacy) and other exploratory (eg, biomarker) endpoints. - Biomarker assessments (molecular and/or cellular features in bone marrow and/or peripheral blood) potentially include, but are not limited to, cytogenetics, DNA methylation, gene variants (single nucleotide polymorphisms [SNPs] and gene sequence) analysis, messenger ribonucleic acid (mRNA) expression, micro RNA (miRNA) expression, RNA methylation, immunophenotyping and plasma protein evaluation. ;Timepoint(s) of evaluation of this end point: Efficacy endpoints including interim OS with exception of AML progression: after all patients have either completed 12 months treatment or discontinued Mature OS: Approx 250 events per arm. | — |
Countries
Australia, Belgium, Canada, Czech Republic, Denmark, Finland, France, Germany, Greece, Hungary, Israel, Italy, Lithuania, Mexico, Netherlands, Norway, Poland, Portugal, Spain, Sweden, United Kingdom, United States
Contacts
Public ContactClinicalTrialDisclosure
Celgene Corporation
Outcome results
None listed