A PHASE 3, MULTICENTER, RANDOMIZED, DOUBLEBLIND STUDY TO COMPARE THE EFFICACY AND SAFETY OF ORAL AZACITIDINE PLUS BEST SUPPORTIVE CARE VERSUS PLACEBO PLUS BEST SUPPORTIVE CARE IN SUBJECTS WITH RED BLOOD CELL TRANSFUSION-DEPENDENT ANEMIA AND THROMBOCYTOPENIA DUE TO IPSS LOWER-RISK MYELODYSPLASTIC SYNDROMES
The goal of this clinical research study is to learn if patients with myelodysplastic syndrome (MDS) need fewer blood transfusions if they take azacitidine given by mouth (CC-486), compared to a placebo. The safety of the study drug will also be studied. Azacitidine is designed to block proteins in cancer cells that stop the function of tumor-fighting genes. When the drug blocks the "bad" proteins, the tumor-fighting proteins may be able to work better. A placebo is not a drug. It looks like the study drug, but is not designed to treat any disease or illness. It is designed to be compared with a study drug to learn if the study drug has any real effect.
Disease Group: Leukemia
Treatment Agent: Azacitidine,Placebo
Treatment Location: Both at MDACC & and Other Sites
Sponsor: Celgene Corporation
Primary Objective The primary objective of the study is to evaluate red blood cell (RBC) transfusion independence in the 2 treatment arms (oral azacitidine plus best supportive care [BSC] versus placebo plus BSC) in subjects with RBC transfusion-dependent anemia and thrombocytopenia due to International Prognostic Scoring System (IPSS) lower-risk myelodysplastic (MDS). Secondary Objectives The secondary objectives of the study are: 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. Exploratory Objectives The exploratory objectives of the study are: To determine plasma concentration of azacitidine and explore exposure-response relationships of efficacy and safety endpoints To evaluate molecular and cellular markers in the BM at baseline that may provide further prognostic classification of MDS subtypes and potentially impact azacitidine efficacy To evaluate molecular and cellular markers in the BM and/or peripheral blood at baseline and during therapy that may provide information on azacitidine mechanism of action and on-therapy markers predictive of response or relapse. Data from exploratory objectives may not be included in the Clinical Study Report.
IRB Review and Approval Date: 02/27/2013
Recruitment Status: Open
Projected Accrual: 386
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 56 days immediately preceding randomization; Hemoglobin levels at the time of or within 7 days prior to administration of an RBC transfusion must have been </= 10.0 g/dL in order for the transfusion to be counted towards RBC transfusion-dependent status. Red blood cell transfusions administered when Hgb levels were > 10.0 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 28 days that are RBC-transfusion-free during the 56 days. Immediately preceding randomization.
4) Have thrombocytopenia as defined by two platelet counts that are </= 75 x 10^9/L and >/= 21 days apart. The second confirmatory platelet count must be obtained </= 14 days prior to randomization;: At least one platelet count must be centrally analyzed within the 56 day screening period with results of </= 75 x 10^9/L; the second platelet count may be centrally or locally analyzed, with results that are also </= 75 x 10^9/L. Prior documented medical history of thrombocytopenia may be used to demonstrate eligibility for the study if at least one historical platelet count of </= 75 x 10^9/L was obtained within 56 days of randomization and >/= 21 days apart from the centrally analyzed platelet count. If additional platelet counts were obtained during the interim period, these must also have been </= 75 x 10^9/L.
5) Continued from #4: If platelet counts within the interim period are > 75 x 10^9/L, this would be acceptable only if directly associated with a platelet transfusion administered within 7 days prior to the date of the platelet count.
6) Have an ECOG performance status of 0, 1, or 2
7) 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)
8) 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
9) Understand and voluntarily sign an informed consent document prior to any study related assessments/procedures being conducted
10) Able to adhere to the study visit schedule and other protocol requirements
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, unless subject received last dose from prior antineoplastic therapy >/= 24 weeks prior to randomization
3) Hypoplastic MDS or other subtype with eligibility for treatment with immunotherapy based on investigator's judgment, unless subject received last dose from prior Chemo~ or Immunotherapy >/=24 weeks prior to randomization
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, unless the subject received the last dose >/= 8 weeks prior to randomization
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 IP 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 medically significant 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). After consultation with the medical monitor, higher than normal range levels may be acceptable if the subject is being treated with a stable dose of anticoagulants for thrombotic prophylaxis (ie with atrial fibrillation, previous thromboembolic event, mechanical cardiac valve replacement or presence of lupus or antiphospholipid antibodies). The decision to include such patients would be the responsibility of the investigator.
17) Any of the following laboratory abnormalities: Serum AST/SGOT or ALT/SGPT > 2.5 x upper limit of normal (ULN) unless these abnormal liver function test(s) can be attributed to iron overload as demonstrated by a serum transferrin saturation of > 65% and a serum ferritin of > 1000 microg/L; 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) or in the presence of known history of Gilbert Syndrome. 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% of indirect bilirubin; Serum creatinine > 2.5 x ULN
18) Known clinically significant anemia due to iron, vitamin B12, or folate deficiencies, or autoimmune or hereditary hemolytic anemia, or gastrointestinal bleeding. Iron deficiency would be determined by a bone marrow aspirate stain for iron, the transferrin saturation (iron/total iron binding capacity [Fe/TIBC] </= 20%), or serum ferritin </= 15 ng/mL
19) Known or suspected hypersensitivity to azacitidine or mannitol
20) Pregnant or lactating females
21) Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study
22) 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) Any condition that confounds the ability to interpret data from the study
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