A PHASE 2, INTERNATIONAL, MULTICENTER, RANDOMIZED, OPEN-LABEL, PARALLEL GROUP STUDY TO EVALUATE THE EFFICACY AND SAFETY OF CC-486 (ORAL AZACITIDINE) ALONE AND IN COMBINATION WITH DURVALUMAB (MEDI4736) IN SUBJECTS WITH MYELODYSPLASTIC SYNDROMES WHO FAIL TO ACHIEVE AN OBJECTIVE RESPONSE TO TREATMENT WITH AZACITIDINE FOR INJECTION OR DECITABINE
You are being asked to take part in this study because you have myelodysplastic syndrome (MDS) and received decitabine or azacitidine by injection but the disease did not improve or you did not tolerate the treatment well. The goal of this clinical research study is to learn if CC-486 alone or in combination with MEDI4736 (durvalumab) can help to control MDS. The safety of CC-486 alone and in combination with durvalumab will also be studied.
Disease Group: Leukemia,Malignant neoplasms stated as primary lymphoid haematopoietic
Treatment Agent: Azacitidine
Treatment Location: Both at MDACC & and Other Sites
Sponsor: Celgene Corporation
Primary Objective The primary objective of this study is to investigate the efficacy of CC-486 as monotherapy, and in combination with anti-PD-L1 monoclonal antibody, durvalumab (MEDI4736), in subjects with myelodysplastic syndrome (MDS) that did not respond to the most recent treatment with an injectable hypomethylating agent (iHMA -- azacitidine for injection or decitabine), or were unable to tolerate treatment with an injectable HMA. Secondary Objectives The secondary objectives of the study are to: Assess the safety and tolerability of CC-486 alone and in combination with durvalumab, as treatment for MDS Describe the clinical relevance of objective hematologic and/or biologic responses associated with treatment with CC-486 alone and in combination with durvalumab Evaluate the impact (if any) of durvalumab on the pharmacokinetics of CC-486 and CC-486 on durvalumab in subjects with MDS Exploratory Objective Determine the immunogenicity of durvalumab when given in combination with CC-486 in subjects with MDS Evaluation molecular and cellular markers in bone marrow and/or peripheral blood that may impact azacitidine efficacy (resistance to azacitidine for injection and/or CC-486 resistance or sensitivity). Establish pharmacokinetic (PK)/pharmacodynamic relationship, explore pharmacodynamic, mechanistic, and predictive biomarkers of CC-486 as a single agent and when given in combination with durvalumab in subjects with MDS Evaluate additional measures of efficacy of monotherapy and combination therapy in subjects with MDS
IRB Review and Approval Date: 07/17/2015
Recruitment Status: Open
Projected Accrual: at least 194
1) Male or female, >/= 18 years of age at the time of signing the
informed consent document
2) Documented diagnosis of MDS, classified according to FAB classification criteria
3) Adequate course of treatment with an injectable hypomethylating agent (azacitidine for injection or decitabine) as the last therapeutic intervention for MDS prior to beginning screening for this study. Adequate is defined as: having received at least 6 consecutive 4-week treatment cycles with azacitidine for injection; or having received at least 4 consecutive 6-week treatment cycles with decitabine (3-day regimen) or at least 6 consecutive 4-week treatment cycles with decitabine (5-day regimen); or having demonstrated inability to tolerate treatment with an injectable hypomethylating agent because of unacceptable drug-related toxicity after at least 3 months of attempted treatment: Three 28-day cycles of azacitidine for injection or decitabine 5-day regimen; two 42-day cycles of decitabine 3-day regimen.
4) Documented disease progression or stable disease as best response to treatment (or attempted treatment) with azacitidine for injection or decitabine. Those achieving an objective response to the most recent treatment regimen with an injectable HMA are excluded from participation in this study. Definitions of disease progression are modified from IWG 2006 criteria and include: 1) Pre-injectable HMA baseline bone marrow myeloblasts--Less than 5%: >/=100% increase to >/=8% blasts; >/=5%: >/=50% increase to >/=10% blasts. Note: >/=30% blasts is considered AML per FAB classification. Subjects known to have >/= 30% blasts are not eligible for inclusion in this study. Recognizing limitations of blast cell quantification, this protocol will allow subjects with pre-enrollment bone marrow blast counts up to 33% on the screening bone marrow examination to be considered for inclusion.
5) Continued from #4: Assessment may be made according to local bone marrow examination to facilitate enrollment of eligible subjects into the treatment phase of the study. 2) Any clinical worsening from pre-injectable HMA baseline condition, including sustained clinically-significant worsening (investigator’s assessment) from baseline granulocyte, platelet, or hemoglobin values (>/=2 values, separated by >/=2 weeks); worsening granulocytes should be >/=50% decrease from pre-injectable HMA baseline value; worsening platelets should be >/=50% decrease from pre-injectable HMA baseline value (untransfused); worsening hemoglobin should be >/=1.5 g/dL decrease from preinjectable HMA baseline value in subjects not receiving RBC transfusions--meaningful worsening in RBC or platelet transfusion requirement.
6) Continued from #5: Definition of stable disease is based on modified IWG 2006 criteria: Failure to achieve any objective response (CR, PR, mCR, or HI), but no evidence of disease progression within the 8 weeks leading to the subject’s first dose of IP in this study (Cycle 1, Day 1).
7) Have the last dose of the prior treatment regimen (injectable HMA--azacitidine for injection or decitabine) not more than 12 weeks prior to screening for this study (date of informed consent signature).
8) No less than 3 weeks between the last dose of the prior treatment regimen (injectable HMA--azacitidine for injection or decitabine) and the planned date of first dose of IP.
9) Have an ECOG performance status of 0, 1, or 2
10) Females of childbearing potential (FCBP) may participate, providing they meet the following conditions: 1) Agree to use at least two effective contraceptive methods (oral, injectable, or implantable hormonal contraceptive; tubal ligation; intra-uterine device; barrier contraceptive with spermicide; true abstinence; or vasectomized partner) throughout the study, and for 90 days following the last dose of IP; and 2) Have a negative serum pregnancy test (sensitivity of at least 25 mIU/mL) at screening; and 3) Have a negative serum or urine pregnancy test (investigator’s discretion) within 72 hours prior to starting treatment with IP (Cycle 1, Day 1), and before beginning each subsequent cycle of treatment. Note that the screening serum pregnancy test can also be used as the test prior to starting IP if it is performed within the 72-hour timeframe.
11) Male subjects with a female partner of childbearing potential must agree to use 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 90 days following the last dose of IP.
12) Understand and voluntarily sign an informed consent document prior to any study-related assessments or procedures are conducted.
13) Understand and voluntarily sign a biomarker-specific component of the informed consent document prior to any study-related procedures conducted.
14) Be able to adhere to the study visit schedule and other protocol requirements.
1) Rapidly-progressing MDS, defined as: Known clinically-significant
doubling in marrow or peripheral blood blast percentage (to >/= 20%)
in the 8-week period leading to the first dose of IP (Cycle 1, Day 1);
>/=100% increase in WBC count (myeloid cell line and monocyte series)
within the 8-week period leading to Cycle 1, Day 1
2) Acute myelogenous leukemia (AML--FAB classification: >/= 30% blasts in bone marrow). Subjects known to have >/= 30% blasts are not eligible for inclusion in this study. Recognizing limitations of blast cell quantification, this protocol will allow subjects with pre-enrollment (screening/baseline) bone marrow blast counts up to 33% to be considered for inclusion.
3) Prior allogeneic or autologous stem cell transplant
4) Prior exposure to the investigational oral formulation of decitabine, or other oral azacitidine derivative
5) Prior or ongoing response (IWG 2006 HI, PR, CR, or marrow CR) to treatment with azacitidine for injection or decitabine, including relapsed disease.
6) Ongoing medically significant adverse events from previous treatment, regardless of the time period
7) Use of any of the following within 28 days prior to the first dose of IP: thrombopoiesis-stimulating agents ([TSAs]; eg, Romiplostim, Eltrombopag, Interleukin-11); ESAs and other RBC hematopoietic growth factors (eg, interleukin-3); hydroxyurea
8) Concurrent use of corticosteroids unless the subject is on a stable or decreasing dose for >/= 1 week prior to enrollment for medical conditions other than MDS
9) 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
10) 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)
11) 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
12) 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)
13) Known Human Immunodeficiency Virus (HIV) or Hepatitis C (HCV) infection, or evidence of active Hepatitis B Virus (HBV) infection
14) Any of the following laboratory abnormalities: Serum AST/SGOT or ALT/SGPT > 2.5 x ULN; Serum total 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). 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; Absolute WBC count >/= 20 x 10^9/L
15) Known or suspected hypersensitivity to azacitidine or mannitol, or durvalumab, its constituents, or to any other humanized monoclonal antibody
16) Pregnant or breast-feeding females
17) Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study
18) Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study
19) Any condition that confounds the ability to interpret data from the study, including known or suspected conditions other than MDS, associated with anemia
20) Having received any prior MAb against CTLA-4, PD-1, or PD-L1 or having received other investigational MAbs within 6 months
21) Clinical evidence of central nervous system (CNS) or pulmonary leukostasis, disseminated intravascular coagulation, or CNS leukemia
22) Current or prior use of immunosuppressive medication within 14 days prior to the first dose of durvalumab. The following are exceptions to this criterion: a. Intranasal, inhaled, topical or local steroid injections (eg, intra-articular injection); b. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or equivalent; c. Steroids as premedication for hypersensitivity reactions (eg, computed tomography [CT] scan premedication).
23) Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis, Crohn’s disease], diverticulitis with the exception of a prior episode that has resolved or diverticulosis, celiac disease, irritable bowel disease, or other serious gastrointestinal chronic conditions associated with diarrhea; systemic lupus erythematosus; Wegener’s syndrome [granulomatosis with polyangiitis]; myasthenia gravis; Graves’ disease; rheumatoid arthritis; hypophysitis, uveitis; etc) within the past 3 years prior to the start of treatment. The following are exceptions to this criterion: a. Subjects with vitiligo or alopecia; b. Subjects with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement for >/= 3 months; or c. Subjects with psoriasis not requiring systemic treatment
24) History of primary immunodeficiency
25) Receipt of live, attenuated vaccine within 30 days prior to the first dose of durvalumab (NOTE: Subjects, if enrolled, should not receive live vaccine during the study and 30 days after the last dose of durvalumab)
Information and next steps
Leukemia,Malignant neoplasms stated as primary lymphoid haematopoietic
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