Phase 1 Study of CC-486 in Japanese Subjects With Hematological Neoplasms

Exclusion Criteria

• •1. Hypoplastic myelodysplastic syndromes defined as bone marrow cellularity of \< 20%;
• •2. Atypical chronic myeloid leukemia and unclassifiable myeloproliferative neoplasms. Subjects with white blood cell counts ≥ 12,000/μL must be excluded (for subjects with acute myeloid leukemia: subjects with white blood cell counts ≥ 15,000/μL must be excluded, and for subjects with chronic myelomonocytic leukemia: subjects with white blood cell counts ≥ 20,000/μL must be excluded);
• •3. Active central nerve system lymphoma unless the subject has been previously treated and remains asymptomatic for 3 months;
• •4. Dry tap bone marrow aspirate due to myelofibrosis, and/or myelofibrosis accompanied by splenomegaly;
• •5. Percentage of neoplasm cells in bone marrow more than 50%;
• •6. Prior treatment with azacitidine or other hypomethylating agent that was discontinued due to adverse event related to that therapy except adverse events related to topical reactions related to injection of azacitidine;
• •7. Prior allogeneic or autologous stem cell transplant;
• •8. 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;
• •9. 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);
• •10. Treatment with any anticancer therapy (standard or investigational) within the previous 21 days prior to the first dose of study drug or less than full recovery (CTCAE grade 1) from the clinically significant toxic effects of that treatment. Treatment with hydroxyurea within the previous 28 days prior to the first dose of study drug must be excluded;
• •11. Concurrent use of corticosteroids, except for subjects on a stable or decreasing dose for at least 1 week prior to starting study treatment for medical conditions other than primary diseases. Topical use of corticosteroids is permitted regardless of dose
• •12. Prior history of malignancies, other than myelodysplastic syndromes, chronic myelomonocytic leukemia, acute myeloid leukemia, multiple myeloma, non-hodgkin lymphoma, or hodgkin lymphoma, unless the subject has been free of the disease for ≥ 3 years. Exceptions include the following:
• •* Basal or squamous cell carcinoma of the skin;
• •* Carcinoma in situ of the cervix or breast;
• •* Incidental histological finding of prostate cancer (Tumor nodes metastasis \[TNM\] stage of T1a N0M0 or T1b N0M0);
• •* Early-stage gastric cancer suitable for endoscopic mucosal resection or endoscopic submucosal dissection;
• •13. Significant active cardiac disease within the previous 6 months, including:
• •* New York Heart Association (NYHA) class III-IV congestive heart failure;
• •* Unstable angina or angina requiring surgical or medical intervention;
• •* 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) positivity (eg, subjects who are receiving antiretroviral therapy for HIV disease);
• •16. Hepatitis Bs (HBs) antigen-positive, or hepatitis C virus (HCV) antibody-positive. In case HBc antibody and/or HBs antibody is positive even if HBs antigen-negative, a hepatitis B virus (HBV) DNA test should be performed and if positive the subject will be excluded;
• •17. Any of the following laboratory abnormalities:
• •* Absolute neutrophil count \< 1,000/μL (except for subjects with acute myeloid leukemia);
• •* Serum glutamic oxaloacetic transaminase/aspartate transaminase or serum glutamic pyruvate transaminase/alanine transaminase \> 2.5 ×upper limit of normal;
• •* Serum bilirubin \> 1.5 × upper limit of normal. High 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 \> 1.5 × upper limit of normal;
• •* Bicarbonate (venous blood) \< 22 mEq/L;
• •* Abnormal coagulation parameters (Prothrombin time-international normalized ratio \> 1.5 or activated partial thromboplastin time \> 40 seconds);
• •* Hemoglobin level \< 8.0 g/dL (for multiple myeloma, non-hodgkin lymphoma, or hodgkin lymphoma only);
• •* Platelet count \< 25,000 /μL (for multiple myeloma, non-hodgkin lymphoma, or hodgkin lymphoma only);
• •18. Known clinically significant anemia due to iron, vitamin B12, or folate deficiencies, or autoimmune or hereditary hemolytic anemia, or gastrointestinal bleeding;
• •19. History of cerebrovascular accident or transient cerebral ischemic attack within 6 months prior to starting study treatment;
• •20. Interstitial lung disease, pulmonary fibrosis, or other severe respiratory disease;
• •21. Hepatic cirrhosis, or other moderate to severe hepatic disease;
• •22. Known or suspected hypersensitivity to azacitidine or mannitol;
• •23. Pregnant or breastfeeding females;
• •24. Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study;
• •25. Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study;
• •26. Any condition that confounds the ability to interpret data from the study.