Ibrutinib and Azacitidine in Treating Patients with Higher Risk Myelodysplastic Syndrome Who Were Previously Treated or Untreated and Unfit for or Refused Intense Therapy

Inclusion Criteria

• Pathologically confirmed diagnosis of myelodysplastic syndrome (including secondary MDS, refractory anemia with excess blasts in transformation [RAEB-T], and chronic myelomonocytic leukemia [CMML, if white blood cells count is < 13,000/mm^3]) as defined by World Health Organization or French-American-British classifications
• Revised international prognostic scoring system (IPSS-R) intermediate, high or very high
• For the dose escalation cohorts, any prior number of MDS therapies, including hypomethylating agents, are permitted; for the dose expansion cohort, subjects must be azacitidine naïve, but otherwise any prior number of MDS therapies are permitted; treatment naïve patients are eligible for both the dose escalation and expansion cohorts if they are unfit for or refuse intense therapy
• No specific hematologic parameters for study entry are required; transfusion-dependent patients are eligible and platelet counts should be maintained greater than 10,000/mm^3
• Serum aspartate transaminase (AST) and alanine transaminase (ALT) =< 3.0 x upper limit of normal (ULN)
• Estimated creatinine clearance >= 30 ml/min (Cockcroft-Gault)
• Bilirubin =< 1.5 x ULN (unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin)
• Prothrombin time (PT)/international normalized ratio (INR) < 1.5 x ULN and partial thromboplastin time (PTT) (activated [a]PTT) < 1.5 x ULN
• Karnofsky performance status (KPS) performance status of 60% or greater
• Female subjects who are of non-reproductive potential (ie, post-menopausal by history - no menses for >= 1 year; OR history of hysterectomy; OR history of bilateral tubal ligation; OR history of bilateral oophorectomy); or, female subjects of childbearing potential must have a negative serum pregnancy test upon study entry
• Male and female subjects who agree to use highly effective methods of birth control (eg, condoms, implants, injectables, combined oral contraceptives, some intrauterine devices [IUDs], sexual abstinence, or sterilized partner) during the period of therapy and for 30 days after the last dose of study drug

Exclusion Criteria

• Known bleeding disorders (eg, von Willebrand’s disease or hemophilia), active bleeding disorders or clinical signs of bleeding (grade >= 2)
• Prior bone marrow transplant within 3 months or with acute graft versus host disease (GVHD)
• Prior treatment with a Bruton's tyrosine kinase (BTK) inhibitor
• Anticancer therapy including chemotherapy, immunotherapy, radiotherapy, hormonal or any investigational therapy within 14 days or 5 half-lives (whichever is shorter) prior to first dose of study drug
• Unresolved toxicities from prior anti-cancer therapy, defined as having not resolved to Common Terminology Criteria for Adverse Event (CTCAE, version 4.03), grade =< 1, or to the levels dictated in the inclusion/exclusion criteria with the exception of alopecia
• History of other malignancies, except: * Malignancy treated with curative intent and with no known active disease present for >= 1 years before the first dose of study drug and felt to be at low risk for recurrence by treating physician * Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease * Adequately treated carcinoma in situ without evidence of disease * Low-risk prostate cancer after curative surgery
• Concurrent systemic immunosuppressant therapy (eg, cyclosporine A, tacrolimus, etc., or chronic administration [> 14 days] of > 60 mg/day of prednisone) within 28 days of the first dose of study drug
• Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug
• Recent infection requiring intravenous systemic treatment that was completed =< 14 days before the first dose of study drug or any uncontrolled active systemic infection
• History of stroke or intracranial hemorrhage within 6 months prior to enrollment
• Known history of human immunodeficiency virus (HIV) or active with hepatitis C virus (HCV) or hepatitis B virus (HBV); subjects who are positive for hepatitis B core antibody or hepatitis B surface antigen must have a negative polymerase chain reaction (PCR) result before enrollment; those who are PCR positive will be excluded
• Major surgery within 4 weeks of first dose of study drug
• Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigator’s opinion, could compromise the subject’s safety or put the study outcomes at undue risk
• Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to enrollment
• Unable to swallow capsules or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction
• Concomitant use of warfarin or other vitamin K antagonists
• Subjects who received a strong CYP3A inhibitor within 7 days prior to the first dose of ibrutinib or subjects who require continuous treatment with a strong CYP3A inhibitor
• Subjects with chronic liver disease with hepatic impairment Child-Pugh class A, B, or C
• Lactating or pregnant
• Unwilling or unable to participate in all required study evaluations and procedures
• Unable to understand the purpose and risks of the study and to provide a signed and dated informed consent form (ICF) and authorization to use protected health information (in accordance with national and local subject privacy regulations)