INCLUSION CRITERIA

   - Diagnosis of systemic mastocytosis per 2008 World Health Organization (WHO) criteria.
   Those with advanced systemic mastocytosis (ASM); mast cell leukemia (MCL); or systemic
   mastocytosis-associated hematological clonal non-mast cell lineage disease (SM-AHNMD)
   required to have at least 1 organ damage finding

   - Serum aspartate transaminase (AST) or alanine transaminase (ALT) ≤ 3.0 x upper limit
   of normal (ULN); if considered related to ASM/MCL ≤ 5 x ULN

   - Estimated creatinine clearance ≥ 30 mL/min (Cockcroft-Gault)

   - Total bilirubin ≤ 1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of
   non-hepatic origin); if considered related to ASM/MCL ≤ 3 x ULN

   - Female subjects must be of non-reproductive potential, or if of childbearing potential
   must have a negative serum pregnancy test upon study entry

   - Must agree to use highly effective methods of birth control

   - Written informed consent

   - Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 3

   - Life expectancy > 12 weeks

EXCLUSION CRITERIA

   - Received any investigational agent, chemotherapy, interferon-alpha, or
   2-chlorodeoxyadenosine (2-CdA, cladribine) within 30 days prior to day 1; or
   monoclonal antibody ≤ 6 weeks prior to first administration of study treatment
   (patients with an AHNMD with progressive leukocytosis who require control of their
   counts are permitted to receive hydroxyurea)

   - Diagnosis of AHNMD requiring immediate cytoreductive therapy or targeted drugs (eg,
   acute myeloid leukemia [AML])

   - History of other malignancies, except:

      - Malignancy treated with curative intent and with no known active disease present
      for ≥ 3 years before the first dose of study drug, and at low risk for recurrence

      - Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
      of disease

      - Adequately treated carcinoma in situ without evidence of disease

   - Concurrent systemic immunosuppressant therapy (eg, cyclosporine A, tacrolimus, etc.,
   or chronic administration [> 14 days] of > 10 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

   - Systemic treatment for infection completed ≤ 14 days before the 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), grade 0 or 1, or
   to the levels dictated in the inclusion/exclusion criteria with the exception of
   alopecia

   - Known bleeding disorders (eg, severe von Willebrand's disease) or severe hemophilia

   - History of stroke or intracranial hemorrhage within 6 months prior to enrollment

   - Known history of human immunodeficiency virus (HIV) or

   - Active infection with hepatitis C virus (HCV) or hepatitis B virus (HBV)

   - Major surgery within 4 weeks of first dose of study drug

   - Any life-threatening illness, medical condition, or organ system dysfunction that
   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 randomization

   - Unable to swallow capsules or malabsorption syndrome

   - Disease significantly affecting gastrointestinal function

   - Resection of the stomach or small bowel

   - Symptomatic inflammatory bowel disease

   - Ulcerative colitis

   - Partial or complete bowel obstruction

   - Requires treatment with a strong cytochrome P450 (CYP) 3A4/5 inhibitor

   - 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)

   - Known hypersensitivity to any excipient contained in the drug

   - Received hematopoietic growth factor support within 14 days of day 1 of ibrutinib
   (Jehovah's witnesses may be given an erythropoiesis-stimulating agent before and
   during the trial in lieu of red blood cell transfusions but anemia and/or red blood
   cell (RBC) transfusion dependence cannot be used for response assessment in these
   patients)

   - Presence of the factor interacting with poly(A) polymerase alpha (PAPOLA) and cleavage
   and polyadenylation specific factor 1 (CPSF1) (FIP1L1)-platelet-derived growth factor
   receptor, alpha polypeptide (PDGFRalpha) fusion even with resistance to imatinib (such
   patients are no longer defined as systemic mastocytosis by the WHO)

   - Received any treatment with ibrutinib prior to study entry

   - The concomitant use of warfarin or other vitamin K antagonists unless felt to be of
   significant clinical need; low molecular weight heparin or other anticoagulants may be
   used instead if anticoagulation is required