Ibrutinib in Treating Patients With Advanced Systemic Mastocytosis

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