Ibrutinib in Treating Patients With Advanced Systemic Mastocytosis

PRIMARY OBJECTIVE:

Evaluate the response rate to ibrutinib in patients with advanced systemic mastocytosis (SM)
(aggressive systemic mastocytosis [ASM] or mast cell leukemia [MCL], or SM-associated
hematologic non-mast cell disorder [AHNMD]) by the end of 6 cycles (6 months).

SECONDARY OBJECTIVES:

- Evaluate the tolerability and safety profile of ibrutinib in patients with advanced SM.

- Evaluate the pharmacokinetic (PK) profile of ibrutinib in a subset of patients with
advanced SM.

- Evaluate changes in histopathology (blood and bone marrow) of patients with advanced SM
in response to ibrutinib therapy.

- Evaluate changes in mastocytosis related symptom scores and quality-of-life (QOL) using
a modified Myeloproliferative Neoplasm Symptom Assessment Form (MPNSAF).

- Evaluate the duration of response (DoR) and time to response (TTR).

- Evaluate progression-free survival (PFS) and overall survival.

OUTLINE:

Patients receive ibrutinib orally (PO) once daily (QD) on days 1 to 28. Treatment repeats
every 28 days for up to 6 months in the absence of disease progression or unacceptable
toxicity. Patients achieving an unconfirmed or confirmed clinical improvement (CI), partial
response (PR), or complete response (CR) by the end of course 6 will be permitted to continue
maintenance courses of ibrutinib on an ongoing basis until loss of response/progressive
disease, or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days and then every 6
months thereafter.

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