Study of the Bruton's Tyrosine Kinase Inhibitor in Subjects With Relapsed/Refractory Marginal Zone Lymphoma

Ibrutinib is a first-in-class, potent, orally administered covalent inhibitor of Bruton's
tyrosine kinase (BTK). Inhibition of BTK blocks downstream B-cell receptor (BCR) signaling
pathways and thus prevents B-cell proliferation. In vitro, ibrutinib inhibits purified BTK
and selected members of the kinase family with 10-fold specificity compared with non-BTK
kinases. Phase 1 and 2 studies of ibrutinib in B-cell malignancies demonstrate modest
toxicity and significant single agent activity in a variety of B-cell malignancies, including
NHL.

Key Inclusion criteria:

- Histologically documented marginal zone lymphoma including splenic, nodal, and
extranodal sub-types; subjects with splenic MZL must have an additional measurable
lesion, nodal or extranodal, as described in inclusion criteria 5

- Previously received one or more lines of therapy including at least one CD20-directed
regimen (either as monotherapy or as chemoimmunotherapy) with documented failure to
achieve at least PR or documented PD after, the most recent systemic treatment regimen

- Men and women ≥18 years of age

- ECOG performance status of ≤2

- ≥1 measurable lesion site on CT scan (>1.5 cm in longest dimension). Lesions in
anatomical locations (such as extremities or soft tissue lesions) that are not well
visualized by CT may be measured by MRI instead. (Subjects with spleen-only disease
are considered as not having measurable disease.)

- Life expectancy of >3 months, in the opinion of the investigator

Key Exclusion criteria:

- Medically apparent CNS lymphoma or leptomeningeal disease

- History of other malignancies except adequately treated non melanoma skin cancer,
curatively treated in-situ cancer, or other solid tumors curatively treated with no
evidence of disease for ≥2 years

- History of allogeneic stem-cell (or other organ) transplantation

- Any chemotherapy, anticancer antibodies, or other systemic anticancer therapy within
21 days of the first dose of study drug

- Any external beam radiation therapy within 6 weeks prior to the first dose of the
study drug

- Concurrent use of warfarin or other vitamin K antagonists

- Concurrent use of a strong CYP3A inhibitor. Subjects who have received a strong CYP3A
inhibitor prior to entering the study must have discontinued therapy for at least 5
half lives of the prohibited medication.

- Recent infection requiring IV anti-infective treatment that was completed ≤14 days
before the first dose of study drug

- Unresolved toxicities from prior anti-cancer therapy, defined as having not resolved
to CTCAE Grade 0 or 1, or to the levels dictated in the eligibility criteria with the
exception of alopecia

- Inadequate organ function as defined on laboratory tests