A Study of PCI-32765 (Ibrutinib) in Patients With Refractory Follicular Lymphoma

This is an open-label (identity of assigned study drug will be known) study of PCI-32765
(ibrutinib) in approximately 110 patients with chemoimmunotherapy-resistant FL whose disease
has relapsed from at least 2 prior lines of therapy, including at least 1 rituximab
combination chemotherapy regimen. Each patient must have resistant disease to the last
therapy (defined as progression of disease [PD] during or within 12 months of the last dose
of chemotherapy in a CD20 antibody combination chemotherapy regimen). The study will include
the following phases: screening (up to 30 days prior to the first dose of study drug),
treatment (until PD or unacceptable toxicity), and posttreatment follow-up (until death,
lost to follow up, withdrawal of consent, or study end [defined as 2 years after the last
patient is enrolled]). Patients will receive 560 mg of PCI-32765 by mouth once daily on a
21-day cycle. Treatment will be continuous (without interruption) and self-administered at
home. The treatment phase will extend from administration of the first dose of study
medication until PD or unacceptable toxicity. If a patient who had radiological evidence of
PD is clinically stable or improving or exhibiting signs of tumor flare without confirmation
of PD by PET or biopsy, they may continue treatment with ibrutinib upon request by the
investigator and approval by the sponsor. Posttreatment follow-up will extend from the end
of treatment until death, lost to follow up, withdrawal of consent, or study end. Every
patient, except for those who explicitly withdraw consent from further site contact, will be
followed for survival status until the study ends. In addition, data on subsequent
antineoplastic therapy will also be collected. Serial pharmacokinetic samples will be
collected and efficacy and safety will be monitored throughout the study. A separate
assessment of pharmacokinetics is planned for patients who receive a strong or moderate
CYP3A4/5 inhibitor while receiving treatment with ibrutinib. For patients who have already
discontinued ibrutinib due to PD, have taken no other anticancer therapy, and now have a
radiologically documented delayed response, resumption of ibrutinib is permitted on a
case-by-case basis, upon request by the investigator and approval of the sponsor.

Inclusion Criteria:

- Histologic proof of Grade 1, 2, or 3a follicular lymphoma (FL) without clinical or
pathological evidence of transformation

- Previously treated with at least 2 prior lines of therapy, including at least 1
rituximab combination chemotherapy regimen; last prior line of therapy includes an
anti CD20 monoclonal antibody-containing chemotherapy regimen (separate lines of
therapy are defined as different regimens that are either separated by disease
progression, refractory disease, or relapsed disease)

- Resistant disease to the last therapy, defined as progression of disease during or
within 12 months of the last dose of chemotherapy in a CD20 antibody combination
chemotherapy regimen

- At least 1 measurable site of disease according to International Working Group
Revised Response Criteria for Malignant Lymphoma

- Eastern Cooperative Oncology Group performance status grade 0 or 1

- Hematology and biochemical laboratory values must be within protocol-defined
parameters within 7 days prior to enrollment

- Agrees to protocol-defined use of effective contraception

- Women of childbearing potential must have a negative serum or urine pregnancy test at
screening

Exclusion Criteria:

- Prior nitrosoureas within 6 weeks, chemotherapy within 3 weeks, therapeutic
anticancer antibodies within 4 weeks, radio- or toxin-immunoconjugates within 10
weeks, radiation therapy or other investigational agents within 3 weeks, or major
surgery within 4 weeks of first dose of study drug

- Prior treatment with PCI-32765 or other Bruton's tyrosine kinase inhibitors (patients
who progressed or became refractory while on treatment with PI3K inhibitors are
excluded)

- Concurrent enrollment in another therapeutic investigational clinical treatment study

- Received a prior allogeneic hematopoietic stem cell transplant (prior autologous
hematopoietic stem cell transplant is allowed)

- Known central nervous system lymphoma

- History of prior malignancy (except malignancy treated with curative intent and with
no known active disease present for >=3 years before enrollment, adequately treated
non-melanoma skin cancer or lentigo maligna without evidence of disease, or
adequately treated cervical carcinoma in situ without evidence of disease)

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

- Requires anticoagulation with warfarin or equivalent vitamin K antagonists

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

- Clinically significant cardiovascular disease such as uncontrolled or symptomatic
arrhythmias, congestive heart failure, or myocardial infarction within 6 months of
screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined
by the New York Heart Association Functional Classification

- Known history of Human Immunodeficiency Virus (HIV) or active infection with
Hepatitis C or active infection with Hepatitis B or any uncontrolled active systemic
infection requiring intravenous antibiotics

- Women who are pregnant or breastfeeding

- Any life-threatening illness, medical condition, or organ system dysfunction which,
in the investigator's opinion, could compromise the patient's safety, interfere with
the absorption or metabolism of PCI-32765 capsules, or put the study outcomes at
undue risk