A Study of the Bruton's Tyrosine Kinase Inhibitor, PCI-32765 (Ibrutinib), in Combination With Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Patients With Newly Diagnosed Non-Germinal Center B-Cell Subtype of Diffuse Large B-Cell Lymphoma

This is a randomized (individuals assigned to study treatment by chance), double-blind
(individuals and study personnel will not know the identity of study treatments), placebo (an
inactive substance that is compared with a drug to test whether the drug has a real effect in
a clinical trial)-controlled study to compare the efficacy and safety of ibrutinib in
combination with R-CHOP versus R-CHOP alone in adult patients newly diagnosed non-GCB DLBCL
selected by IHC or newly diagnosed patients with ABC subtype of DLBCL identified by GEP or
both populations. The study will include screening, active treatment, and posttreatment
follow-up phases. The study will end when 50% of participants have died or 5 years after the
last participant is randomized or the sponsor terminates the study, whichever occurs first.
Approximately 800 participants will be randomly assigned in a 1:1 ratio to receive either
placebo+R-CHOP (treatment arm A) or ibrutinib+R-CHOP (treatment arm B). All participants will
receive R-CHOP as background therapy for 6 or 8 cycles (21 days per cycle) prespecified
according to local practice. After 4 treatment cycles, an interim response assessment will be
performed to evaluate disease progression for each participant. Participants with progressive
disease or relapsed disease after complete response will be discontinued from treatment.
Participants who discontinue R-CHOP without disease progression will continue study drug
(placebo or ibrutinib) until 6 or 8 cycles are completed, disease progression, or
unacceptable toxicity, whichever occurs first. After completion of study drug, participants
will undergo assessment of tumor response based on the Revised Response Criteria for
Malignant Lymphoma. Participants with documented residual disease upon completion of at least
6 cycles of R-CHOP therapy are considered eligible to initiate subsequent antilymphoma
therapy. Serial pharmacokinetic samples will be collected before and after dosing, and safety
will be monitored throughout the study.

Inclusion Criteria:

- No prior treatment for diffuse B-cell lymphoma (DLBCL)

- Histologically-confirmed non-germinal center B-cell subtype DLBCL

- Stage II (not candidates for local x-ray therapy), III, or IV disease by the Ann Arbor
Classification

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

- Revised International Prognostic Index score of >=1

- Eastern Cooperative Oncology Group performance status grade of 0, 1, or 2

- Hematology and biochemical laboratory values within protocol-defined parameters prior
to random assignment and at baseline

- Left ventricular ejection fraction within institutional normal limits, as determined
by echocardiography or multiple uptake gated acquisition (MUGA) scan

- Agrees to protocol-defined use of effective contraception (for women, these
restrictions apply for 12 months after the last dose of rituximab or 1 month after the
last dose of study drug, whichever is later; for men, these restrictions apply for 12
months after the last dose of rituximab or 3 months after the last dose of study drug,
whichever is later)

- Men must agree to not donate sperm during and after the study for 12 months after the
last dose of rituximab or 3 months after the last dose of study drug, whichever is
later

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

Exclusion Criteria:

- Major surgery within 4 weeks of random assignment

- Known central nervous system or primary mediastinal lymphoma

- Prior history of indolent lymphoma

- Diagnosed or treated for malignancy other than DLBCL, except: malignancy treated with
curative intent and with no known active disease present for >=3 years before random
assignment; adequately treated non-melanoma skin cancer or lentigo maligna without
evidence of disease; adequately treated carcinoma in situ without evidence of disease

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

- Requires anticoagulation with warfarin or equivalent vitamin K antagonists

- Requires treatment with strong CYP3A inhibitors

- Prior anthracycline use >=150 mg/m2

- 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 or active hepatitis C virus or active
hepatitis B virus infection 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 ibrutinib capsules, or put the study outcomes at undue
risk