A Study Combining Ibrutinib With Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Patients With CD20-Positive B-Cell Non Hodgkin Lymphoma

This is an open-label (individuals will know the identity of study treatments), dose
escalation study to establish the recommended dose of ibrutinib combined with standard
R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in
approximately 33 adults with CD20-positive B-cell non-Hodgkin lymphoma (NHL) for whom R-CHOP
is an appropriate therapy. There will be 3 periods of the study: a pretreatment (screening)
period of up to 28 days before enrollment; an open-label treatment period (up to 6 cycles of
ibrutinib and R-CHOP; ending at the end-of-treatment visit); and a posttreatment follow-up
period until the end of study (maximum of up to 1 year after the last patient has completed
the end-of-treatment visit). There are 2 parts to the study (dose escalation [Part 1] and
expansion [Part 2]). During the dose escalation period, the "3+3" design will be applied and
approximately 18 patients with CD20 positive B cell NHL (diffuse large B-cell lymphoma
[DLBCL], mantle cell lymphoma [MCL], and follicular lymphoma [FL]) may be enrolled. Patients
will be assigned to cohorts of increasing oral daily doses of ibrutinib (280, 420, and 560
mg) administered in combination with R-CHOP. The maximum tolerated dose (MTD), assessed in
Cycle 1 (dose-limiting toxicity [DLT] period), is defined as the highest dose of the
combination regimen at which <=33% of patients experience DLT. Baseline and follow-up
electrocardiograms will be performed throughout the study. A Study Evaluation Team will
review all available data upon completion of the first cycle for all patients at each dose
cohort to determine DLTs, if dose escalation is acceptable, and subsequently will determine
the recommended Phase 2 dose. Once the recommended Phase 2 dose is determined, approximately
15 patients with newly diagnosed DLBCL will be entered into the expansion cohort at the dose
level selected to further assess the safety, pharmacokinetics, pharmacodynamics,
pharmacogenomics, and activity of the combination. Patients whose disease has not progressed
at the end of Cycle 1 will continue to receive ibrutinib and R CHOP up to a maximum of 6
cycles. During the posttreatment follow-up period, long term safety, survival status,
disease progression, and subsequent antilymphoma therapy will be collected. The study will
end 1 year after the last patient has completed the end of treatment visit.

Inclusion Criteria:

- Histopathologically-confirmed CD20-positive B-cell non Hodgkin lymphoma disease for
whom R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone)
is an appropriate therapy (diffuse large B-cell lymphoma, mantle cell lymphoma, or
follicular lymphoma); for the expansion cohort, at least 1 cohort will only include
patients with newly diagnosed diffuse large B-cell lymphoma

- Stage I AX (bulk defined as single lymph node mass >=10 cm in diameter) to Stage IV
disease

- At least 1 measurable site of disease based on the Revised Response Criteria for
Malignant Lymphoma

- Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2

- Adequate bone marrow, liver, and renal function

Exclusion Criteria:

- History of protocol-defined disallowed therapies

- Prior multidrug chemotherapy treatment for lymphoma

- History of stroke or intracranial hemorrhage within 6 months prior to the first dose
of study drug

- Major surgery within 3 weeks before enrollment

- Known bleeding diatheses, platelet dysfunction disorders, or requires therapeutic
anticoagulation

- Known lymphoma of the central nervous system

- Uncontrolled or severe cardiovascular disease including myocardial infarction within
6 months of enrollment, New York Heart Association Class III or IV heart failure,
uncontrolled angina, pericardial disease, cardiac amyloidosis, clinically significant
cardiac arrhythmia, or left ventricular ejection fraction outside of institutional
limits

- Active systemic infection requiring treatment including hepatitis B and hepatitis C
infection

- Documented or suspected human immunodeficiency virus infection

- Diagnosed or treated for a malignancy other than non-Hodgkin lymphoma except;
adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the
cervix, ductal carcinoma in situ of the breast, or other solid tumors curatively
treated with no evidence of disease for >5 years

- Has any condition that, in the opinion of the investigator, would make study
participation not be in the best interest (eg, compromise the well-being) of the
patient or that could prevent, limit, or confound the protocol-specified assessments