Ibrutinib With Rituximab in Adults With Waldenström's Macroglobulinemia

Eligibility Criteria for the Randomized Study (Arm A and Arm B)

Inclusion Criteria:

- Untreated or previously treated for Waldenström's macroglobulinemia. Previously
treated subjects must have either documented disease progression or had no response
(stable disease) to the most recent treatment regimen.

- Centrally confirmed clinicopathological diagnosis of WM

- Measurable disease defined as serum monoclonal IgM >0.5 g/dL.

- Symptomatic disease meeting at least 1 of the recommendations from the Second
International Workshop on Waldenström Macroglobulinemia for requiring treatment

- Hematology and biochemical values within protocol-defined limits

- Men and women ≥ 18 years of age.

- Eastern Cooperative Oncology Group (ECOG) performance status of ≤2.

Exclusion Criteria:

- Known involvement of the central nervous system by WM.

- Disease that is refractory to the last prior rituximab-containing therapy defined as
either

- Relapse after the last rituximab-containing therapy <12 months since last dose of
rituximab, OR

- Failure to achieve at least a MR after the last rituximab-containing therapy. If
the subject meets this exclusion criterion and therefore is excluded from the
main randomized study, participation in the non randomized substudy (Arm C) may
be considered

- Rituximab treatment within the last 12 months before the first dose of study drug.

- Known anaphylaxis or IgE-mediated hypersensitivity to murine proteins or to any
component of rituximab.

- Prior exposure to ibrutinib or other BTK inhibitors.

- Known bleeding disorders (eg, von Willebrand's disease) or hemophilia.

- History of stroke or intracranial hemorrhage within 12 months prior to enrollment.

- Any uncontrolled active systemic infection.

- Any life-threatening illness, medical condition, or organ system dysfunction that, in
the investigator's opinion, could compromise the subject's safety or put the study
outcomes at undue risk.

- Currently active, clinically significant cardiovascular disease

- Requires treatment with a strong cytochrome P450 (CYP) 3A inhibitor

Eligibility Criteria for Open-label Substudy Treatment Arm C

The Inclusion/Exclusion criteria for the substudy (Arm C) are identical to those described
above for the randomized study but, to be eligible, subjects need to be considered
refractory to the last prior rituximab-containing therapy defined as either

- Relapse after the last rituximab-containing therapy <12 months since last dose of
rituximab, OR

- Failure to achieve at least a MR after the last rituximab-containing therapy.