Ibrutinib With Rituximab in Adults With Waldenström's Macroglobulinemia

iNNOVATE Study: A Randomized, Double-Blind, Placebo- Controlled, Phase 3 Study of Ibrutinib or Placebo in Combination With Rituximab in Subjects With Waldenström's Macroglobulinemia

The purpose of this study is to evaluate the safety and efficacy of ibrutinib in combination with rituximab in participants with Waldenström's macroglobulinemia (WM).

Eligibility Criteria for the Randomized Study

Inclusion Criteria:

• Untreated or previously treated for WM. 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 immunoglobulin M (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 minor response (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 (immunoglobulin E) IgE-mediated hypersensitivity to murine proteins or to any component of rituximab

• Prior exposure to ibrutinib or other Bruton's tyrosine kinase (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.