Materials and methods
B-NHL, diarrhea, WM/lymphoplasmacytic lymphoma, follicular lymphoma, DLBCL, NHL, hemorrhage, infection, cytopenia, CLL/small lymphocytic lymphoma
B-CELL NON-HODGKIN LYMPHOMA, ADVERSE EVENT, CLL, FOLLICULAR LYMPHOMA, DISEASE, SKIN ERUPTION, HEMORRHAGE, MARGINAL ZONE LYMPHOMA, INFECTION, CYTOPENIA, NHL, DIFFUSE LARGE B-CELL LYMPHOMA
The design of the study (trial registration number: JapicCTI-142682), which adhered to relevant ethical guidelines, including Declaration of Helsinki, was described in more detail in our prior report [Patients with a confirmed histopathological diagnosis and documented history of relapsed or refractory B-cell non-Hodgkin lymphoma [B-NHL: diffuse large B-cell lymphoma (DLBCL), MCL, follicular lymphoma (FL), marginal zone lymphoma, or WM/lymphoplasmacytic lymphoma (LPL)] or CLL/small lymphocytic lymphoma were eligible for this study. The enrollment period was January 2015 to February 2016. All patients provided informed consent. Eligibility criteria are listed in full in the ESM Materials.Patients were enrolled into 4 dose cohorts (160 mg QD, 320 mg QD, 480 mg QD, and 300 mg BID; cohorts 1–4) in a 3 + 3 dose-escalation scheme. Tirabrutinib was to be continued until progressive disease, unacceptable AEs, or consent withdrawal. Treatment discontinuation, interruption, resumption, and dose modifications were permitted, and the criteria are described in detail in the prior report [Safety was evaluated in terms of AEs and drug-related AEs, laboratory tests, vital signs, and electrocardiography. AEs were assessed using the Common Terminology Criteria for Adverse Events (version 4.0). Drug-related AEs were AEs that were considered to be definitely related, probably related or possibly related to the investigational drug, or AEs with an uncertain relationship to the investigational drug. Five categories of AEs of special interest were also defined as those related to hemorrhage, cytopenia, infection, skin eruption, and diarrhea.Efficacy was assessed as the best clinical response in accordance with the International Workshop Criteria for NHL, WM, and CLL [The safety analyses were conducted using all enrolled patients who received at least one dose of tirabrutinib (safety analysis set). The efficacy analyses were conducted using all enrolled patients who received at least one dose of tirabrutinib (full analysis set). Data analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC, USA).