A Study of Ibrutinib in Combination With Rituximab, in Japanese Participants With Waldenstrom's Macroglobulinemia (WM)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate overall response rate (ORR) by Independent Review Committee (IRC) assessment, when combined with rituximab in Japanese participants with treatment naïve or relapsed/refractory Waldenstrom's Macroglobulinemia (WM).

Official Title
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Phase 2 Study of Bruton's Tyrosine Kinase (BTK) Inhibitor, Ibrutinib (PCI-32765) in Combination With Rituximab, in Japanese Patients With Waldenstrom's Macroglobulinemia (WM)

Conditions
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Waldenstrom Macroglobulinemia

Intervention / Treatment
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* Drug: Ibrutinib
* Drug: Rituximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinicopathological diagnosis of Waldenstrom's Macroglobulinemia (WM) in accordance with the consensus panel of the second International Workshop on Waldenstrom's Macroglobulinemia (IWWM) Japanese participants with treatment naïve or relapsed/refractory WM Measurable disease defined as serum monoclonal immunoglobulin M (IgM) greater than (>) 0.5 gram per deciliter (g/dL) Symptomatic disease, requiring treatment Eastern Cooperative Oncology Group (ECOG) performance status of less than or equal to (<=) 2 Hematology and biochemical values within protocol-defined limits Female participants of childbearing potential must have a negative serum pregnancy test at screening and agree to use highly effective methods of contraception while taking study drug. Women of childbearing potential must be practicing a highly effective, preferably user independent method of birth control during treatment with any drug in this study and for up to 12 months after the last dose of rituximab, 1 month after last dose of ibrutinib. Male participants must use an effective barrier method of contraception during the study and after receiving the last dose of ibrutinib, and for up to 12 months after last dose of rituximab if sexually active with a female of childbearing potential Must sign an informed consent form (ICF) indicating that he or she understands the purpose of, and procedures required for, the study and is willing to participate in the study. Participants must be willing and able to adhere to the prohibitions and restrictions specified in this protocol Must be willing and able to adhere to the lifestyle restrictions specified in this protocol Exclusion Criteria: Involvement of the central nervous system by WM Prior exposure to ibrutinib or other Bruton's Tyrosine Kinase (BTK) inhibitors Rituximab treatment within the last 12 months before the first dose of study intervention Received any WM-related therapy <=30 days prior to first administration of study treatment Plasmapheresis less than (<) 35 days prior to the initiation of study drug, except when at least one serum IgM central assessment was performed during the screening period and was >35 days from the most recent plasmapheresis procedure History of other malignancies Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug Infection requiring systemic treatment that was completed <=14 days before the first dose of study drug Currently active, clinically significant Child-Pugh Class B or C hepatic impairment Inability or difficulty swallowing capsules, malabsorption syndrome, or any disease or medical condition significantly affecting gastrointestinal function Stroke or intracranial hemorrhage within 12 months prior to enrollment Currently active, clinically significant cardiovascular disease Requires treatment with a strong cytochrome P450 (CYP) 3A inhibitor Infection with human immunodeficiency virus (HIV) or active infection with hepatitis B or hepatitis C virus Major surgery within 4 weeks of first dose of study drug Lactating or pregnant Male participants who plan to father a child while enrolled in this study or within 3 months after the last dose of ibrutinib, and within 12 months after last dose of rituximab Any contraindication to ibrutinib or rituximab including hypersensitivity to the active substance or to any of the excipients of ibrutinib or rituximab per local prescribing information Received an investigational intervention (including investigational vaccines) or used an invasive investigational medical device within 4 weeks before the planned first dose of study intervention or is currently enrolled in an investigational study Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (eg [for example], compromise the wellbeing) or that could prevent, limit, or confound the protocol-specified assessments Employee of the investigator or study site, with direct involvement in the proposed study or other studies under the direction of that investigator or study site, as well as family members of the employees or the investigator

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ibrutinib + Rituximab<br>Participants will receive ibrutinib 420 milligram (mg) orally, once daily, from Day 1 of Week 1 until disease progression or unacceptable toxicity in combination with rituximab 375 milligram per square meter (mg/m^2) intravenously (IV) on Day 1 of Weeks 1 to 4 and Weeks 17 to 20. | Drug: Ibrutinib<br>* Ibrutinib 420 mg will be administered orally.<br>* Other names: PCI-32765;Drug: Rituximab<br>* Rituximab 375 mg/m^2 will be administered intravenously.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) According to the Modified Sixth International Workshop on Waldenstrom's Macroglobulinemia (IWWM) Criteria | ORR is defined as the percentage of participants achieving a best overall response of confirmed complete response (CR), very good partial response (VGPR) or partial response (PR) according to the modified sixth IWWM criteria (National Comprehensive Cancer Network [NCCN] version 2, 2019), as assessed by the Independent Review Committee (IRC). CR: Immunoglobulin M (IgM) in normal range, disappearance of monoclonal protein by immunofixation, no histologic evidence of bone marrow involvement, resolution of any adenopathy/organomegaly (if present at baseline) along with no signs or symptoms attributable to Waldenstrom's Macroglobulinemia (WM); VGPR and PR: greater than or equal to (>=) 90 percent (%) (for VGPR) and >=50% (for PR) reduction of serum IgM, decrease in adenopathy/organomegaly (if present at baseline) on physical examination or computerized tomography (CT) scan, no new symptoms or signs of active disease. | Up to 1 year 11 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | PFS was defined as duration from the date of initial dose of ibrutinib to the date of first documented evidence of disease progression or death, whichever occurred first regardless of the use of subsequent antineoplastic therapy prior to documented disease progression or death. | Up to 1 year 11 months | 
| Plasma Concentrations of Ibrutinib | Plasma concentrations of ibrutinib were reported. | Day 1 of Week 4: Predose, 1 hour, 2 hours, 4 hours, and 6 hours postdose | 
| Plasma Concentrations of PCI-45227 | Plasma concentrations of PCI-45227 were reported. | Day 1 of Week 4: Predose, 1 hour, 2 hours, 4 hours, and 6 hours postdose | 
| Number of Participants With Myeloid Differentiation Primary Response Gene 88 (MYD88) Biomarker | Number of participants with MYD88 biomarker were reported. | Day 1 of Week 1 | 
| Number of Participants With C-X-C Chemokine Receptor Type 4 (CXCR-4) Biomarker | Number of participants with CXCR-4 biomarker were reported. | Day 1 of Week 1 | 
| Number of Participants With Treatment- Emergent Adverse Events (TEAEs) | An adverse event was defined as any untoward medical event that occurred in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. TEAEs were defined as any AE that occurred at or after the initial administration of study intervention through the day of last dose plus 30 days. | Up to 1 year 11 months |