Waldenstrom Macroglobulinemia
Conditions
Brief summary
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).
Interventions
DRUGIbrutinib
Ibrutinib 420 mg will be administered orally.
DRUGRituximab
Rituximab 375 mg/m\^2 will be administered intravenously.
Sponsors
Janssen Pharmaceutical K.K.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) According to the Modified Sixth International Workshop on Waldenstrom's Macroglobulinemia (IWWM) Criteria | Up to 1 year 11 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Concentrations of Ibrutinib | Day 1 of Week 4: Predose, 1 hour, 2 hours, 4 hours, and 6 hours postdose | Plasma concentrations of ibrutinib were reported. |
| Plasma Concentrations of Metabolite PCI-45227 | Day 1 of Week 4: Predose, 1 hour, 2 hours, 4 hours, and 6 hours postdose | Plasma concentrations of metabolite PCI-45227 were reported. |
| Progression Free Survival (PFS) Assessed by Independent Review Committee | From the date of initial dose up to 3 years and 5 months | 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. Kaplan-Meier method was used for the analysis. |
| Number of Participants With C-X-C Chemokine Receptor Type 4 (CXCR-4) Biomarker Mutations | Day 1 of Week 1 | Number of participants with CXCR-4 biomarker mutations were reported. CXCR-4 was assessed using next generation sequencing to detect the somatic mutations in the bone marrow aspiration samples collected during the study. |
| Number of Participants With Treatment- Emergent Adverse Events (TEAEs) | From first dose of study drug up to 30 days post last dose of study drug (that is, up to 40.6 months) | 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. |
| Number of Participants With Myeloid Differentiation Primary Response Gene 88 (MYD88) Biomarker Mutation | Day 1 of Week 1 | Number of participants with MYD88 biomarker mutations were reported. MYD88 was assessed using next generation sequencing to detect the somatic mutations in the bone marrow aspiration samples collected during the study. |
Countries
Japan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ibrutinib + Rituximab Treatment naive or relapsed/refractory Waldenstrom's Macroglobulinemia (WM) Japanese participants received ibrutinib 420 milligrams (mg) (3\*140 mg capsules) orally, once daily, from Day 1 of Week 1 until disease progression or unacceptable toxicity along with rituximab 375 milligrams per square meter (mg/m\^2) intravenously (IV) weekly for 4 consecutive weeks (Day 1 of Weeks 1 to 4), followed by a second course of once-weekly rituximab for 4 consecutive weeks (from Week 17 to 20) after a 12-week interval. | 16 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Ibrutinib + Rituximab |
|---|---|
| Age, Continuous | 67.5 years STANDARD_DEVIATION 11.21 |
| Age, Customized Greater Than 65 | 11 Participants |
| Age, Customized Less Than and Equal to (<=) 65 years | 5 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 16 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 0 Participants |
| Region of Enrollment JAPAN | 16 Participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 16 |
| other Total, other adverse events | 16 / 16 |
| serious Total, serious adverse events | 4 / 16 |
Outcome results
Primary
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.
Time frame: Up to 1 year 11 months
Population: Response evaluable analysis set included all enrolled participants who had measurable disease at baseline, received at least 1 dose of ibrutinib and who had at least 1 adequate postbaseline efficacy assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ibrutinib + Rituximab | Overall Response Rate (ORR) According to the Modified Sixth International Workshop on Waldenstrom's Macroglobulinemia (IWWM) Criteria | 87.5 percentage of participants |
Secondary
Number of Participants With C-X-C Chemokine Receptor Type 4 (CXCR-4) Biomarker Mutations
Number of participants with CXCR-4 biomarker mutations were reported. CXCR-4 was assessed using next generation sequencing to detect the somatic mutations in the bone marrow aspiration samples collected during the study.
Time frame: Day 1 of Week 1
Population: All treated analysis set included all enrolled participants who received at least 1 dose of ibrutinib. Here, 'N' (number of participants analyzed) refers to participants evaluable for this outcome measure.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ibrutinib + Rituximab | Number of Participants With C-X-C Chemokine Receptor Type 4 (CXCR-4) Biomarker Mutations | 2 Participants |
Secondary
Number of Participants With Myeloid Differentiation Primary Response Gene 88 (MYD88) Biomarker Mutation
Number of participants with MYD88 biomarker mutations were reported. MYD88 was assessed using next generation sequencing to detect the somatic mutations in the bone marrow aspiration samples collected during the study.
Time frame: Day 1 of Week 1
Population: All treated analysis set included all enrolled participants who received at least 1 dose of ibrutinib. Here, 'N' (number of participants analyzed) refers to participants evaluable for this outcome measure.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ibrutinib + Rituximab | Number of Participants With Myeloid Differentiation Primary Response Gene 88 (MYD88) Biomarker Mutation | 6 Participants |
Secondary
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.
Time frame: From first dose of study drug up to 30 days post last dose of study drug (that is, up to 40.6 months)
Population: Safety analysis set included all enrolled participants who received at least 1 dose of ibrutinib.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ibrutinib + Rituximab | Number of Participants With Treatment- Emergent Adverse Events (TEAEs) | 16 Participants |
Secondary
Plasma Concentrations of Ibrutinib
Plasma concentrations of ibrutinib were reported.
Time frame: Day 1 of Week 4: Predose, 1 hour, 2 hours, 4 hours, and 6 hours postdose
Population: The Pharmacokinetic (PK) evaluable analysis set included all enrolled participants who had received at least 1 dose of ibrutinib and had at least 1 post-dose PK sample. Here, n (number analyzed) refers to number of participants evaluable for specified timepoints.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ibrutinib + Rituximab | Plasma Concentrations of Ibrutinib | Week 4: Predose | 4.10 nanograms per milliliter (ng/mL) | Standard Deviation 6.15 |
| Ibrutinib + Rituximab | Plasma Concentrations of Ibrutinib | Week 4: 1 hour postdose | 55.6 nanograms per milliliter (ng/mL) | Standard Deviation 74.6 |
| Ibrutinib + Rituximab | Plasma Concentrations of Ibrutinib | Week 4: 2 hours postdose | 94.9 nanograms per milliliter (ng/mL) | Standard Deviation 147 |
| Ibrutinib + Rituximab | Plasma Concentrations of Ibrutinib | Week 4: 4 hours postdose | 89.9 nanograms per milliliter (ng/mL) | Standard Deviation 115 |
| Ibrutinib + Rituximab | Plasma Concentrations of Ibrutinib | Week 4: 6 hours postdose | 50.5 nanograms per milliliter (ng/mL) | Standard Deviation 62.3 |
Secondary
Plasma Concentrations of Metabolite PCI-45227
Plasma concentrations of metabolite PCI-45227 were reported.
Time frame: Day 1 of Week 4: Predose, 1 hour, 2 hours, 4 hours, and 6 hours postdose
Population: The PK evaluable analysis set included all enrolled participants who had received at least 1 dose of ibrutinib and had at least 1 post-dose PK sample. Here, n (number analyzed) refers to number of participants evaluable for specified timepoints.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ibrutinib + Rituximab | Plasma Concentrations of Metabolite PCI-45227 | Week 4: Predose | 13.7 ng/mL | Standard Deviation 14.8 |
| Ibrutinib + Rituximab | Plasma Concentrations of Metabolite PCI-45227 | Week 4: 6 hour postdose | 65.6 ng/mL | Standard Deviation 43.1 |
| Ibrutinib + Rituximab | Plasma Concentrations of Metabolite PCI-45227 | Week 4: 1 hour postdose | 39.9 ng/mL | Standard Deviation 42.3 |
| Ibrutinib + Rituximab | Plasma Concentrations of Metabolite PCI-45227 | Week 4: 2 hours postdose | 63.9 ng/mL | Standard Deviation 62.3 |
| Ibrutinib + Rituximab | Plasma Concentrations of Metabolite PCI-45227 | Week 4: 4 hours postdose | 79.6 ng/mL | Standard Deviation 51.5 |
Secondary
Progression Free Survival (PFS) Assessed by Independent Review Committee
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. Kaplan-Meier method was used for the analysis.
Time frame: From the date of initial dose up to 3 years and 5 months
Population: All treated analysis set included all enrolled participants who received at least 1 dose of ibrutinib.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ibrutinib + Rituximab | Progression Free Survival (PFS) Assessed by Independent Review Committee | NA months |