Waldenstrom Macroglobulinemia
Conditions
Brief summary
The purpose of this study is to evaluate the efficacy of ibrutinib based on overall response rate (ORR) (partial response \[PR\] or better) by investigator assessment per the modified Consensus Response Criteria from the Sixth International Workshop on Waldenstrom's Macroglobulinemia (IWWM) (NCCN 2019), in Chinese participants with relapsed or refractory waldenstrom's macroglobulinemia.
Interventions
DRUGIbrutinib
Ibrutinib will be administered orally, once daily, at a dose of 420 mg (140 mg\*3 capsules taken together at one time).
Sponsors
Janssen Research & Development, LLC
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Men and women greater than or equal to (\>=) 18 years of age * Eastern Cooperative Oncology Group (ECOG) less than or equal to (\<=) 2 * Previously received at least one prior therapy for WM and have had either documented disease progression or had no response to the most recent treatment regimen * Centrally confirmed clinicopathological diagnosis of WM * Measurable disease defined as serum monoclonal immunoglobulin M (IgM) \>0.5 gram per deciliter (g/dL) * Symptomatic disease, requiring treatment * 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. Female participants of childbearing potential should avoid becoming pregnant while taking ibrutinib and for up to 1 month after the last dose of study drug. Male participants must use an effective barrier method of contraception during the study and for 3 months following the last dose of ibrutinib if sexually active with a female of childbearing potential
Exclusion criteria
* Involvement of the central nervous system by WM * Evidence of disease transformation * Prior exposure to BTK inhibitors * Known hypersensitivity reaction to ibrutinib or to the excipients in its formulation * Received any WM-related therapy \<=30 days prior to first administration of study treatment * Received a prior allogeneic hematopoietic stem cell transplant * Plasmapheresis \<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, except: (a) malignancy treated with curative intent and with no known active disease present for \>=2 years before the first dose of study drug and felt to be at low risk for recurrence by treating physician; (b) adequately treated nonmelanoma skin cancer or lentigo maligna without evidence of disease; (c) adequately treated carcinoma in situ without evidence of disease * 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 * Bleeding disorders or hemophilia * Stroke or intracranial hemorrhage within 6 months prior to enrollment * Infection with human immunodeficiency virus (HIV) or active infection with hepatitis B or hepatitis C * Major surgery within 4 weeks of first dose of study drug * Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigator's opinion, could compromise the participant's safety or put the study outcomes at undue risk * Currently active, clinically significant hepatic impairment Child-Pugh Class B or C according to the Child Pugh classification * Currently active, clinically significant cardiovascular disease * Requires or receiving anticoagulation with warfarin or other Vitamin K antagonists * Unable to swallow capsules or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction * Requires treatment with a strong cytochrome P450 (CYP) 3A inhibitor * Lactating or pregnant * Unable to understand the purpose and risks of the study and to provide a signed and dated informed consent form (ICF) and authorization to use protected health information (in accordance with national and local participant privacy regulations)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) | From start of the treatment (Day 1) up to 49.3 months | ORR was defined as the percentage of participants who achieved partial response (PR) or better (VGPR) per the modified consensus response criteria from sixth International Workshop on Waldenstrom's Macroglobulinemia (IWWM) (National Comprehensive Cancer Network \[NCCN\], 2019). PR: greater than or equal to (\>=) 50 percent (%) reduction of serum immunoglobulin M (IgM) from baseline, with reduction in lymphadenopathy/splenomegaly if present at baseline. Very Good Partial Response (VGPR): \>=90% reduction of serum IgM from baseline or normal serum IgM values, with reduction in lymphadenopathy/splenomegaly if present at baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Very Good Partial Response (VGPR) or Better Response Rate | From start of the treatment (Day 1) up to 49.3 months | VGPR or better response rate was defined as the percentage of participants who achieved VGPR or better according to the modified sixth IWWM (NCCN 2019) criteria as assessed by the investigator. VGPR: \>=90% reduction of serum IgM from baseline or normal serum IgM values, with reduction in lymphadenopathy/splenomegaly if present at baseline. |
| Duration of Response (DOR) | From the date of first documented response up to date of first documented PD or death (Day 1 up to 49.3 months) | DOR: duration from date of initial documentation of response (PR/better) to date of first documented progressive disease(PD), death or date of censoring if applicable, for responders (PR/better), as assessed by investigator. VGPR/PR: \>=90% reduction or normal serum IgM values (for VGPR) and \>=50% (for PR) reduction of serum IgM, with reduction in lymphadenopathy/splenomegaly if present at baseline. PD(at least 1): \>=25% IgM increase in serum IgM with \>=500 milligrams per deciliters(mg/dL) increase from nadir(lowest serum IgM value at any time from baseline), confirmation needed if IgM was sole PD criterion; new lymph nodes \>1.5 centimeters(cm), \>=50% increase in nadir in sum of product of diameters; 50% increase in longest diameter of previously identified node \>1cm in short axis; new splenomegaly; new extranodal disease; new/recurrent bone marrow involvement; new symptomatic disease(pleural effusion/Bing Neel syndrome/amyloidosis/light chain deposition/paraprotein mediated disorder). |
| Time to Response (TTR) | From start of the treatment up to first documentation of PR or better (Day 1 up to 49.3 months) | TTR was defined as the time from the date of first dose to the date of initial documentation of a response (PR or better) for responders. PR: \>=50% reduction of serum IgM from baseline, with reduction in lymphadenopathy/splenomegaly if present at baseline. VGPR: \>=90% reduction of serum IgM from baseline or normal serum IgM values, with reduction in lymphadenopathy/splenomegaly if present at baseline. |
| Clinical Response Rate (CRR) | From start of the treatment (Day 1) up to 49.3 months | CRR was defined as the percentage of participants who achieved minor response (MR) or better according to the modified sixth IWWM (NCCN 2019) criteria as assessed by the investigator. MR: \>=25% but less than (\<) 50% reduction of serum IgM from baseline. |
| Overall Survival (OS) | From day of first dose (Day 1) until death due to any cause (up to 49.3 months) | Overall survival was measured from the date of first dose to the date of the participant's death from any cause. |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Grade 3 or Higher TEAEs | From start of the treatment (Day 1) up to 30 days after last dose or initiation of subsequent antineoplastic treatment, whichever occurred first (Day 1 up to 45.9 months) | An adverse event (AE) was any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the intervention. TEAEs were defined as AEs occurring after the first dose of study drugs and within 30 days following the last dose of study drug or initiation of subsequent antineoplastic treatment, whichever occurred earlier. TEAEs were graded based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03 as Grade 1= Mild; Grade 2= Moderate; Grade 3= Severe; Grade 4= Life-threatening and Grade 5= Death. Number of participants with TEAEs and Grade 3 or higher TEAEs (included serious and non-serious events) were reported in this outcome measure. |
| Plasma Concentration of Ibrutinib | Pre-dose on Day 1 of Weeks 1, 5 and 9 | Plasma concentrations of ibrutinib were reported. |
| Progression Free Survival (PFS) | From day of first dose (Day 1) until PD or death (up to 49.3 months) | PFS was defined as duration from the date of first dose to the date of disease progression or death, whichever occurs first, assessed according to the modified sixth IWWM (NCCN 2019) criteria. PD (at least 1 of the following): \>=25% IgM increase in serum IgM with \>=500 mg/dL increase from nadir (lowest serum IgM value at any time from baseline), confirmation needed if IgM was sole PD criterion; new lymph nodes \>1.5 cm, \>=50% increase in nadir in sum of product of diameters; 50% increase in longest diameter of previously identified node \>1 cm in short axis; new splenomegaly; new extranodal disease; new/recurrent bone marrow involvement; new symptomatic disease (pleural effusion, Bing Neel syndrome, amyloidosis, light chain deposition, paraprotein mediated disorder). |
Countries
China
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ibrutinib 420 mg Participants with relapsed or refractory waldenstrom's macroglobulinemia received ibrutinib 420 milligrams (mg) (3\*140 mg capsules) orally once daily from Day 1 of Week 1 until disease progression, unacceptable toxicity, whichever occurs first. | 17 |
| Total | 17 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 3 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Ibrutinib 420 mg |
|---|---|
| Age, Continuous | 64.1 Years STANDARD_DEVIATION 6.95 |
| Race/Ethnicity, Customized Asian/Not Hispanic or Latino | 17 Participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 3 / 17 |
| other Total, other adverse events | 17 / 17 |
| serious Total, serious adverse events | 9 / 17 |
Outcome results
Primary
Overall Response Rate (ORR)
ORR was defined as the percentage of participants who achieved partial response (PR) or better (VGPR) per the modified consensus response criteria from sixth International Workshop on Waldenstrom's Macroglobulinemia (IWWM) (National Comprehensive Cancer Network \[NCCN\], 2019). PR: greater than or equal to (\>=) 50 percent (%) reduction of serum immunoglobulin M (IgM) from baseline, with reduction in lymphadenopathy/splenomegaly if present at baseline. Very Good Partial Response (VGPR): \>=90% reduction of serum IgM from baseline or normal serum IgM values, with reduction in lymphadenopathy/splenomegaly if present at baseline.
Time frame: From start of the treatment (Day 1) up to 49.3 months
Population: All treated analysis set included all enrolled participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ibrutinib 420 mg | Overall Response Rate (ORR) | 70.6 Percentage of Participants |
Secondary
Clinical Response Rate (CRR)
CRR was defined as the percentage of participants who achieved minor response (MR) or better according to the modified sixth IWWM (NCCN 2019) criteria as assessed by the investigator. MR: \>=25% but less than (\<) 50% reduction of serum IgM from baseline.
Time frame: From start of the treatment (Day 1) up to 49.3 months
Population: All treated analysis set included all enrolled participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ibrutinib 420 mg | Clinical Response Rate (CRR) | 100.0 Percentage of Participants |
Secondary
Duration of Response (DOR)
DOR: duration from date of initial documentation of response (PR/better) to date of first documented progressive disease(PD), death or date of censoring if applicable, for responders (PR/better), as assessed by investigator. VGPR/PR: \>=90% reduction or normal serum IgM values (for VGPR) and \>=50% (for PR) reduction of serum IgM, with reduction in lymphadenopathy/splenomegaly if present at baseline. PD(at least 1): \>=25% IgM increase in serum IgM with \>=500 milligrams per deciliters(mg/dL) increase from nadir(lowest serum IgM value at any time from baseline), confirmation needed if IgM was sole PD criterion; new lymph nodes \>1.5 centimeters(cm), \>=50% increase in nadir in sum of product of diameters; 50% increase in longest diameter of previously identified node \>1cm in short axis; new splenomegaly; new extranodal disease; new/recurrent bone marrow involvement; new symptomatic disease(pleural effusion/Bing Neel syndrome/amyloidosis/light chain deposition/paraprotein mediated disorder).
Time frame: From the date of first documented response up to date of first documented PD or death (Day 1 up to 49.3 months)
Population: Analysis population included responders in all treated analysis set who achieved PR or better.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ibrutinib 420 mg | Duration of Response (DOR) | 20.27 Months |
Secondary
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Grade 3 or Higher TEAEs
An adverse event (AE) was any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the intervention. TEAEs were defined as AEs occurring after the first dose of study drugs and within 30 days following the last dose of study drug or initiation of subsequent antineoplastic treatment, whichever occurred earlier. TEAEs were graded based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03 as Grade 1= Mild; Grade 2= Moderate; Grade 3= Severe; Grade 4= Life-threatening and Grade 5= Death. Number of participants with TEAEs and Grade 3 or higher TEAEs (included serious and non-serious events) were reported in this outcome measure.
Time frame: From start of the treatment (Day 1) up to 30 days after last dose or initiation of subsequent antineoplastic treatment, whichever occurred first (Day 1 up to 45.9 months)
Population: Safety analysis set included all enrolled participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ibrutinib 420 mg | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Grade 3 or Higher TEAEs | TEAEs | 17 Participants |
| Ibrutinib 420 mg | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Grade 3 or Higher TEAEs | Grade 3 or Higher TEAEs | 15 Participants |
Secondary
Overall Survival (OS)
Overall survival was measured from the date of first dose to the date of the participant's death from any cause.
Time frame: From day of first dose (Day 1) until death due to any cause (up to 49.3 months)
Population: All treated analysis set included all enrolled participants who received at least 1 dose of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ibrutinib 420 mg | Overall Survival (OS) | NA Months |
Secondary
Plasma Concentration of Ibrutinib
Plasma concentrations of ibrutinib were reported.
Time frame: Pre-dose on Day 1 of Weeks 1, 5 and 9
Population: Pharmacokinetics (PK) evaluable analysis set included all enrolled participants who received at least 1 dose of ibrutinib and had at least 1 available PK sample after treatment. Here, 'n' (number analyzed) signifies number of participants evaluable for specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ibrutinib 420 mg | Plasma Concentration of Ibrutinib | Predose Day 1 Week 1 | NA Nanograms per milliliter (ng/mL) | — |
| Ibrutinib 420 mg | Plasma Concentration of Ibrutinib | Predose Day 1 Week 5 | 3.46 Nanograms per milliliter (ng/mL) | Standard Deviation 3.97 |
| Ibrutinib 420 mg | Plasma Concentration of Ibrutinib | Predose Day 1 Week 9 | 6.27 Nanograms per milliliter (ng/mL) | Standard Deviation 8.36 |
Secondary
Progression Free Survival (PFS)
PFS was defined as duration from the date of first dose to the date of disease progression or death, whichever occurs first, assessed according to the modified sixth IWWM (NCCN 2019) criteria. PD (at least 1 of the following): \>=25% IgM increase in serum IgM with \>=500 mg/dL increase from nadir (lowest serum IgM value at any time from baseline), confirmation needed if IgM was sole PD criterion; new lymph nodes \>1.5 cm, \>=50% increase in nadir in sum of product of diameters; 50% increase in longest diameter of previously identified node \>1 cm in short axis; new splenomegaly; new extranodal disease; new/recurrent bone marrow involvement; new symptomatic disease (pleural effusion, Bing Neel syndrome, amyloidosis, light chain deposition, paraprotein mediated disorder).
Time frame: From day of first dose (Day 1) until PD or death (up to 49.3 months)
Population: All treated analysis set included all enrolled participants who received at least 1 dose of study drug. Here, 'N' (overall number of participants analyzed) refers to the number of participants evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ibrutinib 420 mg | Progression Free Survival (PFS) | 23.95 Months |
Secondary
Time to Response (TTR)
TTR was defined as the time from the date of first dose to the date of initial documentation of a response (PR or better) for responders. PR: \>=50% reduction of serum IgM from baseline, with reduction in lymphadenopathy/splenomegaly if present at baseline. VGPR: \>=90% reduction of serum IgM from baseline or normal serum IgM values, with reduction in lymphadenopathy/splenomegaly if present at baseline.
Time frame: From start of the treatment up to first documentation of PR or better (Day 1 up to 49.3 months)
Population: Analysis population included responders in all treated analysis set who achieved PR or better.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ibrutinib 420 mg | Time to Response (TTR) | 3.71 Months |
Secondary
Very Good Partial Response (VGPR) or Better Response Rate
VGPR or better response rate was defined as the percentage of participants who achieved VGPR or better according to the modified sixth IWWM (NCCN 2019) criteria as assessed by the investigator. VGPR: \>=90% reduction of serum IgM from baseline or normal serum IgM values, with reduction in lymphadenopathy/splenomegaly if present at baseline.
Time frame: From start of the treatment (Day 1) up to 49.3 months
Population: All treated analysis set included all enrolled participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ibrutinib 420 mg | Very Good Partial Response (VGPR) or Better Response Rate | 5.9 Percentage of Participants |