Waldenström's Macroglobulinemia
Conditions
Keywords
Ibrutinib, Pharmacyclics, PCYC, Lymphoma, Btk inhibitor, WM, Rituximab, Rituxan, Waldenström's, Waldenstrom Macroglobulinemia, non-Hodgkin lymphoma, NHL
Brief summary
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).
Interventions
DRUGIbrutinib
Participants will receive 420 mg of Ibrutinib orally.
DRUGPlacebo
Participants will receive placebo capsules orally.
DRUGRituximab
Participants will receive rituximab 375 mg/m\^2 IV.
Sponsors
Janssen Research & Development, LLC
Pharmacyclics LLC.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) Based on Independent Review Committee (IRC) Assessment - Kaplan Meier Landmark Estimates at Month 54 | Month 54 (median time on study: 49.7 months [Ibr+R and Pbo+R] and 57.9 months [Open-Label Ibr]) | PFS was defined as the time from date randomization to date of first IRC-confirmed disease progression (PD) assessed according to the modified VIth International Workshop on Waldenström's Macroglobulinemia (IWWM) criteria (National Comprehensive Cancer Network \[NCCN\] 2014) or death due to any cause, whichever occurs first, regardless of the use of subsequent antineoplastic therapy prior to documented PD or death. As the median PFS was not reached in the Ibrutinib + Rituximab arm at the time of the analysis, Kaplan Meier landmark estimate of the PFS rate at 54 months (that is, the estimated percentage of participants with PFS at Month 54) is presented. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) Based on IRC Assessment Up to 3 Years After Last Participant Randomized | Median time on study: 49.7 months (Ibr+R and Pbo+R) and 57.9 months (Open-Label Ibr) | ORR, defined as the percentage of participants achieving a best overall response of protocol-specified complete response (CR), very good partial response (VGPR), or partial response (PR) per the IRC assessment at or prior to initiation of subsequent antineoplastic therapy and confirmed by 2 consecutive assessments. IRC assessment of response was conducted according to the modified VIth IWWM (NCCN 2014) criteria and incorporated assessments from the central radiology review. CR required complete resolution of lymphadenopathy/splenomegaly if present at baseline. VGPR and PR required reduction in lymphadenopathy/splenomegaly if present at baseline.. Kaplan-Meier estimate. |
| Time to Next Treatment (TnT) Time From the Date of Randomization to the Start Date of Any Subsequent WM Treatment. | Month 54 (median time on study: 49.7 months [Ibr+R and Pbo+R] and 57.9 months [Open-Label Ibr]) | TTnT was measured from the date of randomization to the start date of any subsequent WM treatment. Participants without subsequent treatment were censored at the date of the last study visit. As the median TTnT was not reached in the Ibrutinib + Rituximab arm and the Open-Label Substudy arm at the time of the analysis, Kaplan Meier landmark estimate of the TTnT rate at 54 months (that is, the estimated percentage of participants not receiving subsequent WM treatment at Month 54) are presented. |
| Percentage of Participants With Sustained Hemoglobin (Hgb) Improvement Up to 3 Years After Last Participant Randomized | Median time on study: 49.7 months (Ibr+R and Pbo+R) and 57.9 months (Open-Label Ibr) | Percentage of participants achieving a sustained improvement in Hgb at or prior to initiation of subsequent antineoplastic therapy. Hgb improvement is defined as an increase of ≥ 2 g/dL over baseline regardless of baseline value, or an increase to \>11 g/dL with a ≥0.5 g/dL improvement if baseline is ≤ 11 g/dL. Sustained Hgb improvement is defined as improvement that is sustained continuously for ≥ 56 days (8 weeks) without blood transfusion or growth factors, which includes hemoglobin \> 110 g/L with at least a 5 g/L improvement if baseline ≤110 g/L or increase ≥20 g/L over baseline. |
| Percentage of Participants With ≥ 3 Points Increase From Baseline by Week 25 in the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Subscale Score | Baseline, 25 weeks | Percentage of participants with ≥ 3 points increase from baseline by Week 25 in the FACIT-Fatigue subscale score.The FACIT-Fatigue is a 13-item questionnaire that assesses participant reported fatigue and its impact upon daily activities and function over the past 7 days. Each of the 13 items of the FACIT-Fatigue Scale ranges from 0-4, with a range of possible total scores from 0 (extreme fatigue) to 52 (no fatigue). Scores below 30 indicate severe fatigue. |
| Overall Survival (OS) - Kaplan Meier Landmark Estimates at Month 54 | Month 54 (median time on study: 49.7 months [Ibr+R and Pbo+R] and 57.9 months [Open-Label Ibr]) | OS, defined as the time from the date of randomization to the date of death from any cause. All deaths observed as the time of the analysis were considered as events. For participants who were not known to have died at the time of the analysis, OS data were censored at the date last known alive. As the median OS was not reached in any treatment arm at the time of the analysis, Kaplan Meier point estimates of the OS rate (that is, the estimated percentage of participants still surviving at Month 54) are presented. |
Countries
Australia, Canada, France, Germany, Greece, Italy, Spain, United Kingdom, United States
Participant flow
Recruitment details
This study was conducted in 48 sites (10 in the United States, 30 in Europe, 4 in Canada and 4 in Australia).
Pre-assignment details
Participants were randomized in a 1:1 ratio to receive ibrutinib + rituximab (Ibr+R) or placebo + rituximab (Pbo+R). Separately, participants refractory to treatment with rituximab were enrolled in an open-label ibrutinib monotherapy substudy to further investigate the safety and efficacy of ibrutinib.
Participants by arm
| Arm | Count |
|---|---|
| Ibrutinib + Rituximab Ibrutinib: 420 mg (3 capsules) orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment.
Rituximab: 375 mg/m\^2 IV per package insert weekly for four consecutive weeks (Day 1 of Weeks 1-4), followed by a second four-weekly rituximab course after a three-month interval (Weeks 17-20) for a total of 8 infusions of rituximab. | 75 |
| Placebo + Rituximab Placebo: 3 capsules of placebo orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment.
Rituximab: 375 mg/m\^2 IV per package insert weekly for four consecutive weeks (Day 1 of Weeks 1-4), followed by a second four-weekly rituximab course after a three-month interval (Weeks 17-20) for a total of 8 infusions of rituximab. | 75 |
| Open-Label Substudy: Ibrutinib Ibrutinib: 420 mg (3 capsules) orally administered daily beginning from Day 1 in Week 1 until progression, discontinuation due to toxicity or other reasons to discontinue treatment. Participants (rituximab refractory) were treated in an open-label substudy independently of the 2 randomized main treatment arms. | 31 |
| Total | 181 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 7 | 10 | 8 |
| Overall Study | Lost to Follow-up | 1 | 3 | 0 |
| Overall Study | Other, Not Specified | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 6 | 6 | 1 |
Baseline characteristics
| Characteristic | Open-Label Substudy: Ibrutinib | Total | Ibrutinib + Rituximab | Placebo + Rituximab |
|---|---|---|---|---|
| Age, Customized < 65 years old | 14 Participants | 72 Participants | 28 Participants | 30 Participants |
| Age, Customized >= 65 years old | 17 Participants | 109 Participants | 47 Participants | 45 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 5 Participants | 3 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 30 Participants | 176 Participants | 72 Participants | 74 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 5 Participants | 3 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 30 Participants | 13 Participants | 14 Participants |
| Race (NIH/OMB) White | 26 Participants | 144 Participants | 58 Participants | 60 Participants |
| Sex: Female, Male Female | 11 Participants | 62 Participants | 30 Participants | 21 Participants |
| Sex: Female, Male Male | 20 Participants | 119 Participants | 45 Participants | 54 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 9 / 75 | 10 / 75 | 8 / 31 |
| other Total, other adverse events | 75 / 75 | 75 / 75 | 30 / 31 |
| serious Total, serious adverse events | 40 / 75 | 25 / 75 | 16 / 31 |
Outcome results
Primary
Progression Free Survival (PFS) Based on Independent Review Committee (IRC) Assessment - Kaplan Meier Landmark Estimates at Month 54
PFS was defined as the time from date randomization to date of first IRC-confirmed disease progression (PD) assessed according to the modified VIth International Workshop on Waldenström's Macroglobulinemia (IWWM) criteria (National Comprehensive Cancer Network \[NCCN\] 2014) or death due to any cause, whichever occurs first, regardless of the use of subsequent antineoplastic therapy prior to documented PD or death. As the median PFS was not reached in the Ibrutinib + Rituximab arm at the time of the analysis, Kaplan Meier landmark estimate of the PFS rate at 54 months (that is, the estimated percentage of participants with PFS at Month 54) is presented.
Time frame: Month 54 (median time on study: 49.7 months [Ibr+R and Pbo+R] and 57.9 months [Open-Label Ibr])
Population: Intent to Treat population: all randomized/enrolled participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ibrutinib + Rituximab | Progression Free Survival (PFS) Based on Independent Review Committee (IRC) Assessment - Kaplan Meier Landmark Estimates at Month 54 | 68.0 percentage of participants |
| Placebo + Rituximab | Progression Free Survival (PFS) Based on Independent Review Committee (IRC) Assessment - Kaplan Meier Landmark Estimates at Month 54 | 25.3 percentage of participants |
| Open-Label Substudy: Ibrutinib | Progression Free Survival (PFS) Based on Independent Review Committee (IRC) Assessment - Kaplan Meier Landmark Estimates at Month 54 | 39.7 percentage of participants |
p-value: <0.000195% CI: [0.148, 0.42]Log Rank
Secondary
Overall Response Rate (ORR) Based on IRC Assessment Up to 3 Years After Last Participant Randomized
ORR, defined as the percentage of participants achieving a best overall response of protocol-specified complete response (CR), very good partial response (VGPR), or partial response (PR) per the IRC assessment at or prior to initiation of subsequent antineoplastic therapy and confirmed by 2 consecutive assessments. IRC assessment of response was conducted according to the modified VIth IWWM (NCCN 2014) criteria and incorporated assessments from the central radiology review. CR required complete resolution of lymphadenopathy/splenomegaly if present at baseline. VGPR and PR required reduction in lymphadenopathy/splenomegaly if present at baseline.. Kaplan-Meier estimate.
Time frame: Median time on study: 49.7 months (Ibr+R and Pbo+R) and 57.9 months (Open-Label Ibr)
Population: Intent to Treat population: all randomized/enrolled participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ibrutinib + Rituximab | Overall Response Rate (ORR) Based on IRC Assessment Up to 3 Years After Last Participant Randomized | 76.0 percentage of participants |
| Placebo + Rituximab | Overall Response Rate (ORR) Based on IRC Assessment Up to 3 Years After Last Participant Randomized | 30.7 percentage of participants |
| Open-Label Substudy: Ibrutinib | Overall Response Rate (ORR) Based on IRC Assessment Up to 3 Years After Last Participant Randomized | 77.4 percentage of participants |
p-value: <0.000195% CI: [1.753, 3.639]Cochran-Mantel-Haenszel
Secondary
Overall Survival (OS) - Kaplan Meier Landmark Estimates at Month 54
OS, defined as the time from the date of randomization to the date of death from any cause. All deaths observed as the time of the analysis were considered as events. For participants who were not known to have died at the time of the analysis, OS data were censored at the date last known alive. As the median OS was not reached in any treatment arm at the time of the analysis, Kaplan Meier point estimates of the OS rate (that is, the estimated percentage of participants still surviving at Month 54) are presented.
Time frame: Month 54 (median time on study: 49.7 months [Ibr+R and Pbo+R] and 57.9 months [Open-Label Ibr])
Population: Intent to Treat population: all randomized/enrolled participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ibrutinib + Rituximab | Overall Survival (OS) - Kaplan Meier Landmark Estimates at Month 54 | 86.4 percentage of participants |
| Placebo + Rituximab | Overall Survival (OS) - Kaplan Meier Landmark Estimates at Month 54 | 84.2 percentage of participants |
| Open-Label Substudy: Ibrutinib | Overall Survival (OS) - Kaplan Meier Landmark Estimates at Month 54 | 73.4 percentage of participants |
Comparison: Data cutoff 18 December 2019p-value: 0.64395% CI: [0.328, 1.99]Log Rank
Secondary
Percentage of Participants With ≥ 3 Points Increase From Baseline by Week 25 in the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Subscale Score
Percentage of participants with ≥ 3 points increase from baseline by Week 25 in the FACIT-Fatigue subscale score.The FACIT-Fatigue is a 13-item questionnaire that assesses participant reported fatigue and its impact upon daily activities and function over the past 7 days. Each of the 13 items of the FACIT-Fatigue Scale ranges from 0-4, with a range of possible total scores from 0 (extreme fatigue) to 52 (no fatigue). Scores below 30 indicate severe fatigue.
Time frame: Baseline, 25 weeks
Population: Intent to Treat population: all randomized/enrolled participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ibrutinib + Rituximab | Percentage of Participants With ≥ 3 Points Increase From Baseline by Week 25 in the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Subscale Score | 68.0 percentage of participants |
| Placebo + Rituximab | Percentage of Participants With ≥ 3 Points Increase From Baseline by Week 25 in the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Subscale Score | 54.7 percentage of participants |
| Open-Label Substudy: Ibrutinib | Percentage of Participants With ≥ 3 Points Increase From Baseline by Week 25 in the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Subscale Score | 87.1 percentage of participants |
p-value: 0.105995% CI: [0.955, 1.603]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With Sustained Hemoglobin (Hgb) Improvement Up to 3 Years After Last Participant Randomized
Percentage of participants achieving a sustained improvement in Hgb at or prior to initiation of subsequent antineoplastic therapy. Hgb improvement is defined as an increase of ≥ 2 g/dL over baseline regardless of baseline value, or an increase to \>11 g/dL with a ≥0.5 g/dL improvement if baseline is ≤ 11 g/dL. Sustained Hgb improvement is defined as improvement that is sustained continuously for ≥ 56 days (8 weeks) without blood transfusion or growth factors, which includes hemoglobin \> 110 g/L with at least a 5 g/L improvement if baseline ≤110 g/L or increase ≥20 g/L over baseline.
Time frame: Median time on study: 49.7 months (Ibr+R and Pbo+R) and 57.9 months (Open-Label Ibr)
Population: Intent to Treat population: all randomized/enrolled participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ibrutinib + Rituximab | Percentage of Participants With Sustained Hemoglobin (Hgb) Improvement Up to 3 Years After Last Participant Randomized | 77.3 percentage of participants |
| Placebo + Rituximab | Percentage of Participants With Sustained Hemoglobin (Hgb) Improvement Up to 3 Years After Last Participant Randomized | 42.7 percentage of participants |
| Open-Label Substudy: Ibrutinib | Percentage of Participants With Sustained Hemoglobin (Hgb) Improvement Up to 3 Years After Last Participant Randomized | 71.0 percentage of participants |
p-value: <0.000195% CI: [1.357, 2.421]Chi-squared
Secondary
Time to Next Treatment (TnT) Time From the Date of Randomization to the Start Date of Any Subsequent WM Treatment.
TTnT was measured from the date of randomization to the start date of any subsequent WM treatment. Participants without subsequent treatment were censored at the date of the last study visit. As the median TTnT was not reached in the Ibrutinib + Rituximab arm and the Open-Label Substudy arm at the time of the analysis, Kaplan Meier landmark estimate of the TTnT rate at 54 months (that is, the estimated percentage of participants not receiving subsequent WM treatment at Month 54) are presented.
Time frame: Month 54 (median time on study: 49.7 months [Ibr+R and Pbo+R] and 57.9 months [Open-Label Ibr])
Population: Intent to Treat population: all randomized/enrolled participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ibrutinib + Rituximab | Time to Next Treatment (TnT) Time From the Date of Randomization to the Start Date of Any Subsequent WM Treatment. | 87.4 percentage of participants |
| Placebo + Rituximab | Time to Next Treatment (TnT) Time From the Date of Randomization to the Start Date of Any Subsequent WM Treatment. | 29.4 percentage of participants |
| Open-Label Substudy: Ibrutinib | Time to Next Treatment (TnT) Time From the Date of Randomization to the Start Date of Any Subsequent WM Treatment. | 64.6 percentage of participants |
p-value: <0.000195% CI: [0.049, 0.212]Log Rank