TriangleNCT02165397 · CITED IN SOURCE DOCUMENTS
Ibrutinib With Rituximab in Adults With Waldenström's Macroglobulinemia
An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.
- Phase
- PHASE3
- Status at capture
- COMPLETED
- Registry last update
- 2021-03-03
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).
Open the original ClinicalTrials.gov record → · Download preserved record
What did the study report?
Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.
Participant flow
Baseline characteristics
Progression Free Survival (PFS) Based on Independent Review Committee (IRC) Assessment - Kaplan Meier Landmark Estimates at Month 54
Overall Response Rate (ORR) Based on IRC Assessment Up to 3 Years After Last Participant Randomized
Time to Next Treatment (TnT) Time From the Date of Randomization to the Start Date of Any Subsequent WM Treatment.
Percentage of Participants With Sustained Hemoglobin (Hgb) Improvement Up to 3 Years After Last Participant Randomized
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
Overall Survival (OS) - Kaplan Meier Landmark Estimates at Month 54
Adverse events
Limitations, agreements, and source contact
Who could take part
- eligibility 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/exclusion criteria for the substudy (Arm C) are identical to those described above for the randomized study but, to be eligible, subjects need to be considered 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 MR after the last rituximab-containing therapy.
- healthy Volunteers
- false
- minimum Age
- 18 Years
- sex
- ALL
- std Ages
- ADULT
- OLDER_ADULT
Treatment arms and interventions
- arm Groups
- description
- Ibrutinib: 420 mg (3 capsules x 140 mg) orally administered daily beginning from Day 1. Rituximab: 375 mg/m\^2 intravenous (IV) per package insert weekly for four consecutive weeks, followed by a second four-weekly rituximab course after a three-month interval.
- intervention Names
- Drug: Ibrutinib
- Drug: Rituximab
- label
- Randomized Study (Ibrutinib + Rituximab)
- type
- EXPERIMENTAL
- description
- Placebo: 3 capsules of placebo orally administered daily beginning from Day 1. Rituximab: 375 mg/m\^2 IV per package insert weekly for four consecutive weeks, followed by a second four-weekly rituximab course after a three-month interval.
- intervention Names
- Drug: Placebo
- Drug: Rituximab
- label
- Randomized Study (Placebo + Rituximab)
- type
- EXPERIMENTAL
- description
- Ibrutinib: 420 mg (3 capsules) orally administered daily beginning from Day 1.
- intervention Names
- Drug: Ibrutinib
- label
- Open-Label Substudy (Ibrutinib)
- type
- EXPERIMENTAL
- interventions
- arm Group Labels
- Open-Label Substudy (Ibrutinib)
- Randomized Study (Ibrutinib + Rituximab)
- description
- Participants will receive 420 mg of Ibrutinib orally.
- name
- Ibrutinib
- other Names
- PCI-32765
- type
- DRUG
- arm Group Labels
- Randomized Study (Placebo + Rituximab)
- description
- Participants will receive placebo capsules orally.
- name
- Placebo
- type
- DRUG
- arm Group Labels
- Randomized Study (Ibrutinib + Rituximab)
- Randomized Study (Placebo + Rituximab)
- description
- Participants will receive rituximab 375 mg/m\^2 IV.
- name
- Rituximab
- other Names
- Rituxan
- type
- DRUG
Study design
- allocation
- RANDOMIZED
- intervention Model
- PARALLEL
- masking Info
- masking
- DOUBLE
- who Masked
- PARTICIPANT
- INVESTIGATOR
- primary Purpose
- TREATMENT
Enrollment
- count
- 181
- type
- ACTUAL
Registered outcome plans (not posted results)
- primary Outcomes
- description
- 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.
- measure
- Progression Free Survival (PFS) Based on Independent Review Committee (IRC) Assessment - Kaplan Meier Landmark Estimates at Month 54
- time Frame
- Month 54 (median time on study: 49.7 months [Ibr+R and Pbo+R] and 57.9 months [Open-Label Ibr])
- secondary Outcomes
- description
- 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.
- measure
- Overall Response Rate (ORR) Based on IRC Assessment Up to 3 Years After Last Participant Randomized
- time Frame
- Median time on study: 49.7 months (Ibr+R and Pbo+R) and 57.9 months (Open-Label Ibr)
- description
- 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.
- measure
- Time to Next Treatment (TnT) Time From the Date of Randomization to the Start Date of Any Subsequent WM Treatment.
- time Frame
- Month 54 (median time on study: 49.7 months [Ibr+R and Pbo+R] and 57.9 months [Open-Label Ibr])
- description
- 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.
- measure
- Percentage of Participants With Sustained Hemoglobin (Hgb) Improvement Up to 3 Years After Last Participant Randomized
- time Frame
- Median time on study: 49.7 months (Ibr+R and Pbo+R) and 57.9 months (Open-Label Ibr)
- description
- 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.
- measure
- 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
- time Frame
- Baseline, 25 weeks
- description
- 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.
- measure
- Overall Survival (OS) - Kaplan Meier Landmark Estimates at Month 54
- time Frame
- Month 54 (median time on study: 49.7 months [Ibr+R and Pbo+R] and 57.9 months [Open-Label Ibr])
Full study description
- 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).
Source references
- references
- citation
- Dimopoulos MA, Tedeschi A, Trotman J, Garcia-Sanz R, Macdonald D, Leblond V, Mahe B, Herbaux C, Tam C, Orsucci L, Palomba ML, Matous JV, Shustik C, Kastritis E, Treon SP, Li J, Salman Z, Graef T, Buske C; iNNOVATE Study Group and the European Consortium for Waldenstrom's Macroglobulinemia. Phase 3 Trial of Ibrutinib plus Rituximab in Waldenstrom's Macroglobulinemia. N Engl J Med. 2018 Jun 21;378(25):2399-2410. doi: 10.1056/NEJMoa1802917. Epub 2018 Jun 1.
- pmid
- 29856685
- type
- BACKGROUND
- citation
- Dimopoulos MA, Trotman J, Tedeschi A, Matous JV, Macdonald D, Tam C, Tournilhac O, Ma S, Oriol A, Heffner LT, Shustik C, Garcia-Sanz R, Cornell RF, de Larrea CF, Castillo JJ, Granell M, Kyrtsonis MC, Leblond V, Symeonidis A, Kastritis E, Singh P, Li J, Graef T, Bilotti E, Treon S, Buske C; iNNOVATE Study Group and the European Consortium for Waldenstrom's Macroglobulinemia. Ibrutinib for patients with rituximab-refractory Waldenstrom's macroglobulinaemia (iNNOVATE): an open-label substudy of an international, multicentre, phase 3 trial. Lancet Oncol. 2017 Feb;18(2):241-250. doi: 10.1016/S1470-2045(16)30632-5. Epub 2016 Dec 10.
- pmid
- 27956157
- type
- BACKGROUND
- citation
- Guijosa A, Ramirez-Gamero A, Sarosiek S, Branagan AR, von Keudell G, Treon SP, Castillo JJ. Ibrutinib plus rituximab vs ibrutinib monotherapy in patients with Waldenstrom macroglobulinemia: a pooled analysis. Blood Adv. 2025 Sep 23;9(18):4705-4715. doi: 10.1182/bloodadvances.2025016536.
- pmid
- 40674744
- type
- DERIVED
- citation
- Buske C, Tedeschi A, Trotman J, Garcia-Sanz R, MacDonald D, Leblond V, Mahe B, Herbaux C, Matous JV, Tam CS, Heffner LT, Varettoni M, Palomba ML, Shustik C, Kastritis E, Treon SP, Ping J, Hauns B, Arango-Hisijara I, Dimopoulos MA. Plain Language Summary of the iNNOVATE study: ibrutinib plus rituximab is well-tolerated and effective in people with Waldenstrom's macroglobulinemia. Future Oncol. 2023 Feb;19(5):345-353. doi: 10.2217/fon-2022-1015. Epub 2023 Feb 23.
- pmid
- 36815271
- type
- DERIVED
- citation
- Buske C, Tedeschi A, Trotman J, Garcia-Sanz R, MacDonald D, Leblond V, Mahe B, Herbaux C, Matous JV, Tam CS, Heffner LT, Varettoni M, Palomba ML, Shustik C, Kastritis E, Treon SP, Ping J, Hauns B, Arango-Hisijara I, Dimopoulos MA. Ibrutinib Plus Rituximab Versus Placebo Plus Rituximab for Waldenstrom's Macroglobulinemia: Final Analysis From the Randomized Phase III iNNOVATE Study. J Clin Oncol. 2022 Jan 1;40(1):52-62. doi: 10.1200/JCO.21.00838. Epub 2021 Oct 4.
- pmid
- 34606378
- type
- DERIVED
- citation
- Trotman J, Buske C, Tedeschi A, Matous JV, MacDonald D, Tam CS, Tournilhac O, Ma S, Treon SP, Oriol A, Ping J, Briso EM, Arango-Hisijara I, Dimopoulos MA. Single-Agent Ibrutinib for Rituximab-Refractory Waldenstrom Macroglobulinemia: Final Analysis of the Substudy of the Phase III InnovateTM Trial. Clin Cancer Res. 2021 Nov 1;27(21):5793-5800. doi: 10.1158/1078-0432.CCR-21-1497. Epub 2021 Aug 11.
- pmid
- 34380643
- type
- DERIVED
Source notices and limitations
Discovery and provenance
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Preserved source evidence · Not medical advice