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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT02165397
Registration number
NCT02165397
Ethics application status
Date submitted
9/06/2014
Date registered
17/06/2014
Date last updated
3/03/2021
Titles & IDs
Public title
Ibrutinib With Rituximab in Adults With Waldenström's Macroglobulinemia
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Scientific title
iNNOVATE Study: A Randomized, Double-Blind, Placebo- Controlled, Phase 3 Study of Ibrutinib or Placebo in Combination With Rituximab in Subjects With Waldenström's Macroglobulinemia
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Secondary ID [1]
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PCYC-1127-CA
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Waldenström's Macroglobulinemia
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Condition category
Condition code
Cancer
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Lymphoma (non Hodgkin's lymphoma) - High grade lymphoma
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Cancer
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Lymphoma (non Hodgkin's lymphoma) - Low grade lymphoma
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Cancer
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Children's - Leukaemia & Lymphoma
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - Ibrutinib
Treatment: Drugs - Placebo
Treatment: Drugs - Rituximab
Experimental: Randomized Study (Ibrutinib + Rituximab) - 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.
Experimental: Randomized Study (Placebo + Rituximab) - 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.
Experimental: Open-Label Substudy (Ibrutinib) - Ibrutinib: 420 mg (3 capsules) orally administered daily beginning from Day 1.
Treatment: Drugs: Ibrutinib
Participants will receive 420 mg of Ibrutinib orally.
Treatment: Drugs: Placebo
Participants will receive placebo capsules orally.
Treatment: Drugs: Rituximab
Participants will receive rituximab 375 mg/m^2 IV.
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Progression Free Survival (PFS) Based on Independent Review Committee (IRC) Assessment - Kaplan Meier Landmark Estimates at Month 54
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Assessment method [1]
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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.
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Timepoint [1]
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Month 54 (median time on study: 49.7 months [Ibr+R and Pbo+R] and 57.9 months [Open-Label Ibr])
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Secondary outcome [1]
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Overall Response Rate (ORR) Based on IRC Assessment Up to 3 Years After Last Participant Randomized
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Assessment method [1]
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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.
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Timepoint [1]
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Median time on study: 49.7 months (Ibr+R and Pbo+R) and 57.9 months (Open-Label Ibr)
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Secondary outcome [2]
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Time to Next Treatment (TnT) Time From the Date of Randomization to the Start Date of Any Subsequent WM Treatment.
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Assessment method [2]
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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.
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Timepoint [2]
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Month 54 (median time on study: 49.7 months [Ibr+R and Pbo+R] and 57.9 months [Open-Label Ibr])
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Secondary outcome [3]
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Percentage of Participants With Sustained Hemoglobin (Hgb) Improvement Up to 3 Years After Last Participant Randomized
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Assessment method [3]
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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.
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Timepoint [3]
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Median time on study: 49.7 months (Ibr+R and Pbo+R) and 57.9 months (Open-Label Ibr)
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Secondary outcome [4]
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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
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Assessment method [4]
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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.
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Timepoint [4]
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Baseline, 25 weeks
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Secondary outcome [5]
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Overall Survival (OS) - Kaplan Meier Landmark Estimates at Month 54
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Assessment method [5]
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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.
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Timepoint [5]
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Month 54 (median time on study: 49.7 months [Ibr+R and Pbo+R] and 57.9 months [Open-Label Ibr])
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Eligibility
Key inclusion criteria
Eligibility Criteria for the Randomized Study
- 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
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Minimum age
18
Years
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key 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.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Blinded (masking used)
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Who is / are masked / blinded?
The people receiving the treatment/s
The people analysing the results/data
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 3
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
7/07/2014
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
7/11/2019
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Sample size
Target
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Accrual to date
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Final
181
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Recruitment in Australia
Recruitment state(s)
ACT,NSW,SA,VIC
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Recruitment hospital [1]
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The Canberra Hospital - Garran
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Recruitment hospital [2]
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Concord Repartriation General Hospital - Concord
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Recruitment hospital [3]
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Flinders Medical Center - Bedford Park
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Recruitment hospital [4]
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Peter MacCallum Cancer Center - Melbourne
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Recruitment postcode(s) [1]
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2605 - Garran
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Recruitment postcode(s) [2]
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2139 - Concord
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Recruitment postcode(s) [3]
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05042 - Bedford Park
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Recruitment postcode(s) [4]
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3000 - Melbourne
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Recruitment outside Australia
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United States of America
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California
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United States of America
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Colorado
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United States of America
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Georgia
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Illinois
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Massachusetts
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New Jersey
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New York
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United States of America
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Tennessee
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Canada
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Alberta
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Canada
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Nova Scotia
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Canada
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Ontario
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Canada
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Bouches-du-Rhône
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France
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Finistère
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Loire-Atlantique
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France
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Meurthe-et-Moselle
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France
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Nord
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France
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Puy-de-Dôme
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France
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Rhône
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France
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France
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Paris
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Germany
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Baden-Württemberg
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Germany
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Rheinland-Pfalz
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Germany
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Saarland
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Germany
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Bremen
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Germany
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München
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Greece
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Achaia
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Greece
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Attiki
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Greece
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Macedonia
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Greece
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Athens
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Italy
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Piemonte
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Italy
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Milano
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Italy
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Pavia
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Italy
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Udine
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Spain
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Barcelona
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Spain
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Castilla Y León
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Spain
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Madrid
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United Kingdom
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Dorset
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
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Name
Pharmacyclics LLC.
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Address
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Other collaborator category [1]
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Commercial sector/Industry
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Name [1]
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Janssen Research & Development, LLC
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Ethics approval
Ethics application status
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Summary
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).
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Trial website
https://clinicaltrials.gov/ct2/show/NCT02165397
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Trial related presentations / publications
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.
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.
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Public notes
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Contacts
Principal investigator
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Bernhard Hauns, MD
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Address
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Pharmacyclics LLC (An AbbVie Company)
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT02165397
Download to PDF