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Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT02165397
Other study ID # PCYC-1127-CA
Secondary ID
Status Completed
Phase Phase 3
First received
Last updated
Start date July 7, 2014
Est. completion date November 7, 2019

Study information

Verified date December 2020
Source Pharmacyclics LLC.
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial 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).


Recruitment information / eligibility

Status Completed
Enrollment 181
Est. completion date November 7, 2019
Est. primary completion date November 7, 2019
Accepts healthy volunteers No
Gender All
Age group 18 Years and older
Eligibility 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.

Study Design


Intervention

Drug:
Ibrutinib
Participants will receive 420 mg of Ibrutinib orally.
Placebo
Participants will receive placebo capsules orally.
Rituximab
Participants will receive rituximab 375 mg/m^2 IV.

Locations

Country Name City State
Australia Flinders Medical Center Bedford Park South Australia
Australia Concord Repartriation General Hospital Concord New South Wales
Australia The Canberra Hospital Garran Australian Capital Territory
Australia Peter MacCallum Cancer Center Melbourne Victoria
Canada Cross Cancer Institute Edmonton Alberta
Canada Queen Elizabeth II Health Sciences Center Halifax Nova Scotia
Canada McGill University Health Center Montreal Quebec
Canada Princess Margaret Hospital Toronto Ontario
France CHU Estaing Clermont-Ferrand Puy-de-Dôme
France Hopital Henri Mondor Créteil
France Hôpital Claude Huriez Lille Nord
France Institut Paoli-Calmettes Marseille Bouches-du-Rhône
France Hôtel Dieu Nantes Loire-Atlantique
France Groupe Hospitalier Pitié Salpétrière Paris
France Hôpital Saint Louis Paris
France Centre Hospitalier Lyon Sud Pierre-benite Rhône
France Centre Hospitalier de Saint Brieuc Hopital Yves le Foll Saint-Brieuc Finistère
France CHU de Nancy-Hopital Brabois Adulte Vandoeuvre-lès-nancy Meurthe-et-Moselle
Germany DIAKO Evangelische Diakonie Krankenhaus gGmbH Bremen
Germany Universität Des Saarlandes Homburg Saarland
Germany Universitätsmedizin der Johannes Gutenberg-Universität Mainz Mainz Rheinland-Pfalz
Germany LMU Klinikum der Universität München München
Germany Stauferklinikum Schwäbisch Gmünd Mutlangen Baden-Württemberg
Greece Alexandra Hospital Athens Attiki
Greece Laiko General Hospital of Athens Athens
Greece University General Hospital of Patras Patras Achaia
Greece University General Hospital of Thessaloniki "AHEPA" Thessaloniki Macedonia
Italy ASST Grande Ospedale Metropolitano Niguarda Milano
Italy Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico Milano
Italy ASST di Pavia - Fondazione IRCCS Policlinico San Matteo di Pavia Pavia
Italy Azienda Ospedaliera Città della Salute e della Scienza di Torino Torino Piemonte
Italy Azienda Ospedaliero Universitaria Santa Maria della Misericordia di Udine Udine
Spain Hospital Universitari Germans Trias i Pujol Badalona Barcelona
Spain Hospital Clinic de Barcelona Barcelona
Spain Hospital de La Santa Creu i Sant Pau Barcelona
Spain Hospital Universitario Infanta Leonor Madrid
Spain Hospital Universitario de Salamanca Salamanca Castilla Y León
United Kingdom Royal Bournemouth Hospital Bournemouth Dorset
United States Emory University Hospital Atlanta Georgia
United States Dana Farber Cancer Institute Boston Massachusetts
United States Northwestern Memorial Hospital Chicago Illinois
United States Colorado Blood Cancer Institute Denver Colorado
United States Hackensack University Medical Center Hackensack New Jersey
United States University of California Los Angeles Los Angeles California
United States Vanderbilt University Medical Center Nashville Tennessee
United States Memorial Sloan Kettering Cancer Center New York New York
United States Weill Cornell Medical Center New York New York
United States Stanford Cancer Center Palo Alto California

Sponsors (2)

Lead Sponsor Collaborator
Pharmacyclics LLC. Janssen Research & Development, LLC

Countries where clinical trial is conducted

United States,  Australia,  Canada,  France,  Germany,  Greece,  Italy,  Spain,  United Kingdom, 

References & Publications (2)

Dimopoulos MA, Tedeschi A, Trotman J, García-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 Waldenström's Macroglobulinemia. Phase 3 Trial of Ibrutinib plus Rituximab in Waldenström's Macroglobulinemia. N Engl J Med. 2018 Jun 21;378(25):2399-2410. doi: 10.1056/NEJMoa1802917. Epub 2018 Jun 1. — View Citation

Dimopoulos MA, Trotman J, Tedeschi A, Matous JV, Macdonald D, Tam C, Tournilhac O, Ma S, Oriol A, Heffner LT, Shustik C, García-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 Waldenström's Macroglobulinemia. Ibrutinib for patients with rituximab-refractory Waldenström'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. — View Citation

Outcome

Type Measure Description Time frame Safety issue
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.
Month 54 (median time on study: 49.7 months [Ibr+R and Pbo+R] and 57.9 months [Open-Label Ibr])
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. Median time on study: 49.7 months (Ibr+R and Pbo+R) and 57.9 months (Open-Label Ibr)
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.
Month 54 (median time on study: 49.7 months [Ibr+R and Pbo+R] and 57.9 months [Open-Label Ibr])
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. Median time on study: 49.7 months (Ibr+R and Pbo+R) and 57.9 months (Open-Label Ibr)
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. Baseline, 25 weeks
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.
Month 54 (median time on study: 49.7 months [Ibr+R and Pbo+R] and 57.9 months [Open-Label Ibr])
See also
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