Ibrutinib With Rituximab in Adults With Waldenström's Macroglobulinemia
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
1 other identifier
interventional
181
9 countries
48
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).
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P25-P50 for phase_3
Started Jul 2014
Longer than P75 for phase_3
48 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
June 9, 2014
CompletedFirst Posted
Study publicly available on registry
June 17, 2014
CompletedStudy Start
First participant enrolled
July 7, 2014
CompletedPrimary Completion
Last participant's last visit for primary outcome
November 7, 2019
CompletedStudy Completion
Last participant's last visit for all outcomes
November 7, 2019
CompletedResults Posted
Study results publicly available
November 16, 2020
CompletedMarch 3, 2021
December 1, 2020
5.3 years
June 9, 2014
October 20, 2020
February 9, 2021
Conditions
Keywords
Outcome Measures
Primary Outcomes (1)
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 Outcomes (5)
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)
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])
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 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
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])
Study Arms (3)
Randomized Study (Ibrutinib + Rituximab)
EXPERIMENTALIbrutinib: 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.
Randomized Study (Placebo + Rituximab)
EXPERIMENTALPlacebo: 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.
Open-Label Substudy (Ibrutinib)
EXPERIMENTALIbrutinib: 420 mg (3 capsules) orally administered daily beginning from Day 1.
Interventions
Participants will receive 420 mg of Ibrutinib orally.
Participants will receive rituximab 375 mg/m\^2 IV.
Eligibility Criteria
You may qualify if:
- 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
You may not qualify if:
- 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
- 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
- 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.
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- Pharmacyclics LLC.lead
- Janssen Research & Development, LLCcollaborator
Study Sites (48)
University of California Los Angeles
Los Angeles, California, 90404, United States
Stanford Cancer Center
Palo Alto, California, 94305, United States
Colorado Blood Cancer Institute
Denver, Colorado, 80218, United States
Emory University Hospital
Atlanta, Georgia, 30322, United States
Northwestern Memorial Hospital
Chicago, Illinois, 60611, United States
Dana Farber Cancer Institute
Boston, Massachusetts, 02215, United States
Hackensack University Medical Center
Hackensack, New Jersey, 07601, United States
Memorial Sloan Kettering Cancer Center
New York, New York, 10065, United States
Weill Cornell Medical Center
New York, New York, 10065, United States
Vanderbilt University Medical Center
Nashville, Tennessee, 37204, United States
The Canberra Hospital
Garran, Australian Capital Territory, 2605, Australia
Concord Repartriation General Hospital
Concord, New South Wales, 2139, Australia
Flinders Medical Center
Bedford Park, South Australia, 05042, Australia
Peter MacCallum Cancer Center
Melbourne, Victoria, 3000, Australia
Cross Cancer Institute
Edmonton, Alberta, T6G1Z2, Canada
Queen Elizabeth II Health Sciences Center
Halifax, Nova Scotia, B3H 2Y9, Canada
Princess Margaret Hospital
Toronto, Ontario, M5G 2M9, Canada
McGill University Health Center
Montreal, Quebec, H4A3J1, Canada
Institut Paoli-Calmettes
Marseille, Bouches-du-Rhône, 13273, France
Centre Hospitalier de Saint Brieuc Hopital Yves le Foll
Saint-Brieuc, Finistère, 22027, France
Hôtel Dieu
Nantes, Loire-Atlantique, 44093, France
CHU de Nancy-Hopital Brabois Adulte
Vandœuvre-lès-Nancy, Meurthe-et-Moselle, 54511, France
Hôpital Claude Huriez
Lille, Nord, 59037, France
CHU Estaing
Clermont-Ferrand, Puy-de-Dôme, 63000, France
Centre Hospitalier Lyon Sud
Pierre-Bénite, Rhône, 69495, France
Hopital Henri Mondor
Créteil, 94010, France
Hôpital Saint Louis
Paris, 75010, France
Groupe Hospitalier Pitié Salpétrière
Paris, 75651 Cedex 13, France
Stauferklinikum Schwäbisch Gmünd
Mutlangen, Baden-Wurttemberg, 73557, Germany
Universitätsmedizin der Johannes Gutenberg-Universität Mainz
Mainz, Rhineland-Palatinate, 55131, Germany
Universität Des Saarlandes
Homburg, Saarland, 66421, Germany
DIAKO Evangelische Diakonie Krankenhaus gGmbH
Bremen, 28239, Germany
LMU Klinikum der Universität München
München, 81377, Germany
University General Hospital of Patras
Pátrai, Achaia, 26500, Greece
Alexandra Hospital
Athens, Attica, 11528, Greece
University General Hospital of Thessaloniki "AHEPA"
Thessaloniki, Macedonia, 54621, Greece
Laiko General Hospital of Athens
Athens, 11527, Greece
Azienda Ospedaliera Città della Salute e della Scienza di Torino
Turin, Piedmont, 10126, Italy
Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico
Milan, 20122, Italy
ASST Grande Ospedale Metropolitano Niguarda
Milan, 20162, Italy
ASST di Pavia - Fondazione IRCCS Policlinico San Matteo di Pavia
Pavia, 27100, Italy
Azienda Ospedaliero Universitaria Santa Maria della Misericordia di Udine
Udine, 33100, Italy
Hospital Universitari Germans Trias i Pujol
Badalona, Barcelona, 08916, Spain
Hospital Universitario de Salamanca
Salamanca, Castille and León, 37007, Spain
Hospital Clinic de Barcelona
Barcelona, 08036, Spain
Hospital de La Santa Creu i Sant Pau
Barcelona, 08041, Spain
Hospital Universitario Infanta Leonor
Madrid, 28031, Spain
Royal Bournemouth Hospital
Bournemouth, Dorset, BH7 7DW, United Kingdom
Related Publications (6)
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: 29856685BACKGROUNDDimopoulos 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: 27956157BACKGROUNDGuijosa 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: 40674744DERIVEDBuske 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: 36815271DERIVEDBuske 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: 34606378DERIVEDTrotman 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: 34380643DERIVED
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Results Point of Contact
- Title
- Lori Styles
- Organization
- Pharmacyclics LLC, An AbbVie Company
Study Officials
- STUDY DIRECTOR
Bernhard Hauns, MD
Pharmacyclics LLC.
Publication Agreements
- PI is Sponsor Employee
- No
- Restriction Type
- OTHER
- Restrictive Agreement
- Yes
Study Design
- Study Type
- interventional
- Phase
- phase 3
- Allocation
- RANDOMIZED
- Masking
- DOUBLE
- Who Masked
- PARTICIPANT, INVESTIGATOR
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- INDUSTRY
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
June 9, 2014
First Posted
June 17, 2014
Study Start
July 7, 2014
Primary Completion
November 7, 2019
Study Completion
November 7, 2019
Last Updated
March 3, 2021
Results First Posted
November 16, 2020
Record last verified: 2020-12
Data Sharing
- IPD Sharing
- Will share
Requests for access to individual participant data from clinical studies conducted by Pharmacyclics LLC, an AbbVie Company, can be submitted through Yale Open Data Access (YODA) Project site at the following link.