AzTrials
AzTrials

Waldenström's MacroglobulinemiaPhase 3NCT02165397

Ibrutinib With Rituximab in Adults With Waldenström's Macroglobulinemia

A Phase 3 study testing Ibrutinib and Rituximab in people with Waldenström's Macroglobulinemia, run by Pharmacyclics LLC. at 48 sites in 9 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

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). Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Waldenström's Macroglobulinemia
What is being tested?
Ibrutinib and Rituximab
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
181 participants
Where
48 sitesin 9 countries
Study dates
7 Jul 2014to 7 Nov 2019
Phase
Phase 3
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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

Who cannot join

  • 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
Show all 17Show fewer
  • 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.

Trial locations and contacts

48 sites in 9 countries.

48 sites in 9 countries

United States10 sites

  • Emory University Hospital

    Atlanta, Georgia, 30322

  • Dana Farber Cancer Institute

    Boston, Massachusetts, 02215

  • Northwestern Memorial Hospital

    Chicago, Illinois, 60611

  • Colorado Blood Cancer Institute

    Denver, Colorado, 80218

  • Hackensack University Medical Center

    Hackensack, New Jersey, 07601

  • University of California Los Angeles

    Los Angeles, California, 90404

  • Vanderbilt University Medical Center

    Nashville, Tennessee, 37204

  • Memorial Sloan Kettering Cancer Center

    New York, New York, 10065

  • Weill Cornell Medical Center

    New York, New York, 10065

  • Stanford Cancer Center

    Palo Alto, California, 94305

Other trials in United States

France10 sites

  • CHU Estaing

    Clermont-Ferrand, Puy-de-Dôme, 63000

  • Hopital Henri Mondor

    Créteil, 94010

  • Hôpital Claude Huriez

    Lille, Nord, 59037

  • Institut Paoli-Calmettes

    Marseille, Bouches-du-Rhône, 13273

  • Hôtel Dieu

    Nantes, Loire-Atlantique, 44093

  • Hôpital Saint Louis

    Paris, 75010

  • Groupe Hospitalier Pitié Salpétrière

    Paris, 75651 Cedex 13

  • Centre Hospitalier Lyon Sud

    Pierre-Bénite, Rhône, 69495

  • Centre Hospitalier de Saint Brieuc Hopital Yves le Foll

    Saint-Brieuc, Finistère, 22027

  • CHU de Nancy-Hopital Brabois Adulte

    Vandœuvre-lès-Nancy, Meurthe-et-Moselle, 54511

Other trials in France

Germany5 sites

  • DIAKO Evangelische Diakonie Krankenhaus gGmbH

    Bremen, 28239

  • Universität Des Saarlandes

    Homburg, Saarland, 66421

  • Universitätsmedizin der Johannes Gutenberg-Universität Mainz

    Mainz, Rhineland-Palatinate, 55131

  • LMU Klinikum der Universität München

    München, 81377

  • Stauferklinikum Schwäbisch Gmünd

    Mutlangen, Baden-Wurttemberg, 73557

Other trials in Germany

Italy5 sites

  • Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico

    Milan, 20122

  • ASST Grande Ospedale Metropolitano Niguarda

    Milan, 20162

  • ASST di Pavia - Fondazione IRCCS Policlinico San Matteo di Pavia

    Pavia, 27100

  • Azienda Ospedaliera Città della Salute e della Scienza di Torino

    Turin, Piedmont, 10126

  • Azienda Ospedaliero Universitaria Santa Maria della Misericordia di Udine

    Udine, 33100

Other trials in Italy

Spain5 sites

  • Hospital Universitari Germans Trias i Pujol

    Badalona, Barcelona, 08916

  • Hospital Clinic de Barcelona

    Barcelona, 08036

  • Hospital de La Santa Creu i Sant Pau

    Barcelona, 08041

  • Hospital Universitario Infanta Leonor

    Madrid, 28031

  • Hospital Universitario de Salamanca

    Salamanca, Castille and León, 37007

Other trials in Spain

Australia4 sites

  • Flinders Medical Center

    Bedford Park, South Australia, 05042

  • Concord Repartriation General Hospital

    Concord, New South Wales, 2139

  • The Canberra Hospital

    Garran, Australian Capital Territory, 2605

  • Peter MacCallum Cancer Center

    Melbourne, Victoria, 3000

Other trials in Australia

Canada4 sites

  • Cross Cancer Institute

    Edmonton, Alberta, T6G1Z2

  • Queen Elizabeth II Health Sciences Center

    Halifax, Nova Scotia, B3H 2Y9

  • McGill University Health Center

    Montreal, Quebec, H4A3J1

  • Princess Margaret Hospital

    Toronto, Ontario, M5G 2M9

Other trials in Canada

Greece4 sites

  • Alexandra Hospital

    Athens, Attica, 11528

  • Laiko General Hospital of Athens

    Athens, 11527

  • University General Hospital of Patras

    Pátrai, Achaia, 26500

  • University General Hospital of Thessaloniki "AHEPA"

    Thessaloniki, Macedonia, 54621

Other trials in Greece

United Kingdom1 site

  • Royal Bournemouth Hospital

    Bournemouth, Dorset, BH7 7DW

Other trials in United Kingdom

About this study

Official 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

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).

Being tested
Ibrutinib, Placebo, Rituximab
Keywords
Ibrutinib, Pharmacyclics, PCYC, Lymphoma, Btk inhibitor, WM, Rituximab, Rituxan, Waldenström's, Waldenstrom Macroglobulinemia, non-Hodgkin lymphoma, NHL
Medical subject headings
Waldenstrom Macroglobulinemia, Lymphoma, Lymphoma, Non-Hodgkin

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • IbrutinibDrug

    Also called PCI-32765

    Participants will receive 420 mg of Ibrutinib orally.

  • PlaceboDrug

    Participants will receive placebo capsules orally.

  • RituximabDrug

    Also called Rituxan

    Participants will receive rituximab 375 mg/m^2 IV.

Study groups in NCT02165397
Study groupRoleWhat they receive
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.
Receives: Drug: Ibrutinib; Drug: Rituximab
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.
Receives: Drug: Placebo; Drug: Rituximab
Open-Label Substudy (Ibrutinib)ExperimentalIbrutinib: 420 mg (3 capsules) orally administered daily beginning from Day 1.
Receives: Drug: Ibrutinib

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: Month 54 (median time on study: 49.7 months [Ibr+R and Pbo+R] and 57.9 months [Open-Label Ibr])

Secondary outcomes (5)

  1. 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.

    Measured: Median time on study: 49.7 months (Ibr+R and Pbo+R) and 57.9 months (Open-Label Ibr)

  2. 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.

    Measured: Month 54 (median time on study: 49.7 months [Ibr+R and Pbo+R] and 57.9 months [Open-Label Ibr])

  3. 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.

    Measured: Median time on study: 49.7 months (Ibr+R and Pbo+R) and 57.9 months (Open-Label Ibr)

  4. 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.

    Measured: Baseline, 25 weeks

  5. 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.

    Measured: Month 54 (median time on study: 49.7 months [Ibr+R and Pbo+R] and 57.9 months [Open-Label Ibr])

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted17 Jun 2014 (estimated)
  2. Study start7 Jul 2014
  3. Primary completion7 Nov 2019
  4. Study completion7 Nov 2019

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Double blind
Who is masked
Participant, Investigator
Enrolment
181 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02165397
Sponsor's protocol ID
PCYC-1127-CA
Status last verified
Dec 2020
First submitted
9 Jun 2014
Last updated
3 Mar 2021
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Yes: 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.

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.

    PubMed 29856685

  • 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.

    PubMed 27956157

  • 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.

    PubMed 40674744

  • 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.

    PubMed 36815271

  • 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.

    PubMed 34606378

  • 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.

    PubMed 34380643

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Ibrutinib and Rituximab in people with Waldenström's Macroglobulinemia, run by Pharmacyclics LLC. at 48 sites in 9 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 7 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 3 Mar 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 48 sites in United States, France, Germany, Italy, Spain and 4 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 16 Nov 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome 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])). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02165397, which also lists 6 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Mar 2021.

AzTrials uses cookies for analytics and advertising. You can accept or reject them; the site works either way. Privacy Policy.

Free account

Log in to keep searching

You’ve used your 3 free searches. AzTrials is free: log in or create a free account to keep searching clinical trials and save the ones you want to follow.

Create a free accountLog in