Ibrutinib With Rituximab in Adults With Waldenström's Macroglobulinemia

February 9, 2021 updated by: Pharmacyclics LLC.

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).

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

181

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Australia
    • Australian Capital Territory
      • Garran, Australian Capital Territory, Australia, 2605
        • The Canberra Hospital
    • New South Wales
      • Concord, New South Wales, Australia, 2139
        • Concord Repartriation General Hospital
    • South Australia
      • Bedford Park, South Australia, Australia, 05042
        • Flinders Medical Center
    • Victoria
      • Melbourne, Victoria, Australia, 3000
        • Peter MacCallum Cancer Center
  • Canada
    • Alberta
      • Edmonton, Alberta, Canada, T6G1Z2
        • Cross Cancer Institute
    • Nova Scotia
      • Halifax, Nova Scotia, Canada, B3H 2Y9
        • Queen Elizabeth II Health Sciences Center
    • Ontario
      • Toronto, Ontario, Canada, M5G 2M9
        • Princess Margaret Hospital
    • Quebec
      • Montreal, Quebec, Canada, H4A3J1
        • McGill University Health Center
  • France
      • Créteil, France, 94010
        • Hopital Henri Mondor
      • Paris, France, 75010
        • Hôpital Saint louis
      • Paris, France, 75651 Cedex 13
        • Groupe Hospitalier Pitie Salpetriere
    • Bouches-du-Rhône
      • Marseille, Bouches-du-Rhône, France, 13273
        • Institut Paoli-Calmettes
    • Finistère
      • Saint-Brieuc, Finistère, France, 22027
        • Centre Hospitalier de Saint Brieuc Hopital Yves le Foll
    • Loire-Atlantique
      • Nantes, Loire-Atlantique, France, 44093
        • Hotel Dieu
    • Meurthe-et-Moselle
      • Vandoeuvre-lès-nancy, Meurthe-et-Moselle, France, 54511
        • CHU de Nancy-Hopital Brabois Adulte
    • Nord
      • Lille, Nord, France, 59037
        • Hôpital Claude Huriez
    • Puy-de-Dôme
      • Clermont-Ferrand, Puy-de-Dôme, France, 63000
        • Chu Estaing
    • Rhône
      • Pierre-benite, Rhône, France, 69495
        • Centre Hospitalier Lyon Sud
  • Germany
      • Bremen, Germany, 28239
        • DIAKO Evangelische Diakonie Krankenhaus gGmbH
      • München, Germany, 81377
        • LMU Klinikum der Universitat Munchen
    • Baden-Württemberg
      • Mutlangen, Baden-Württemberg, Germany, 73557
        • Stauferklinikum Schwäbisch Gmünd
    • Rheinland-Pfalz
      • Mainz, Rheinland-Pfalz, Germany, 55131
        • Universitätsmedizin der Johannes Gutenberg-Universität Mainz
    • Saarland
      • Homburg, Saarland, Germany, 66421
        • Universität des Saarlandes
  • Greece
      • Athens, Greece, 11527
        • Laiko General Hospital of Athens
    • Achaia
      • Patras, Achaia, Greece, 26500
        • University General Hospital of Patras
    • Attiki
      • Athens, Attiki, Greece, 11528
        • Alexandra Hospital
    • Macedonia
      • Thessaloniki, Macedonia, Greece, 54621
        • University General Hospital of Thessaloniki "Ahepa"
  • Italy
      • Milano, Italy, 20122
        • Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico
      • Milano, Italy, 20162
        • Asst Grande Ospedale Metropolitano Niguarda
      • Pavia, Italy, 27100
        • ASST di Pavia - Fondazione IRCCS Policlinico San Matteo di Pavia
      • Udine, Italy, 33100
        • Azienda Ospedaliero Universitaria Santa Maria della Misericordia di Udine
    • Piemonte
      • Torino, Piemonte, Italy, 10126
        • Azienda Ospedaliera Citta della Salute e della Scienza di Torino
  • Spain
      • Barcelona, Spain, 08036
        • Hospital Clinic De Barcelona
      • Barcelona, Spain, 08041
        • Hospital De La Santa Creu I Sant Pau
      • Madrid, Spain, 28031
        • Hospital Universitario Infanta Leonor
    • Barcelona
      • Badalona, Barcelona, Spain, 08916
        • Hospital Universitari Germans Trias i Pujol
    • Castilla Y León
      • Salamanca, Castilla Y León, Spain, 37007
        • Hospital Universitario de Salamanca
  • United Kingdom
    • Dorset
      • Bournemouth, Dorset, United Kingdom, BH7 7DW
        • Royal Bournemouth Hospital
  • United States
    • California
      • Los Angeles, California, United States, 90404
        • University of California Los Angeles
      • Palo Alto, California, United States, 94305
        • Stanford Cancer Center
    • Colorado
      • Denver, Colorado, United States, 80218
        • Colorado Blood Cancer Institute
    • Georgia
      • Atlanta, Georgia, United States, 30322
        • Emory University Hospital
    • Illinois
      • Chicago, Illinois, United States, 60611
        • Northwestern Memorial Hospital
    • Massachusetts
      • Boston, Massachusetts, United States, 02215
        • Dana Farber Cancer Institute
    • New Jersey
      • Hackensack, New Jersey, United States, 07601
        • Hackensack University Medical Center
    • New York
      • New York, New York, United States, 10065
        • Memorial Sloan Kettering Cancer Center
      • New York, New York, United States, 10065
        • Weill Cornell Medical Center
    • Tennessee
      • Nashville, Tennessee, United States, 37204
        • Vanderbilt University Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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 Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
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.
Drug: Ibrutinib
Participants will receive 420 mg of Ibrutinib orally.
Other Names:
  • PCI-32765
Drug: Rituximab
Participants will receive rituximab 375 mg/m^2 IV.
Other Names:
  • Rituxan
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.
Drug: Rituximab
Participants will receive rituximab 375 mg/m^2 IV.
Other Names:
  • Rituxan
Drug: Placebo
Participants will receive placebo capsules orally.
Experimental: Open-Label Substudy (Ibrutinib)
Ibrutinib: 420 mg (3 capsules) orally administered daily beginning from Day 1.
Drug: Ibrutinib
Participants will receive 420 mg of Ibrutinib orally.
Other Names:
  • PCI-32765

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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])

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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
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)
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)
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])

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])
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)
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)
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
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
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])

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])

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Pharmacyclics LLC.

Collaborators

Janssen Research & Development, LLC

Investigators

  • Study Director: Bernhard Hauns, MD, Pharmacyclics LLC (An AbbVie Company)

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

July 7, 2014

Primary Completion (Actual)

November 7, 2019

Study Completion (Actual)

November 7, 2019

Study Registration Dates

First Submitted

June 9, 2014

First Submitted That Met QC Criteria

June 13, 2014

First Posted (Estimate)

June 17, 2014

Study Record Updates

Last Update Posted (Actual)

March 3, 2021

Last Update Submitted That Met QC Criteria

February 9, 2021

Last Verified

December 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • PCYC-1127-CA

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Yes

IPD Plan Description

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.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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