Clinical trial NCT02165397: Ibrutinib With Rituximab in Adults With Waldenström's Macroglobulinemia
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Waldenström's Macroglobulinemia
Keywords: Ibrutinib
Pharmacyclics
PCYC
Lymphoma
Btk inhibitor
WM
Rituximab
Rituxan
Waldenström's
Waldenstrom Macroglobulinemia
non-Hodgkin lymphoma
NHL
Lead sponsor: Pharmacyclics LLC.
Sponsor class: INDUSTRY
Collaborators: name: Janssen Research & Development, LLC
First posted: 2014-06-17
Enrollment: 181
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).


Eligibility criteria: 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.

Primary outcomes:
measure: Progression Free Survival (PFS) Based on Independent Review Committee (IRC) Assessment - Kaplan Meier Landmark Estimates at Month 54
timeFrame: Month 54 (median time on study: 49.7 months [Ibr+R and Pbo+R] and 57.9 months [Open-Label Ibr])
Secondary outcomes:
measure: Overall Response Rate (ORR) Based on IRC Assessment Up to 3 Years After Last Participant Randomized
timeFrame: Median time on study: 49.7 months (Ibr+R and Pbo+R) and 57.9 months (Open-Label Ibr)
measure: Time to Next Treatment (TnT) Time From the Date of Randomization to the Start Date of Any Subsequent WM Treatment.
timeFrame: Month 54 (median time on study: 49.7 months [Ibr+R and Pbo+R] and 57.9 months [Open-Label Ibr])
measure: Percentage of Participants With Sustained Hemoglobin (Hgb) Improvement Up to 3 Years After Last Participant Randomized
timeFrame: Median time on study: 49.7 months (Ibr+R and Pbo+R) and 57.9 months (Open-Label Ibr)
measure: 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
timeFrame: Baseline, 25 weeks
measure: Overall Survival (OS) - Kaplan Meier Landmark Estimates at Month 54
timeFrame: Month 54 (median time on study: 49.7 months [Ibr+R and Pbo+R] and 57.9 months [Open-Label Ibr])
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of California Los Angeles
state: California
city: Palo Alto
country: United States
facility: Stanford Cancer Center
state: California
city: Denver
country: United States
facility: Colorado Blood Cancer Institute
state: Colorado
city: Atlanta
country: United States
facility: Emory University Hospital
state: Georgia
city: Chicago
country: United States
facility: Northwestern Memorial Hospital
state: Illinois
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: New York
country: United States
facility: Weill Cornell Medical Center
state: New York
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Garran
country: Australia
facility: The Canberra Hospital
state: Australian Capital Territory
city: Concord
country: Australia
facility: Concord Repartriation General Hospital
state: New South Wales
city: Bedford Park
country: Australia
facility: Flinders Medical Center
state: South Australia
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Center
state: Victoria
city: Edmonton
country: Canada
facility: Cross Cancer Institute
state: Alberta
city: Halifax
country: Canada
facility: Queen Elizabeth II Health Sciences Center
state: Nova Scotia
city: Toronto
country: Canada
facility: Princess Margaret Hospital
state: Ontario
city: Montreal
country: Canada
facility: McGill University Health Center
state: Quebec
city: Marseille
country: France
facility: Institut Paoli-Calmettes
state: Bouches-du-Rhône
city: Saint-Brieuc
country: France
facility: Centre Hospitalier de Saint Brieuc Hopital Yves le Foll
state: Finistère
city: Nantes
country: France
facility: Hôtel Dieu
state: Loire-Atlantique
city: Vandoeuvre-lès-nancy
country: France
facility: CHU de Nancy-Hopital Brabois Adulte
state: Meurthe-et-Moselle
city: Lille
country: France
facility: Hôpital Claude Huriez
state: Nord
city: Clermont-Ferrand
country: France
facility: CHU Estaing
state: Puy-de-Dôme
city: Pierre-benite
country: France
facility: Centre Hospitalier Lyon Sud
state: Rhône
city: Créteil
country: France
facility: Hopital Henri Mondor
city: Paris
country: France
facility: Hôpital Saint Louis
city: Paris
country: France
facility: Groupe Hospitalier Pitié Salpétrière
city: Mutlangen
country: Germany
facility: Stauferklinikum Schwäbisch Gmünd
state: Baden-Württemberg
city: Mainz
country: Germany
facility: Universitätsmedizin der Johannes Gutenberg-Universität Mainz
state: Rheinland-Pfalz
city: Homburg
country: Germany
facility: Universität Des Saarlandes
state: Saarland
city: Bremen
country: Germany
facility: DIAKO Evangelische Diakonie Krankenhaus gGmbH
city: München
country: Germany
facility: LMU Klinikum der Universität München
city: Patras
country: Greece
facility: University General Hospital of Patras
state: Achaia
city: Athens
country: Greece
facility: Alexandra Hospital
state: Attiki
city: Thessaloniki
country: Greece
facility: University General Hospital of Thessaloniki "AHEPA"
state: Macedonia
city: Athens
country: Greece
facility: Laiko General Hospital of Athens
city: Torino
country: Italy
facility: Azienda Ospedaliera Città della Salute e della Scienza di Torino
state: Piemonte
city: Milano
country: Italy
facility: Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico
city: Milano
country: Italy
facility: ASST Grande Ospedale Metropolitano Niguarda
city: Pavia
country: Italy
facility: ASST di Pavia - Fondazione IRCCS Policlinico San Matteo di Pavia
city: Udine
country: Italy
facility: Azienda Ospedaliero Universitaria Santa Maria della Misericordia di Udine
city: Badalona
country: Spain
facility: Hospital Universitari Germans Trias i Pujol
state: Barcelona
city: Salamanca
country: Spain
facility: Hospital Universitario de Salamanca
state: Castilla Y León
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Barcelona
country: Spain
facility: Hospital de La Santa Creu i Sant Pau
city: Madrid
country: Spain
facility: Hospital Universitario Infanta Leonor
city: Bournemouth
country: United Kingdom
facility: Royal Bournemouth Hospital
state: Dorset
Study officials:
affiliation: Pharmacyclics LLC.
name: Bernhard Hauns, MD
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.