Ibrutinib With Rituximab in Adults With Waldenström's Macroglobulinemia

Waldenström's Macroglobulinemia Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02165397
• Other study ID #: PCYC-1127-CA
• Status: Completed
• Phase: Phase 3
• 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
• 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.

Related Conditions & MeSH terms

• Waldenstrom Macroglobulinemia
• Waldenström's Macroglobulinemia

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])