Ibrutinib With Rituximab in Adults With Waldenström's Macroglobulinemia
- Conditions
- Waldenström's Macroglobulinemia
- Interventions
- Registration Number
- NCT02165397
- Lead Sponsor
- Pharmacyclics LLC.
- 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).
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 181
- 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
-
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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Randomized Study (Placebo + Rituximab) Placebo 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. Randomized Study (Placebo + Rituximab) 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. Randomized Study (Ibrutinib + Rituximab) Ibrutinib 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. Randomized Study (Ibrutinib + Rituximab) 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. Open-Label Substudy (Ibrutinib) Ibrutinib Ibrutinib: 420 mg (3 capsules) orally administered daily beginning from Day 1.
- Primary Outcome Measures
Name Time Method Progression Free Survival (PFS) Based on Independent Review Committee (IRC) Assessment - 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]) 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.
- Secondary Outcome Measures
Name Time Method 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]) 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.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 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.
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) 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.
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 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.
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]) 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.
Trial Locations
- Locations (48)
University of California Los Angeles
🇺🇸Los Angeles, California, United States
Princess Margaret Hospital
🇨🇦Toronto, Ontario, Canada
Stanford Cancer Center
🇺🇸Palo Alto, California, United States
Colorado Blood Cancer Institute
🇺🇸Denver, Colorado, United States
Emory University Hospital
🇺🇸Atlanta, Georgia, United States
Memorial Sloan Kettering Cancer Center
🇺🇸New York, New York, United States
Weill Cornell Medical Center
🇺🇸New York, New York, United States
Concord Repartriation General Hospital
🇦🇺Concord, New South Wales, Australia
Vanderbilt University Medical Center
🇺🇸Nashville, Tennessee, United States
Flinders Medical Center
🇦🇺Bedford Park, South Australia, Australia
CHU de Nancy-Hopital Brabois Adulte
🇫🇷Vandoeuvre-lès-nancy, Meurthe-et-Moselle, France
CHU Estaing
🇫🇷Clermont-Ferrand, Puy-de-Dôme, France
Hôtel Dieu
🇫🇷Nantes, Loire-Atlantique, France
Hôpital Claude Huriez
🇫🇷Lille, Nord, France
Hopital Henri Mondor
🇫🇷Créteil, France
Hôpital Saint Louis
🇫🇷Paris, France
Groupe Hospitalier Pitié Salpétrière
🇫🇷Paris, France
Stauferklinikum Schwäbisch Gmünd
🇩🇪Mutlangen, Baden-Württemberg, Germany
Universitätsmedizin der Johannes Gutenberg-Universität Mainz
🇩🇪Mainz, Rheinland-Pfalz, Germany
DIAKO Evangelische Diakonie Krankenhaus gGmbH
🇩🇪Bremen, Germany
LMU Klinikum der Universität München
🇩🇪München, Germany
Alexandra Hospital
🇬🇷Athens, Attiki, Greece
University General Hospital of Thessaloniki "AHEPA"
🇬🇷Thessaloniki, Macedonia, Greece
Laiko General Hospital of Athens
🇬🇷Athens, Greece
Azienda Ospedaliera Città della Salute e della Scienza di Torino
🇮🇹Torino, Piemonte, Italy
Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico
🇮🇹Milano, Italy
ASST Grande Ospedale Metropolitano Niguarda
🇮🇹Milano, Italy
Hospital Universitari Germans Trias i Pujol
🇪🇸Badalona, Barcelona, Spain
Hospital Universitario de Salamanca
🇪🇸Salamanca, Castilla Y León, Spain
Hospital Clinic de Barcelona
🇪🇸Barcelona, Spain
Hospital de La Santa Creu i Sant Pau
🇪🇸Barcelona, Spain
Hospital Universitario Infanta Leonor
🇪🇸Madrid, Spain
Universität Des Saarlandes
🇩🇪Homburg, Saarland, Germany
Institut Paoli-Calmettes
🇫🇷Marseille, Bouches-du-Rhône, France
ASST di Pavia - Fondazione IRCCS Policlinico San Matteo di Pavia
🇮🇹Pavia, Italy
Azienda Ospedaliero Universitaria Santa Maria della Misericordia di Udine
🇮🇹Udine, Italy
Hackensack University Medical Center
🇺🇸Hackensack, New Jersey, United States
Northwestern Memorial Hospital
🇺🇸Chicago, Illinois, United States
Centre Hospitalier Lyon Sud
🇫🇷Pierre-benite, Rhône, France
Dana Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States
McGill University Health Center
🇨🇦Montreal, Quebec, Canada
Centre Hospitalier de Saint Brieuc Hopital Yves le Foll
🇫🇷Saint-Brieuc, Finistère, France
The Canberra Hospital
🇦🇺Garran, Australian Capital Territory, Australia
Cross Cancer Institute
🇨🇦Edmonton, Alberta, Canada
Peter MacCallum Cancer Center
🇦🇺Melbourne, Victoria, Australia
University General Hospital of Patras
🇬🇷Patras, Achaia, Greece
Queen Elizabeth II Health Sciences Center
🇨🇦Halifax, Nova Scotia, Canada
Royal Bournemouth Hospital
🇬🇧Bournemouth, Dorset, United Kingdom