Ibrutinib With Rituximab in Adults With Waldenström's Macroglobulinemia

• ClinicalTrials.gov Identifier: NCT02165397
• Recruitment Status: Completed
• First Posted: June 17, 2014
• Results First Posted: November 16, 2020
• Last Update Posted: March 3, 2021
• Sponsor: Pharmacyclics LLC.
• Collaborator: Janssen Research & Development, LLC
• Information provided by (Responsible Party): Pharmacyclics LLC.

Tracking Information

• First Submitted Date: June 9, 2014
• First Posted Date: June 17, 2014
• Results First Submitted Date: October 20, 2020
• Results First Posted Date: November 16, 2020
• Last Update Posted Date: March 3, 2021
• Actual Study Start Date: July 7, 2014
• Actual Primary Completion Date: November 7, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 20, 2020)

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.

• Original Primary Outcome Measures (submitted: June 13, 2014): Progression Free Survival [ Time Frame: Up to 3 years after last subject is randomized ]

Current Secondary Outcome Measures (submitted: December 7, 2020)

• 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.
• 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.
• 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.
• 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.
• 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.

Original Secondary Outcome Measures (submitted: June 13, 2014)

• Overall Response Rate (ORR) [ Time Frame: At disease progression, up to 3 years after last subject is randomized ]
• Hematological improvement measured by hemoglobin [ Time Frame: At disease progression, up to 3 years after last subject is randomized ]
• Time to next Treatment (TTnT) [ Time Frame: End-of-treatment visit, up to 3 years after last subject is randomized ]
• Overall Survival [ Time Frame: At disease progression, up to 3 years after last subject is randomized ]
• Number of participants with adverse events as a measure of safety and tolerability within each treatment arm [ Time Frame: Up to 30 days following the last dose of study drug ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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 Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Waldenström's Macroglobulinemia

Intervention

• Drug: Ibrutinib
  Participants will receive 420 mg of Ibrutinib orally.
  Other Name: PCI-32765
• Drug: Placebo
  Participants will receive placebo capsules orally.
• Drug: Rituximab
  Participants will receive rituximab 375 mg/m^2 IV.
  Other Name: Rituxan

Study Arms

• 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.
  Interventions:

  • Drug: Ibrutinib
  • Drug: Rituximab
• 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.
  Interventions:

  • Drug: Placebo
  • Drug: Rituximab
• Experimental: Open-Label Substudy (Ibrutinib)
  Ibrutinib: 420 mg (3 capsules) orally administered daily beginning from Day 1.
  Intervention: Drug: Ibrutinib

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.
• 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.
• 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.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: January 25, 2016): 181
• Original Estimated Enrollment (submitted: June 13, 2014): 180
• Actual Study Completion Date: November 7, 2019
• Actual Primary Completion Date: November 7, 2019 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Canada, France, Germany, Greece, Italy, Spain, United Kingdom, United States

Administrative Information

• NCT Number: NCT02165397
• Other Study ID Numbers: PCYC-1127-CA
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• 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.
• URL: http://yoda.yale.edu

• Current Responsible Party: Pharmacyclics LLC.
• Original Responsible Party: Same as current
• Current Study Sponsor: Pharmacyclics LLC.
• Original Study Sponsor: Same as current
• Collaborators: Janssen Research & Development, LLC

Investigators

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

• PRS Account: Pharmacyclics LLC.
• Verification Date: December 2020