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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT02165397




Registration number
NCT02165397
Ethics application status
Date submitted
9/06/2014
Date registered
17/06/2014
Date last updated
5/05/2020

Titles & IDs
Public title
Ibrutinib With Rituximab in Adults With Waldenström's Macroglobulinemia
Scientific 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
Secondary ID [1] 0 0
PCYC-1127-CA
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Waldenström's Macroglobulinemia 0 0
Condition category
Condition code
Cancer 0 0 0 0
Lymphoma (non Hodgkin's lymphoma) - High grade lymphoma
Cancer 0 0 0 0
Lymphoma (non Hodgkin's lymphoma) - Low grade lymphoma
Cancer 0 0 0 0
Children's - Leukaemia & Lymphoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Ibrutinib
Treatment: Drugs - Placebo
Treatment: Drugs - Rituximab

Experimental: Treatment Arm A (Ibrutinib + Rituximab) - Ibrutinib: 420 mg (3 capsules x 140 mg) orally administered daily beginning from Day 1 Rituximab: 375 mg/m2 IV per package insert weekly for four consecutive weeks, followed by a second four-weekly rituximab course after a three-month interval.

Experimental: Treatment Arm B (Placebo + Rituximab) - Placebo: 3 capsules of placebo orally administered daily beginning from Day 1 Rituximab: 375 mg/m2 IV per package insert weekly for four consecutive weeks, followed by a second four-weekly rituximab course after a three-month interval.

Experimental: Treatment Arm C (Ibrutinib) - Ibrutinib: 420 mg (3 capsules) orally administered daily beginning from Day 1


Treatment: Drugs: Ibrutinib
Subjects will receive 420 mg of Ibrutinib orally. Other Name: PCI-32765

Treatment: Drugs: Placebo
Subjects will receive placebo capsules orally.

Treatment: Drugs: Rituximab
Drug: rituximab Subjects will receive rituximab 375mg/m2 intravenously Other Name: Rituxan

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Progression Free Survival
Timepoint [1] 0 0
Up to 3 years after last subject is randomized
Secondary outcome [1] 0 0
Overall Response Rate (ORR)
Timepoint [1] 0 0
At disease progression, up to 3 years after last subject is randomized
Secondary outcome [2] 0 0
Hematological improvement measured by hemoglobin
Timepoint [2] 0 0
At disease progression, up to 3 years after last subject is randomized
Secondary outcome [3] 0 0
Time to next Treatment (TTnT)
Timepoint [3] 0 0
End-of-treatment visit, up to 3 years after last subject is randomized
Secondary outcome [4] 0 0
Overall Survival
Timepoint [4] 0 0
At disease progression, up to 3 years after last subject is randomized
Secondary outcome [5] 0 0
Number of participants with adverse events as a measure of safety and tolerability within each treatment arm
Timepoint [5] 0 0
Up to 30 days following the last dose of study drug
Secondary outcome [6] 0 0
Proportion of subjects with = 3 points increase from baseline by Week 25 in the FACIT-Fatigue subscale score - Proportion of subjects with = 3 points increase from baseline by Week 25 in the FACIT-Fatigue subscale score
Timepoint [6] 0 0
25 Weeks

Eligibility
Key inclusion criteria
Eligibility Criteria for the Randomized Study (Arm A and Arm B)



- Untreated or previously treated for Waldenström's macroglobulinemia. 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 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.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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 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 IgE-mediated hypersensitivity to murine proteins or to any
component of rituximab.

- Prior exposure to ibrutinib or other 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
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,SA,VIC
Recruitment hospital [1] 0 0
The Canberra Hospital - Garran
Recruitment hospital [2] 0 0
Concord Repartriation General Hospital - Concord
Recruitment hospital [3] 0 0
Flinders Medical Center - Bedford Park
Recruitment hospital [4] 0 0
Peter MacCallum Cancer Center - Melbourne
Recruitment postcode(s) [1] 0 0
2605 - Garran
Recruitment postcode(s) [2] 0 0
2139 - Concord
Recruitment postcode(s) [3] 0 0
05042 - Bedford Park
Recruitment postcode(s) [4] 0 0
3000 - Melbourne
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Colorado
Country [3] 0 0
United States of America
State/province [3] 0 0
Georgia
Country [4] 0 0
United States of America
State/province [4] 0 0
Illinois
Country [5] 0 0
United States of America
State/province [5] 0 0
Massachusetts
Country [6] 0 0
United States of America
State/province [6] 0 0
New Jersey
Country [7] 0 0
United States of America
State/province [7] 0 0
New York
Country [8] 0 0
United States of America
State/province [8] 0 0
Tennessee
Country [9] 0 0
Canada
State/province [9] 0 0
Alberta
Country [10] 0 0
Canada
State/province [10] 0 0
Nova Scotia
Country [11] 0 0
Canada
State/province [11] 0 0
Ontario
Country [12] 0 0
Canada
State/province [12] 0 0
Quebec
Country [13] 0 0
France
State/province [13] 0 0
Bouches-du-Rhône
Country [14] 0 0
France
State/province [14] 0 0
Finistère
Country [15] 0 0
France
State/province [15] 0 0
Loire-Atlantique
Country [16] 0 0
France
State/province [16] 0 0
Meurthe-et-Moselle
Country [17] 0 0
France
State/province [17] 0 0
Nord
Country [18] 0 0
France
State/province [18] 0 0
Puy-de-Dôme
Country [19] 0 0
France
State/province [19] 0 0
Rhône
Country [20] 0 0
France
State/province [20] 0 0
Créteil
Country [21] 0 0
France
State/province [21] 0 0
Paris
Country [22] 0 0
Germany
State/province [22] 0 0
Baden-Württemberg
Country [23] 0 0
Germany
State/province [23] 0 0
Rheinland-Pfalz
Country [24] 0 0
Germany
State/province [24] 0 0
Saarland
Country [25] 0 0
Germany
State/province [25] 0 0
Bremen
Country [26] 0 0
Germany
State/province [26] 0 0
München
Country [27] 0 0
Greece
State/province [27] 0 0
Achaia
Country [28] 0 0
Greece
State/province [28] 0 0
Attiki
Country [29] 0 0
Greece
State/province [29] 0 0
Macedonia
Country [30] 0 0
Greece
State/province [30] 0 0
Athens
Country [31] 0 0
Italy
State/province [31] 0 0
Piemonte
Country [32] 0 0
Italy
State/province [32] 0 0
Milano
Country [33] 0 0
Italy
State/province [33] 0 0
Pavia
Country [34] 0 0
Italy
State/province [34] 0 0
Udine
Country [35] 0 0
Spain
State/province [35] 0 0
Barcelona
Country [36] 0 0
Spain
State/province [36] 0 0
Castilla Y León
Country [37] 0 0
Spain
State/province [37] 0 0
Madrid
Country [38] 0 0
United Kingdom
State/province [38] 0 0
Dorset

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Pharmacyclics LLC.
Address
Country
Other collaborator category [1] 0 0
Commercial sector/Industry
Name [1] 0 0
Janssen Research & Development, LLC
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
The purpose of this study is to evaluate the safety and efficacy of Ibrutinib in combination
with Rituximab in subjects with Waldenström's Macroglobulinemia.
Trial website
https://clinicaltrials.gov/show/NCT02165397
Trial related presentations / publications
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.
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.
Public notes

Contacts
Principal investigator
Name 0 0
Bernhard Hauns, MD
Address 0 0
Pharmacyclics LLC (An AbbVie Company)
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications