- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03226301
A Prospective, Multicenter, Phase-II Trial of Ibrutinib Plus Venetoclax in Patients With Creatinine Clearance >= 30 ml/Min Who Have Relapsed or Refractory Chronic Lymphocytic Leukemia (RR-CLL) With or Without TP53 Aberrations
Study Overview
Status
Study Type
Enrollment (Anticipated)
Phase
- Phase 2
Contacts and Locations
Study Locations
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Antwerpen, Belgium
- BE-Antwerpen-ZNASTUIVENBERG
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Brugge, Belgium
- BE-Brugge-AZBRUGGE
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Brussels, Belgium
- BE-Bruxelles-STLUC
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Haine-Saint-Paul, Belgium
- BE-Haine-Saint-Paul-JOLIMONT
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Leuven, Belgium
- BE-Leuven-UZLEUVEN
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Aalborg, Denmark
- DK-Aalborg-AALBORGUH
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Copenhagen, Denmark
- DK-Copenhagen-RIGSHOSPITALET
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Herlev, Denmark
- DK-Herlev-HERLEV
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Holstebro, Denmark
- DK-Holstebro-HOLSTEBRO
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Odense, Denmark
- DK-Odense-OUH
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Roskilde, Denmark
- DK-Roskilde-ROSKILDE
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Helsinki, Finland
- FI-Helsinki-HUS
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Jyväskylä, Finland
- FI-Jyvaskyla-KSSHP
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Kuopio, Finland
- FI-Kuopio-KYS
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Tampere, Finland
- FI-Tampere-TAYS
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Turku, Finland
- FI-Turku-TYKS
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Alkmaar, Netherlands
- NL-Alkmaar-NWZ
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Amersfoort, Netherlands
- NL-Amersfoort-MEANDERMC
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Amsterdam, Netherlands
- NL-Amsterdam-AMC
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Amsterdam, Netherlands
- NL-Amsterdam-VUMC
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Amsterdam, Netherlands
- NL-Amsterdam-AVL
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Arnhem, Netherlands
- NL-Arnhem-RIJNSTATE
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Breda, Netherlands
- NL-Breda-AMPHIA
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Delft, Netherlands
- NL-Delft-RDGG
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Den Haag, Netherlands
- NL-Den Haag-HAGA
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Dordrecht, Netherlands
- NL-Dordrecht-ASZ
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Enschede, Netherlands
- NL-Enschede-MST
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Gouda, Netherlands
- NL-Gouda-GROENEHART
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Groningen, Netherlands
- NL-Groningen-UMCG
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Heerlen, Netherlands
- NL-Heerlen-ATRIUMMC
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Helmond, Netherlands
- NL-Helmond-ELKERLIEK
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Nieuwegein, Netherlands
- NL-Nieuwegein-ANTONIUS
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Nijmegen, Netherlands
- NL-Nijmegen-CWZ
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Rotterdam, Netherlands
- NL-Rotterdam-ERASMUSMC
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Rotterdam, Netherlands
- NL-Rotterdam-MAASSTADZIEKENHUIS
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Sittard, Netherlands
- NL-Sittard-Geleen-ZUYDERLAND
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Sneek, Netherlands
- NL-Sneek-ANTONIUSSNEEK
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Tilburg, Netherlands
- NL-Tilburg-ETZ
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Uden, Netherlands
- NL-Uden-BERNHOVEN
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Utrecht, Netherlands
- NL-Utrecht-UMCUTRECHT
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Zaandam, Netherlands
- NL-Zaandam-ZAANSMC
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Zwolle, Netherlands
- NL-Zwolle-ISALA
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Lørenskog, Norway
- NO-Lørenskog-AKERSHUS
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Trondheim, Norway
- NO-Trondheim-STOLAV
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Borås, Sweden
- SE-Boras-SASBORAS
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Linköping, Sweden
- SE-Linköping-REGIONOSTERGOTLAND
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Luleå, Sweden
- SE-Luleå-SUNDERBY
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Lund, Sweden
- SE-Lund-SUH
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Uppsala, Sweden
- SE-Uppsala-UPPSALAUH
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
Documented CLL or SLL requiring treatment according to IWCLL criteria after either being refractory to first line therapy or relapse after initial therapy.
- Age at least 18 years.
Adequate bone marrow function defined as:
- Absolute neutrophil count (ANC) >0.75 x 109/L
- Platelet count >30,000 /μL 30 x 109/L.
- Hemoglobin >8.0 g/dL (5 mmol/L) Unless directly attributable to CLL infiltration of the bone marrow, proven by bone marrow biopsy
- Creatinine clearance (CrCL) ≥ 30ml/min calculated according to the modified formula of Cockcroft and Gault or directly measured with 24hr urine collection.
Adequate liver function as indicated
- Serum aspartate transaminase (AST) or alanine transaminase (ALT) ≤ 3.0 x upper limit of normal (ULN)
- Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of nonhepatic origin)
- Prothrombin time (PT)/International normal ratio (INR) <1.5 x ULN and PTT (activated partial thromboplastin time [aPTT]) <1.5 x ULN (unless abnormalities are related to coagulopathy or bleeding disorder).
- Negative serological testing for hepatitis B (HBsAg negative and anti-HBc negative; patients positive for anti-HBc may be included if PCR for HBV DNA is negative and HBV-DNA PCR is performed every month until 12 months after last dose), negative testing for hepatitis C RNA within 42 days prior to registration.
- WHO/ECOG performance status 0-3 (appendix C), stage 3 only if attributable to CLL.
- Negative pregnancy test at study entry (for women of childbearing potential).
- Male and female subjects of reproductive potential must agree to use both a highly effective method of birth control (e.g. implants, injectables, combined oral contraceptives, some intrauterine devices [IUDs], complete abstinence , or sterilized partner) and a barrier method (e.g., condoms, cervical ring, sponge, etc.) during the period of therapy and for 90 days after the last dose of study drug.
- Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements.
- Written informed consent.
Exclusion Criteria:
- Any prior therapy with ibrutinib and/or venetoclax.
- Transformation of CLL (Richter's transformation).
- Patients with a history of confirmed progressive multifocal leukoencephalopathy (PML).
- Malignancies other than CLL currently requiring systemic therapies or not being treated in curative intention before or showing signs of progression after curative treatment.
- Known allergy to xanthine oxidase inhibitors and/or rasburicase.
- Known bleeding disorders (e.g., von Willebrand's disease or hemophilia).
- Uncontrolled or active infection.
- Patients requiring treatment with a strong cytochrome P450 (CYP) 3A inhibitor (see appendix K). or anticoagulant therapy with warfarin or phenoprocoumon or other vitamin K antagonists. Please note: Patients being treated with NOACs can be included, but must be properly informed about the potential risk of bleeding under treatment with ibrutinib.
- History of stroke or intracranial hemorrhage within 6 months prior to registration.
- Major surgery within 28 days prior to registration.
- Use of investigational agents which might interfere with the study drug within 28 days prior to registration.
- Vaccination with live vaccines within 28 days prior to registration
- Steroid therapy within 7 days prior to registration, with the exception of inhaled steroids for asthma, topical steroids, steroids up to 25 mg of prednisolone daily to control autoimmune phenomenon's, or replacement/stress corticosteroids.
- Pregnant women and nursing mothers.
- Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Crossover Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Experimental: Ibrutinib until progression/relapse
All patients receive ibrutinib + venetoclax (with delayed start and ramp up of venetoclax from cycle 3) for the 15 cycles. MRDpositive patients (PB and BM) will continue on Ibrutinib maintenance (non-randomized group) until progression/relapse |
Cycle 1 + 2: 420 mg ibrutinib, day 1-28 | Cycle 3: 420 mg ibrutinib, day 1-28 | 20 mg venetoclax, day 1-7 | 50 mg venetoclax, day 8-14 | 100 mg venetoclax, day 15-21 | 200 mg venetoclax, day 22-28 | Cycle 4-15: 420 mg ibrutinib, day 1-28 + 400mg venetoclax, day 1-28
420mg ibrutinib daily until progression/relapse
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Experimental: Arm A
All patients receive ibrutinib + venetoclax (with delayed start and ramp up of venetoclax from cycle 3) for the 15 cycles. MRD negative patients (PB and BM) will be randomized to Arm A or Arm B. Arm A: Ibrutinib until progression/relapse (Continuous ibrutinib treatment until toxicity or progression) |
Cycle 1 + 2: 420 mg ibrutinib, day 1-28 | Cycle 3: 420 mg ibrutinib, day 1-28 | 20 mg venetoclax, day 1-7 | 50 mg venetoclax, day 8-14 | 100 mg venetoclax, day 15-21 | 200 mg venetoclax, day 22-28 | Cycle 4-15: 420 mg ibrutinib, day 1-28 + 400mg venetoclax, day 1-28
420mg ibrutinib daily until progression/relapse
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Experimental: Arm B
All patients receive ibrutinib + venetoclax (with delayed start and ramp up of venetoclax from cycle 3) for the 15 cycles. MRD negative patients (PB and BM) will be randomized to Arm A or Arm B. Arm B: Observation until event. Patients randomized to Arm B will get reinitiation of therapy during the observation period in case of:
Treatment reinitiation will consist of ibrutinib and venetoclax (with ramp up of venetoclax from cycle 1) for 12 cycles |
Cycle 1 + 2: 420 mg ibrutinib, day 1-28 | Cycle 3: 420 mg ibrutinib, day 1-28 | 20 mg venetoclax, day 1-7 | 50 mg venetoclax, day 8-14 | 100 mg venetoclax, day 15-21 | 200 mg venetoclax, day 22-28 | Cycle 4-15: 420 mg ibrutinib, day 1-28 + 400mg venetoclax, day 1-28
Cycle 1: 420 mg ibrutinib | 20 mg venetoclax, day 1-7 | 50 mg venetoclax, day 8-14 | 100 mg venetoclax, day 15-21 | 200 mg venetoclax, day 22-28 | cycles 2-12: 420 mg ibrutinib, day 1-28 + 400 mg venetoclax, day 1-28
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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Number of patients with progression free survival 27 months after starting treatment
Time Frame: 27 months after last patient in trial
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arm B of the study
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27 months after last patient in trial
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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Number of patients with MRD negativity 27 months after starting treatment
Time Frame: 27 months after last patient in trial
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all arms of the study
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27 months after last patient in trial
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Number of patients with progression free survival
Time Frame: 7 years after last patient in
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all arms of the study
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7 years after last patient in
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Number of patients reinitiating treatment
Time Frame: 7 years after last patient in
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arm B of the study
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7 years after last patient in
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Number of patients with treatment failure after reinitiating treatment
Time Frame: 7 years after last patient in
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arm B of the study
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7 years after last patient in
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Number of patients initiating new CLL treatment
Time Frame: 7 years after last patient in
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all arms of the study
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7 years after last patient in
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Number of patients with MRD negativity 12 (peripheral blood) and 15 months (peripheral blood and bone marrow) after starting treatment
Time Frame: 15 months after last patient in trial
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all arms of the study
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15 months after last patient in trial
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Number of patients alive
Time Frame: 7 years after last patient in
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all arms of the study
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7 years after last patient in
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Number of patients with complete remission, partial remission and stable disease and the duration of remission for each group
Time Frame: 7 years after last patient in
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all arms of the study
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7 years after last patient in
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Number and grading of adverse events, serious adverse events and adverse events of special interest (bleeding, atrial fibrillation and tumorlysis)
Time Frame: 7 years after last patient in
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all arms of the study
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7 years after last patient in
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Number of patients with improved quality of life (by EORTC QLQ-C30 and QLQ-CLL16 questionnaires)
Time Frame: 51 months after last patient in trial
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all arms of the study
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51 months after last patient in trial
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Collaborators and Investigators
Collaborators
Publications and helpful links
General Publications
- Kater AP, Levin MD, Dubois J, Kersting S, Enggaard L, Veldhuis GJ, Mous R, Mellink CHM, van der Kevie-Kersemaekers AF, Dobber JA, Poulsen CB, Frederiksen H, Janssens A, Schjodt I, Dompeling EC, Ranti J, Brieghel C, Mattsson M, Bellido M, Tran HTT, Nasserinejad K, Niemann CU. Minimal residual disease-guided stop and start of venetoclax plus ibrutinib for patients with relapsed or refractory chronic lymphocytic leukaemia (HOVON141/VISION): primary analysis of an open-label, randomised, phase 2 trial. Lancet Oncol. 2022 Jun;23(6):818-828. doi: 10.1016/S1470-2045(22)00220-0.
- Levin MD, Kater AP, Mattsson M, Kersting S, Ranti J, Thi Tuyet Tran H, Nasserinejad K, Niemann CU. Protocol description of the HOVON 141/VISION trial: a prospective, multicentre, randomised phase II trial of ibrutinib plus venetoclax in patients with creatinine clearance >/=30 mL/min who have relapsed or refractory chronic lymphocytic leukaemia (RR-CLL) with or without TP53 aberrations. BMJ Open. 2020 Oct 15;10(10):e039168. doi: 10.1136/bmjopen-2020-039168.
Helpful Links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Anticipated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- HO141 CLL / VIsion trial
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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