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
NCT ID: NCT03226301
Last Updated: 2022-08-02
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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ACTIVE_NOT_RECRUITING
PHASE2
230 participants
INTERVENTIONAL
2017-06-23
2026-06-21
Brief Summary
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Detailed Description
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Conditions
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Study Design
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RANDOMIZED
CROSSOVER
TREATMENT
NONE
Study Groups
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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
Ibrutinib + Venetoclax 15 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
Ibrutinib until progression/relapse
420mg ibrutinib daily until progression/relapse
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)
Ibrutinib + Venetoclax 15 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
Ibrutinib until progression/relapse
420mg ibrutinib daily until progression/relapse
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:
* progression according to IWCLL criteria or
* MRD≥10-3 (PB) and at least one month later MRD ≥10-2 (PB).
Treatment reinitiation will consist of ibrutinib and venetoclax (with ramp up of venetoclax from cycle 1) for 12 cycles
Ibrutinib + Venetoclax 15 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
Possible reinitiation treatment: Ibrutinib + Venetoclax 12 cycles
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
Interventions
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Ibrutinib + Venetoclax 15 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
Ibrutinib until progression/relapse
420mg ibrutinib daily until progression/relapse
Possible reinitiation treatment: Ibrutinib + Venetoclax 12 cycles
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
Eligibility Criteria
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Inclusion Criteria
* 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
* 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.
18 Years
ALL
No
Sponsors
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Nordic CLL Study Group
UNKNOWN
Stichting Hemato-Oncologie voor Volwassenen Nederland
OTHER
Responsible Party
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Locations
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BE-Antwerpen-ZNASTUIVENBERG
Antwerp, , Belgium
BE-Brugge-AZBRUGGE
Bruges, , Belgium
BE-Bruxelles-STLUC
Brussels, , Belgium
BE-Haine-Saint-Paul-JOLIMONT
Haine-Saint-Paul, , Belgium
BE-Leuven-UZLEUVEN
Leuven, , Belgium
DK-Aalborg-AALBORGUH
Aalborg, , Denmark
DK-Copenhagen-RIGSHOSPITALET
Copenhagen, , Denmark
DK-Herlev-HERLEV
Herlev, , Denmark
DK-Holstebro-HOLSTEBRO
Holstebro, , Denmark
DK-Odense-OUH
Odense, , Denmark
DK-Roskilde-ROSKILDE
Roskilde, , Denmark
FI-Helsinki-HUS
Helsinki, , Finland
FI-Jyvaskyla-KSSHP
Jyväskylä, , Finland
FI-Kuopio-KYS
Kuopio, , Finland
FI-Tampere-TAYS
Tampere, , Finland
FI-Turku-TYKS
Turku, , Finland
NL-Alkmaar-NWZ
Alkmaar, , Netherlands
NL-Amersfoort-MEANDERMC
Amersfoort, , Netherlands
NL-Amsterdam-AMC
Amsterdam, , Netherlands
NL-Amsterdam-AVL
Amsterdam, , Netherlands
NL-Amsterdam-VUMC
Amsterdam, , Netherlands
NL-Arnhem-RIJNSTATE
Arnhem, , Netherlands
NL-Breda-AMPHIA
Breda, , Netherlands
NL-Delft-RDGG
Delft, , Netherlands
NL-Dordrecht-ASZ
Dordrecht, , Netherlands
NL-Enschede-MST
Enschede, , Netherlands
NL-Gouda-GROENEHART
Gouda, , Netherlands
NL-Groningen-UMCG
Groningen, , Netherlands
NL-Heerlen-ATRIUMMC
Heerlen, , Netherlands
NL-Helmond-ELKERLIEK
Helmond, , Netherlands
NL-Nieuwegein-ANTONIUS
Nieuwegein, , Netherlands
NL-Nijmegen-CWZ
Nijmegen, , Netherlands
NL-Rotterdam-ERASMUSMC
Rotterdam, , Netherlands
NL-Rotterdam-MAASSTADZIEKENHUIS
Rotterdam, , Netherlands
NL-Sittard-Geleen-ZUYDERLAND
Sittard, , Netherlands
NL-Sneek-ANTONIUSSNEEK
Sneek, , Netherlands
NL-Den Haag-HAGA
The Hague, , Netherlands
NL-Tilburg-ETZ
Tilburg, , Netherlands
NL-Uden-BERNHOVEN
Uden, , Netherlands
NL-Utrecht-UMCUTRECHT
Utrecht, , Netherlands
NL-Zaandam-ZAANSMC
Zaandam, , Netherlands
NL-Zwolle-ISALA
Zwolle, , Netherlands
NO-Lørenskog-AKERSHUS
Lørenskog, , Norway
NO-Trondheim-STOLAV
Trondheim, , Norway
SE-Boras-SASBORAS
Borås, , Sweden
SE-Linköping-REGIONOSTERGOTLAND
Linköping, , Sweden
SE-Luleå-SUNDERBY
Luleå, , Sweden
SE-Lund-SUH
Lund, , Sweden
SE-Uppsala-UPPSALAUH
Uppsala, , Sweden
Countries
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References
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Niemann CU, Dubois J, Nasserinejad K, da Cunha-Bang C, Kersting S, Enggaard L, Veldhuis GJ, Mous R, Mellink CHM, van der Kevie-Kersemaekers AF, Dobber JA, Poulsen CB, Razawy W, Hollestein R, Frederiksen H, Janssens A, Schjodt I, Dompeling EC, Ranti J, Brieghel C, Mattsson M, Bellido M, Tran HTT, Kater AP, Levin MD. Long-term follow-up of MRD-guided ibrutinib plus venetoclax in relapsed CLL: phase 2 VISION/HO141 trial. Blood Adv. 2025 Aug 12;9(15):3665-3675. doi: 10.1182/bloodadvances.2024015180.
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.
Related Links
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Related Info
Other Identifiers
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HO141 CLL / VIsion trial
Identifier Type: -
Identifier Source: org_study_id
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