NCT03226301

Brief Summary

The aim of the current trial is to evaluate if combination treatment with venetoclax + ibrutinib in patients with relapsed or refractory chronic lymphocytic leukemia (RR CLL) can lead to MRD negativity, which may induce long lasting remissions for MRD-negative patients randomized to stopping treatment after 15 induction cycles.

Trial Health

82
On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
230

participants targeted

Target at P75+ for phase_2

Timeline
2mo left

Started Jun 2017

Longer than P75 for phase_2

Geographic Reach
6 countries

49 active sites

Status
active not recruiting

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

Study Progress99%
Jun 2017Jun 2026

First Submitted

Initial submission to the registry

May 15, 2017

Completed
1 month until next milestone

Study Start

First participant enrolled

June 23, 2017

Completed
28 days until next milestone

First Posted

Study publicly available on registry

July 21, 2017

Completed
3.9 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

June 30, 2021

Completed
5 years until next milestone

Study Completion

Last participant's last visit for all outcomes

June 21, 2026

Expected
Last Updated

August 2, 2022

Status Verified

August 1, 2022

Enrollment Period

4 years

First QC Date

May 15, 2017

Last Update Submit

August 1, 2022

Conditions

Chronic Lymphocytic Leukemia in RelapseChronic Lymphocytic Leukemia in Remission

Outcome Measures

Primary Outcomes (1)

  • Number of patients with progression free survival 27 months after starting treatment

    arm B of the study

    27 months after last patient in trial

Secondary Outcomes (10)

  • Number of patients with MRD negativity 27 months after starting treatment

    27 months after last patient in trial

  • Number of patients with progression free survival

    7 years after last patient in

  • Number of patients reinitiating treatment

    7 years after last patient in

  • Number of patients with treatment failure after reinitiating treatment

    7 years after last patient in

  • Number of patients initiating new CLL treatment

    7 years after last patient in

  • +5 more secondary outcomes

Study Arms (3)

Ibrutinib until progression/relapse

EXPERIMENTAL

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

Drug: Ibrutinib + Venetoclax 15 cyclesDrug: Ibrutinib until progression/relapse

Arm A

EXPERIMENTAL

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)

Drug: Ibrutinib + Venetoclax 15 cyclesDrug: Ibrutinib until progression/relapse

Arm B

EXPERIMENTAL

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

Drug: Ibrutinib + Venetoclax 15 cyclesDrug: Possible reinitiation treatment: Ibrutinib + Venetoclax 12 cycles

Interventions

Ibrutinib + Venetoclax 15 cyclesDRUG

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

Arm AArm BIbrutinib until progression/relapse
Ibrutinib until progression/relapseDRUG

420mg ibrutinib daily until progression/relapse

Arm AIbrutinib until progression/relapse
Possible reinitiation treatment: Ibrutinib + Venetoclax 12 cyclesDRUG

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

Arm B

Eligibility Criteria

Age18 Years+
Sexall
Healthy VolunteersNo
Age GroupsAdult (18-64), Older Adult (65+)

You may qualify if:

  • 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.
  • +2 more criteria

You may not qualify if:

  • 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.

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (49)

BE-Antwerpen-ZNASTUIVENBERG

Antwerp, Belgium

Location

BE-Brugge-AZBRUGGE

Bruges, Belgium

Location

BE-Bruxelles-STLUC

Brussels, Belgium

Location

BE-Haine-Saint-Paul-JOLIMONT

Haine-Saint-Paul, Belgium

Location

BE-Leuven-UZLEUVEN

Leuven, Belgium

Location

DK-Aalborg-AALBORGUH

Aalborg, Denmark

Location

DK-Copenhagen-RIGSHOSPITALET

Copenhagen, Denmark

Location

DK-Herlev-HERLEV

Herlev, Denmark

Location

DK-Holstebro-HOLSTEBRO

Holstebro, Denmark

Location

DK-Odense-OUH

Odense, Denmark

Location

DK-Roskilde-ROSKILDE

Roskilde, Denmark

Location

FI-Helsinki-HUS

Helsinki, Finland

Location

FI-Jyvaskyla-KSSHP

Jyväskylä, Finland

Location

FI-Kuopio-KYS

Kuopio, Finland

Location

FI-Tampere-TAYS

Tampere, Finland

Location

FI-Turku-TYKS

Turku, Finland

Location

NL-Alkmaar-NWZ

Alkmaar, Netherlands

Location

NL-Amersfoort-MEANDERMC

Amersfoort, Netherlands

Location

NL-Amsterdam-AMC

Amsterdam, Netherlands

Location

NL-Amsterdam-AVL

Amsterdam, Netherlands

Location

NL-Amsterdam-VUMC

Amsterdam, Netherlands

Location

NL-Arnhem-RIJNSTATE

Arnhem, Netherlands

Location

NL-Breda-AMPHIA

Breda, Netherlands

Location

NL-Delft-RDGG

Delft, Netherlands

Location

NL-Dordrecht-ASZ

Dordrecht, Netherlands

Location

NL-Enschede-MST

Enschede, Netherlands

Location

NL-Gouda-GROENEHART

Gouda, Netherlands

Location

NL-Groningen-UMCG

Groningen, Netherlands

Location

NL-Heerlen-ATRIUMMC

Heerlen, Netherlands

Location

NL-Helmond-ELKERLIEK

Helmond, Netherlands

Location

NL-Nieuwegein-ANTONIUS

Nieuwegein, Netherlands

Location

NL-Nijmegen-CWZ

Nijmegen, Netherlands

Location

NL-Rotterdam-ERASMUSMC

Rotterdam, Netherlands

Location

NL-Rotterdam-MAASSTADZIEKENHUIS

Rotterdam, Netherlands

Location

NL-Sittard-Geleen-ZUYDERLAND

Sittard, Netherlands

Location

NL-Sneek-ANTONIUSSNEEK

Sneek, Netherlands

Location

NL-Den Haag-HAGA

The Hague, Netherlands

Location

NL-Tilburg-ETZ

Tilburg, Netherlands

Location

NL-Uden-BERNHOVEN

Uden, Netherlands

Location

NL-Utrecht-UMCUTRECHT

Utrecht, Netherlands

Location

NL-Zaandam-ZAANSMC

Zaandam, Netherlands

Location

NL-Zwolle-ISALA

Zwolle, Netherlands

Location

NO-Lørenskog-AKERSHUS

Lørenskog, Norway

Location

NO-Trondheim-STOLAV

Trondheim, Norway

Location

SE-Boras-SASBORAS

Borås, Sweden

Location

SE-Linköping-REGIONOSTERGOTLAND

Linköping, Sweden

Location

SE-Luleå-SUNDERBY

Luleå, Sweden

Location

SE-Lund-SUH

Lund, Sweden

Location

SE-Uppsala-UPPSALAUH

Uppsala, Sweden

Location

Related Publications (3)

  • 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.

    PMID: 40249856DERIVED

  • 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.

    PMID: 35654052DERIVED

  • 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.

    PMID: 33060089DERIVED

Related Links

MeSH Terms

Interventions

ibrutinib

Study Design

Study Type
interventional
Phase
phase 2
Allocation
RANDOMIZED
Masking
NONE
Purpose
TREATMENT
Intervention Model
CROSSOVER
Model Details: All patients receive ibrutinib + venetoclax (with delayed start and ramp up of venetoclax from cycle 3) for the 15 cycles. Patients not achieving MRD negativity after cycle 12 (PB) AND/OR cycle 15 (PB+BM) continue on ibrutinib maintenance (non-randomized group). Patients achieving MRD negativity after cycle 12 (PB) AND cycle 15 (PB+BM) are randomized 1:2 between ibrutinib maintenance (arm A) and stopping treatment (observation, arm B).
Sponsor Type
OTHER
Responsible Party
SPONSOR

Study Record Dates

First Submitted

May 15, 2017

First Posted

July 21, 2017

Study Start

June 23, 2017

Primary Completion

June 30, 2021

Study Completion (Estimated)

June 21, 2026

Last Updated

August 2, 2022

Record last verified: 2022-08

Data Sharing

IPD Sharing
Will not share

Locations

BE(5)NL(26)FI(5)NO(2)DK(6)SE(5)