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CLLPhase 2NCT04639362

CLL Induction Treatment With Venetoclax and Ibrutinib, Followed by Ibrutinib and Obinutuzumab in Patients With MRD.

A Phase 2 study testing ibrutinib, venetoclax, obinutuzumab and ibrutinib, venetoclax in people with CLL, run by Stichting Hemato-Oncologie voor Volwassenen Nederland at 27 sites in 2 countries.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record
Search all trials

Trial summary

A recent study showed that 6 cycles of obinutuzumab when given after at least 1 year of ibrutinib did result in MRD conversion in a significant proportion of patients (50%). The precise influence, timing and interplay of venetoclax, ibrutinib and obinutuzumab on clearance of CLL cells in different compartments (PB… Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
CLL
What is being tested?
ibrutinib, venetoclax, obinutuzumab and ibrutinib, venetoclax
Could I receive a placebo?
No, everyone receives an active treatment
How many people
85 participants
Where
27 sitesin 2 countries
Study dates
29 Dec 2020to 1 Dec 2028
Phase
Phase 2
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Documented CLL or SLL requiring treatment according to IWCLL criteria33, including minimal required markers (CD5/CD19/CD23 triple positive with light chain restriction);
  • WHO performance status 0-3 (appendix C), stage 3 only if attributable to CLL/SLL;
  • No prior treatment for CLL/SLL;
  • Age at least 18 years;
  • Adequate BM function defined as:
  • Hb > 5 mmol/l or Hb > 8 g/dL
Show all 17Show fewer
  • Absolute neutrophil count (ANC) ≥ 0.75 x 109/L or 750/μL
  • Platelet count ≥ 50 x 109/L or 50,000 /μL Unless directly attributable to CLL/SLL infiltration of the BM, proven by BM biopsy;
  • Estimated Glomerular Filtration Rate (eGFR) (MDRD) or estimated creatinine clearance (CrCl) ≥ 30ml/min (Cockcroft-Gault appendix E); Please note: in case eGFR or CrCl is <50ml/min the patient needs to be considered high risk for TLS
  • Adequate liver function as indicated:
  • Serum aspartate transaminase (ASAT) and alanine transaminase (ALAT) ≤ 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 activated partial thromboplastin time (aPTT) <1.5 x ULN;
  • Negative serological testing for hepatitis B virus (Hepatitis B surface antigen (HBsAg) negative and hepatitis B core antibody (anti-HBc) negative) and hepatitis C virus (hepatitis C antibody). Subjects who are positive for hepatitis B core antibody, hepatitis B surface antigen, or hepatitis C antibody must have a negative PCR result before enrollment. Those who are PCR positive will be excluded;
  • Ability and willingness to adhere to the study visit schedule and other protocol requirements;
  • Patient is capable of giving informed consent;
  • Written informed consent.

Who cannot join

  • Transformation of CLL (Richter's transformation);
  • Malignancies other than CLL/SLL currently requiring systemic therapy or not being treated in curative intention or showing signs of progression after curative treatment;
  • Patient with CNS involvement
  • Known allergy to xanthine oxidase inhibitors and/or rasburicase;
  • Intolerance of exogenous protein administration;
  • History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies. Known sensitivity or allergy to murine products;
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  • Active fungal, bacterial, and/or viral infection that requires systemic therapy; Please note: active controlled as well as chronic/recurrent infections are at risk of reactivation/infection during treatment (see section 9.2.3.1);
  • Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled: infection, auto-immune hemolysis, immune thrombocytopenia, diabetes, hypertension, hyperthyroidism or hypothyroidism etc.);
  • Patients known to be HIV-positive;
  • Patient requiring treatment with a strong cytochrome P450 (CYP) 3A inhibitor (see appendix K) or anticoagulant therapy with warfarin or phenprocoumon n or other vitamin K antagonists; Please note: Patients being treated with DOACs apixaban, edoxaban or rivaroxaban can be included, but must be properly informed about the potential risk of bleeding under treatment with ibrutinib. Treatment with dabigatran should be avoided, due to risk of toxicity based on P-gp substrate (see appendix K)
  • History of stroke or intracranial hemorrhage within 6 months prior to registration;
  • Severe cardiovascular disease (arrhythmias requiring chronic treatment, congestive heart failure or symptomatic ischemic heart disease) (CTCAE grade III-IV, see appendix D);
  • Severe pulmonary dysfunction (CTCAE grade III-IV, see appendix D);
  • Patient with Child Pugh C
  • Severe neurological or psychiatric disease (CTCAE grade III-IV, see appendix D);
  • Vaccination with live vaccines within 28 days prior to registration;
  • Use of any other experimental drug or therapy within 28 days prior to registration
  • Major surgery within 28 days prior to registration;
  • Steroid therapy within 10 days prior to registration, with the exception of inhaled steroids for asthma, topical steroids, steroids up to 20 mg of dose equivalents of prednisolone daily to control autoimmune phenomenon's, or replacement/stress corticosteroids;
  • Pregnant women and nursing mothers;
  • Fertile men or women of childbearing potential unless: (1) surgically sterile or ≥ 2 years after the onset of menopause, and/or (2) willing to use a highly effective contraceptive method such as oral contraceptives, intrauterine device, sexual abstinence or barrier method of contraception in conjunction with spermicidal jelly during study treatment and in female patients for 3 months after end of induction treatment and 18 months after end of treatment with obinutuzumab and male patients for 6 months after end of treatment;
  • Current participation in other clinical trial;
  • Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule.

Trial locations and contacts

27 sites in 2 countries.

27 sites in 2 countries

Netherlands23 sites

  • NL-Almere-FLEVOZIEKENHUIS

    Almere Stad

  • NL-Amersfoort-MEANDERMC

    Amersfoort

  • NL-Amsterdam-AMC

    Amsterdam

  • NL-Amsterdam-VUMC

    Amsterdam

  • NL-Dordrecht-ASZ

    Dordrecht

  • NL-Ede-ZGV

    Ede

  • NL-Eindhoven-CATHARINA

    Eindhoven

  • NL-Enschede-MST

    Enschede

  • NL-Gouda-GROENEHART

    Gouda

  • NL-Groningen-UMCG

    Groningen

  • NL-Hilversum-TERGOOI

    Hilversum

  • NL-Hoofddorp-SPAARNEGASTHUIS

    Hoofddorp

  • NL-Roermond-LZR

    Roermond

  • NL-Rotterdam-IKAZIA

    Rotterdam

  • NL-Sittard-Geleen-ZUYDERLAND

    Sittard

  • NL-Sneek-ANTONIUSSNEEK

    Sneek

  • NL-Terneuzen-ZORGSAAM

    Terneuzen

  • NL-Den Haag-HAGA

    The Hague

  • NL-Den Haag-HMCWESTEINDE

    The Hague

  • NL-Tilburg-ETZ

    Tilburg

  • NL-Uden-BERNHOVEN

    Uden

  • NL-Utrecht-UMCUTRECHT

    Utrecht

  • NL-Zwolle-ISALA

    Zwolle

Other trials in Netherlands

Denmark4 sites

  • DK-Aalborg-AALBORGUH

    Aalborg

  • DK-Herlev-HERLEV

    Herlev

  • DK-Odense-OUH

    Odense

  • DK-Roskilde-ROSKILDE

    Roskilde

Other trials in Denmark

About this study

Official title: First Line Treatment With VeNEtoclaX and ibruTinib Induction Followed by Obinutuzumab intenSificaTion Exclusively in CLL/SLL Patients Not in Complete Remission and/or With Detectable Bone Marrow Minimal Residual Disease (NEXT STEP Trial)

A recent study showed that 6 cycles of obinutuzumab when given after at least 1 year of ibrutinib did result in MRD conversion in a significant proportion of patients (50%). The precise influence, timing and interplay of venetoclax, ibrutinib and obinutuzumab on clearance of CLL cells in different compartments (PB, BM, LN), and achievement of uMRD and complete remission (CR) are not well known.

Therefore, the investigators set out a study to evaluate whether patients who are not in CR or who have detectable MRD after 12 months of combination treatment with ibrutinib and venetoclax (15 months total treatment including three months ibrutinib lead-in) could be converted into uMRD CR with an additional 6 cycles obinutuzumab in combination with ibrutinib.

Read the detailed description

The BCL-2 antagonist venetoclax, specifically if combined with a CD20 antibody proved highly active in clearance of chronic lymphocytic leukemia (CLL) cells in peripheral blood (PB) and bone marrow (BM) but less so in lymph nodes (LN), probably due to the abundant expression of additional anti-apoptotic proteins within the LN compartment. The investigators hypothesize that due to the forced egress from the LN by ibrutinib, leukemic cells cannot escape from the apoptosis initiating effects of venetoclax, making combination of these drugs highly effective. Preliminary data from multiple ongoing trials on this combination are indeed promising, with not only superior rates of undetectable minimal residual disease (uMRD) than other ibrutinib combinations but perhaps more important, achievement of complete LN responses in the majority of patients. Yet, also with this combination, a significant subgroup of patients are expected to remain with detectable MRD. A recent study showed that 6 cycles of obinutuzumab when given after at least 1 year of ibrutinib did result in MRD conversion in a significant proportion of patients (50%). The precise influence, timing and interplay of venetoclax, ibrutinib and obinutuzumab on clearance of CLL cells in different compartments (PB, BM, LN), and achievement of uMRD and complete remission (CR) are not well known.

Therefore, the investigators set out a study to evaluate whether patients who are not in CR or who have detectable MRD after 12 months of combination treatment with ibrutinib and venetoclax (15 months total treatment including three months ibrutinib lead-in) could be converted into uMRD CR with an additional 6 cycles obinutuzumab in combination with ibrutinib. In addition to efficacy, as measured by undetectable MRD rate, emphasis of this trial will be on clearance of different compartments (PB, BM, LN) at different time points on protocol and in follow up. In addition, the toxicity profile is taken into consideration.

Conditions
CLL
Being tested
ibrutinib, venetoclax, obinutuzumab, ibrutinib, venetoclax

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • ibrutinib, venetoclax, obinutuzumabDrug

    Also called Intensification

    Patients will receive 3 cycles lead-in with ibrutinib 420 mg/day. Here-after, patients will continue with 13 induction cycles (including one bridging cycle) combining ibrutinib 420 mg/day and venetoclax 400 mg/day (including a ramp up of 5 weeks). Patients who are not in CR or who have detectable MRD after 15 cycles (3 cycles lead-in and 12 cycles induction) will continue with 6 intensification cycles ibrutinib in combination with obinutuzumab day 1, 2, 8, 15 for the first cycle and with obinutuzumab day 1 for the following 5 cycles.

  • ibrutinib, venetoclaxDrug

    Also called Observation

    Patients will receive 3 cycles lead-in with ibrutinib 420 mg/day. Here-after, patients will continue with 13 induction cycles (including one bridging cycle) combining ibrutinib 420 mg/day and venetoclax 400 mg/day (including a ramp up of 5 weeks). Patients who are in CR or have no detectable MRD will be observed.

Study groups in NCT04639362
Study groupRoleWhat they receive
IntensificationExperimentalPatients will receive 3 cycles lead-in with ibrutinib 420 mg/day. Here-after, patients will continue with 13 induction cycles (including one bridging cycle) combining ibrutinib 420 mg/day and venetoclax 400 mg/day (including a ramp up of 5 weeks). Patients who are not in CR or who have detectable MRD after 15 cycles (3 cycles lead-in and 12 cycles induction) will continue with 6 intensification cycles ibrutinib in combination with obinutuzumab day 1, 2, 8, 15 for the first cycle and with obinutuzumab day 1 for the following 5 cycles.
Receives: Drug: ibrutinib, venetoclax, obinutuzumab
ObservationExperimentalPatients will receive 3 cycles lead-in with ibrutinib 420 mg/day. Here-after, patients will continue with 13 induction cycles (including one bridging cycle) combining ibrutinib 420 mg/day and venetoclax 400 mg/day (including a ramp up of 5 weeks). Patients who are in CR or have no detectable MRD will be observed.
Receives: Drug: ibrutinib, venetoclax

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. BM uMRD CR 3 months after end of intensification with ibrutinib/obinutuzumab in patients who were not in CR or who had detectable MRD on combination ibrutinib and venetoclax.

    Intensification arm

    Measured: 5 years

Secondary outcomes (13)

  1. BM uMRD CR 9 months after registration 2 in all subjects

    Intensification arm

    Measured: 5 years

  2. Best BM MRD level on protocol

    Intensification arm

    Measured: 5 years

  3. MRD level in BM and PB at different time points on protocol and in follow up

    Intensification arm

    Measured: 5 years

  4. Best response by IWCLL on protocol

    Intensification arm

    Measured: 5 years

  5. Response by IWCLL at different time points

    Intensification arm

    Measured: 5 years

  6. Response by Deauville criteria on PET scan at different time points

    Intensification arm

    Measured: 5 years

  7. Progression free survival (PFS), defined as time from registration 1 and from registration 2 to progression or death from any cause, whichever comes first

    Intensification arm

    Measured: 5 years

  8. Event free survival (EFS), defined as time from registration 1 and from registration 2 to start new CLL treatment, progression or death, whichever comes first

    Intensification arm

    Measured: 5 years

  9. Overall survival (OS), defined as time from registration 1 and from registration 2 to death from any cause

    Intensification arm

    Measured: 5 years

  10. Treatment free interval (TFI), defined as date of last protocol treatment to start date of first CLL treatment off protocol, or death from any cause whichever comes first

    Intensification arm

    Measured: 5 years

  11. Predictive value of prognostic markers at diagnosis on uMRD and ORR by IWCLL and Deauville criteria at end of ibrutinib/venetoclax and ibrutinib/obinutuzumab

    Intensification arm

    Measured: 5 years

  12. CTCAE grade ≥2 toxicities

    Intensification arm

    Measured: 5 years

  13. IWCLL hematological grade ≥2toxicities

    Intensification arm

    Measured: 5 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted20 Nov 2020
  2. Study start29 Dec 2020
  3. Primary completion1 Dec 2025 (estimated)
  4. Study completion1 Dec 2028 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Factorial
Model description
After 15 to 16 cycles of treatment the PI will assign patients to either observation (no further treatment) or intensification (treatment with ibrutinib and obinutuzumab), based on MRD results.
Masking
None (open label)
Enrolment
85 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04639362
Sponsor's protocol ID
HO158
Other IDs
2019-002528-34, 2019
Status last verified
Aug 2021
First submitted
5 Nov 2020
Last updated
23 Aug 2021
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • Kater AP, Kersting S, Dubois JM, van der Holt B, da Cunha-Bang C, Te Raa D, Idink C, de Boer F, Droogendijk J, de Heer K, van der Burg L, Nijziel MR, Tick L, Levenga H, Silbermann M, Ludwig I, Beeker A, Bellido M, Dobber JA, Evers LM, van der Kevie-Kersemaekers AM, Mellink C, Meulendijks I, Cunha S, Abrahamse-Testroote M, Zwezerijnen G, Zijlstra J, Niemann CU, Levin MD. Fixed-duration ibrutinib-venetoclax with MRD-guided ibrutinib-obinutuzumab intensification in first-line chronic lymphocytic leukaemia (HOVON 158/NEXT STEP): primary analysis of a multicentre, open-label, phase 2 trial. Lancet Haematol. 2025 Dec;12(12):e935-e945. doi: 10.1016/S2352-3026(25)00288-1.

    PubMed 41338862

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing ibrutinib, venetoclax, obinutuzumab and ibrutinib, venetoclax in people with CLL, run by Stichting Hemato-Oncologie voor Volwassenen Nederland at 27 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 17 inclusion and 23 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: under way, not looking for participants, as of the sponsor's last update on 23 Aug 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 27 sites in Netherlands, Denmark. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

BM uMRD CR 3 months after end of intensification with ibrutinib/obinutuzumab in patients who were not in CR or who had detectable MRD on combination ibrutinib and venetoclax. (time frame: 5 years). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04639362, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Aug 2021.

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