NCT04639362

Brief 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, 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.

Trial Health

78
On Track

Trial Health Score

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

Enrollment
85

participants targeted

Target at P50-P75 for phase_2

Timeline
31mo left

Started Dec 2020

Longer than P75 for phase_2

Geographic Reach
2 countries

27 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 Progress68%
Dec 2020Dec 2028

First Submitted

Initial submission to the registry

November 5, 2020

Completed
15 days until next milestone

First Posted

Study publicly available on registry

November 20, 2020

Completed
1 month until next milestone

Study Start

First participant enrolled

December 29, 2020

Completed
4.9 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

December 1, 2025

Completed
3 years until next milestone

Study Completion

Last participant's last visit for all outcomes

December 1, 2028

Expected
Last Updated

August 23, 2021

Status Verified

August 1, 2021

Enrollment Period

4.9 years

First QC Date

November 5, 2020

Last Update Submit

August 20, 2021

Conditions

CLL

Outcome Measures

Primary Outcomes (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

    5 years

Secondary Outcomes (13)

  • BM uMRD CR 9 months after registration 2 in all subjects

    5 years

  • Best BM MRD level on protocol

    5 years

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

    5 years

  • Best response by IWCLL on protocol

    5 years

  • Response by IWCLL at different time points

    5 years

  • +8 more secondary outcomes

Study Arms (2)

Intensification

EXPERIMENTAL

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.

Drug: ibrutinib, venetoclax, obinutuzumab

Observation

EXPERIMENTAL

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.

Drug: ibrutinib, venetoclax

Interventions

ibrutinib, venetoclax, obinutuzumabDRUG

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.

Also known as: Intensification
Intensification
ibrutinib, venetoclaxDRUG

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.

Also known as: Observation
Observation

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 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
  • 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;
  • +2 more criteria

You may not qualify if:

  • 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;
  • 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);
  • +8 more criteria

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (27)

DK-Aalborg-AALBORGUH

Aalborg, Denmark

Location

DK-Herlev-HERLEV

Herlev, Denmark

Location

DK-Odense-OUH

Odense, Denmark

Location

DK-Roskilde-ROSKILDE

Roskilde, Denmark

Location

NL-Almere-FLEVOZIEKENHUIS

Almere Stad, Netherlands

Location

NL-Amersfoort-MEANDERMC

Amersfoort, Netherlands

Location

NL-Amsterdam-AMC

Amsterdam, Netherlands

Location

NL-Amsterdam-VUMC

Amsterdam, Netherlands

Location

NL-Dordrecht-ASZ

Dordrecht, Netherlands

Location

NL-Ede-ZGV

Ede, Netherlands

Location

NL-Eindhoven-CATHARINA

Eindhoven, Netherlands

Location

NL-Enschede-MST

Enschede, Netherlands

Location

NL-Gouda-GROENEHART

Gouda, Netherlands

Location

NL-Groningen-UMCG

Groningen, Netherlands

Location

NL-Hilversum-TERGOOI

Hilversum, Netherlands

Location

NL-Hoofddorp-SPAARNEGASTHUIS

Hoofddorp, Netherlands

Location

NL-Roermond-LZR

Roermond, Netherlands

Location

NL-Rotterdam-IKAZIA

Rotterdam, Netherlands

Location

NL-Sittard-Geleen-ZUYDERLAND

Sittard, Netherlands

Location

NL-Sneek-ANTONIUSSNEEK

Sneek, Netherlands

Location

NL-Terneuzen-ZORGSAAM

Terneuzen, Netherlands

Location

NL-Den Haag-HAGA

The Hague, Netherlands

Location

NL-Den Haag-HMCWESTEINDE

The Hague, Netherlands

Location

NL-Tilburg-ETZ

Tilburg, Netherlands

Location

NL-Uden-BERNHOVEN

Uden, Netherlands

Location

NL-Utrecht-UMCUTRECHT

Utrecht, Netherlands

Location

NL-Zwolle-ISALA

Zwolle, Netherlands

Location

Related Publications (1)

  • 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.

    PMID: 41338862DERIVED

Related Links

MeSH Terms

Interventions

ibrutinibvenetoclaxobinutuzumabObservation

Intervention Hierarchy (Ancestors)

MethodsInvestigative Techniques

Study Officials

  • Arnon Kater, PhD

    Amsterdam UMC

    PRINCIPAL INVESTIGATOR

Study Design

Study Type
interventional
Phase
phase 2
Allocation
NON RANDOMIZED
Masking
NONE
Purpose
TREATMENT
Intervention Model
FACTORIAL
Model Details: 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.
Sponsor Type
OTHER
Responsible Party
SPONSOR

Study Record Dates

First Submitted

November 5, 2020

First Posted

November 20, 2020

Study Start

December 29, 2020

Primary Completion

December 1, 2025

Study Completion (Estimated)

December 1, 2028

Last Updated

August 23, 2021

Record last verified: 2021-08

Data Sharing

IPD Sharing
Will not share

Locations

NL(23)DK(4)