NCT04639362

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

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)

• Status: Active Not Recruiting
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 85 (actual)
• Sponsor: Stichting Hemato-Oncologie voor Volwassenen Nederland · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

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.

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

Interventions

Type	Name	Description
DRUG	ibrutinib, venetoclax, obinutuzumab	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	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.

Timeline

• Start date: 2020-12-29
• Primary completion: 2025-12-01
• Completion: 2028-12-01
• First posted: 2020-11-20
• Last updated: 2021-08-23

Locations

27 sites across 2 countries: Denmark, Netherlands