3002 - Zanubrutinib and venetoclax as initial therapy for CLL with obinutuzumab triplet consolidation in patients with minimal residual disease positivity (BruVenG)

Background:
Bruton’s tyrosine kinase inhibitors (BTKi), anti-CD20 antibodies, and B cell lymphoma 2 inhibitors (BCL-2i) are essential therapeutic drug classes in the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Current evidence demonstrates clinical synergy between BTKi and BCL-2i, which allows for an all-oral regimen, that can be safely administered in a clinic setting for most patients (Tam et al., 2022; Wierda et al., 2021). This combination can achieve high rates of minimal residual disease (MRD) negativity and offer a fixed duration therapeutic approach (Kater et al., 2022). Still, it remains uncertain if anti-CD20 therapy meaningfully adds to the effectiveness of oral combination therapy. Recent reports of triplet regimens demonstrate modest improvement in MRD negativity with similar overall response rates when compared to oral doublets (Davids et al., 2021; Soumerai et al., 2021; Wierda et al., 2021). Additionally, anti-CD20 antibody use causes significant B cell depletion resulting in prolonged immune suppression. Lastly, evidence suggests BTKi use may impair clinical activity of anti-CD20 antibodies when used early in combination with BTKi. This is mitigated by using more selective BTKi or incorporating anti-CD20 later in the treatment course with lower disease burden (Da Roit et al., 2015; Flinsenberg et al., 2020; Pavlasova et al., 2016; Rawstron et al., 2018). Therefore, anti-CD20 therapy may not be required for all patients and could be best utilized within a response-adapted strategy. This trial has been developed to assess efficacy of a response adapted consolidative treatment approach utilizing obinutuzumab triplet consolidation in CLL/SLL patients who remain MRD positive after completion of an oral doublet fixed duration treatment with zanubrutinib and venetoclax. This strategy has the potential to minimize obinutuzumab use, spare toxicity, while maximizing MRD negativity. This study will utilize once daily zanubrutinib for which there is limited data in regard to safety and efficacy particularly in combination with venetoclax.

Study Design and Endpoints:
We will conduct a single center, open label, phase II, investigator initiated clinical trial enrolling 50 subjects evaluating the safety and efficacy of zanubrutinib and venetoclax with obinutuzumab triplet consolidation in subjects who remain MRD positive (BruVenG). Eligible patients must have treatment naïve CLL/SLL and confirmed treatment indications per International Workshop on CLL 2018 guidelines. Subjects with Richter’s transformation are excluded.

Treatment will consist of lead-in, combination, and consolidation phases. All subjects will be treated with a 3-cycle lead-in of 320mg, oral, once daily zanubrutinib monotherapy. Venetoclax will be incorporated at cycle 4, per the standard prescriber insert ramp-up schedule. A final dose of 400mg oral, once daily venetoclax, in combination with 320mg oral, once daily zanubrutinib will be used in all subsequent cycles after ramp-up. At cycle 16, MRD will be assessed in the peripheral blood (PB) and bone marrow (BM) via clonoSEQ (Adaptive Biotechnologies). Subjects who are MRD negative ( < 1x10-4 ) in both compartments will stop therapy. Subjects who are MRD positive in PB or BM will continue zanubrutinib and venetoclax for an additional 6 cycles. Obinutuzumab will be added to the oral doublet starting at cycle 17. Standard intravenous obinutuzumab lead-in will occur during cycle 17, followed by standard monthly intravenous dosing of 1000mg through cycle 22.

Depending on MRD status, subjects will be treated for 16 or 22 cycles. All subjects who receive consolidation will stop treatment at cycle 23 regardless of end of treatment MRD status. The primary endpoint is cycle 16 PB and BM MRD negativity rates. A co-primary endpoint will be cycle 23 PB and BM MRD negativity rates in subjects who were MRD positive at C16 and who went on to receive at least 1 dose of obinutuzumab. Key secondary endpoints will include cycle 16 overall response rate, 36-month progression free survival, 36-month overall survival, 36-month time to next treatment, 24- and 36-month PB MRD negativity rates, tumor lysis risk reduction rates, and safety. Exploratory endpoints will assess the positive predicative value of the ∆400 biomarker (Soumerai et al., 2021) on MRD negativity at cycle 16. This biomarker will be assessed between cycle 4 and 6.
The MRD negative rates at cycle 16 and cycle 23 will be estimated with a 90% confidence interval using the Clopper-Pearson method based on exact binomial distribution.

Enrollment:
Begins May 2023

Clinical Trials Registry #:
NCT05650723