Zanubrutinib and Venetoclax As Initial Therapy for CLL/SLL 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). Clinical synergy of BTKi and BCL-2i combinations have been observed, which allow for an oral regimen, that can be safely administered in a clinic setting for most patients (Tam et al., 2022; Wierda et al., 2021). Still, it remains uncertain if anti-CD20 antibodies meaningfully add to the effectiveness of oral combination therapy. Recent reports of triplet regimens demonstrate modest improvement in minimal residual disease (MRD) negativity with similar 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. Recent reports suggest BTKi use may in fact impair clinical activity of anti-CD20 antibodies, which can be mitigated by using selective BTKi and incorporating anti-CD20 later in the treatment course when lower disease burden is present (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 optimized within a response-adapted strategy. This trial has been developed to assess efficacy and safety of a response adapted consolidative treatment approach utilizing obinutuzumab triplet consolidation in CLL/SLL patients who remain MRD positive after an oral doublet fixed duration treatment with zanubrutinib and venetoclax. This approach looks to maximize MRD negative remissions, spare toxicity by limiting anti-CD20 exposure, and provide a finite therapy. 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:

This is a single center, open label, phase II, investigator initiated clinical trial enrolling 50 subjects evaluating the efficacy and safety of zanubrutinib and venetoclax with obinutuzumab triplet consolidation in subjects who remain MRD positive (BruVenG). Eligible patients must have treatment naïve CLL/SLL and treatment indications per the 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.