CELESTIAL-TNCLL: an ongoing, open-label, multiregional, phase 3 study ofsonrotoclax (BGB-11417) + zanubrutinib vs venetoclax + obinutuzumab for treatmentnaive (TN) CLL

Authors: Piers Patten,1,2 Arnon P. Kater,3 Jennifer Ann Woyach,4 Jianyong Li,5 Talha Munir,6Tommi Salmi,7 Patrick Phuong,8 Tian Tian,8 Mazyar Shadman9
Affiliations: 1Comprehensive Cancer Centre, King's College London, London, UK; 2King's
College Hospital, London, UK; 3Lymphoma and Myeloma Research Amsterdam, Amsterdam,
the Netherlands; 4Ohio State University Comprehensive Cancer Center, Columbus, OH,USA; 5The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital,Nanjing, China; 6St James's Hospital, Leeds Teaching Hospitals NHS Trust, Leeds, UK;7

BeiGene International GmbH, Basel, Switzerland; 8BeiGene USA, Inc, San Mateo, CA, USA;

9Fred Hutchinson Cancer Research Center, Seattle, WA, USA

Background: The combination of venetoclax (ven), the first-generation BCL2 apoptosis
regulator (BCL2) inhibitor, and ibrutinib, a BTK inhibitor, has demonstrated efficacy in patientswith CLL (Wierda et al. J Clin Oncol. 2021). However, the toxicity profile of this regimen
suggests a need for a more tolerable combination of BTK and BCL2 inhibitors. Sonrotoclax, anext-generation BCL2 inhibitor, is a more selective and more pharmacologically potent
inhibitor of BCL2 than ven. Z . In a phase 1 study in patients with TN CLL treated withsonrotoclax + zanubrutinib, efficacy data was promising, with ORR and 1-year progressionfree survival (PFS) rate of 100% and deep responses on the basis of undetectablemeasurable residual disease at <10-4 sensitivity (uMRD4). The most common grade ≥3 TEAE
was neutropenia, and no tumor lysis syndrome or cardiac toxicity was observed (Tam et al.
Blood. 2023). Presented here is the design of a phase 3 trial aimed at comparing the efficacyof sonrotoclax + zanubrutinib vs ven + obinutuzumab (obi) in patients with TN CLL.
Methods: CELESTIAL-TNCLL (BGB-11417-301; NCT06073821) is a randomized, openlabel, phase 3 study. Eligible patients must have previously untreated CLL that requires
treatment per 2018 iwCLL criteria, measurable disease by CT/MRI, an ECOG performance
score of 0 to 2, and adequate hematologic and organ function. Approximately 640 patients
will be randomized 1:1 to receive either three cycles of oral zanubrutinib monotherapy (320mg daily) followed by zanubrutinib + sonrotoclax for 12 cycles, or standard ven + obi
EHA 2024

treatment for 12 cycles. Randomization will be stratified by age (<65 vs ≥65 years) and IGHVand del(17p)/TP53 mutation status. The primary endpoint is PFS as assessed byindependent review committee (IRC) according to 2018 iwCLL guidelines, with modifications
for treatment-related lymphocytosis in patients with CLL (Cheson et al. J Clin Oncol. 2012).
Key secondary endpoints include complete response rate (CRR), defined as CR or CR withincomplete hematopoietic recovery, assessed by IRC; rates of uMRD4 in bone marrow andperipheral blood at the first post-treatment follow-up visit based on next-generation
sequencing by clonoSEQ (Adaptive Biotechnologies, Seattle, WA); and overall survival.
Other secondary endpoints include PFS as assessed by investigator (INV); CRR by INV; rateof uMRD4 based on flow cytometry; overall response rate by IRC and INV; duration ofresponse by IRC and INV; patient-reported outcomes; and safety and tolerability.
Recruitment is ongoing.

EHA 2024