3008 - An ongoing first-in-human phase 1 trial of NX-5948, an oral Bruton’s tyrosine kinase (BTK) degrader, in patients with relapsed/refractory B cell malignancies, including chronic lymphocytic leukemia (CLL)

Background: BTK plays a central role in the B cell receptor (BCR) signaling pathway and is involved in the pathogenesis of several B cell malignancies. In various B cell malignancies, including CLL, BTK mutations confer broad resistance to both covalent and non-covalent BTK inhibitors, limiting their utility in later lines of therapy. Surprisingly, some of these mutations render BTK ‘kinase dead’ while preserving enhanced oncogenic BCR signaling, pointing to a scaffolding function of BTK. Novel therapeutics that can overcome emerging resistance mutations may represent an alternative treatment option for patients with CLL who have developed resistance to BTK inhibitors or in B cell indications where treatment with BTK inhibitors has been less effective [Wang et al. N Engl J Med 2022]. NX-5948 is a novel, orally administered small molecule that induces BTK degradation via recruitment of the cereblon E3 ubiquitin ligase complex, without inducing degradation of other cereblon neo-substrates. NX-5948 induces sub-nanomolar potency degradation of both wild-type and known mutant forms of BTK in vitro [Noviski et al. AACR 2023], demonstrating rapid in vivo degradation in mouse and non-human primate B cells within two hours of oral administration [Robbins et al. ASH 2021]. In addition to efficacy in subcutaneous tumor models, NX-5948 can cross the blood-brain barrier and degrade BTK intracranially, translating to preclinical efficacy in mouse brain lymphoma disease models [Robbins et al. ASH 2021]. This abstract describes the design and status of an ongoing phase 1 trial of NX-5948 in patients with relapsed/refractory B cell malignancies, including CLL.

Methods: NX-5948-301 is a first-in-human, dose-escalation (phase 1a) and cohort-expansion (phase 1b) study designed to evaluate the safety, tolerability, and preliminary efficacy of NX-5948 in adult patients with relapsed/refractory B cell malignancies, including CLL (NCT05131022; see figure). Phase 1a will evaluate safety and tolerability of NX-5948 in patients with relapsed/refractory CLL, small lymphocytic lymphoma (SLL), non-germinal center B-cell (non-GCB) diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), and Waldenström macroglobulinemia (WM), including those with secondary central nervous system (CNS) involvement in any disease indication listed or primary CNS lymphoma (PCNSL). Phase 1b will investigate longer-term safety and anti-tumor activity of NX-5948 at the recommended dose(s) selected in phase 1a in patients with relapsed/refractory B cell malignancies across four cohorts. Key eligibility criteria include: ≥two prior lines of therapy; measurable disease per indication-specific response criteria; and an Eastern Cooperative Oncology Group (ECOG) score of 0–2. NX-5948 is given orally, once daily, with dose escalation according to a standard 3+3 design. Dose-limiting toxicities will be assessed following the first cycle (28 days) of therapy. The recommended phase 1b dose(s) will be determined following assessment of PK/PD, safety, and anti-tumor activity. Approximately 110 patients (30 in phase 1a, 80 in phase 1b) may be enrolled and treated until confirmed progression or unacceptable toxicity. Enrollment in the phase 1a portion of this study is underway in the UK and the US, and is anticipated to begin in the Netherlands in 2023.