BELLWAVE-003: A phase 2 dose escalation, confirmation, and cohort expansion study of nemtabrutinib in hematologic malignancies.

TPS7593 Background: Bruton tyrosine kinase (BTK) inhibitors (BTKi) have transformed the treatment of several hematologic malignancies. However, acquired resistance, commonly associated with BTK C481S mutations, can develop. Nemtabrutinib (MK-1026, formerly ARQ 531) is a noncovalent, competitive inhibitor of both wild type and C481S-mutant BTK that has shown promising antitumor activity at 65 mg once daily (QD) in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). BELLWAVE-003 (NCT04728893) is an open-label, phase 2 study investigating the safety and efficacy of nemtabrutinib in patients (pts) with R/R B-cell malignancies. Methods: BELLWAVE-003 includes a dose escalation and confirmation phase (part 1) and a cohort expansion phase (part 2). Enrollment of 450 pts is planned. Part 1 will enroll approximately 30 pts, with a minimum of 6 and maximum of 20 per dose level. Part 2 will enroll approximately 420 pts. All pts must be ≥18 years and have an ECOG performance status of 0 to 2. Part 1 will enroll pts with CLL/SLL that was R/R after ≥2 prior therapies. Part 2 will enroll pts in 8 cohorts: CLL/SLL that is R/R to a covalent irreversible BTKi and a BCL2 inhibitor, and, for pts with CLL, R/R to or ineligible for a PI3K inhibitor (cohort A); R/R CLL/SLL that is BTKi–naive (cohort B); del17p or TP53-mutant R/R CLL/SLL (cohort C); R/R Richter transformation (cohort D); R/R mantle cell lymphoma, including prior covalent BTKi (cohort E); R/R marginal zone lymphoma, including prior covalent BTKi (cohort F); R/R follicular lymphoma (cohort G); and R/R Waldenström’s macroglobulinemia, including prior covalent BTKi (cohort H). Initially, pts received nemtabrutinib 80 mg QD orally at dose level 1. Data from BELLWAVE-001 and BELLWAVE-003 subsequently established nemtabrutinib 65 mg QD as the recommended phase 2 dose (RP2D) for future pt enrollment. Treatment will continue until unacceptable toxicity, disease progression, or withdrawal. Adverse events will be monitored throughout and graded using NCI CTCAE version 5.0. Hematologic toxicities in pts with CLL will be assessed using iwCLL 2018 criteria. CT/MRI and/or PET will be performed every 12 weeks, unless needed more frequently. For part 1, the primary end points are safety and tolerability and establishing the RP2D; secondary end points are pharmacokinetics (PK), ORR, and DOR. For part 2, the primary end point is ORR; secondary end points are safety and tolerability, PK, and DOR; and exploratory end points include PFS, OS, and health-related quality of life. Safety and efficacy will be assessed in all pts who receive ≥1 dose of study drug. Pts receiving nemtabrutinib 80 mg and 65 mg QD will be analyzed separately. Safety will be summarized descriptively. ORR and 95% CI will be estimated using an exact binomial method. DOR, PFS, and OS will be estimated using the Kaplan-Meier method. Enrollment for this study is ongoing. Clinical trial information: NCT04728893 .