Waveline-006: A Phase 2 Study of the Safety and Efficacy of Zilovertamab Vedotin As Monotherapy or in Combination in Patients (pts) with Aggressive and Indolent B-cell Malignancies.

TPS7595 Background: ROR1 is a transmembrane protein expressed in hematologic malignancies. Zilovertamab vedotin (ZV) is an antibody-drug conjugate comprising a humanized IgG1 monoclonal anti-ROR1, a proteolytically cleavable linker, and the antimicrotubule agent monomethyl auristatin E. Nemtabrutinib is a reversible inhibitor of Bruton’s tyrosine kinase (BTK). The combination of ZV and a BTKi has the potential for improved responses in B-cell malignancies. The waveLINE-006 study (NCT05458297) is designed to investigate safety and efficacy of ZV as monotherapy or in combination with nemtabrutinib in pts with B-cell malignancies. Methods: Eligible pts are ≥18 years old with biopsy-proven and/or histologically confirmed mantle cell lymphoma (MCL), Richter’s transformation (RT), chronic lymphocytic leukemia (CLL), or follicular lymphoma (FL), relapsed or refractory (R/R) disease, ECOG performance status of 0 to 2, and adequate organ function (table). Approximately 275 pts will be enrolled in 6 cohorts (A-F; see table). In cohorts A and B, patients will receive ZV 2.5 mg/kg IV Q3W. In cohort C, 30 patients will be enrolled in a safety run-in phase of ZV in combination with nemtabrutinib, then an additional 15 patients will receive the RP2D of the combination. Patients in cohort D (schedule optimization) will be randomized 1:1 to receive ZV 2.5 mg/kg IV Q3W (arm 1) or ZV 2.0 mg/kg IV Q2/3W (arm 2). Patients in cohorts E and F (efficacy expansion) will receive the dose and schedule of ZV determined during schedule optimization. Each recipient of ZV or nemtabrutinib will receive the assigned intervention until disease progression, unacceptable toxicity, or other discontinuation criteria are met. Tumor scans will be performed at baseline, then Q12W up to week 108, then Q24W thereafter. Adverse events (AEs) will be monitored and will be graded per NCI CTCAE version 5. The primary end points are the safety and tolerability of ZV alone (cohort D) and in combination with nemtabrutinib (cohort C), and the objective response rate of ZV alone (cohorts A, B, D, E, and F) and in combination with nemtabrutinib (cohort C). The secondary end points are the duration of response of ZV alone (cohorts A, B, D, E, and F) and in combination with nemtabrutinib (cohort C) and the safety and tolerability of ZV alone (cohorts A, B, E, and F). Clinical trial information: NCT05458297 . [Table: see text]