A phase 1a/b study of RGT-61159, an oral MYB splicing modulator, in patients with advanced adenoid cystic carcinoma and colorectal cancer.

3089 Background: MYB is a master regulator of cell proliferation, self-renewal, and differentiation processes and its aberrant expression is found in multiple forms of human cancer including adenoid cystic carcinoma (ACC), acute myeloid leukemia, T-cell acute lymphoblastic leukemia, colorectal cancer (CRC), small cell lung cancer, and breast cancer. RGT-61159 is an orally available small molecule designed to selectively modulate splicing of the oncogenic transcription factor MYB, resulting in downregulation of MYB protein levels and tumor cell death. Methods: This ongoing Phase 1a/b, multi-center, open-label clinical trial evaluates RGT-61159 in patients (pts) with advanced, relapsed or refractory ACC or CRC. Pts with ACC must have disease progression within 12 months of study entry. The study employs a 3+3 dose-escalation design with daily oral dosing in 21-day cycles, starting at 6 mg and escalating using a Fibonacci scheme. Primary objectives are to assess safety and tolerability and determine the recommended Phase 2 dose (RP2D). Secondary objectives include characterization of pharmacokinetics (PK), pharmacodynamics (PD), and preliminary anti-tumor activity. Results: As of 22 December 2025, 44 pts (86% ACC, 14% CRC) were treated across 8 dose levels (6–144 mg). In pts with ACC, median age was 61 years (range: 33–77) and median prior lines of therapy was 1 (range: 0-6); 47% were female. In pts with CRC, median age was 63 years (range: 44–72) and median prior lines of therapy was 5.5 (range: 4-8); 50% were female. Dose-limiting toxicities (DLTs) occurred in three pts: G3 nausea and muscle weakness, G3 fatigue, and missed doses due to G2 atrial flutter. Treatment-emergent adverse events (TEAEs) observed in ≥20% of pts were diarrhea, nausea, fatigue, dyspnea, and anemia. One G3 vasculitis (144 mg) and dose-related inflammatory edema events (G2 at 108/144 mg; G1 at lower doses) occurred; none were protocol-defined DLTs. Overall, RGT-61159 was well tolerated at or below the provisional RP2D of 84mg. 19 pts remain on treatment, including 9 pts (all with ACC) treated from 24 to 60mg who have been on study for more than 6 months with durable stable disease. In 35 evaluable pts, 18 have had tumor regressions with one partial response (RECIST v1.1) observed in a pt with ACC treated at 60mg. After the data cut, another pt with ACC treated at 84mg also achieved a partial response. Dose-dependent, robust knockdown of MYB in the peripheral blood was observed (up to 75% at 84mg). Plasma exposure increased approximately dose-proportionally with low to moderate variability. Conclusions: RGT-61159 is well tolerated at doses at or below the provisional RP2D. Robust peripheral knockdown of MYB was observed in a dose-dependent fashion at clinically relevant doses. Clinical activity manifested as prolonged stable disease and a partial responses primarily in pt with ACC. Clinical trial information: NCT06462183 .