Preliminary safety, pharmacokinetics and pharmacodynamics of SGR-3515, a Wee1/Myt1 dual inhibitor from an ongoing Phase 1 study in participants with advanced solid tumors (SGR-3515-101)

Introduction: SGR-3515 is an oral, small molecule co-inhibitor targeting Wee1 and Myt1 kinases, which play a crucial role in regulating cell cycle and are synthetic lethal based on preclinical data. SGR-3515 has shown preclinical antitumor activity superior to single target inhibition, and is being evaluated in a Phase 1, first-in-human, dose-escalation study, SGR-3515-101, in participants with advanced solid tumors. The primary objectives of this study are to evaluate the safety, tolerability, dose-limiting toxicities (DLTs), to identify the maximum tolerated dose and recommended Phase 2 dose. Other objectives include evaluating pharmacokinetics, antitumor activity and pharmacodynamics of SGR-3515. Methods: Participants received SGR-3515 once daily on an intermittent schedule in 28-day cycles in a BOIN dose escalation design. Safety was evaluated weekly for 2 cycles, and every 2 weeks thereafter. Target inhibition of Wee1 and Myt1 in paired tumor biopsies was measured by modulation of the pCDK1 Y15 and pCDK1 T14 signal, respectively, using IHC assays. Disease assessments occurred every 8 weeks using RECIST v1.1. Results: As of 31-Oct-2025, 33 participants have been treated across 7 dose levels (15 mg-175 mg). Tumor histologies were predominantly ovarian cancer (20), ER+ breast cancer (5) and uterine cancer (5). Median lines of prior therapy: 5 (range 1-10). Eleven (11) participants remain on treatment and 22 are discontinued, mostly due to disease progression (19). Dose escalation is ongoing. The overall incidence of treatment-emergent adverse events (TEAE, any grade, ≥ G3) was 79%, 37%; treatment-related adverse events (TRAE, any grade, ≥ G3): 64%, 15%; no G5 events. Common TRAEs (≥ 10%) were nausea (27%), diarrhea (21%), fatigue (18%) and neutrophil count decreased (15%). The 4 G3 TRAEs were diarrhea (1), nausea (1), fatigue (1) and liver function tests (LFT) increased (1). The 2 G4 TRAEs were both neutrophil count decreased. Drug-related serious AEs were G3 nausea (1) and G3 LFT increased (1). There were no DLTs and 1 drug related treatment discontinuation, G3 LFT increased. Preliminary PK results demonstrated a dose-related increase in SGR-3515 plasma exposure (15-135 mg). Target inhibition of Wee1 and Myt1 was observed in paired tumor biopsies at dose levels between 30-135 mg. Preliminary antitumor activity data include stable disease in 8 of the 23 (35%) participants evaluable for efficacy across all dose levels. At 100-135 mg, 7 of the 9 (78%) evaluable participants demonstrated stable disease, 6 of which remain on treatment, median treatment duration: 165 days (range 110-292 days). Conclusion: SGR-3515 was generally well tolerated and demonstrated initial evidence of co-inhibition of Wee1 and Myt1 in tumor biopsies. Preliminary antitumor activity was demonstrated by stable disease. SGR-3515-101 (NCT06463340) continues to enroll participants that may benefit from the co-inhibition.