Early results from the first-in-human phase 1 study of WEE1 inhibitor APR-1051 in patients with advanced solid tumors (ACESOT-1051).

Abstract

3107 Background: WEE1 tyrosine kinase regulates cell cycle checkpoints (G1-S, G2-M) and DNA damage responses. Inhibiting WEE1 can force premature mitotic entry and subsequent apoptosis. APR-1051 is a highly potent, orally bioavailable WEE1 inhibitor (WEE1i) with in vivo anti-proliferative activity. Low off-target inhibition of APR-1051 on PLK kinases (PLK1, PLK2, PLK3) differentiates it from other WEE1i’s and may confer improved safety. Methods: This open-label dose escalation (BOIN) and dose selection optimization study is evaluating APR-1051 using a once-daily (QD) regimen. The study is currently enrolling at 220 mg at three US sites (NCT06260514). Primary study objectives are to characterize the safety, dose-limiting toxicity (DLT), maximum tolerated dose/maximum administered dose, and recommended phase 2 dose of APR-1051. Secondary objectives include evaluating APR-1051 pharmacokinetic properties and preliminary efficacy (RECIST v1.1; PCWG3 criteria for mCRPC). Key inclusion criteria are age ≥ 18 years with advanced solid tumor and cancer-associated gene alterations, prior standard-of-care systemic treatment, and ECOG PS 0 or 1. Key exclusion criteria are prior WEE1i use, CNS metastases/unstable involvement, secondary malignancies requiring therapy, and concomitant moderate/strong inhibitors/inducers of CYP3A4/5, MDR1, or BCRP. Results: As of January 16, 2026, 22 patients (median age 62 years [range: 40–86]; have been enrolled up to the 220 mg dose level. Most (n=13, 59%) cases were colorectal cancers (colon [n=9, 41%], rectal [n=4, 18%]) followed by uterine (n=3, 14%), pancreatic (n=2, 9%), and breast, gastric, oropharyngeal, and soft tissue cancer (each n=1, 5%). The median prior lines of treatments was 3. Any grade adverse event (AE) was report in 21 (95%) patients. Treatment-related AEs were reported in 12 (55%) patients; 10 (45%) patients had non-serious gastrointestinal events. Twelve (55%) patients had 18 unique serious AEs, including one death on treatment unrelated to APR-1051 and one DLT of grade 3 elevated liver enzymes (AST, ALT) probably related to APR-1051 (n=1, 5%). Antitumor activity was observed in one (5%) patient with uterine serous carcinoma treated with APR-1051 150 mg who had an unconfirmed partial response—50% reduction in target lesion size (RECIST v1.1) and > 90% reduction in CA-125 tumor marker—at per protocol 8-week assessment. Five (23%) patients had stable disease: oropharyngeal cancer (APR-1051 70 mg [n=1, 5%]); colon, rectal, uterine cancer (100 mg [n=3, 14%]); colon cancer (150 mg [n=1, 5%]). A dose proportional increase in exposure was observed. Conclusions: In the ongoing trial, continuous, oral APR-1051 QD has a manageable safety profile with preliminary signals of antitumor activity in patients with pretreated advanced solid tumors. Clinical trial information: NCT06260514 .