The WEE1 Inhibitor APR-1051 Shows Early Safety and Tolerability in Advanced, Mutated Solid Tumors

Treatment with the orally bioavailable, small molecule inhibitor APR-1051 appears safe and well tolerated in patients with advanced solid tumors and select cancer-associated gene alterations, according to preliminary data from the first-in-human phase 1 ACESOT-1051 study (NCT06260514) presented at the 36th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics.

Investigators shared data on 3 patients enrolled onto the study, stating that as of October 7, 2024, 1 patient who was treated with 30 mg of the agent had been on treatment for 6 days; 1 patient treated with 20 mg of the agent remained on treatment for 36 days; and 1 patient treated with 10 mg of the agent was treated for 50 days. The first patient is continuing treatment, the second patient withdrew consent, and the third patient had progressive disease.

“Preliminary results indicate APR-1051 is safe and well tolerated with no hematologic toxicity and 1 possible treatment-related grade 1 AE at the dose levels assessed,” study authors wrote in a poster presentation of the data.

In several cancer models, APR-1051 has previously demonstrated in vivo anti-proliferative activity, positioning it as a potential therapeutic anticancer agent with high potency and selectivity with favorable drug exposure and tumor concentration. This is due to the agent’s low off-target inhibition of PLK1, PLK2, and PLK3, which differentiates it from other WEE1 inhibitors and may confer an improved toxicity profile compared with other inhibitors in this class. These findings led investigators to assess the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of single-agent APR-1051 in patients with advanced solid tumors harboring cancer-associated gene alterations.

Eligible patients for ACESOT-1051 include those who are 18 years of age or older with an ECOG performance status of 0 or 1 (or a Karnofsky performance sale of at least 70); a diagnosis of an advanced or metastatic solid tumor that is locally advanced and not amenable to curative therapy or a diagnosis of stage IV disease with specific gene alterations; measurable disease per RECIST 1.1 criteria; no grade 2 or higher adverse effects (AEs) from prior treatment, and adequate bone marrow and organ function. Patients with uterine serous carcinoma are permitted to enroll regardless of biomarker status.

Exclusion criteria for the study include prior systemic anticancer therapy within 3 weeks or at least 5 half-lives prior to the first day of APR-1051 treatment; treatment with an investigational agent within 30 days or 5 half-lives before the first day of APR-1051 treatment; prior WEE1 inhibitor therapy; or concomitant treatment with other anticancer therapy.

Part 1 of the 2-part study is designed to investigate dose escalation in up to 39 patients. Part 2 will investigate dose selection in up to 40 patients. In the dose-escalation portion of the investigation, the doses begin at 10 mg at dose level 1 and continue through 150 mg at dose level 8. In part 2, patients will be randomly assigned 1:1 to receive APR-1051 at 1 of 2 selected dose levels and continue treatment until a recommended phase 2 dose (RP2D) is determined.

The primary objectives of the study include the characterization of safety, dose-limiting toxicity (DLT), the maximum tolerated dose (MTD) or maximum administered dose, and the RP2D. The primary end points consist of AEs; DLTs; and changes in physical examinations, performance status, and clinical laboratory values from baseline.

Secondary objectives include the characterization of pharmacokinetics and evaluation of the preliminary efficacy of the treatment. Secondary end points include the measurement of AUC_0-t, AUC_0-∞, T_max, C_max, t_1/2, C_min, and the use of RECIST 1.1 and Prostate Cancer Clinical Trials Working Group 3 guidelines to assess metastatic castration-resistant prostate cancer.

Exploratory objectives and end points include pharmacodynamic effects, as well as CCNE1 or CCNE2 overexpression, FBXW7 loss-of-function mutation, PPP2R1A loss-of-function mutation, and KRAS GLY12 or GLY13 with TP53 co-mutation evaluation assessment.

Regarding the patient characteristics of the 3 enrolled patients in the preliminary analysis, 2 were male, 1 was female, and the median age was 70 years (range, 53-80). One patient was American Indian or Native Alaskan, 1 patient was White, and 1 patient did not report their race. All 3 patients had an ECOG performance status of 1. Additionally, the median number of prior lines of systemic chemotherapies was 3 (range, 3-5); 2 patients had received 3 to 4 prior lines, and 1 patient received more than 4 prior lines.

All 3 patients had previously received taxane-based treatment, and 2 had received platinum-containing chemotherapy; 1 patient each was previously treated with an EGFR inhibitor, a VEGF inhibitor, a topoisomerase inhibitor, and an investigational agent, respectively. All 3 patients presented with CCNE1 mutations, 2 patients had KRAS mutations, and 2 patients had TP53 mutations. Two patients had pancreatic cancer, and 1 patient had gastric cancer.

Regarding all-cause AEs, patients experienced grade 1 and 2 constipation, grade 1 and 2 vomiting, grade 3 gastric obstruction, grade 1 hypoalbuminemia, grade 1 hypocalcemia, grade 1 hyperkalemia, grade 2 decreased appetite, grade 2 fatigue, grade 1 general edema, and grade 2 hiccups. Notably, 1 instance of grade 1 abdominal distension was reported to be possibly related to APR-1051.

“The study is currently enrolling into cohort 3 of the accelerated titration dose-escalation [portion],” study authors concluded in the poster. “Active enrollment is ongoing at 3 sites in the United States with additional sites planned.”

Reference

Yap TA, Sommerhalder D, Cheedella NKS, et al. Preliminary results of APR-1051, a WEE1 inhibitor, in a phase 1 study of patients with cancer-associated gene alterations (ACESOT-1051). Presented at: EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics; October 23-25, 2024; Barcelona, Spain. Poster PB065.