APR-1051, an orally bioavailable small molecule WEE1 inhibitor, is showing promising early safety and tolerability in patients with advanced solid tumors harboring cancer-associated gene alterations. These findings come from preliminary data of the first-in-human phase 1 ACESOT-1051 study (NCT06260514).
Initial Patient Data
As of October 7, 2024, data were shared on three patients enrolled in the study. One patient, treated with 30 mg of APR-1051, had been on treatment for 6 days. Another patient, receiving 20 mg, remained on treatment for 36 days, while the third patient, treated with 10 mg, was treated for 50 days. While the first patient continued treatment, the second withdrew consent, and the third experienced progressive disease.
According to the study authors, the preliminary results suggest that APR-1051 is safe and well-tolerated, with no hematologic toxicity observed and only one possible treatment-related grade 1 adverse event (AE) reported at the dose levels evaluated.
Mechanism and Rationale
APR-1051 has demonstrated in vivo anti-proliferative activity in several cancer models, marking it as a potential therapeutic anticancer agent. It exhibits high potency and selectivity, with favorable drug exposure and tumor concentration. This is attributed to the agent’s low off-target inhibition of PLK1, PLK2, and PLK3, differentiating it from other WEE1 inhibitors and potentially leading to an improved toxicity profile.
Investigators are assessing the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of single-agent APR-1051 in patients with advanced solid tumors with cancer-associated gene alterations.
Study Design and Eligibility
The ACESOT-1051 trial includes patients aged 18 years or older with an ECOG performance status of 0 or 1, diagnosed with advanced or metastatic solid tumors not amenable to curative therapy or stage IV disease with specific gene alterations. Measurable disease per RECIST 1.1 criteria, no grade 2 or higher AEs from prior treatment, and adequate bone marrow and organ function are also required. Patients with uterine serous carcinoma are eligible regardless of biomarker status.
Exclusion criteria include prior systemic anticancer therapy within 3 weeks or 5 half-lives before APR-1051 treatment, treatment with an investigational agent within 30 days or 5 half-lives, prior WEE1 inhibitor therapy, or concomitant anticancer therapy.
Trial Structure and Objectives
The study is divided into two parts. Part 1 involves dose escalation in up to 39 patients, starting at 10 mg and increasing to 150 mg. Part 2 will investigate dose selection in up to 40 patients, randomized 1:1 to receive APR-1051 at one of two selected dose levels, continuing until a recommended phase 2 dose (RP2D) is determined.
The primary objectives are to characterize safety, dose-limiting toxicity (DLT), the maximum tolerated dose (MTD) or maximum administered dose, and the RP2D. Primary endpoints include AEs, DLTs, and changes in physical examinations, performance status, and clinical laboratory values from baseline.
Secondary objectives include characterizing pharmacokinetics and evaluating preliminary efficacy, with endpoints including AUC0-t, AUC0-∞, Tmax, Cmax, t1/2, Cmin, and assessment using RECIST 1.1 and Prostate Cancer Clinical Trials Working Group 3 guidelines.
Exploratory objectives include assessing pharmacodynamic effects, CCNE1 or CCNE2 overexpression, FBXW7 loss-of-function mutation, PPP2R1A loss-of-function mutation, and KRAS GLY12 or GLY13 with TP53 co-mutation.
Patient Characteristics and Adverse Events
The preliminary analysis included two male and one female patient, with a median age of 70 years (range, 53-80). All three patients had an ECOG performance status of 1 and a median of 3 prior lines of systemic chemotherapies (range, 3-5). All patients had previously received taxane-based treatment, and two had received platinum-containing chemotherapy. Common mutations included CCNE1, KRAS, and TP53. Two patients had pancreatic cancer, and one had gastric cancer.
Reported all-cause AEs included 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. One instance of grade 1 abdominal distension was possibly related to APR-1051.
Ongoing Enrollment
The study is currently enrolling into cohort 3 of the accelerated titration dose-escalation portion, with active enrollment ongoing at three sites in the United States and additional sites planned.
