First-in-human phase 1 dose escalation and expansion study of PIN-5018, a CK1α-selective molecular glue degrader, in patients with advanced solid tumors.

Abstract

TPS3168 Background: Casein kinase 1 alpha (CK1α) is a serine/threonine kinase involved in multiple oncogenic signaling pathways regulating cell proliferation, differentiation, and survival. Dysregulation of CK1α has been implicated across several solid tumor types, supporting its evaluation as a therapeutic target. PIN-5018 is an orally administered, CK1α-selective molecular glue degrader designed to induce targeted proteasomal degradation of CK1α via cereblon-mediated ubiquitination. Previously presented preclinical studies have demonstrated selective CK1α degradation and antitumor activity in multiple solid tumor models, providing the scientific rationale for first-in-human clinical evaluation. In addition to safety and dose optimization, the study incorporates tumor- and blood-based correlative analyses to characterize CK1α degradation and downstream pathway modulation. Methods: PIN-5018-001 is an ongoing, first-in-human, open-label, multicenter phase 1 study evaluating PIN-5018 in patients with progressive, locally advanced (unresectable), or metastatic solid tumors who have exhausted standard treatment options. The study consists of a dose escalation phase followed by dose expansion at selected dose levels based on safety, pharmacokinetics, and preliminary antitumor activity. PIN-5018 is administered orally once daily in 21-day cycles (14 days on treatment followed by 7 days off). Dose escalation evaluates six planned dose levels (10–100 mg) using a Bayesian Optimal Interval (BOIN) design with a target dose-limiting toxicity rate of 25%. Dose-limiting toxicities are assessed during Cycle 1. Up to 36 patients may be enrolled in dose escalation, with plan to add dose optimization and dose expansion cohorts. Eligible patients are adults (≥18 years) with ECOG performance status 0–1 and at least one measurable lesion per RECIST v1.1. Mandatory pre-treatment and on-treatment tumor biopsies are required when medically feasible to support correlative biomarker analyses. Enrollment has begun. Cohort 1 has been completed without DLT, and enrollment to subsequent cohorts is ongoing. Clinical trial information: KCT0011322.