Phase 1/2 study of ARTS-021, a potent, oral administrated, selective CDK2 inhibitor, in advanced or metastatic solid tumors.

Abstract

e17546 Background: ARTS-021 is an investigational, reversible, orally available CDK2 selective inhibitor that inhibits CDK2 at nanomolar potency and with over 600-fold selectivity against CDK1 (Liang J et al. AACR 2022). ARTS-021 has shown promising preclinical data, including strong single agent antitumor activity in CCNE1 amplified patient derived xenografts (PDX). Furthermore, consistent with the hypothesis that CDK2 activity may mediate resistance to CDK4/6 inhibitors, ARTS-021 significantly enhanced Palbociclib anti-tumor activity in an estrogen positive (ER+) breast cancer xenograft model. Taken together, these data support the clinical development of ARTS-021 as a monotherapy in CCNE1-amplified cancers and in combination with CDK4/6 inhibitors in ER+ breast cancer. Methods: A first in human, open label, multicenter phase1/2 dose escalation and dose expansion study will be conducted to evaluate the safety, tolerability, PK, pharmacodynamics (PD), and anti-tumor activity of ARTS-021 1) as a single agent in advanced or metastatic solid tumors harboring CCNE-1 gene amplification; 2) in combination with carboplatin to treat refractory/resistant CCNE-1 amplified ovarian cancer that has failed standard therapies; 3) in combination with endocrine therapy and CDK4/6 inhibitor to treat ER+/HER2- breast cancer patients have failed standard therapies. The phase 1 (dose-escalation) portion of the trial will have an accelerated dose escalation followed by a Bayesian Optimal Interval (BOIN) design. After the monotherapy recommended phase 2 dose (R2PD) is identified, the combination arms will be initiated at one dose level below the monotherapy R2PD. Phase1 primary endpoints are assessment of safety, tolerability, and pharmacokinetics (PK). The secondary endpoint is preliminary efficacy. Once the RP2D is defined for both monotherapy and in combination, the trial will be advanced into three Phase 2 expansion cohorts: monotherapy cohort (basket cohort), combination with carboplatin (ovarian cohort), and combination with endocrine therapy + CDK4/6 inhibitor (ER+ breast cancer cohort). The phase 2 primary end point is to estimate the anti-tumor efficacy in CCNE1 amplified cancer patients or CDK4/6 inhibitor resistant breast cancer patients. Objective tumor response rate will be measured per RECIST v1.1. The secondary endpoint of Phase 2 study will be safety/tolerability. Archival tumor and paired fresh tumor biopsy will be collected throughout the study for exploratory pharmacodynamics (PD) and biomarker evaluation. Results: ARTS-021 clinical study is ongoing. Conclusions: ARTS-021 shows potential anti-tumor activities.