PS5-12-17: A phase 1/2 study of AVZO-023, a next-generation selective cyclin-dependent kinase 4 inhibitor (CDK4i), as a single agent and in combination with AVZO-021, a selective cyclin-dependent kinase 2 inhibitor (CDK2i), and/or endocrine therapy in patients with advanced solid tumors

Abstract Background CDK4/6 inhibitors (CDK4/6i) have revolutionized the treatment of HR+/HER2- breast cancer (BC) but they have dose-limiting CDK6i-related hematologic toxicity, and their efficacy is also limited due to resistance secondary to CDK2 activation. Selective CDK4i may have reduced hematological toxicity and enhanced CDK4 inhibition vs CDK4/6i. In addition, combining selective CDK4i with selective CDK2i can overcome resistance. AVZO-023 is an oral, potent, next-generation CDK4i with high selectivity over CDK6 that may offer improved efficacy and tolerability vs current CDK4/6i for patients with HR+/HER2- BC. AVZO-023 showed strong anti-tumor activity in vivo, which was further enhanced in combination with the selective CDK2i AVZO-021 in palbociclib-sensitive and palbociclib-resistant xenograft models. Trial Design This Phase 1 AVZO-023-1001 trial (NCT06998407) will assess the safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity of AVZO-023 as a single agent and in combination with endocrine therapy and/or AVZO-021. HR+/HER2- BC patients represent the key patient population of interest that will be enrolled in this study. Eligible patients have ECOG PS of ≤1, ≤3 lines of chemotherapy/antibody-drug conjugate therapy, no prior exposure to investigational CDKi, and no unstable CNS metastases. Part A will study AVZO-023 monotherapy. Accelerated titration will be used for the first 3 dose levels of AVZO-023, followed by additional dose levels using a BOIN design. A food effect cohort will also be enrolled. Part B will study the combination of AVZO-023 + AVZO-021. Patients with HR+/HER2- BC enrolled in Parts A or B will have the option to add fulvestrant to their study treatment. Part C will study the combination of AVZO-023 + letrozole ± AVZO-021. Backfill enrollment of patients is planned in this study. Primary objectives are safety/tolerability and secondary objectives include preliminary anti-tumor activity. The trial has activated and will enroll patients at approximately 50 centers across North America, Europe and the Asia-Pacific region. Citation Format: T. A. Yap, N. P. McAndrew, D. K. Marks, A. I. Spira, D. Sommerhalder, M. Hirmand, S. Thamake, M. Mehta, A. Giordano. A phase 1/2 study of AVZO-023, a next-generation selective cyclin-dependent kinase 4 inhibitor (CDK4i), as a single agent and in combination with AVZO-021, a selective cyclin-dependent kinase 2 inhibitor (CDK2i), and/or endocrine therapy in patients with advanced solid tumors [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-12-17.