439TiP - AVZO-021-1001: A first-in-human open-label, multicenter phase I/II dose-escalation and expansion study evaluating AVZO-021 in adult patients with advanced solid tumors

Background

CDK2 is a novel target in cancer treatment, particularly for overcoming resistance to CDK4/6 inhibitors (CDK4/6i) in metastatic breast cancer (mBC) and targeting CCNE1-amplified tumors associated with poor clinical outcomes. AVZO-021 is an investigational, reversible, oral CDK2 inhibitor that shows nanomolar potency against CDK2 and >600-fold selectivity against CDK1 in enzymatic assays. Preclinical data support AVZO-021 as a monotherapy in CCNE1-amplified cancers and in combination with CDK4/6i in HR+/HER2- BC. Additional combinations with expected improved clinical outcomes based on mechanism of action are also planned for enrollment.

Trial design

AVZO-021-1001 trial is studying the safety, tolerability, PK, PD, and anti-tumor activity of AVZO-021. In Ph1 (Part 1a), accelerated dose-escalation followed by a BOIN design with backfilling at select doses will determine monotherapy RP2D/MTD in patients with advanced solid tumors; additionally, the food effect within a subgroup will be explored. Combination dose-escalation will be initiated with fulvestrant and current CDK4/6 inhibitors (Part 1b) in patients with HR+/HER2- mBC, and an additional combination with carboplatin (Part 1c) in patients with CCNE1-amplified metastatic endometrial ovarian cancer (EOC). Ph2 will use RP2D of monotherapy (Part 2a in CCNE1-amplified tumors) and combinations (Part 2b in HR+/HER2- BC; Part 2c in CCNE1-amplified EOC). Patients with confirmed locally advanced/metastatic disease with ≤2 lines of systemic chemotherapy, ≥1 measurable lesion by RECIST 1.1, ECOG PS ≤1, no prior treatment with CDK2, PKMYT1 or WEE1 inhibitor, and no unstable CNS metastases will be included. Ph1 primary endpoints are safety, tolerability, and PK. Ph2 primary endpoint is objective tumor response assessment by BICR per RECIST v1.1. Secondary endpoints are DOR, PFS, OS, PK, and safety; exploratory endpoints include PD and biomarker analyses. The trial is ongoing and plans to enroll patients at ∼50 centers across the US, Europe, and Australia.

Clinical trial identification

NCT05867251; AVZO-021-1001 (Release date: March 14, 2024).

Editorial acknowledgement

Medical writing and editorial support were funded by Avenzo and provided by Anuradha Kumari, PhD, of BluPrint Oncology Concepts, LLC.

Legal entity responsible for the study

Avenzo Therapeutics, Inc.

Funding

Avenzo Therapeutics, Inc.

Disclosure

A. Dowlati: Financial Interests, Advisory Board: Jazz Pharmaceuticals, AstraZeneca, Puma Biotechnology, Prelude Therapeutics, Amgen, AbbVie. D.L. Richardson: Financial Interests, Other, Advisory Board/Consulting: ImmunoGen, AstraZeneca, GSK, Mersana Therapeutics, Daiichi Sankyo, ProfoundBio, Eisai. P. Lorusso: Financial Interests, Advisory Board: AbbVie, Takeda, Agenus, IQVIA, Pfizer, GSK, QED Therapeutics, AstraZeneca, EMD Serono, Kyowa Kirin Pharmaceutical Development, Kineta, Inc., Zentalis Pharmaceuticals, Molecular Templates, ABL Bio, STCube Pharmaceuticals, I-Mab, Seagen, imCheck, Relay Therapeutics, Stemline, Compass BADX, Mekanistic, Mersana Therapeutics, BAKX Therapeutics, Scenic Biotech, Qualigen, NeuroTrials, Actuate Therapeutics, Atreca Development, Cullinan, Quanta Therapeutics, Schrodinger, Boehrigner Ingelheim; Financial Interests, Other, Advisory/Consulting Role: Roche-Genentech, SOTIO, I-Mab, Roivant Sciences; Financial Interests, Other, Data Monitoring Committee: Amgen; Financial Interests, Other, Data Safety Monitoring Board: DrenBio. A.I. Spira: Financial Interests, Advisory Role: Incyte, Amgen, Novartis, Mirati Therapeutics, Gritstone Oncology, Jazz Pharmaceuticals, Takeda, Janssen Research & Development, Mersana Therapeutics, Gritstone Bio, Daiichi Sankyo/AstraZeneca, Regeneron, Eli Lilly, Black Diamond Therapeutics, Sanofi, Array BioPharma, AstraZeneca/MedImmune, Merck, Bristol-Myers Squibb, Blueprint Medicines, BluPrint Oncology; Financial Interests, Other, Stock Options: Eli Lilly; Financial Interests, Research Funding: LAM Therapeutics, Regeneron, Roche, AstraZeneca, Boehringer Ingelheim, Astellas Pharma, MedImmune, Novartis, Incyte, AbbVie, Ignyta, Takeda, Macrogenics, CytomX Therapeutics, Astex Pharmaceuticals, Bristol-Myers Squibb, Loxo, Arch Therapeutics, Gritstone Bio, Plexxikon, Amgen, Daiichi Sankyo, ADCT, Janssen Oncology, Mirati Therapeutics, Rubius, Synthekine, Mersana Therapeutics, Blueprint Medicines, Alkermes, Revolution Medicines, Medikine, Black Diamond Therapeutics, Nalo Therapeutics, Scorpion Therapeutics, ArriVent Biopharma. B. Bashir: Financial Interests, Institutional, Research Funding: Defense Congressionally Directed Medical Research Program # W81XWH-22-1-0208, Amgen, Boehringer Ingelheim, Bicycle Therapeutics, Elucida Oncology, Gritstone Bio, Ikena Oncology, Jazz Pharmaceuticals, KAHR Medical, Lyell Immunopharma, Merck, Pionyr Immunopharma, Rascal Therapeutics, Syros Pharmaceuticals, Tarveda Therapeutics, Avenzo Therapeutics; Financial Interests, Advisory Role: Merck/Eisai, Fate Therapeutics, KAHR Medical. M. Hirmand; M. Mehta: Financial Interests, Other, Employment, Leadership Role, and Stocks/Stock Options: Avenzo Therapeutics. M.R. Patel: Financial Interests, Institutional, Research Funding: Avenzo Therapeutics.