819TiP - FONTANA: A phase I/IIa study of AZD5335 as monotherapy and in combination with anti-cancer agents in patients with solid tumours

Background

Folate receptor α (FRα), a cell-surface protein encoded by the folate receptor 1 gene, is upregulated in epithelial ovarian cancers and lung adenocarcinomas. AZD5335 is an antibody-drug conjugate comprising an antibody portion that binds with high affinity to FRα conjugated to a topoisomerase 1 inhibitor (TOP1i) payload. Upon binding, AZD5335 releases TOP1i within the cell. The TOP1i payload then traps TOP1 on the replicating DNA and induces DNA double-strand breaks, ultimately resulting in cell death. AZD5335 is active in preclinical models of high-grade ovarian cancer (Gymnopoulos et al. Presented at AACR 2023; abstract LB025).

Trial design

FONTANA (NCT05797168) is a modular, first-in-human, open-label, multicentre study of AZD5335 in patients with advanced solid tumours. The study will evaluate AZD5335 as monotherapy in patients with ovarian cancer or lung adenocarcinoma (Module 1), or AZD5335 in combination with AZD5305, a selective poly(ADP-ribose) polymerase 1 inhibitor, in patients with ovarian cancer (Module 2). Each module consists of a dose-escalation and dose-optimisation cohort. Key features of this study include the use of randomised dose-optimisation cohorts and a Bayesian-logistic regression model-based dose escalation in Module 2. Eligible patients are aged ≥18 years, ECOG performance status 0–1, must have received prior therapy, and have adequate organ and marrow function. Asymptomatic and stable brain metastases are allowed. The primary objectives are to assess the safety and tolerability, and to establish the dose limiting toxicity. Secondary objectives include assessment of objective response rate, duration of response, disease control rate, and progression-free survival by RECIST v1.1, and overall survival; characterising the pharmacokinetics of AZD5335 when given as monotherapy or in combination; and assessing immunogenicity. The study will be open to recruitment by 25 May 2023.

Clinical trial identification

NCT05797168.

Editorial acknowledgement

This study was funded by AstraZeneca. Medical writing support for this abstract, under the direction of the authors, was provided by Asad Mustafa of Ashfield MedComms, an Inizio company, and was funded by AstraZeneca.

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Disclosure

F. Meric-Bernstam: Financial Interests, Personal, Other, Consultant: AstraZeneca, F. Hoffmann-La Roche Ltd., Zymeworks, OnCusp Therapeutics; Financial Interests, Personal, Advisory Board, Advisory Board/Consultant: Seagen; Financial Interests, Personal, Advisory Board: Zentalis, Karyopharm, Biovica, Eisai, Protai, TheraTechnologies; Financial Interests, Personal, Other, Consulting: Tallac Therapeutics, Lengo Therapeutics, Loxo Oncology, Black Diamond, Infinity Pharmaceuticals, AbbVie, GT Aperion, Ecor1; Financial Interests, Personal, Other, Consutling: Menarini Group; Financial Interests, Institutional, Other, Local PI / Research Grant: Aileron Therapeutics, Bayer Healthcare, CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., eFFECTOR Therapeutics, Taiho Pharmaceutical Co.; Financial Interests, Institutional, Other, Local PI / Research Grant / Coordinating PI: AstraZeneca; Financial Interests, Institutional, Local PI: Calithera Biosciences, Curis Inc., Debiopharm International, Guardant Health Inc., Klus Pharma, Novartis; Financial Interests, Institutional, Other, Local PI / Steering Committee Member: Genentech Inc.; Financial Interests, Institutional, Research Grant: Takeda Pharmaceutical Co., Puma Biotechnology Inc., Repare; Other, Travel support: European Organisation for Research and Treatment of Cancer (EORTC), European Society for Medical Oncology (ESMO); Other, Travel Support: Cholangiocarcinoma Foundation. S.N. Westin: Financial Interests, Institutional, Research Grant: AstraZeneca, AvengeBio, Bayer, BioPath, Clovis Oncology, GSK, Mereo, Novartis, Roche/Genentech, Zentalis; Financial Interests, Principal Investigator: AstraZeneca, Mereo, Zentalis; Financial Interests, Personal, Advisory Role: AstraZeneca, Caris, Clovis Oncology, Eisai, EQRX, GSK, ImmunoGen, Lilly, Merck, Mereo, Mersana, NGM Bio, Nuvectis, Roche/Genentech, Seagen, Verastem, Vincerx, Zentalis, ZielBio. G. Au-Yeung: Financial Interests, Institutional, Research Grant: AstraZeneca, Roche/Genentech. P. Mitchell, C. Myers, M. Gymnopoulos, M. Nawinne: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. P.G. Fraenkel, T. Brier: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. L. Mileshkin: Financial Interests, Institutional, Coordinating PI, Institutional funding from BeiGene for an investigator-initiated trial: BeiGene; Non-Financial Interests, Other, Co-chair of the Steering Committee for the CUPISCO trial in CUP (non-remunerated): Roche; Non-Financial Interests, Member, Member of multiple other cancer organisations as above: ASCO, MOGA, COSA, IGCS, GCIG. All other authors have declared no conflicts of interest.