2028TiP - Phase I, non-randomised, open-label, multi-centre dose escalation trial of BI 764532 (DLL3/CD3 IgG-like T cell engager [TcE]) + ezabenlimab (anti-PD-1 antibody) in patients (pts) with small cell lung cancer (SCLC) and other neuroendocrine carcinomas (NECs) expressing DLL3

Background

The inhibitory Notch ligand, DLL3, is highly expressed on the cell surface of SCLC and NECs, and is a promising drug target. BI 764532 is a DLL3/CD3 IgG-like TcE that has shown potent preclinical anti-tumour activity in DLL3-positive cells and xenograft models. Preliminary results from an ongoing phase I dose-escalation study (NCT04429087) show that BI 764532 has manageable toxicity and promising efficacy. The mode of action of BI 764532 has been shown to upregulate the PD-(L)1 pathway in preclinical studies, as a result of inducing an inflamed tumour environment. Further in vitro investigation demonstrated that BI 764532-induced upregulation of PD-(L)1 may reduce its potency, but that this could be overcome by the addition of ezabenlimab (anti-PD-1 antibody). Therefore, this trial is being conducted to explore the combination of BI 764532 + ezabenlimab in a clinical setting.

Trial design

This is a phase I, non-randomised, open-label, multicentre dose-escalation trial of BI 764532 + ezabenlimab in ∼30 pts with DLL3-positive SCLC/NECs who have failed/are not eligible for available standard therapy. Pts recruited from ∼5–10 centres across several regions globally will receive intravenous BI 764532 + ezabenlimab. Key inclusion criteria will include: ≥18 years of age; Eastern Cooperative Oncology Group performance status 0/1 and ≥1 measurable target lesion (RECIST v1.1). Key exclusion criteria will include: previous TcE/DLL3-targeting therapies; active autoimmune disease and prior anti-cancer therapy. The primary objectives are to evaluate the dose-toxicity relationship and to determine the maximum tolerated dose (MTD) of BI 764532 + fixed-dose ezabenlimab; a recommended dose for expansion/recommended phase II dose will also be determined. In the dose escalation part, the primary endpoint is dose-limiting toxicity (DLT) occurrence in the MTD evaluation period; secondary endpoints include DLT occurrence in the on-treatment period, objective response and pharmacokinetics. Enrolment is ongoing.

Clinical trial identification

Editorial acknowledgement

Medical writing support for the development of this abstract, under the direction of the authors, was provided by Steven Kirkham, PhD, of Ashfield MedComms, an Inizio company, and funded by Boehringer Ingelheim.

Legal entity responsible for the study

Boehringer Ingelheim.

Funding

Boehringer Ingelheim.

Disclosure

J. Mazieres: Financial Interests, Personal, Speaker, Consultant, Advisor: Roche, AstraZeneca, BMS, MSD, Daiichi Sankyo, Novartis, Amgen; Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Pierre Fabre, Takeda, BMS, MSD, Jiangsu Hengruii, Blueprint, Daiichi Sankyo, Novartis, Amgen, Lilly, Merck; Financial Interests, Institutional, Research Grant: Roche, AstraZeneca, Pierre Fabre, BMS; Financial Interests, Institutional, Principal Investigator: Roche, AstraZeneca, Pierre Fabre, Takeda, BMS, MSD, Jiangsu Hengruii, Blueprint, Daiichi Sankyo, Novartis, Amgen, Sanofi, Pfizer, Merck, Boehringer. M. Duruisseaux: Financial Interests, Personal, Advisory Board: Amgen, Pfizer, Novartis, Eli Lilly, Boehringer Ingelheim, BMS, MSD, Roche, AbbVie, Takeda, AstraZeneca, Janssen-Cilag, GSK, Sanofi; Financial Interests, Personal, Other, Travel: Amgen, Pfizer, Novartis, Eli Lilly, Boehringer Ingelheim, BMS, MSD, Roche, AbbVie, Takeda, AstraZeneca, Janssen-Cilag, GSK, Sanofi. C. Morizane: Financial Interests, Personal, Other, Honoraria: Novartis, Yakult Honsha, Teijin Pharma, Taiho Pharmaceutical, Eisai, MSD K.K., AstraZeneca; Financial Interests, Personal, Speaker, Consultant, Advisor: Boehringer Ingelheim, Merck, Taiho Pharmaceutical, AstraZeneca, SERVIER, MSD K.K., Yakult Honsha; Financial Interests, Institutional, Research Funding: Boehringer Ingelheim, Eisai, Yakult Honsha, ONO PHARMACEUTICAL, Taiho Pharmaceutical, J-Pharma, AstraZeneca, Merck biopharma, Daiichi Sankyo RD Novare, Hitachi. R. Galot: Non-Financial Interests, Personal, Advisory Board: Innate Pharma. S. Rottey: Financial Interests, Institutional, Advisory Board: Pfizer, Merck, Roche, Ipsen, BMS; Financial Interests, Institutional, Invited Speaker: Ipsen, BMS, Astellas; Financial Interests, Institutional, Research Grant: MSD, Roche, BMS; Non-Financial Interests, Principal Investigator, It is my main task in the hospital to attract and perform clinical trials in oncology phase I-III: all companies performing clinical trials in oncology in Europe. J.A. Stratmann: Financial Interests, Personal, Invited Speaker: LEO, Amgen, Roche; Non-Financial Interests, Personal, Writing Engagement: Pfizer; Financial Interests, Personal, Advisory Board: Boehringer Ingelheim, AstraZeneca, Roche, BMS, Amgen, LEO pharma, Novartis, Takeda; Financial Interests, Institutional, Research Grant: AstraZeneca; Non-Financial Interests, Personal, Advisory Role: Previpharma, Oncopeptides. Y. Ma, M. Bouzaggou, L. Geng: Financial Interests, Personal, Full or part-time Employment: Boehringer Ingelheim. M. Wermke: Financial Interests, Personal, Other, Honoraria: Lily, Boehringer Ingelheim, SYNLAB, Janssen, Merck Serono, GWT, Novartis; Financial Interests, Personal, Speaker, Consultant, Advisor: BMS, Novartis, Boehringer Ingelheim, ISA Pharmaceuticals, Amgen, immatics, Bayer, ImCheck Therapeutics; Financial Interests, Institutional, Research Funding: Roche; Financial Interests, Personal, Other, Travel, Accommodation, Expenses: Pfizer, BMS, AstraZeneca, Amgen, GEMoaB, Sanofi/Aventis, immatics, Merck Serono. All other authors have declared no conflicts of interest.