711TiP - A phase I/II, first-in-human, open-label, dose-escalation study of TAK-186, an EGFR × CD3ε COBRA T cell engager, in adult patients with unresectable, locally advanced, or metastatic solid tumors

Background

TAK-186 is a COnditional Bispecific Redirected Activation (COBRA) T-cell engager designed to bind to epidermal growth factor receptor (EGFR). Protease-mediated activation of the prodrug, primarily in the tumor microenviroment, generates an active dimer of EGFR-bound TAK-186 which engages CD3 T cells via the CD3ε binding domain. As the tumor microenvironment has increased protease activity vs healthy tissues, TAK-186 could potentially have an improved safety profile and therapeutic efficacy in solid tumors compared with other T-cell engagers that do not depend on conditional activation.

Trial design

This is a first-in-human, open-label, phase 1/2 study of TAK-186 (NCT04844073), with a planned enrollment of ∼123 patients (pts) with unresectable, locally advanced/metastatic EGFR-expressing solid tumors, including but not limited to non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and head and neck squamous cell cancer (HNSCC). Eligibility criteria include age ≥18 yr, ECOG PS ≤1, and measurable disease per RECIST v1.1. Pts who received an immune checkpoint inhibitor (ICI) prior to enrollment must have ICI immune-related toxicity resolved to Grade ≤1 or baseline (prior to ICI). Key exclusion criteria include history of autoimmune disease, major surgery ≤8 wks or radiation therapy <2 wks before first dose of TAK-186, history of clinically significant cardiac or gastrointestinal disorders. The study will be conducted in two phases: a dose-escalation phase (sequential cohorts of escalating doses) followed by a cohort-expansion phase (advanced/metastatic EGFR-expressing NSCLC, CRC, HNSCC). Pts will be followed for survival after treatment discontinuation. The primary objective is characterization of safety, tolerability, and dose-limiting toxicities. Secondary objectives include characterization of pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary anti-tumor activity. Tumor evaluation will be done using RECIST 1.1 and modified RECIST 1.1. Safety data will be summarized by CTCAE v5.0. Cytokine release syndrome will be reported by ASTCT consensus grading. Recruitment is ongoing.

Clinical trial identification

NCT04844073.

Editorial acknowledgement

Under the direction of the authors, Sweta Rathore, PhD, (Caudex, Toronto, Canada), provided writing assistance, and Hannah Lederman, MPhil, (Caudex, New York, USA), provided editorial assistance. Medical writing and editorial services were funded by Takeda Development Center Americas, Inc.

Legal entity responsible for the study

Takeda Development Center Americas, Inc.

Funding

Takeda Development Center Americas, Inc.

Disclosure

A.J. Weickhardt: Financial Interests, Personal, Other, Honoraria: Eisai, Merck Sharp & Dohme; Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Merck Sharp & Dohm; Financial Interests, Personal, Speaker, Consultant, Advisor: Astellas Pharma; Financial Interests, Personal, Other, Travel, accommodations, expenses: Astellas Pharma, Ipsen, Merck Sharp & Dohme; Financial Interests, Personal, Research Grant: Merck. S. Frentzas: Financial Interests, Personal, Advisory Board: GOG Foundation, MSD Oncology. J. Srimani: Financial Interests, Personal, Full or part-time Employment: Takeda; Financial Interests, Personal, Stocks/Shares: Takeda, BMRN, PFE, GILD. J. Yin: Financial Interests, Personal, Full or part-time Employment: Takeda; Financial Interests, Personal, Stocks/Shares: Takeda. W.L. Trepicchio: Financial Interests, Personal, Full or part-time Employment: Takeda; Financial Interests, Personal, Stocks/Shares: Takeda; Financial Interests, Personal, Licencing Fees or royalty for IP: Takeda. C. Gorgun: Financial Interests, Personal, Full or part-time Employment: Takeda; Financial Interests, Personal, Stocks/Shares: Takeda. G. Kichenadasse: Financial Interests, Personal, Full or part-time Employment: Southern Oncology Clinical Research Unit; Financial Interests, Personal, Leadership Role: Southern Oncology Clinical Research Unit; Financial Interests, Personal, Research Grant: Aucentra, Henlius, Takeda. All other authors have declared no conflicts of interest.