A phase 1/2, first-in-human, open-label, dose-escalation and -expansion study of TAK-188, a novel antibody-drug conjugate (ADC) targeting CCR8 ⁺ regulatory T cells, in adult patients with locally advanced or metastatic solid tumors.

Abstract

TPS3155 Background: Regulatory T cells (Tregs) are key contributors to an immunosuppressive tumor microenvironment (TME). Their abundance in solid tumors is often linked to poor patient prognosis, decreased overall survival, and resistance to immunotherapy. Tumor-infiltrating Tregs express high levels of chemokine receptor CCR8, making CCR8 an attractive target for immunotherapy. TAK-188 is a first-in-class anti-CCR8 ADC that aims to enhance patients’ own antitumor activity by selectively eliminating CCR8-positive Tregs within the TME. It uses a novel amanitin payload capable of killing both actively dividing and non-dividing cells and is linked to the antibody via a cleavable linker. The nonclinical toxicology profile demonstrated monitorable and partially-to-completely reversible toxicities at doses exceeding projected clinically efficacious exposures. Preclinical evaluation of TAK-188 showed robust and deep depletion of CCR8 + cells in vitro and in vivo , and demonstrated anti-tumor activity as a single agent in non-clinical models (Casson et al. AACR 2026). Methods: This phase 1/2 study (NCT07205718) is enrolling adult patients with locally advanced or metastatic solid tumors known to express high levels of CCR8 on Tregs in the TME (gastroesophageal adenocarcinoma [GC] and esophageal squamous cell carcinoma [ESCC], pancreatic ductal adenocarcinoma, non-squamous and squamous non-small cell lung cancer [NSCLC], head & neck SCC [SCCHN], or colorectal cancer), and whose disease has progressed on, or are intolerant to, all standard therapies. Eligible patients must have Eastern Cooperative Oncology Group performance status ≤1 and radiographically measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. In phase 1, TAK-188 is intravenously administered weekly at escalating dose levels following a Bayesian Optimal Interval design, to determine the recommended phase 2 dose (RP2D) and dosing schedules for the cohort-expansion phase. The primary objective is to determine the safety and tolerability of TAK-188 in phase 1 and to assess the preliminary efficacy in phase 2 in NSCLC, SCCHN and GC. Secondary objectives include characterization of the RP2D and pharmacokinetic parameters for TAK-188, changes in T cell populations (abundance and ratio of Tregs and effector T cells) within the tumor post-treatment, and preliminary efficacy in select cancer types. Exploratory objectives include the impact of TAK-188 on CCR8 + Tregs, molecular response determined by circulating tumor DNA (ctDNA) analysis, and changes in cytokines and chemokines in peripheral blood. The study plans to enroll up to 223 patients in the USA (47 patients across 15 sites for dose-escalation; 62–176 patients across ~35 sites in cohort-expansion). Clinical trial information: NCT07205718 .