TAK-500 / Takeda - LARVOL DELTA

A Study of TAK-500 With or Without Pembrolizumab in Adults With Select Locally Advanced or Metastatic Solid Tumors (clinicaltrials.gov) - P1/2 | N=61 | Terminated | Sponsor: Takeda | Recruiting ➔ Terminated | Trial primary completion date: Aug 2026 ➔ Jan 2025 | N=313 ➔ 61 | Trial completion date: Aug 2026 ➔ Jan 2025; Clinical Futility of TAK 500 met. No further development with this compound

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Breast Cancer • Esophageal Cancer • Gastric Cancer • Genito-urinary Cancer • Head and Neck Cancer • Hepatocellular Cancer • Hepatology • Kidney Cancer • Liver Cancer • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Mesothelioma • Nasopharyngeal Carcinoma • Non Small Cell Lung Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Renal Cell Carcinoma • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer

Selective STING Activation in Intratumoral Myeloid Cells via CCR2-Directed Antibody Drug Conjugate TAK-500. (PubMed, Cancer Immunol Res) - "Spatially resolved analysis of CCR2 and immune cell markers in the TME of >1,000 primary human tumors showed the CCR2 protein was predominantly expressed in intratumoral myeloid cells. Collectively, these data highlight the clinical potential of delivering a STING agonist to CCR2+ cells."

Journal • Oncology • Solid Tumor • CCR2 • STING

Preclinical impact of pretreatment with CRS mitigation agents on pharmacodynamic response to TAK-500, a systemically delivered CCR2-targeted STING agonist iADC (AACR 2024) - "Premedication of TAK-500 and mTAK-500 with dexamethasone or anti-IL-6R antibodies does not substantially impact STING-mediated innate immune activation, mobilization of adaptive immune responses or anti-tumor efficacy, despite altered cytokine profiles compared to (m)TAK-500 without premedication. Clinically, these premedication strategies have been effective in mitigating immunotherapy-associated CRS with T cell therapeutics, and here resulted in maintained anti-tumor activity when used in combination with TAK-500, suggesting a viable potential strategy for mitigation of STING-induced immunotoxicities in patients."

PK/PD data • Preclinical • Oncology • CCR2 • CD8 • IL10 • STING

Immunomodulatory and anti-tumor effect of a CCR2-targeted STING agonist iADC in human lung cancer (AACR 2024) - "Our results reveal prominent myeloid CCR2 expression in a subset of human NSCLCs with distinct clinicopathologic/molecular characteristics. Using a novel lung cancer explant ex vivo system, we demonstrate a CCR2-dependent immunomodulatory and anti-tumor effect of TAK-500 iADC."

Immunomodulating • IO biomarker • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • CASP3 • CCR2 • CD20 • CD4 • CD68 • CD8 • GZMB • ITGAM • KRAS • PD-L1 • TFRC

Sting-Mediated Interferon Signaling Exerts Potent Antileukemic Effects in High-Risk Myeloid and Monocytic Malignancies (ASH 2023) - "Evaluation of the efficacy of TAK-500 and dazostingag in patient-derived xenograft models of primary CMML samples is planned. Taken together, our data suggests that CCR2-directed STING activation might have therapeutic potential in HR-MyMo neoplasms by depleting CCR2+ cells and impairing clonal HSPC repopulation potential."

Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • CASP3 • CCR2 • CD34 • GLI2 • IL15 • KDM6B • STING • TET2

A Study of TAK-500 With or Without Pembrolizumab in Adults With Select Locally Advanced or Metastatic Solid Tumors (clinicaltrials.gov) - P1/2 | N=313 | Recruiting | Sponsor: Takeda | Phase classification: P1a/1b ➔ P1/2 | N=118 ➔ 313 | Trial completion date: Mar 2025 ➔ Aug 2026 | Trial primary completion date: Mar 2025 ➔ Aug 2026

Enrollment change • Phase classification • Trial completion date • Trial primary completion date • Breast Cancer • Esophageal Cancer • Gastric Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Head and Neck Cancer • Hepatocellular Cancer • Hepatology • Kidney Cancer • Liver Cancer • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Mesothelioma • Nasopharyngeal Carcinoma • Non Small Cell Lung Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Renal Cell Carcinoma • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer

TAK-500 as a single agent and in combination with pembrolizumab in patients (pts) with advanced solid tumors: Rationale and design of a phase I/II study (ESMO 2023) - P1a/1b | "Background TAK-500 is a novel immune-cell-directed antibody drug conjugate comprising the STING agonist TAK-676 conjugated to a human IgG1 anti-C-C chemokine receptor 2 (CCR2) antibody. A single-stage statistical design will be utilized for 3rd-line NS NSCLC and RCC. As of May 2023, 6 sites in the United States are recruiting; the global phase 2 is planned to start in 2024."

Clinical • Combination therapy • Metastases • P1/2 data • Clear Cell Renal Cell Carcinoma • Gastrointestinal Cancer • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Renal Cell Carcinoma • Solid Tumor • CCR2

Targeting STING to CCR2+ Cells via an Immune Cell Directed Antibody Drug Conjugate (iADC) (ADC-USA 2023) - "Narrating an overview of the murine surrogate iADC, mTAK-500, which was designed to selectively deliver the a STING agonist to CCR2+ cells; Discussing the of nonclinical data and mechanistic insight that have motivated design and clinical testing of TAK-500, a CCR2-targeted STING ISAC comprising the clinical STING agonist TAK-676 and a high affinity antibody targeting human CCR2"

Immune cell • CCR2 • STING

Targeting STING to CCR2+ Cells via an Immune Stimulating Antibody Conjugate (PEGS 2023) - "STING signaling in intratumor myeloid cells can enhance interferon (IFN) production, boost local adaptive anti-tumor immunity, and could synergize with other anti-cancer therapies. We discuss nonclinical data for a novel iADC, TAK-500, which selectively activates STING in CCR2-expressing cells to enable systemic delivery, favor intratumor accumulation of the active compound, and achieve anti-tumor immunity."

Immune Modulation • Oncology • Solid Tumor • CCR2 • STING

TAK-500 is a clinical stage immune-cell directed antibody drug conjugate (iADC) inducing STING activation in CCR2-expressing intratumor myeloid cells and favorable immunomodulation (AACR 2023) - P1a/1b | "The iADC TAK-500 and mTAK-500 induces CCR2-dependent immune cell activation and anti-tumor effect. CCR2 is highly expressed in intratumor myeloid cells from NSCLC. High CCR2 is associated with enhanced local adaptive immune responses and specific clinical/molecular tumor subsets."

Clinical • Immune cell • Immunomodulating • IO biomarker • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Microsatellite Instability • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CCR2 • CD68 • CD8 • EGFR • ITGAM • KRAS • MSI • PD-L1 • STING

Preclinical activity of C-C chemokine receptor 2 (CCR2)-targeted immune stimulating antibody conjugate (ISAC), motivating clinical testing of TAK-500 (SITC 2022) - P1a/1b | "Single agent α-PD-1 treatment also resulted in a 12.5% CR rate, however, when combined, mTAK-500 and α-PD-1 treatment achieved enhanced anti-tumor response with a 37.5% CR rate. Conclusions Nonclinical antitumor activity and mechanistic insight have motivated design and clinical testing of TAK-500, a CCR2-targeted STING ISAC comprising the clinical stage STING agonist TAK-676 and a high-affinity antibody targeting human CCR2, as a single agent and in combination with pembrolizumab in adults with select locally advanced or metastatic solid tumors ( NCT05070247 )."

IO biomarker • Preclinical • Oncology • Solid Tumor • CCR2 • CD8 • STING

CCR2-targeted STING ISAC TAK-500 shows promising results as cancer immunotherapeutic (Bioworld) - "Activation of the cGAS-STING pathway activates the immune system through the production of type I interferons. There is knowledge that myeloid cell populations are among the most sensitive to STING agonism. Investigators at Takeda Pharmaceutical Co. Ltd. presented results on TAK-500, an immune stimulant antibody-drug conjugate (ISAC) composed of an antibody linked to a STING agonist for delivery to CCR2+ cells."

Preclinical • Oncology

Phase 1a/1b study design of the novel STING agonist, immune-stimulating antibody-conjugate (ISAC) TAK-500, with or without pembrolizumab in patients with advanced solid tumors. (ASCO 2022) - P1, P1a/1b | "TAK-500 is a novel ISAC comprising a STING agonist (based on TAK-676, which is currently in phase 1 clinical trials [NCT04420884, NCT04879849]), an IgG1 anti-cysteine-cysteine chemokine receptor 2 (CCR2) antibody, and a self-immolating maleimide-containing protease-cleavable peptide linker. In the dose expansion phase, only the combination of TAK-500 + pembrolizumab will be evaluated. Primary objectives of this study are safety and tolerability; secondary objectives include determination of the PAD range, the recommended phase 2 dose, pharmacokinetics, pharmacodynamics, and antitumor activity of TAK-500 as a single agent and in combination with pembrolizumab."

Clinical • P1 data • Breast Cancer • Esophageal Adenocarcinoma • Esophageal Cancer • Gastric Cancer • Gastrointestinal Cancer • Head and Neck Cancer • Hepatocellular Cancer • Hepatology • Immune Modulation • Inflammation • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Mesothelioma • Non Small Cell Lung Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer • CD8 • STING

First-in-human study of TAK-500, a novel STING agonist immune stimulating antibody conjugate (ISAC), alone and in combination with pembrolizumab in patients with select advanced solid tumors (AACR 2022) - P1, P1a/1b | "TAK-500 is an ISAC that consists of three parts: a STING agonist payload based on TAK-676 (currently under phase 1 clinical evaluation [NCT04420884, NCT04879849]), the IgG1 anti-CCR2 antibody (previously evaluated in early phase studies), and a self-immolating maleimide-containing protease-cleavable peptide linker. A subsequent dose expansion phase will evaluate TAK-500 in combination with pembrolizumab. Planned enrollment for both escalation and expansion cohorts is ~106 patients."

Clinical • Combination therapy • P1 data • Breast Cancer • Esophageal Adenocarcinoma • Esophageal Cancer • Gastric Cancer • Gastrointestinal Cancer • Head and Neck Cancer • Hepatocellular Cancer • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Mesothelioma • Non Small Cell Lung Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer • CD8 • STING

Preclinical activity of C-C chemokine receptor 2 (CCR2)-targeted immune stimulating antibody conjugate (ISAC), motivating clinical testing of TAK-500 (AACR-NCI-EORTC 2022) - No abstract available

Preclinical • Oncology • CCR2

A Study of TAK-500 With or Without Pembrolizumab in Adults With Select Locally Advanced or Metastatic Solid Tumors (clinicaltrials.gov) - P1a/1b | N=106 | Recruiting | Sponsor: Takeda | Not yet recruiting ➔ Recruiting

Combination therapy • Enrollment open • Breast Cancer • Esophageal Cancer • Gastric Cancer • Gastrointestinal Cancer • Head and Neck Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Mesothelioma • Non Small Cell Lung Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer • STING