dargistotug (M6223) / EMD Serono - LARVOL DELTA

A Study of the Safety and Efficacy of Various Combinations of Avelumab as Therapy in Locally Advanced or Metastatic Urothelial Carcinoma (JAVELIN Bladder Medley) (clinicaltrials.gov) - P2 | N=256 | Active, not recruiting | Sponsor: EMD Serono Research & Development Institute, Inc. | Trial completion date: Jan 2025 ➔ Jul 2026 | Trial primary completion date: Jan 2025 ➔ Jun 2025

Trial completion date • Trial primary completion date • Bladder Cancer • Oncology • Solid Tumor • Urothelial Cancer

TIGIT inhibitor M6223 as monotherapy or in combination with bintrafusp alfa in patients with advanced solid tumors: a first-in-human, phase 1, dose-escalation trial. (PubMed, J Immunother Cancer) - P1, P2 | "M6223±BA had a manageable safety profile, with RDEs defined for both monotherapy and combination therapy. Further evaluation of M6223 is ongoing in combination with the PD-L1 inhibitor avelumab in patients with advanced urothelial carcinoma (JAVELIN Bladder Medley; NCT05327530)."

Journal • Monotherapy • P1 data • Bladder Cancer • Endocrine Disorders • Hematological Disorders • Nephrology • Oncology • Renal Disease • Solid Tumor • Urothelial Cancer • TGFB1 • TIGIT

Model-Informed Selection of the Recommended Phase 2 Dosage for Anti-TIGIT Immunotherapy Leveraging co-Expressed PD-1 Inhibitor Target Engagement. (PubMed, Clin Pharmacol Ther) - "We then assess the applicability of this PD-1 model to elucidate the relationship between drug concentration and target engagement for tiragolumab, an anti-TIGIT antibody, across various doses...The approach is then extended to project efficacious doses for M6223, another anti-TIGIT antibody, using the established PD-1 model, by leveraging the M6223 clinical PK and PD data, as well as virtual population analysis. This work provides a case study of a possible framework for refining dose projections via quantitative estimation of drug-target relationship at the site of action by leveraging established drug-target relationships. Through extrapolating information from a well-characterized pathway, we offer a method to inform dose optimization strategies with limited data using model-informed drug development."

IO biomarker • Journal • P2 data • Oncology • TIGIT

A Study of the Safety and Efficacy of Various Combinations of Avelumab as Therapy in Locally Advanced or Metastatic Urothelial Carcinoma (JAVELIN Bladder Medley) (clinicaltrials.gov) - P2 | N=256 | Active, not recruiting | Sponsor: EMD Serono Research & Development Institute, Inc. | Recruiting ➔ Active, not recruiting

Combination therapy • Enrollment closed • Metastases • Bladder Cancer • Oncology • Solid Tumor • Urothelial Cancer

First-in-human trial of TIGIT inhibitor M6223 as monotherapy or in combination with bintrafusp alfa (BA) in patients (pts) with advanced solid unresectable tumors (AACR 2024) - P1, P2 | "Introduction: M6223 is an intravenous (IV), fully human, antagonistic, anti-TIGIT antibody with an Fc-mediated effector region. M6223 monotherapy and in combination with BA had a manageable safety profile, and RDEs for both mono- and combination therapy were defined. Further evaluation of M6223 is ongoing in combination with PD-L1 inhibitor avelumab (JAVELIN Bladder Medley; NCT05327530)."

Clinical • Combination therapy • Metastases • Monotherapy • P1 data • Oncology • Solid Tumor • TGFB1 • TIGIT

First in Human Study of M6223 (clinicaltrials.gov) - P1 | N=58 | Completed | Sponsor: EMD Serono Research & Development Institute, Inc. | Active, not recruiting ➔ Completed

Trial completion • Oncology • Solid Tumor

Multizentrische, randomisierte, offene Parallelarm-Umbrella-Studie JAVELIN Bladder Medley der Phase II zu Avelumab (MSB0010718C) in Kombination mit Sacituzumab Govitecan, M6223 und NKTR-255 als Erhaltungstherapie bei Teilnehmern mit lokal fortgeschrittenem oder metastasiertem Urothelkarzinom, deren Erkrankung unter einer platinhaltigen Erstlinien(1L)-Chemotherapie nicht fortgeschritten ist. –... (PubMed, Aktuelle Urol) - No abstract available

Journal • P2 data

The JAVELIN Bladder Medley trial: avelumab-based combinations as first-line maintenance in advanced urothelial carcinoma. (PubMed, Future Oncol) - P2 | "Overall, 252 patients with advanced UC who are progression-free following first-line platinum-based chemotherapy will be randomized 1:2:2:2 to receive maintenance therapy with avelumab alone (control group) or combined with sacituzumab govitecan (anti-Trop-2/topoisomerase inhibitor conjugate), M6223 (anti-TIGIT) or NKTR-255 (recombinant human IL-15). Primary end points are progression-free survival per investigator and safety/tolerability of the combination regimens. Secondary end points include overall survival, objective response and duration of response per investigator, and pharmacokinetics."

Journal • Metastases • Review • Oncology • Solid Tumor • Urothelial Cancer • TIGIT

A Study of the Safety and Efficacy of Various Combinations of Avelumab as Therapy in Locally Advanced or Metastatic Urothelial Carcinoma (JAVELIN Bladder Medley) (clinicaltrials.gov) - P2 | N=252 | Recruiting | Sponsor: EMD Serono Research & Development Institute, Inc. | Trial completion date: Aug 2026 ➔ Jan 2025 | Trial primary completion date: Aug 2026 ➔ Jan 2025

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Bladder Cancer • Oncology • Solid Tumor • Urothelial Cancer

JAVELIN Bladder Medley: a phase 2 trial of avelumab in combination with other antitumor drugs as first-line maintenance therapy for advanced urothelial carcinoma (SITC 2022) - P2, P3 | "Eligible patients aged ≥18 years should have unresectable locally advanced or metastatic UC that has not progressed (complete or partial response, or stable disease) after 4-6 cycles of 1L chemotherapy (gemcitabine + cisplatin or carboplatin) and ECOG PS 0-1. After 4-10 weeks from end of chemotherapy, 252 patients will be randomized 1:2:2:2 to avelumab 800 mg every 2 weeks as monotherapy (control) or combined with sacituzumab govitecan (anti-Trop2/topoisomerase inhibitor conjugate) 10 mg/kg on days 1 and 8 of 21-day cycles, M6223 (anti-TIGIT) 1600 mg every 2 weeks, or NKTR-255 (IL-15 agonist) 3 μg/kg every 4 weeks...Secondary endpoints include OS, objective response and duration of response based on investigator assessment (RECIST 1.1), and pharmacokinetics. The trial opened in June 2022 with sites planned to recruit in the US, Europe, Asia, and Australia."

Clinical • Combination therapy • P2 data • Oncology • Solid Tumor • Urothelial Cancer • IL15 • TIGIT

Evaluation of novel anti-TIGIT antibody M6223 as a single agent and in combination with avelumab on human natural killer (NK) cell cytotoxicity (SITC 2022) - P2 | "Conclusions This study confirmed that NK cell cytotoxicity plays an important role in the anti-tumor activity of M6223 and demonstrated the additive effect of avelumab and M6223 in enhancing NK cell activation, especially in CD155+ human leukocyte antigen (HLA) class I-deficient target tumors. Currently, M6223 plus avelumab is being studied as first-line maintenance therapy for advanced UC in the phase 2 JAVELIN Bladder Medley umbrella trial ( NCT05327530 )."

Combination therapy • IO biomarker • Genito-urinary Cancer • Merkel Cell Carcinoma • Neuroendocrine Tumor • Non-melanoma Skin Cancer • Oncology • Renal Cell Carcinoma • Skin Cancer • Solid Tumor • Urothelial Cancer • B2M • NECTIN2 • PVR • TIGIT

Evaluation of the TIGIT+ immune subset depletion effect of the anti-TIGIT antibody M6223 (SITC 2022) - P2 | "Conclusions The results demonstrate that innate depletion of TIGIT+ immune subsets by Fc-mediated effector function plays an important role in anti-tumor immunity and suggest that immune pharmacodynamics in clinical trials should be closely monitored at early time points. Currently, M6223 is being evaluated in combination with avelumab as first-line maintenance therapy for advanced urothelial carcinoma in the phase 2 JAVELIN Bladder Medley umbrella trial ( NCT05327530 )."

IO biomarker • Bladder Cancer • Oncology • Solid Tumor • Urothelial Cancer • CD8 • TIGIT

The anti-TIGIT antibody M6223 induces significant anti-tumor efficacy and immune response via multiple mechanisms of action (SITC 2021) - P1 | "Our data demonstrate that these complementary mechanisms orchestrate the anti-tumor activity of M6223. A Phase I, first-in-human clinical trial (NCT04457778) is underway to determine the safety, tolerability, maximum tolerated dose and recommended dose for expansion of M6223 as a single agent (Part 1A) and in combination with bintrafusp alfa (Part 1B) in patients with metastatic or locally advanced solid unresectable tumors."

Clinical • IO biomarker • Oncology • CD8 • NECTIN2 • TIGIT

Anti-tumor immunity and efficacy of combination treatment of M6223 and bintrafusp alfa versus the combination of M6223 and anti-PD-L1 in preclinical tumor models (AACR 2022) - P1 | "These complementary mechanisms of M6223 and bintrafusp alfa orchestrate antitumor activity in preclinical tumor models. Currently, M6223 and bintrafusp alfa combination is being investigated in a Phase I clinical trial (NCT04457778) in patients with metastatic or locally advanced solid unresectable tumors."

IO biomarker • Preclinical • Oncology • CD8 • TGFB1 • TIGIT

First in Human Study of M6223 (clinicaltrials.gov) - P1 | N=58 | Active, not recruiting | Sponsor: EMD Serono Research & Development Institute, Inc. | Recruiting ➔ Active, not recruiting

Combination therapy • Enrollment closed • Metastases • Oncology • Solid Tumor

A first-in-human phase I study of M6223 (TIGIT inhibitor) as monotherapy or in combination with bintrafusp alfa in patients with metastatic or locally advanced solid unresectable tumors (SITC 2021) - P1 | "The study is currently ongoing in the United States and Canada. Trial Registration NCT04457778"

Clinical • Combination therapy • Monotherapy • P1 data • Oncology • Solid Tumor • PD-1 • TGFB1 • TIGIT

Phase I study of TIGIT inhibitor M6223 as monotherapy or in combination with bintrafusp alfa (BA) in patients (pts) with metastatic/locally advanced solid unresectable tumours (ESMO 2022) - P1 | "9/24 and 2/17 pts receiving M6223 and M6223 + BA, respectively, achieved clinical benefit (stable disease at first on-Tx assessment); 3/24 and 2/17 patients, respectively, were on Tx for ≥20 weeks. Conclusions M6223 ± BA had an acceptable safety profile with favourable PK and target modulation effect."

Clinical • Combination therapy • IO biomarker • Monotherapy • P1 data • Oncology • Solid Tumor • TIGIT

First in Human Study of M6223 (clinicaltrials.gov) - P1 | N=55 | Recruiting | Sponsor: EMD Serono Research & Development Institute, Inc. | N=35 ➔ 55 | Trial completion date: Sep 2022 ➔ Jun 2023 | Trial primary completion date: Sep 2022 ➔ May 2023

Combination therapy • Enrollment change • Trial completion date • Trial primary completion date • Oncology • Solid Tumor

A Study of the Safety and Efficacy of Various Combinations of Avelumab as Therapy in Locally Advanced or Metastatic Urothelial Carcinoma (JAVELIN Bladder Medley) (clinicaltrials.gov) - P2 | N=252 | Recruiting | Sponsor: EMD Serono Research & Development Institute, Inc. | Not yet recruiting ➔ Recruiting | Initiation date: May 2022 ➔ Aug 2022

Combination therapy • Enrollment open • Trial initiation date • Bladder Cancer • Oncology • Solid Tumor • Urothelial Cancer

A Study of the Safety and Efficacy of Various Combinations of Avelumab as Therapy in Locally Advanced or Metastatic Urothelial Carcinoma (JAVELIN Bladder Medley) (clinicaltrials.gov) - P2 | N=252 | Not yet recruiting | Sponsor: EMD Serono Research & Development Institute, Inc.

Combination therapy • New P2 trial • Bladder Cancer • Oncology • Solid Tumor • Urothelial Cancer

First in Human Study of M6223 in Participants With Metastatic or Locally Advanced Solid Unresectable Tumors (clinicaltrials.gov) - P1; N=35; Not yet recruiting; Sponsor: EMD Serono Research & Development Institute, Inc.

Clinical • Combination therapy • New P1 trial • Oncology • Solid Tumor

First in Human Study of M6223 in Participants With Metastatic or Locally Advanced Solid Unresectable Tumors (clinicaltrials.gov) - P1; N=35; Recruiting; Sponsor: EMD Serono Research & Development Institute, Inc.; Not yet recruiting ➔ Recruiting

Clinical • Combination therapy • Enrollment open • Oncology • Solid Tumor