10O - First-in-human, dose escalation of MT-8421: A novel engineered toxin body (ETB) targeting CTLA-4, in patients with select advanced solid tumors

Background

MT-8421 is an engineered toxin body (ETB) combining a Shiga-like Toxin A (SLT-A) subunit with two anti-CTLA4 VHH fragments. By exploiting SLT-A’s internalization and ribosomal toxicity, MT-8421 targets CTLA-4-expressing regulatory T cells in the tumor microenvironment for destruction while aiming to minimize peripheral immune-related adverse events seen with approved anti-CTLA4 monoclonal antibodies.

Methods

This phase 1, open-label, multicenter study assessed the safety, tolerability, efficacy, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of MT-8421 in patients with advanced solid tumors. Primary endpoints included adverse event incidence, dose-limiting toxicities (DLTs), and maximum tolerated dose. Secondary endpoints included objective response rate and drug PK. MT-8421 was administered intravenously over 30 minutes on days 1, 8, 15, and 22 of 28-day cycles. Dose escalation was guided by a modified toxicity probability interval (mTPI-2) design.

Results

Fifteen patients (53% female, median age 63) with melanoma (n=8), NSCLC (n=2), HNSCC (n=2), RCC (n=1), HCC (n=1), and cervical cancer (n=1) were treated across 3 dose levels (32, 48, 72 μg/kg). Most had prior anti-PD-1 therapy (93%) and anti-CTLA4 (53%). No DLTs were observed. Treatment-related adverse events were all Grade 1–2, including infusion reactions (33%), fatigue (27%), pruritus (27%), chills (27%), and rash (20%). All grade 3 treatment emergent adverse events were unrelated to study treatment. No Grade 4–5 events occurred. PK analysis showed a biphasic serum concentration decline, with depletion of T regulatory cells and a shift to a T cell effector phenotype, evidenced by increased CD8:CD4 ratios. No objective responses were observed in 9 evaluable patients, but 3 achieved stable disease as best objective response (2 melanoma and 1 HNSCC) (DCR=22%). One dual checkpoint experienced melanoma patient experienced non-target lesion regression and ctDNA clearance for >9 months.

Conclusions

MT-8421 demonstrated an acceptable safety profile with no DLT or drug-related Grade 3–5 toxicities. MTD was not reached. Further evaluation of CTLA4-targeting ETBs is warranted.

Clinical trial identification

NCT06034860.

Editorial acknowledgement

Legal entity responsible for the study

Molecular Templates, Inc.

Funding

Molecular Templates, Inc.

Disclosure

J.T. Moyers: Financial Interests, Personal, Advisory Board: Pfizer, Merck; Financial Interests, Personal, Speaker’s Bureau: Clinical Care Options. A. Spira: Financial Interests, Personal, Other, Consulting or Advisory Role: Incyte, Mirati Therapeutics, Gritstone Oncology, Jazz Pharmaceuticals, Janssen Research & Development, Mersana, Gritstone Bio, Daiichi Sankyo/AstraZeneca, Array Biopharma, Blueprint Medicines, Regeneron, Lilly, Black Diamond Therapeutics, Sanofi; Financial Interests, Personal, Other, Consulting or Advisory Role Honoraria: Amgen, Novartis, Takeda, AstraZeneca/MedImmune, Merck, Bristol Myers Squibb; Financial Interests, Personal, Other, Honoraria: CytomX Therapeutics, Janssen Oncology, Bayer; Financial Interests, Institutional, Officer, CEO: NEXT Oncology Virginia; Financial Interests, Personal, Stocks/Shares: Eli Lilly; Financial Interests, Institutional, Invited Speaker: LAM Therapeutics, Roche, AstraZeneca, Boehringer Ingelheim, Astellas Pharma, MedImmune, Novartis, Newlink Genetics, Incyte, AbbVie, Ignyta, Trovagene, Takeda, Macrogenics, CytomX Therapeutics, Astex Pharmaceuticals, Bristol Myers Squibb, Loxo, Arch Therapeutics, Gritstone, Plexxikon, Amgen, Daiichi Sankyo, ADCT, Janssen Oncology, Mirati Therapeutics, Rubius, Synthekine, Mersana, Blueprint Medicines, Kezar, Revolution Med, Regeneron, Loxo, Alkermes, Medikine, Black Diamond Therapeutics, Nalo Therapeutics, Scorpion Therapeutics, Arrivent Biopharma, GV20 Therapeutics. S. Chandra: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Novartis, Pfizer, Regeneron; Financial Interests, Institutional, Invited Speaker: Bristol Myers Squibb, Novartis, Regeneron, Pfizer, Merck; Financial Interests, Personal and Institutional, Invited Speaker: Bristol Myers Squibb; Financial Interests, Personal, Other, DMC: Alkermes. I. Mehmi: Financial Interests, Personal, Invited Speaker: Immunocore, BMS; Financial Interests, Personal, Stocks/Shares: Delcath, Immunocore, Ideaya, In8Bio, Iovance. A.C. Pavlick: Financial Interests, Personal, Advisory Role: Merck, Pfizer, Replimmune; Financial Interests, Institutional, Research Grant: Tallac, Merck, Replimmune, Immuneering. C. Moore, K. Dabovic, S. Khanna: Financial Interests, Personal, Full or part-time Employment: Molecular Templates. S. Charoenthongtrakul: Financial Interests, Personal, Full or part-time Employment: Molecular Templates. E. Poma: Financial Interests, Personal, Full or part-time Employment: Molecular Templates. J.D. Wolchok: Financial Interests, Personal, Other, Consultant and stock options: Apricity Therapeutics; Financial Interests, Personal, Advisory Board, consultant and stock options: Ascentage Pharmaceuticals; Financial Interests, Personal, Other, Consultant and Honorarium: Bristol Meyers Squibb; Financial Interests, Personal, Other, Consultant: Daiichi Sankyo, Imvaq Therapeutics, Psioxus, Takeda Pharmaceuticals, Bicara Therapeutics; Financial Interests, Personal, Other, consultant: Tizona Therapuetics; Financial Interests, Personal, Advisory Board, data safety board: ImmunoCore; Financial Interests, Personal, Member of Board of Directors: Ludwig Institute for Cancer Research; Financial Interests, Personal, Other, Stock options: Apricity Therapeutics; Financial Interests, Personal, Other, Royalties: CellCarta; Financial Interests, Personal, Other, Stock Options: Ascentage Therapeutics, Imvaq Therapeutics, Georgiamune, Xenimmune Therapeutics; Financial Interests, Personal, Other, stock options: Tizona Therapeutics; Financial Interests, Institutional, Royalties, Xenogeneic DNA Vaccines: Merial; Financial Interests, Institutional, Royalties, Newcastle Disease viruses for Cancer Therapy: Merck; Financial Interests, Institutional, Royalties, prediction of responsiveness to treatment with immunomodulatory therapeutics and method of: CellCarta; Financial Interests, Institutional, Royalties, Myeloid-derived suppressor cell (MDSC) assay: Caprion; Financial Interests, Institutional, Royalties, Anti-PD1 Antibody; Anti-CTLA4 antibodies; Anti-GITR antibodies and methods of use thereof: Agenus; Financial Interests, Institutional, Research Grant: Bristol Meyers Squibb, Enterome. O. Hamid: Financial Interests, Personal, Advisory Board: Alkermes, Amgen, BMS, Bactonix, Beigene, Bioatla, Esai, GSK, Georgiamune, GigaGen, Grit Bio, IO Biotech, Idera, Immunocore, Incyte, Instil Bio, Iovance, Janssen, KSQ, Merck, Novartis, Obsidian, Pfizer, Roche Genentech, Seagen, Sanofi / Regeneron, Tempus, Vial, Zelluna; Financial Interests, Personal, Invited Speaker: BMS, Immunocore, Novartis, Pfizer, Sanofi / Regeneron; Financial Interests, Personal, Stocks/Shares: Bactonix; Financial Interests, Institutional, Invited Speaker: Aduro, Akeso, Amgen, Arcus, BMS, Bioatla, CytomX, Exelixis, GSK, Idera, Immunocore, Incyte, Iovance, Merck, Merck Serono, Moderna, Nextcure, Novartis, Pfizer, Roche Genentech, SEAGEN, Sanofi / Regeneron, Torque, Zelluna. B.A. Van Tine: Financial Interests, Personal, Advisory Board, Attended Advisory Board Meeting: Apexigen Inc; Financial Interests, Personal, Advisory Board, Attended an Advisory Board Meeting: Daiichi Sankyo; Financial Interests, Personal, Other, Consulting: Advenchen, Putnam, Salarius Pharm, Boxer Capital LLC, Acuta Capital Partners, LLC, Aadi; Financial Interests, Personal, Invited Speaker, 2023 West Oncology Talk. Travel provided: Total Health conference; Financial Interests, Personal, Advisory Board, Also paid for travel to the meeting: Kronos; Financial Interests, Personal, Other, Travel: Polaris; Financial Interests, Personal, Invited Speaker, Sigma-2 Receptor Ligands and Therapeutic uses therefor (006766), Modular Platform for Targeted Therapeutic Delivery (006755), Sigma-2 Receptor Ligand Drug Conjugates as Antitumor Compounds, Methods of synthesis and Uses Thereof (014229): Accuronix Therapeutics; Financial Interests, Personal and Institutional, Research Grant, Research Grant for trial: Polaris; Non-Financial Interests, Personal, Other, Non-paid Safety Monitor Board Member: Polaris. All other authors have declared no conflicts of interest.