Abstract 6860: MTL-004, a promising new therapeutic for post-resection treatment of glioblastoma

Abstract Objectives: Glioblastomas (GBM), are exceptionally hard to treat, aggressive and genetically heterogeneous tumors. We report the tolerance, biodistribution and excretion of MTL-004 (5-(aziridine-1- yl)-4 hydroxylamino-2-nitrobenzamide) in healthy animals, along with data its effect when delivered as a single intra-cranial dose in a bioresorbable paste (poly DL-lactic acid-co-glycolic acid and poly ethylene glycol (PGLA/PEG)) following surgical resection of primary GBM, on tumor growth and survival. Experimental procedures Tolerance and biodistribution of MTL-004: Healthy Wistar Han male and female rats were subjected to intravenous (IV) escalating or repeated doses of MTL-004. Body weight and behaviour of animals were monitored to assess toxicity. Healthy Wistar Han female rats were subjected to single intracranial (IC) or IV administration of radiolabelled 14CMTL004 to assess its excretion and biodistribution. Sequential collection of blood and organs were performed and radioactivity was measured. Efficacy of MTL-004 on tumor bearing rats: On day 0, tumors were orthotopically induced by implanting 9L fragments into the brain of Fischer 344 female and male rats.On day 5, developing tumors were surgically resected, and rats were subsequently treated with either temozolomide (TMZ), the current standard of care model, orally (PO) for 5 consecutive days, a single application of a bioresorbable paste containing MTL-004, or both treatments combined. Results: Tolerance and biodistribution of MTL-004: Based on IV dosing, 5 mg/kg/day was considered to be the maximum tolerated dose of MTL-004. A dose of 1 mg/kg/day was considered to be the highest dose suitable for repeated IV treatments, and was the safe dose selected for all in vivo studies.Following IC and IV administration of 14CMTL004, plasma exposure profile and pharmacokinetic half-life were similar. The retention / half-life of 14CMTL004 in brain was longer than in plasma, suggesting that its elimination, along with metabolites, took longer in brain than in plasma. MTL-004 was mainly excreted through urine. Efficacy of MTL-004 on tumor bearing rats: Male and female rats treated with a single IC dose of MTL-004 following tumor resection demonstrated a significantly higher survival compared to both placebo and TMZ groups and remained in apparent good health for the duration of the study.Combination of both PO TMZ and IC MTL-004 doses was assessed in female rats, where no significant increase of survival was observed compared to IC administered MTL-004 alone. Conclusions: MTL-004 was found to be safe and well-tolerated at a dose of 1 mg/kg, and was excreted mainly through urine.Following resection, PO TMZ seemed to have a transient impact on tumor growth, but minimal survival gains compared to placebo. In contrast, a single IC treatment with MTL-004 in paste provided prolonged control of tumor recurrence leading to a significantly increased survival of animals. Citation Format: Mike Hudson, Elisabeth Bertrand, Sylvie Maubant, Marie Lux, Elodie Marie Dit Chatel, Jordan Longin, Sophie Chaumeron, Maxime Beauchet, Anne-Pascale Luzy, Pauline Bornert, Olivier Duchamp. MTL-004, a promising new therapeutic for post-resection treatment of glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6860.