Title:
Intra-cranial administration of MTL-004, a promising post-resection treatment for glioblastoma
Autors:
Mike Hudson1, Sylvie Maubant², Elisabeth Bertrand², Marie Lux², Jordan Longin², Elodie Marie Dit Chatel², Maxime Ramelet², Olivier Duchamp²
1: Gordian Pharma Ltd., Pentre Bach, Brecon, United Kingdom. 2: Oncodesign Services, Dijon, France.
Abstract :
Objectives :
Gliomas (GBM), are exceptionally hard to treat, aggressive and genetically heterogeneous tumors. This study reports the control of tumour recurrence and improved survival in male and female rats by combining a single intra-cranial dose of MTL-004 (5-(aziridine-1- yl)-4 hydroxylamino-2-nitrobenzamide), in a bioresorbable paste (a blend of poly DL-lactic acid-co-glycolic acid; (PLGA) and poly ethylene glycol; (PEG)) following surgical resection of primary glioma tumors. Comparison is made with oral temozolomide (TMZ) following resection, the current standard of care model.
Experimental procedures
Subcutaneous GS-9L tumors were surgically excised from female Fischer 344 rats and cut into 2 mm3 fragments.
On day 0, tumor fragments were implanted into the brains of healthy female and male rats.
On Day 5 rats were anesthetized, the incision was re-opened and the actively growing tumor removed using microsurgery. Treatments started as follows:
- Group 1 (Placebo) received a single intracranial dose of excipient powder in PGLA/PEG paste
- Group 2 (Standard of Care) received 5 daily oral doses of temozolomide at 50 mg/kg
- Group 3 (MTL-004) received a single intracranial dose of 1 mg/kg MTL-004 in PGLA/PEG paste
Results Body Weight Between day 0 and 5, no groups had statistically significant body weight changes. Between days 5 to 9, mean body weight of rats receiving TMZ was significantly reduced.
Tumor Volumes Tumor volumes from MRI were evaluated when at least 80% of rats were still alive in each group (day 14 post tumor resection / treatment initiation). Mean tumor volume was significantly higher in the placebo groups compared to MTL-004 and TMZ treatments.
Survival Rats were studied for 58-days post tumor resection/treatment. At this time out of twelve rats per group, none or one survived on TMZ, two or no animals were still alive on placebo, and seven or ten rats treated with MTL-004 were still alive (male/female respectively).
Post resection median survival time was between 20.5 to 27.5 days for rats treated with oral placebo or TMZ. Rats treated with MTL-004 had a significantly higher survival compared to both placebo and TMZ groups and remained in apparent good health for the duration of the study.
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