Minerval (2OHOA) is an orally bioavailable synthetic derivative of oleic acid that crosses the Blood Brain Barrier and activates sphingomyelin
synthase 1 (SMS1), a key enzyme that catalyses the reversible conversion of PC, PE or PS into SM and DAG, leading to an increased concentration of
sphingomyelin (SM) in the cancer cell membrane. This mislocalizes K/H-Ras from the Plasma Membrane and inhibits its nanoclustering, short-cutting Ras-
associated proliferative signalling pathways, which exhibit an aberrant activity in at least one third of all human cancers
of Minerval (IC50) on a variety of cancer cell lines strongly correlates with basal levels of MRC5
SMS1 mRNA expression (the beginning) and with a decrease of HES1 mRNA expression 100
SNB75
U87MG
after 24h treatment, expressed in % of basal levels (untreated controls). Regulation of
HES1 (transcription factor at the end of Ras/Notch/autophagic antiproliferative signal 50
SF268
U251
transduction pathways) confirms the modulation of Ras signalling by Minerval SF295
U118
0
0 500 1000
IC50 (M)
Top. Minervals (2OHOA) efficacy against human glioma in nude mice bearing human gliomas
MIN-001-1203: A phase I/IIa open-label dose escalation study of Minerval in subjects with advanced
solid tumors including malignant glioma
Study design
Case study 1: response in GBM patient 010202 (54y old male)
Part A. Dose escalating study. Up to 30 patients.
Apr 2012: Partial debulking surgery followed by radical chemo-radiotherapy
21-day cycles. Glioma and other solid tumours
Aug-Sep 2012: Adjuvant Temozolomide, with PD after 3 cycles
Part B. Exploratory study. Up to 20 patients in
Nov-Feb 2013: PCV chemotherapy with PD after 4 cycles
two groups. 21-day cycles. 1st group with glioma
Aug 2013: enrolled in MIN-001-1203 trial (2nd cohort, 1g/day BID)
patients. 2nd group with biopsiable solid-tumours
patients for biomarker and efficacy evaluation.
Objectives
Dose-escalation, multicentre phase I clinical trial
of 2-OHOA in advanced solid tumours including
refractory malignant glioma
Exploratory objectives:
To evaluate the effect of 2-OHOA on glial fibrillary
acidic protein (GFAP) in glioma pts
To study miRNA as a potential response biomarker
22AUG13 22OCT13 17MAR14 27MAR15 01FEB16
Main results
Part A highlights (completed): Top. Pt 010202. Partial Response (PR) by RANO (tumour shrinkage of 93% on primary lesion lasting for almost 3 years)
7 cohorts completed. 32 pts (28 evaluable) treated Minerval in recurrent GBM patients in MIN-001-1203 PI study
No relevant safety issues (only GI effects 200% Recurrent glioblastoma patients in MIN-001-1203 study (n=13)
Target lesion. Best response 010202* 145,4
030603 26,7
010302# 3,6
Encouraging sings of efficacy, specially in rGBM pts: -75%
030201A 3,1
objective clinical benefit (6 months) by RANO 13 rGBM patients completed at least 1 cycle of treatment with Minerval. Most pts had received 2 or more previous lines of
Almost all (4/5) of rGBM pts treated for 2 cycles, (experimental) chemotherapy treatment. 4/13 rGBM patients treated had overall clinical benefit. Of the 9 rGBM pts eligible for
not treated before with Avastin, had clinical benefit DLT assessment that did not experienced clinical benefit, at least 5 had previously failed another experimental treatment (4 of them
with bevacizumab) 4/9 rGBM pts not previously treated with bevacizumab had clinical benefit with Minerval
1 rGBM pt PR lasting for almost 3 years 8 rGBM patients completed at least 2 cycles of treatment and had their planned reassessment scan at 6 weeks. 4 of them (50%)
1 oligodendroglioma pt SD for 9 months had objective clinical benefit by RANO. Of the 4 rGBM pts treated with Minerval for at least 2 cycles with no clinical benefit, 3 of
1 rGBM pt SD for 7 months them had previously failed another experimental treatment (2 of them with bevacizumab)
2 rGBM pts SD for 6 months 4/6 rGBM pts treated for 2 or more cycles with Minerval and that were bevacizumab naive had objective clinical benefit