Discussion
diarrhoea, nausea, death, HGG, cancer, vomiting, PD, tumour, Glioma, gliomas
PROLIFERATION, CANCER, EMA, TUMOUR, EVENTS, GLIOMA, GLIOMAS, MALIGNANT DISEASE
Given the lack of effective therapies for HGG, the investigation of novel therapies is a clinical priority. 2-OHOA is a synthetic lipid able to modulate the sphingolipids metabolism that in consequence modifies the membrane composition and properties impacting on the cell signalling and avoiding cancer cell proliferation.In this first-in-human Phase 1/2A study, 2-OHOA monotherapy was well-tolerated, with the most common AEs being diarrhoea, nausea and vomiting. Events were dose-related and anticipated given the patient population as well as the nature of the oral suspension formulation of 2-OHOA. There were no SAEs attributable to study drug or AEs resulting in death. 2-OHOA was well-tolerated at the RP2D of 4000 mg TID.2-OHOA plasma concentrations were quantifiable across the dose range studied. Power models demonstrated dose proportionality in terms of A limitation of this study is that tumour type heterogeneity, as well as advanced tumour stage, further hinders obtaining robust results showing the effects of lipid modulation or mRNA expression on PD, but this is being explored in subsequent studies.2-OHOA monotherapy demonstrated promising anti-tumour activity, particularly in patients with HGG. Eight (38.1%) HGG patients experienced either a PR or SD by RANO criteria, with clinical benefit lasting at least 6 months in five patients. One patient with GBM who had been heavily pre-treated experienced a sustained partial response lasting for more than 3 years (Fig. The encouraging clinical response observed in a population with such a poor prognosis and clear unmet medical needs has supported the designation of Orphan Medicinal Product and Orphan Drug by the EMA (2011) and FDA (2021), respectively for the indication of Glioma; meriting further investigation. Three further trials have been performed. A Phase Ib trial to evaluate the safety of 2-OHOA in combination with the standard of care (chemoradiotherapy) in newly diagnosed GBM patients (NCT03867123), has completed with encouraging results to be published in 2022–2023; Second, an international pivotal Phase IIB/III study, under scientific advice by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA), investigating 2-OHOA efficacy in newly diagnosed GBM adult patients is currently underway (NCT04250922) with preliminary results expected in 2023, which, if providing promising and reassuring outcomes may prove to be sufficient to support a Conditional Marketing Authorisation (CMA) following careful regulatory assessment; and third, a paediatric IB/IIA trial in USA (NCT04299191), expected to be completed in 2023.In conclusion, monotherapy with the first-in-class orphan drug 2-OHOA has shown encouraging anti-tumour activity, particularly in HGG, in conjunction with a manageable safety profile up to very high doses; placing it as an ideal candidate for further investigation in gliomas and, potentially, other malignant diseases.