2026-04-13T00:08:46Zhttps://recercat.cat/oai/requestoai:recercat.cat:11351/104182025-10-24T10:17:08Zcom_2072_378070com_2072_378040col_2072_378092
RECERCAT
author
Lopez, Juanita
author
Lai-Kwon, Julia
author
Molife, L. R.
author
Welsh, Liam
author
Tunariu, Nina
author
Roda, Desamparados
author
Azaro Pedrazzoli, Analía Beatriz
author
Rodon, Jordi
2025-10-24T10:17:08Z
2025-10-24T10:17:08Z
2023-10-09T09:14:57Z2023-10-09T09:14:57Z2023-09-21
http://hdl.handle.net/11351/10418
Cancer therapy; Phase I trialsTeràpia del càncer; Assajos de fase ITerapia del cáncer; Ensayos de fase IBackground
The first-in-class brain-penetrating synthetic hydroxylated lipid idroxioleic acid (2-OHOA; sodium 2-hydroxyoleate), activates sphingomyelin synthase expression and regulates membrane-lipid composition and mitochondrial energy production, inducing cancer cell autophagy. We report the findings of a multicentric first-in-human Phase 1/2A trial (NCT01792310) of 2-OHOA, identifying the maximum tolerated dose (MTD) and assessing safety and preliminary efficacy.
Methods
We performed an open-label, non-randomised trial to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and anti-tumour activity of daily oral treatment with 2-OHOA monotherapy (BID/TID) in 54 patients with glioma and other advanced solid tumours. A dose-escalation phase using a standard 3 + 3 design was performed to determine safety and tolerability. This was followed by two expansion cohorts at the MTD to determine the recommended Phase-2 dose (RP2D).
Results
In total, 32 recurrent patients were enrolled in the dose-escalation phase (500–16,000 mg/daily). 2-OHOA was rapidly absorbed with dose-proportional exposure. Treatment was well-tolerated overall, with reversible grade 1–2 nausea, vomiting, and diarrhoea as the most common treatment-related adverse events (AEs). Four patients had gastrointestinal dose-limiting toxicities (DLTs) of nausea, vomiting, diarrhoea (three patients at 16,000 mg and one patient at 12,000 mg), establishing an RP2D at 12,000 mg/daily. Potential activity was seen in patients with recurrent high-grade gliomas (HGG). Of the 21 patients with HGG treated across the dose escalation and expansion, 5 (24%) had the clinical benefit (RANO CR, PR and SD >6 cycles) with one exceptional response lasting >2.5 years.
Conclusions
2-OHOA demonstrated a good safety profile and encouraging activity in this difficult-to-treat malignant brain-tumour patient population, placing it as an ideal potential candidate for the treatment of glioma and other solid tumour malignancies.
Clinical trial registration
EudraCT registration number: 2012-001527-13; Clinicaltrials.gov registration number: NCT01792310.This study was supported in part by Laminar Pharmaceuticals. Financial support was also provided by the Govern de les Illes Balears i del Fons Social Europeu (ES01/TCAI/53_2016, ES01/TCAI/21_2017, ES01/TCAI/24_2018 and PROCOE/5/2017), the European Commission (H2020 Framework Programmes Project CLINGLIO 755179), Cancer Research UK (C9380/A25138) and the Experimental Cancer Medicine Centre Network (C9380/A25169). VL was supported by a Torres-Quevedo Research contract from the Spanish Ministerio de Economía y Competitividad (PTQ-17-09056), co-funded by the FSE.
Attribution 4.0 International http://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess
Gliomes - Tractament
Esfingolípids
Posologia
CHEMICALS AND DRUGS::Lipids::Membrane Lipids::Sphingolipids
DISEASES::Neoplasms::Neoplasms by Histologic Type::Neoplasms, Germ Cell and Embryonal::Neuroectodermal Tumors::Neoplasms, Neuroepithelial::Glioma
Other subheadings::Other subheadings::Other subheadings::/drug therapy
ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT::Investigative Techniques::Toxicity Tests::Maximum Tolerated Dose
COMPUESTOS QUÍMICOS Y DROGAS::lípidos::lípidos de membranas::esfingolípidos
ENFERMEDADES::neoplasias::neoplasias por tipo histológico::neoplasias de células germinales y embrionarias::tumores neuroectodérmicos::neoplasias neuroepiteliales::glioma
Otros calificadores::Otros calificadores::Otros calificadores::/farmacoterapia
TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS::técnicas de investigación::pruebas de toxicidad::dosis máxima tolerada
A Phase 1/2A trial of idroxioleic acid: first-in-class sphingolipid regulator and glioma cell autophagy inducer with antitumor activity in refractory glioma
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion