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A Phase 1/2A trial of idroxioleic acid: first-in-class sphingolipid regulator and glioma cell autophagy inducer with antitumor activity in refractory glioma Lopez, Juanita Lai-Kwon, Julia Molife, L. R. Welsh, Liam Tunariu, Nina Roda, Desamparados Azaro Pedrazzoli, Analía Beatriz Rodon, Jordi Institut Català de la Salut [Lopez J, Lai-Kwon J, Molife R, Welsh L, Tunariu N, Roda D] The Royal Marsden Hospital and the Institute of Cancer Research, Sutton, UK. [Azaro A, Rodón J] Vall d’Hebron Hospital Universitari, Barcelona, Spain Vall d'Hebron Barcelona Hospital Campus 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 Cancer therapy; Phase I trials Teràpia del càncer; Assajos de fase I Terapia del cáncer; Ensayos de fase I Background 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. 2023-10-09T09:14:57Z 2023-10-09T09:14:57Z 2023-09-21 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Lopez J, Lai-Kwon J, Molife R, Welsh L, Tunariu N, Roda D, et al. A Phase 1/2A trial of idroxioleic acid: first-in-class sphingolipid regulator and glioma cell autophagy inducer with antitumor activity in refractory glioma. Br J Cancer. 2023 Sep 29;129:811–818. 0007-0920 https://hdl.handle.net/11351/10418 10.1038/s41416-023-02356-1 37488446 001035687800003 http://hdl.handle.net/11351/10418 eng British Journal of Cancer;129 https://doi.org/10.1038/s41416-023-02356-1 Attribution 4.0 International http://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess application/pdf application/pdf Springer Nature Scientia