PMID- 37488446 OWN - NLM STAT- MEDLINE DCOM- 20230830 LR - 20230830 IS - 1532-1827 (Electronic) IS - 0007-0920 (Print) IS - 0007-0920 (Linking) VI - 129 IP - 5 DP - 2023 Sep TI - A Phase 1/2A trial of idroxioleic acid: first-in-class sphingolipid regulator and glioma cell autophagy inducer with antitumor activity in refractory glioma. PG - 811-818 LID - 10.1038/s41416-023-02356-1 [doi] AB - 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. CI - (c) 2023. Crown. FAU - Lopez, Juanita AU - Lopez J AUID- ORCID: 0000-0001-8321-4212 AD - The Royal Marsden Hospital and the Institute of Cancer Research, Sutton, UK. Juanita.Lopez@icr.ac.uk. FAU - Lai-Kwon, Julia AU - Lai-Kwon J AD - The Royal Marsden Hospital and the Institute of Cancer Research, Sutton, UK. FAU - Molife, Rhoda AU - Molife R AD - The Royal Marsden Hospital and the Institute of Cancer Research, Sutton, UK. FAU - Welsh, Liam AU - Welsh L AD - The Royal Marsden Hospital and the Institute of Cancer Research, Sutton, UK. FAU - Tunariu, Nina AU - Tunariu N AD - The Royal Marsden Hospital and the Institute of Cancer Research, Sutton, UK. FAU - Roda, Desamparados AU - Roda D AD - The Royal Marsden Hospital and the Institute of Cancer Research, Sutton, UK. FAU - Fernandez-Garcia, Paula AU - Fernandez-Garcia P AUID- ORCID: 0000-0002-8128-7028 AD - Laminar Pharmaceuticals, Palma de Mallorca, Spain. FAU - Llado, Victoria AU - Llado V AD - Laminar Pharmaceuticals, Palma de Mallorca, Spain. FAU - McNicholl, Adrian G AU - McNicholl AG AD - Laminar Pharmaceuticals, Palma de Mallorca, Spain. FAU - Rossello, Catalina A AU - Rossello CA AD - Laminar Pharmaceuticals, Palma de Mallorca, Spain. FAU - Taylor, Richard J AU - Taylor RJ AD - Laminar Pharmaceuticals, Palma de Mallorca, Spain. FAU - Azaro, Analia AU - Azaro A AD - Hospital Vall d'Hebron, Barcelona, Spain. FAU - Rodon, Jordi AU - Rodon J AUID- ORCID: 0000-0001-6467-3632 AD - Hospital Vall d'Hebron, Barcelona, Spain. FAU - Sludden, Julieann AU - Sludden J AD - Northern Centre for Cancer Care, Newcastle upon Tyne, UK. FAU - Veal, Gareth J AU - Veal GJ AD - Northern Centre for Cancer Care, Newcastle upon Tyne, UK. FAU - Plummer, Ruth AU - Plummer R AUID- ORCID: 0000-0003-0107-1444 AD - Northern Centre for Cancer Care, Newcastle upon Tyne, UK. FAU - Urruticoechea, Ander AU - Urruticoechea A AD - Gipuzkoa Cancer Unit, OSID-Onkologikoa, San Sebastian, Spain. FAU - Lahuerta, Ainhara AU - Lahuerta A AD - Gipuzkoa Cancer Unit, OSID-Onkologikoa, San Sebastian, Spain. FAU - Mujika, Karmele AU - Mujika K AD - Gipuzkoa Cancer Unit, OSID-Onkologikoa, San Sebastian, Spain. FAU - Escriba, Pablo V AU - Escriba PV AD - Laminar Pharmaceuticals, Palma de Mallorca, Spain. LA - eng SI - ClinicalTrials.gov/NCT01792310 PT - Clinical Trial, Phase I PT - Clinical Trial, Phase II PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230724 PL - England TA - Br J Cancer JT - British journal of cancer JID - 0370635 RN - 0 (Sphingolipids) SB - IM MH - Humans MH - Diarrhea MH - *Glioma/drug therapy MH - Maximum Tolerated Dose MH - Nausea MH - Neoplasm Recurrence, Local MH - *Neoplasms/drug therapy MH - Sphingolipids/therapeutic use MH - Vomiting PMC - PMC10449773 COIS- VL, PF-G, AM, CAR and PVE work for and are Laminar Pharmaceuticals shareholders, the sponsor of this study. RJT is a consultant to Laminar Pharmaceuticals. The remaining authors declare no competing interests. EDAT- 2023/07/25 01:09 MHDA- 2023/08/28 07:16 PMCR- 2023/07/24 CRDT- 2023/07/24 23:36 PHST- 2022/11/28 00:00 [received] PHST- 2023/06/28 00:00 [accepted] PHST- 2023/06/25 00:00 [revised] PHST- 2023/08/28 07:16 [medline] PHST- 2023/07/25 01:09 [pubmed] PHST- 2023/07/24 23:36 [entrez] PHST- 2023/07/24 00:00 [pmc-release] AID - 10.1038/s41416-023-02356-1 [pii] AID - 2356 [pii] AID - 10.1038/s41416-023-02356-1 [doi] PST - ppublish SO - Br J Cancer. 2023 Sep;129(5):811-818. doi: 10.1038/s41416-023-02356-1. Epub 2023 Jul 24.