dc.contributor.author | Lopez, J | |
dc.contributor.author | Lai-Kwon, J | |
dc.contributor.author | Molife, R | |
dc.contributor.author | Welsh, L | |
dc.contributor.author | Tunariu, N | |
dc.contributor.author | Roda, D | |
dc.contributor.author | Fernández-García, P | |
dc.contributor.author | Lladó, V | |
dc.contributor.author | McNicholl, AG | |
dc.contributor.author | Rosselló, CA | |
dc.contributor.author | Taylor, RJ | |
dc.contributor.author | Azaro, A | |
dc.contributor.author | Rodón, J | |
dc.contributor.author | Sludden, J | |
dc.contributor.author | Veal, GJ | |
dc.contributor.author | Plummer, R | |
dc.contributor.author | Urruticoechea, A | |
dc.contributor.author | Lahuerta, A | |
dc.contributor.author | Mujika, K | |
dc.contributor.author | Escribá, PV | |
dc.coverage.spatial | England | |
dc.date.accessioned | 2023-09-19T09:21:03Z | |
dc.date.available | 2023-09-19T09:21:03Z | |
dc.date.issued | 2023-09-21 | |
dc.identifier | 10.1038/s41416-023-02356-1 | |
dc.identifier.citation | British Journal of Cancer, 2023, 129 (5), pp. 811 - 818 | en_US |
dc.identifier.issn | 0007-0920 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/5971 | |
dc.identifier.eissn | 1532-1827 | |
dc.identifier.eissn | 1532-1827 | |
dc.identifier.doi | 10.1038/s41416-023-02356-1 | |
dc.description.abstract | 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. | |
dc.format | Print-Electronic | |
dc.format.extent | 811 - 818 | |
dc.language | eng | |
dc.language.iso | eng | en_US |
dc.publisher | SPRINGERNATURE | en_US |
dc.relation.ispartof | British Journal of Cancer | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | en_US |
dc.subject | Humans | |
dc.subject | Diarrhea | |
dc.subject | Glioma | |
dc.subject | Maximum Tolerated Dose | |
dc.subject | Nausea | |
dc.subject | Neoplasm Recurrence, Local | |
dc.subject | Neoplasms | |
dc.subject | Sphingolipids | |
dc.subject | Vomiting | |
dc.title | A Phase 1/2A trial of idroxioleic acid: first-in-class sphingolipid regulator and glioma cell autophagy inducer with antitumor activity in refractory glioma. | en_US |
dc.type | Journal Article | |
dcterms.dateAccepted | 2023-06-28 | |
dc.date.updated | 2023-09-19T08:47:29Z | |
rioxxterms.version | VoR | en_US |
rioxxterms.versionofrecord | 10.1038/s41416-023-02356-1 | en_US |
rioxxterms.licenseref.startdate | 2023-09-21 | |
rioxxterms.type | Journal Article/Review | en_US |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/37488446 | |
pubs.issue | 5 | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Early Phase Drug Development | |
pubs.publication-status | Published | |
pubs.publisher-url | http://dx.doi.org/10.1038/s41416-023-02356-1 | |
pubs.volume | 129 | |
icr.researchteam | Early Phase Drug Develop | en_US |
dc.contributor.icrauthor | Lopez, Juanita | |
dc.contributor.icrauthor | Tunariu, Nina | |
icr.provenance | Deposited by Dr Juanita Lopez on 2023-09-19. Deposit type is initial. No. of files: 1. Files: A Phase 12A trial of idroxioleic acid first-in-class sphingolipid regulator and glioma cell autophagy inducer with antitumor.pdf | |
icr.provenance | Deposited by Dr Juanita Lopez on 2023-09-19. Deposit type is subsequent. No. of files: 1. Files: 2023BrJCancer.pdf | |