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dc.contributor.authorHalford, S.
dc.contributor.authorVeal, G. J.
dc.contributor.authorWedge, S. R.
dc.contributor.authorPayne, G. S.
dc.contributor.authorBacon, C. M.
dc.contributor.authorSloan, P.
dc.contributor.authorDragoni, I.
dc.contributor.authorHeinzmann, K.
dc.contributor.authorPotter, S.
dc.contributor.authorSalisbury, B. M.
dc.contributor.authorChénard-Poirier, M.
dc.contributor.authorGreystoke, A.
dc.contributor.authorHowell, E. C.
dc.contributor.authorInnes, W. A.
dc.contributor.authorMorris, Karen
dc.contributor.authorPlummer, C.
dc.contributor.authorRata, M.
dc.contributor.authorPetrides, G.
dc.contributor.authorKeun, H. C.
dc.contributor.authorBanerji, U.
dc.contributor.authorPlummer, R.
dc.date.accessioned2023-02-23T15:17:13Z
dc.date.available2023-02-23T15:17:13Z
dc.date.issued2023en
dc.identifier.citationHalford S, Veal GJ, Wedge SR, Payne GS, Bacon CM, Sloan P, et al. A Phase I Dose-Escalation Study of AZD3965, an Oral Monocarboxylate Transporter 1 Inhibitor, in Patients with Advanced Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research. 2023 Jan 18. PubMed PMID: 36652553. Epub 2023/01/19. eng.en
dc.identifier.pmid36652553en
dc.identifier.doi10.1158/1078-0432.ccr-22-2263en
dc.identifier.urihttp://hdl.handle.net/10541/626009
dc.description.abstractPurpose: Inhibition of monocarboxylate transporter (MCT) 1-mediated lactate transport may have cytostatic/cytotoxic effects on tumour cells. We report results from the dose-escalation part of a first‑in‑human trial of AZD3965, a first-in-class MCT1 inhibitor, in advanced cancer. Experimental design: This multicentre, Phase 1, dose-escalation and dose-expansion trial enrolled patients with advanced solid tumours or lymphoma and no standard therapy options. Exclusion criteria included history of retinal/cardiac disease, due to MCT1 expression in the eye and heart. Patients received daily oral AZD3965 according to a 3+3 then rolling 6 design. Primary objectives were to assess safety and determine the maximum tolerated dose and/or recommended Phase 2 dose (RP2D). Secondary objectives for dose-escalation included measurement of pharmacokinetics and pharmacodynamic activity. Exploratory biomarkers included tumour expression of MCT1 and MCT4, functional imaging of biological impact and metabolomics. Results: During dose-escalation, 40 patients received AZD3965 at 5-30 mg once daily or 10 or 15 mg twice daily (BD). Treatment‑emergent adverse events were primarily Grade 1/2, most commonly electroretinogram changes (retinopathy), fatigue, anorexia and constipation. Seven patients receiving ≥20 mg daily experienced dose-limiting toxicities (DLTs): Grade 3 cardiac troponin rise (n=1), asymptomatic ocular DLTs (n=5) and Grade 3 acidosis (n=1). Plasma pharmacokinetics demonstrated attainment of target concentrations; pharmacodynamic measurements indicated on‑target activity. Conclusions: AZD3965 is tolerated at doses that produce target engagement. DLTs were on-target and primarily dose-dependent, asymptomatic, reversible ocular changes. An RP2D of 10 mg BD was established for use in dose-expansion in cancers that generally express high MCT1/low MCT4 (not yet published).en
dc.language.isoenen
dc.relation.urlhttps://dx.doi.org/10.1158/1078-0432.ccr-22-2263en
dc.titleA - phase I dose-escalation study of AZD3965, an oral monocarboxylate transporter 1 inhibitor, in patients with advanced canceren
dc.typeArticleen
dc.contributor.departmentCancer Research UK, London, United Kingdomen
dc.identifier.journalClinical Cancer Researchen
dc.description.noteen]


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