A - phase I dose-escalation study of AZD3965, an oral monocarboxylate transporter 1 inhibitor, in patients with advanced cancer
Halford, S. Veal, G. J. Wedge, S. R. Payne, G. S. Bacon, C. M. Sloan, P. Dragoni, I. Heinzmann, K. Potter, S. Salisbury, B. M.
Halford, S.
Veal, G. J.
Wedge, S. R.
Payne, G. S.
Bacon, C. M.
Sloan, P.
Dragoni, I.
Heinzmann, K.
Potter, S.
Salisbury, B. M.
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Abstract
Purpose: 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).
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Date
2023
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Article
Citation
Halford 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.