Dataset Information

A Phase I Dose-escalation Study of AZD3965, an Oral Monocarboxylate Transporter 1 Inhibitor, in Patients with Advanced Cancer.

ABSTRACT:

Purpose

Inhibition of monocarboxylate transporter (MCT) 1-mediated lactate transport may have cytostatic and/or cytotoxic effects on tumor 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.

Patients and methods

This multicentre, phase I, dose-escalation and dose-expansion trial enrolled patients with advanced solid tumors or lymphoma and no standard therapy options. Exclusion criteria included history of retinal and/or cardiac disease, due to MCT1 expression in the eye and heart. Patients received daily oral AZD3965 according to a 3+3 then rolling six design. Primary objectives were to assess safety and determine the MTD and/or recommended phase II dose (RP2D). Secondary objectives for dose escalation included measurement of pharmacokinetic and pharmacodynamic activity. Exploratory biomarkers included tumor 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. Treatment-emergent adverse events were primarily grade 1 and/or 2, most commonly electroretinogram changes (retinopathy), fatigue, anorexia, and constipation. Seven patients receiving ≥20 mg daily experienced dose-limiting toxicities (DLT): 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 twice daily was established for use in dose expansion in cancers that generally express high MCT1/low MCT4).

SUBMITTER: Halford S

PROVIDER: S-EPMC7614436 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Publications

A Phase I Dose-escalation Study of AZD3965, an Oral Monocarboxylate Transporter 1 Inhibitor, in Patients with Advanced Cancer.

Halford Sarah S Veal Gareth J GJ Wedge Stephen R SR Payne Geoffrey S GS Bacon Chris M CM Sloan Philip P Dragoni Ilaria I Heinzmann Kathrin K Potter Sarah S Salisbury Becky M BM Chénard-Poirier Maxime M Greystoke Alastair A Howell Elizabeth C EC Innes William A WA Morris Karen K Plummer Chris C Rata Mihaela M Petrides George G Keun Hector C HC Banerji Udai U Plummer Ruth R

Clinical cancer research : an official journal of the American Association for Cancer Research 20230401 8

<h4>Purpose</h4>Inhibition of monocarboxylate transporter (MCT) 1-mediated lactate transport may have cytostatic and/or cytotoxic effects on tumor 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.<h4>Patients and methods</h4>This multicentre, phase I, dose-escalation and dose-expansion trial enrolled patients with advanced solid tumors or lymphoma and no standard therapy options. Exclusion criteria in ...[more]

PMID: 36652553

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Dataset Information

A Phase I Dose-escalation Study of AZD3965, an Oral Monocarboxylate Transporter 1 Inhibitor, in Patients with Advanced Cancer.

Purpose

Patients and methods

Results

Conclusions

Publications

A Phase I Dose-escalation Study of AZD3965, an Oral Monocarboxylate Transporter 1 Inhibitor, in Patients with Advanced Cancer.

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