A phase I dose-escalation study of AZD3965, an oral monocarboxylate transporter 1 inhibitor, in patients with advanced cancer
Author(s)
Type
Journal Article
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).
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).
Date Issued
2023-04-15
Date Acceptance
2023-01-13
Citation
Clinical Cancer Research, 2023, 29 (8), pp.1429-1439
ISSN
1078-0432
Publisher
American Association for Cancer Research
Start Page
1429
End Page
1439
Journal / Book Title
Clinical Cancer Research
Volume
29
Issue
8
Copyright Statement
2023 American Association for Cancer Research
Sarah Halford, Gareth J. Veal, Stephen R. Wedge, Geoffrey S. Payne, Chris M. Bacon, Philip Sloan, Ilaria Dragoni, Kathrin Heinzmann, Sarah Potter, Becky M. Salisbury, Maxime Chénard-Poirier, Alastair Greystoke, Elizabeth C. Howell, William A. Innes, Karen Morris, Chris Plummer, Mihaela Rata, George Petrides, Hector C. Keun, Udai Banerji, Ruth Plummer; A Phase I Dose-escalation Study of AZD3965, an Oral Monocarboxylate Transporter 1 Inhibitor, in Patients with Advanced Cancer. Clin Cancer Res 15 April 2023; 29 (8): 1429–1439. https://doi.org/10.1158/1078-0432.CCR-22-2263
Sarah Halford, Gareth J. Veal, Stephen R. Wedge, Geoffrey S. Payne, Chris M. Bacon, Philip Sloan, Ilaria Dragoni, Kathrin Heinzmann, Sarah Potter, Becky M. Salisbury, Maxime Chénard-Poirier, Alastair Greystoke, Elizabeth C. Howell, William A. Innes, Karen Morris, Chris Plummer, Mihaela Rata, George Petrides, Hector C. Keun, Udai Banerji, Ruth Plummer; A Phase I Dose-escalation Study of AZD3965, an Oral Monocarboxylate Transporter 1 Inhibitor, in Patients with Advanced Cancer. Clin Cancer Res 15 April 2023; 29 (8): 1429–1439. https://doi.org/10.1158/1078-0432.CCR-22-2263
Identifier
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000972399400001&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=a2bf6146997ec60c407a63945d4e92bb
Subjects
AZD3965
CANCER METABOLISM
HEART
INTRACELLULAR PH
Life Sciences & Biomedicine
LYMPHOMA
MITOCHONDRIAL METABOLISM
Oncology
PET
Science & Technology
TRANSPORTERS MCT1
TUMORS
Publication Status
Published
Date Publish Online
2023-04-14