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/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).

Lactate transport inhibition therapeutically reprograms fibroblast metabolism in experimental pulmonary fibrosis

“…Pharmacologic interest in lactate transporters has been driven by the recognition of increased lactate transporter expression in a variety of cancers ( 69 ). AZD3965 was selected for this study as it has been investigated in human clinical trials for advanced solid organ malignancies ( 22 ). In this Phase 1 study, AZD3965 was generally well-tolerated with 7 of 40 patients experiencing dose-limiting toxicities including asymptomatic, reversible ocular changes; acidosis; and increased troponin.…”

“…Inhibitors targeting these transporters have been actively explored in clinical trials for oncological conditions where glycolytic reprogramming also features prominently in disease pathobiology ( 20, 21 ). Importantly, MCT inhibitors present favorable pharmacologic profiles compared to previously studied glycolysis inhibitors, with successful translation to human clinical trials for advanced solid tumors ( 22 ). Before the promise of this therapeutic approach in IPF may be realized, however, the preclinical efficacy and molecular mechanisms-of-action of lactate transport inhibitors must be demonstrated experimentally.…”

Feedback loop between hypoxia and energy metabolic reprogramming aggravates the radioresistance of cancer cells

“…The use of lactate by cancer cells is dependent on the expression of monocarboxylic acid transporters (MCTs). Clinical trials of the MCT inhibitor AZD3965 in the treatment of B-cell lymphoma cancer are also underway (NCT01791595) [ 227 ]. And the combination of AZD3965 with radiotherapy prolongs survival and improves radiosensitivity [ 228 ].…”

A review of lactate-lactylation in malignancy: its potential in immunotherapy

“…However, this positive outcome was not observed when combining MCT1 inhibitor AZD3965 ( 44 ) with anti-PD-L1 therapy. Notably, AZD 3965 is currently undergoing a dose-escalation Phase I trial for the treatment of advanced solid tumors and lymphomas (NCT 01791595) ( 40 ).…”

“…Moreover, the risk lies in the expression of MCT1 in normal tissues, particularly the retina and heart. There have been reports of reversible vision loss and elevations in cardiac troponin levels in patients undergoing MCT1-targeted therapies, which are indicators of retinal effects and myocardial injury, respectively ( 40 ). It is imperative to carefully consider the balance between potential benefits and risks when pursuing targeted lactate therapy and explore strategies to mitigate these side effects.…”