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).

Figure 1. AZD3965 Dose Escalation

^a An additional two patients were enrolled in the 20 mg OD cohort but were withdrawn prior to receiving AZD3965. ^b Two events of Grade 3 increased cardiac troponin I were reported for the same patient. ^c ERG change DLTs were reported as AEs of retinopathy or eye disorders – other (ERG changes). All were Grade 1. One event was reported as Grade 2 but it was later confirmed by the Chief Investigator (Principal Investigator at the site) that this should have been recorded as Grade 1 since the patient was asymptomatic and had no change in visual acuity ^d The DLT of Grade 3 acidosis occurred after the single dosing day of 20 mg OD at D-7; the patient was withdrawn from the trial prior to commencing daily dosing at 10 mg BD. Abbreviations: BD, twice daily; DLT, dose limiting toxicity; ERG, electroretinogram; OD, once daily.

Figure 2. Summary of Pharmacokinetics: (A) AUC and (B) C_max versus Dose of AZD3965 at D-7

Dose level of 20 mg includes data from AZD3965 20 mg OD and 10 mg BD dose cohorts (both received 20 mg on D-7) and dose level of 30 mg includes data from AZD3965 30 mg OD and 15 mg BD dose cohorts (both received 30 mg on D-7). Both panels show individual data per patient. Abbreviations: AUC, area under the curve; C_max, maximum plasma concentration; D=day.

Figure 3. Average Urinary Metabolite Excretion (A) Over Time Across All Patients, (B) of Total MCT1 Substrates Over Time Across All Patients by Cohort, and (C) Effect Rates at Each Timepoint According to Urinary Metabolite Excretion Across Cohorts 3–6

Number of patients for each analysis shown in numerals above relevant bars in panels (A) and (B); the analysis population for panel (C) is the same as for panel (B). Urinary effect defined as 5×median urinary concentration of total MCT1 substrates (lactate and ketone bodies) across all patients at baseline (463.9 μmol/mmol creatinine). Abbreviations: BD, twice daily; C, cycle; D, day; MCT, monocarboxylate transporter; OD, once daily.