Imperial College London
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DrAlexandrosSiskos

Faculty of Medicine, Department of Surgery & Cancer

Honorary Research Fellow
 
 
 
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Contact

 

a.siskos Website

 
 
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Location

 

Institute of Reproductive and Developmental BiologyHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@inproceedings{Halford:2021:10.1200/JCO.2021.39.15_suppl.3115,
author = {Halford, SER and Walter, H and McKay, P and Townsend, W and Linton, K and Heinzmann, K and Dragoni, I and Brotherton, L and Veal, G and Siskos, A and Keun, HC and Bacon, C and Wedge, S and Dyer, MJS and Plummer, ER},
doi = {10.1200/JCO.2021.39.15_suppl.3115},
pages = {3115--3115},
publisher = {American Society of Clinical Oncology},
title = {Phase I expansion study of the first-in-class monocarboxylate transporter 1 (MCT1) inhibitor AZD3965 in patients with diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL).},
url = {http://dx.doi.org/10.1200/JCO.2021.39.15_suppl.3115},
year = {2021}
}
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RIS format (EndNote, RefMan)

TY  - CPAPER
AB  - Background: Tumours rely on lactate transporters (MCT1-4) to maintain glycolytic flux and avoid intracellular acidification. In haematological tumours the MCT1 transporter acts as a lactate and pyruvate exporter. AZD3965 is a potent and specific inhibitor of MCT1 causing intracellular lactate accumulation. In vivo efficacy was observed in xenografts of DLBCL and BL, expressing high levels of MCT1 and no or low levels of MCT4. In the AZD3965 phase I (NCT01791595) dose-escalation an oral recommended phase 2 dose (RP2D) of 10mg twice-daily (bd) was determined. Pharmacokinetic (PK) showed exposure estimated to produce a minimum MCT1 occupancy of 90% (based on modelling). DLTs were primarily on-target dose-dependent, reversible, asymptomatic alterations in retinal function seen on ERG. Methods: This expansion cohort enrolled patients with relapsed/refractory DLBCL and BL. Expression of MCT1/MCT4 was assessed by immunohistochemistry. Pharmacokinetic (PK) sampling was performed and pharmacodynamic assessments included [18F]FDG-PET/CT imaging and plasma/urine metabolomics. Results: 11 DLBCL patients were treated with AZD3965 10mg bd. PK showed exposure to be broadly in line with the escalation cohort. No significant ERG changes were observed. One patient experienced a dose-limiting SUSAR of Troponin I increase. MCT1 is expressed in erythrocytes, however no serious events of anaemia were seen, with one non-clinically significant episode of grade 3 anaemia reported. Urine analysis showed increased excretion of lactate and ketone bodies post AZD3965 treatment consistent with renal target engagement. No alteration was detected in plasma. Ongoing stable disease at cycle 5 was observed in one patient and an additional patient had a confirmed complete response (CR) lasting 15 months, with no significant toxicity. In the patient showing CR a reduction in tumour FDG uptake was observed on day 3 of cycle 1. The other four patients who consented to research imaging did not have a clin
AU  - Halford,SER
AU  - Walter,H
AU  - McKay,P
AU  - Townsend,W
AU  - Linton,K
AU  - Heinzmann,K
AU  - Dragoni,I
AU  - Brotherton,L
AU  - Veal,G
AU  - Siskos,A
AU  - Keun,HC
AU  - Bacon,C
AU  - Wedge,S
AU  - Dyer,MJS
AU  - Plummer,ER
DO  - 10.1200/JCO.2021.39.15_suppl.3115
EP  - 3115
PB  - American Society of Clinical Oncology
PY  - 2021///
SN  - 0732-183X
SP  - 3115
TI  - Phase I expansion study of the first-in-class monocarboxylate transporter 1 (MCT1) inhibitor AZD3965 in patients with diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL).
UR  - http://dx.doi.org/10.1200/JCO.2021.39.15_suppl.3115
UR  - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000708120601289&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - https://ascopubs.org/doi/10.1200/JCO.2021.39.15_suppl.3115
UR  - http://hdl.handle.net/10044/1/94005
ER  -
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