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)
AuthorsHalford, S. E. R.
Linton, Kim M
Keun, H. C.
Dyer, M. J. S.
Plummer, E. R.
AffiliationCancer Research UK Centre for Drug Development, London,
MetadataShow full item record
AbstractBackground: 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 clinical response and no changes were observed on FDG-PET. Conclusions: AZD3965 can be safely administered at 10mg bd. In one DLBCL patient monotherapy activity was observed with changes in FDG-PET providing evidence indicative of proof of mechanism. These changes in FDG uptake as early as on day 3 in the responding patient warrant further investigation of FDG-PET as a predictive biomarker. Further biomarker analysis and preclinical studies are ongoing to understand the biology and explore effective combinations with other agents targeting tumour cell metabolism
CitationHalford SER, Walter H, McKay P, Townsend W, Linton K, Heinzmann K, et al. 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). Vol. 39, Journal of Clinical Oncology. American Society of Clinical Oncology (ASCO); 2021. p. 3115–3115.
JournalJournal of Clinical Oncology
TypeMeetings and Proceedings