A case of malignant hyperlactaemic acidosis appearing upon treatment with the mono-carboxylase transporter 1 inhibitor AZD3965

Abstract

A 47-year-old man with metastatic melanoma presented with refractory hyperlactaemic acidosis following the first dose of the mono-carboxylase transporter 1 inhibitor AZD3965 within a "first time in man" clinical trial. The mechanism of the agent and the temporal relationship suggested that this event was potentially drug related and recruitment was suspended. However, urinary metabolomics showed extensive abnormalities even prior to drug administration, leading to investigations for an underlying metabolic disorder. The lack of clinical symptoms from the elevated lactate and low blood glucose suggested a diagnosis of "hyper-Warburgism", where the high tumour burden was associated with extensive glucose uptake and lactate efflux from malignant cells, and the subsequent impact on blood biochemistry. This was supported by an FDG-PET scan showing extensive glucose uptake in numerous metastases and lack of uptake in the brain. A review of the literature showed 16 case reports of "hyper-Warburgism" in non-haematological malignancies, none of them with melanoma, with most associated with a poor outcome. The patient was treated symptomatically, but died 2 months later. The development of AZD3965 continues with the exclusion of patients with elevated plasma lactate at screening added to the protocol as a safety measure.Trial identification number ClinicalTrials.Gov. NCT01791595.

Fig. 1. Lactate, arterial pH and blood glucose measured during initial admission to the intensive care unit.

Blood glucose was measured on arterial blood gas except on days 9 and 10, where it was recorded as capillary blood glucose. Lactate and pH were not measured on day 11. The highest recorded lactate values and the lowest recorded pH values are shown for each day. A, admission to the ITU. B, started continuous veno-venous haemodiafiltration (CVVHDF). C, started 20% intravenous dextrose. D, stopped intravenous dextrose. E, started intravenous vitamin supplementation (pabrinex). F, stopped CVVHDF. G, started 10% intravenous dextrose. Started oral bicarbonate therapy (2 g of BD). H, oral bicarbonate increased (2 g of TDS). I, transferred to the ward.

Fig. 2. Urinary lactate in the patient before and following treatment with one dose of AZD3965 and stay in the intensive care unit with administration of IV 20% dextrose.

Compared with other patients in the clinical trial treated at the same dose of AZD3965. Urinary lactate was measured with ¹H nuclear magnetic resonance spectroscopy metabolomics analysis.

Fig. 3

FDG PET showing extensive uptake in tumour metastases throughout the body on maximum intensity projections (a). Reduced uptake in the brain (b, c) is shown on the maximum intensity projection and fused axial images (hot iron scale) and compared with a cross section of FDG-avid nodal and bone metastases in the thorax (d, indicated by white arrows). The PET scan was performed on a GE 710 PET-CT scanner with a dose of 3.5 MBq/kg 18^F fludeoxyglucose in 3-min bed positions.