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).

The calculated normal reference range in this study was found to be less than that used in our own and many other UK institutions. The results demonstrate the importance of periodic evaluation of normal uptake values and provide support for prospective studies defining the normal reference range to be performed.

Positron emission tomography-magnetic resonance (PET-MR) scanners could improve radiotherapy planning through combining PET and MR functional imaging. This depends on acquiring high quality and quantitatively accurate images in the radiotherapy position. This study evaluated PET-MR image quality using a flat couch and coil bridge for pelvic radiotherapy. MR and PET image quality phantoms were imaged in three setups: phantom on the PET-MR couch with anterior coil on top (diagnostic), phantom on a flat couch with coil on top (couch), and phantom on the flat couch with coil on a coil bridge (radiotherapy). PET images were also acquired in each setup without the anterior coil. PET attenuation correction of the flat couch and coil bridge were generated using kilovoltage computed tomography (CT) images and of the anterior coil using megavoltage CT images. MR image quality was substantially affected, with MR signal to noise ratio (SNR) relative to the diagnostic setup of 89% ± 2% (mean ± standard error of the mean, couch) and 54% ± 1% (radiotherapy), likely due to the increased distance between the patient and receive coils. The reduction impacted the low-contrast detectability score: 23 ± 1 (diagnostic), 19.7 ± 0.3 (couch) and 15 ± 1 (radiotherapy). All other MR metrics agreed within one standard error. PET quantitative accuracy was also affected, with measured activity with anterior coil being different to diagnostic without anterior coil by −16.7% ± 0.2% (couch) and −17.7 ± 0.1% (radiotherapy), without attenuation correction modification. Including the couch and coil bridge attenuation correction reduced this difference to −7.5% ± 0.1%, and including the anterior coil reduced this to −2.7% ± 0.1%. This was better than the diagnostic setup with anterior coil (difference −8.3% ± 0.2%). This translated into greater PET SNR performance for the fully corrected radiotherapy setup compared to diagnostic with coil. However contrast recovery was unchanged by the modified attenuation correction, with the diagnostic setup remaining ∼2% better. Quantitative PET in the radiotherapy setup is possible if appropriate attenuation correction is used. Pelvic radiotherapy PET-MR imaging protocols will need to consider the impact on PET-MR image quality.

FLT PET/CT detected changes in proliferation, with early increase in SUV60,max predicting progressive disease with a high specificity and PPV. Therefore, FLT PET/CT could be used as an early response biomarker for gemcitabine-based chemotherapy, to select a poor prognostic group who may benefit from novel therapeutic agents in advanced and metastatic pancreatic cancer.