Discussion
diarrhoea, nausea, fatigue, decrease in systolic blood pressure, vomiting, tumour, hypotension
LIVER METASTASES, TUMOUR
In this study, we explored the possibility of targeting The patients enroled in this first-in-human phase I study displayed characteristics representative of the MUM patient population. Liver metastases were present in 88% of the patients, and baseline LDH was >ULN in 56%. The majority of patients (86.8%) had received prior systemic therapy, including immunotherapy in 53%, and had not achieved a response to prior therapy.Overall, LXS196 was generally well tolerated as a single agent, with the majority of patients not requiring interruption of LXS196 or a dose reduction from their assigned dose level. Non-clinical data suggested patients may experience a decrease in systolic blood pressure, and indeed hypotension was observed in a number of patients on study at doses ≥500 mg QD. All patients experiencing symptomatic hypotension achieved complete recovery within minutes to a few hours, some following infusion of intravenous fluids. Active management of symptomatic hypotension was recommended per protocol and regular vital signs (including blood pressure and heart rate) and ECG monitoring were required throughout the study at regular study visits. Investigators were encouraged to temporarily withhold concomitant medications that may cause hypotension prior to the first dose of LXS196 and implement more frequent blood pressure monitoring throughout the study as deemed necessary per clinical need. The exact mechanism by which PKC inhibition may lead to hypotension warrants further investigation, however, as PKC is known to play a role in vascular smooth muscle (VSM) function, one possible hypothesis is that inhibition of PKCα could lead to a decrease in mean arterial pressure by a reduction in vascular smooth muscle contractility [The most frequent AEs suspected to be related to LXS196 in patients across both dosing schedules included nausea, diarrhoea, vomiting, hypotension, increased ALT and fatigue. Most GI and constitutional AEs were mild to moderate (grade 1/2) and manageable. BID dosing was better tolerated than QD dosing, with fewer grade 3/4 AEs reported and fewer drug-related SAEs. In this study, MTDs were determined to be 500 mg QD and 400 mg BID, and the RDE was declared to be 300 mg BID.During the dose escalation part of the study, following oral doses of 100–1000 mg QD and 200–400 mg BID, total plasma concentration profiles of LXS196 showed rapid absorption in fasting conditions with a LXS196 reduces pMARCKS and pPKCd, suggesting target engagement in on-treatment tumour biopsies. A decrease in pMARCKS/MARCKS was observed by C1D15 in patient tumour samples; however, no clear associations were detected between the extent of pMARCKS suppression and LXS196 treatment group. Consistent with this, a decrease in pPKCd was observed by C1D15, but no correlation was seen between the extent of suppression and the LXS196 treatment group. The decrease in pPKCd was also observed in PBMCs, which are not expected to carry mutations in the Exploratory analysis of RasGRP3 reveals a potential biomarker for predicting efficacy and evidence of a transcriptional regulatory feedback on RasGRP3 by PKC inhibition and warrants further investigation.Compared to the first-generation PKC inhibitor AEB071 [