Materials and methods
toxicity, cancer, impaired GI function, tumours, impaired cardiac function, PD, tumour, Cancer
DISEASE PROGRESSION, ADVERSE EVENT, CARDIAC DISEASES, TUMOURS, CANCER, DISEASE, ADVERSE EVENT, METASTATIC TUMOUR, TUMOUR, ONCOLOGY, CANCER
This was a phase I, first-in human, multicentre, open-label study (NCT02601378), designed and sponsored by Novartis Pharmaceuticals Corporation and initiated on 1 February 2016. The study protocol and amendments were approved by the Independent Ethics Committee or Institutional Review Board for each centre, and all patients provided written informed consent. The study was conducted according to the principles of the Declaration of Helsinki and performed in compliance with Good Clinical Practice. All patients were aged ≥18 years old and had biopsy-proven MUM with progressive and measurable disease. Patients were either treatment naïve or their disease had progressed (radiologically or clinically) on their most recent therapy. There was no eligibility limit to the number of prior lines of therapy, including PKC inhibitors other than LXS196. Patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status of ≤1 and requested to provide a tumour biopsy at baseline (pre-treatment) and on treatment at day 15 of cycle 1 (C1D15). Exclusion criteria included impaired cardiac function or clinically significant cardiac diseases, receipt of concomitant medications known to be strong inducers or inhibitors of cytochrome P450 3A4/5 or known for QT prolongation risk, and impaired GI function that could interfere with absorption of LXS196.The primary objectives were to characterise the safety and tolerability and identify the MTD and/or RDE of LXS196 as a single agent in patients with MUM. Secondary objectives included investigation of the preliminary antitumour activity of LXS196 and evaluation of the PK and PD of LXS196. Exploratory objectives included assessment of mutations in cancer driver genes by transcriptome and targeted DNA sequencing of baseline tumour biopsies.During dose escalation, patients received oral LXS196 either once daily (QD; 100–1000 mg) or twice daily (BID; 200–400 mg) in 28-day cycles until disease progression, intolerable toxicity or withdrawal of consent (Supplementary Fig. Routine safety assessments, including laboratory assessments, physical examinations, vital signs and electrocardiograms (ECGs), were conducted at regular intervals throughout the study and more frequently as needed following patient assessment by the treating physician. Adverse events (AEs) were assessed continuously according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4.03. For patients who did not tolerate their assigned dosing schedule due to a treatment-related AE, dose adjustments were permitted to allow the patient to continue study treatment once the AE had resolved to ≤grade 1.Tumour response was assessed locally by computed tomography (CT) and/or magnetic resonance imaging (MRI) of the chest, abdomen and pelvis, according to Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 at baseline, on C3D1 and every two cycles thereafter until cycle 11. After 11 cycles of treatment, response was evaluated every three cycles until the end of treatment.In the dose escalation part of the study, PK samples were collected at various pre- and post-dose time points on C1D1, D2, D3, D15 and D16. Drug concentrations were assessed using a validated liquid chromatography-tandem mass spectrometry assay. PK parameters included area under the curve (AUCFresh metastatic tumour biopsies were collected at baseline (prior to first dose) and on treatment at C1D15 to evaluate the modulation of PKC substrate proteins in tumours following exposure to LXS196 and to perform exploratory transcriptome and targeted DNA sequencing. Whole blood samples (peripheral blood mononuclear cells; PBMCs) were collected pre-dose on C1D1 and D15, and at various time points post-dose on C1D1, D2, D3, D15 and D16 to evaluate the modulation of PKC substrate proteins in a surrogate tissue. Owing to the exploratory nature of this phase I study, formal statistical tests were not planned to be performed. Data are presented using descriptive statistics and visualisations. Continuous variables are described with the mean and range. Categorical variables are described using counts and percentages. PFS is described using the Kaplan–Meier (KM) method.