Study assessments
tumor, Tumor, cancer, PK/PD, partial loss, PD
TUMOR, TUMOR, ADVERSE EVENT, CANCER, BLOOD
Adverse events were coded using the standard MedDRA groupings and graded according to NCI-CTCAE version 5.0. Clinical chemistry, urinalysis, and coagulation tests were performed predose on days 1, 8, 15, 22, and weekly thereafter. Tumor imaging occurred every 8 weeks until week 33, and then every 16 weeks thereafter.In both the dose-escalation and PK/PD cohorts, plasma samples for PK analysis were obtained following dosing on day 1 and pre- and postdose on days 2, 3, 4, 8, 15, 16, 22, and predose every 4 weeks thereafter. Plasma concentrations for GSK3368715 and its metabolites (GSK3963583, GSK3983164, and GSK3510519) were quantified using a validated ultra high-performance liquid chromatography-mass spectrometry-mass spectrometry (LC-MS-MS) method. PK parameters were analyzed using noncompartmental methods.MTAP loss was determined by IHC using formalin-fixed paraffin. A positive result was defined by a complete loss (absence of IHC cytoplasmic staining) in tumor cells or partial loss (reduced cytoplasmic staining or heterogeneous staining). A negative result was defined by retained staining (no loss of cytoplasmic staining) of tumor cells as compared with the retained staining of the internal control lymphocytes. MTAP status was distinctly binary where the cytoplasmic expression for a whole tumor sample was determined to be either lost (positive) or retained (negative).Tumor cell and plasma target engagement PD biomarkers were assessed in the dose-escalation cohort on days 1, 8, 15, and 22. In the PK/PD cohort, urine for PK and metabolite profiling was collected postdose on day 1 and through 48 h postdose on day 2, and for 24 h postdose on day 15. Participants underwent an on-treatment tumor biopsy on day 15. Asymmetric arginine 225 (R225) methylation of heterogeneous nuclear ribonucleoprotein A1 (hnRNP-A1) was identified as a target engagement PD of type I PRMT inhibition; treatment with GSK3368715 results in the reduction of asymmetric dimethylarginine 225 (ADMA-R225) on hnRNP-A1 protein in cancer cell lines and peripheral blood mononuclear cells (PBMCs). Noto et al. describe in detail the identification of hnRNP-A1 as a pharmacodynamic biomarker of type I PRMT inhibition, and the development of novel methodologies to accurately and precisely quantitate changes in the levels of ADMA on hnRNP-A1 in both blood and tumor compartments [To measure the ADMA-R225-hnRNP-A1 in the PBMCs, blood was collected using the standard technique for BD Vacutainer® Evacuated Blood Collection Tubes. The PBMC aspirate prepared was used for the ADMA analyses as previously described by the LC-MS method [