Dataset Information

Safety and Efficacy of NEO212 in Patients With Astrocytoma IDH-mutant, Glioblastoma IDH-wildtype or Brain Metastasis

ABSTRACT: This multi-site, Phase 1/2 clinical trial is an open-label study to identify the safety, pharmacokinetics, and efficacy of a repeated dose regimen of NEO212 for the treatment of patients with radiographically-confirmed progression of Astrocytoma IDH-mutant, Glioblastoma IDH-wildtype, and the safety, pharmacokinetics and efficacy of a repeated dose regimen of NEO212 when given with select SOC for the treatment of solid tumor patients with radiographically confirmed uncontrolled brain metastasis. The study will have three phases, Phase 1, Phase 2a and Phase 2b.

DISEASE(S): Microsatellite Instability,Carcinoma,Small Cell Lung Cancer,Glioblastoma,Colorectal Cancer,Urothelial Carcinoma,Lung Neoplasms,Carcinoma, Merkel Cell,Neoplasms,Mismatch Repair Deficient Colorectal Cancer,Brain Neoplasms,Neoplasm Metastasis,Gastric Cancer,Squamous Cell Carcinoma,Colorectal Neoplasms,Renal Cell Carcinoma,Head And Neck Squamous Cell Carcinoma,Diffuse Astrocytoma, Idh-mutant,Astrocytoma,Esophageal Squamous Cell Carcinoma,Microsatellite Instability-high Solid Malignant Tumor,Cervical Cancer,Brain Metastases, Adult,Mismatch Repair Deficient Solid Malignant Tumor,Melanoma,Small Cell Lung Carcinoma,Merkel Cell Carcinoma,Microsatellite Instability-high Colorectal Cancer,Carcinoma, Squamous Cell,Squamous Cell Carcinoma Of Head And Neck,Gastroesophageal Junction Adenocarcinoma,Glioblastoma, Idh-wildtype,Non-small Cell Lung Cancer,Esophageal Cancer

PROVIDER: 92735 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:Many of the enzymes involved in xenobiotic metabolism are maintained at a low basal level and are only synthesized in response to activation of upstream sensor/effector proteins. This induction can have implications in a variety of contexts, particularly during the study of the pharmacokinetics, pharmacodynamics and drug-drug interaction profile of a candidate therapeutic compound. Previously, we combined in vivo SILAC material with a targeted high resolution single ion monitoring (tHR/SIM) LC-MS/MS approach for quantification of 197 peptide pairs, representing 51 drug metabolism enzymes (DME), in mouse liver. However, as important enzymes (for example, cytochromes P450 (Cyp) of the 1a and 2b subfamilies) are maintained at low or undetectable levels in the liver of unstimulated metabolically-labelled mice, quantification of these proteins was unreliable. In the present study, we induced DME expression in labelled mice through synchronous ligand-mediated activation of multiple upstream nuclear receptors, thereby enhancing signals for proteins including Cyps 1a, 2a, 2b, 2c and 3a. With this enhancement, 115 unique, lysine-containing, Cyp-derived peptides were detected in the liver of a single animal, as opposed to 56 in a pooled sample from three uninduced animals. A total of 386 peptide pairs were quantified by tHR/SIM, representing 68 Phase I, 30 Phase II and 8 control proteins. This method was employed to quantify changes in DME expression in the hepatic cytochrome P450 reductase null (HRN) mouse. We observed compensatory induction of several enzymes, including Cyps 2b10, 2c29, 2c37, 2c54, 2c55, 2e1, 3a11 and 3a13, carboxylesterase (Ces) 2a and glutathione S-transferases (Gst) m2 and m3, along with down-regulation of hydroxysteroid dehydrogenases (Hsd) 11b1 and 17b6. Using DME-enhanced in vivo SILAC material with tHR/SIM, therefore, permits the robust analysis of multiple DME of import to xenobiotic metabolism, with improved utility for the study of drug pharmacokinetics, pharmacodynamics, and of chemically-treated and genetically-modified mouse models.

Dataset Information

Safety and Efficacy of NEO212 in Patients With Astrocytoma IDH-mutant, Glioblastoma IDH-wildtype or Brain Metastasis

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