期刊
CLINICAL LUNG CANCER
卷 22, 期 1, 页码 67-70出版社
CIG MEDIA GROUP, LP
DOI: 10.1016/j.cllc.2020.10.006
关键词
Glutaminolysis; Glycolysis; KEAP1; NRF2; Squamous-cell lung cancer
类别
资金
- NCI Cancer Therapy Evaluation Program (CTEP) [UM1-CA186717]
This study aims to evaluate the safety and preliminary efficacy of the combination therapy of MLN0128 and CB-839 in lung cancer, with a focus on subsets of LSCC and KRAS-mutant LUAD patients harboring NFE2L2 or KEAP1 mutations.
Introduction: There are currently no approved targeted therapies for lung squamous-cell carcinoma (LSCC) and KRAS-mutant lung adenocarcinoma (LUAD). About 30% of LSCC and 25% of KRAS-mutant LUAD exhibit hyperactive NRF2 pathway activation through mutations in NFE2L2 (the gene encoding NRF2) or its negative regulator, KEAP1. Preclinical data demonstrate that these tumors are uniquely sensitive to dual inhibition of glycolysis and glutaminolysis via mammalian target of rapamycin (mTOR) and glutaminase inhibitors. This phase 1 study was designed to assess safety and preliminary activity of the mTOR inhibitor MLN0128 (sapanisertib) in combination with the glutaminase inhibitor CB-839 HCI. Methods: Phase 1 dose finding will use the queue-based variation of the 3 + 3 dose escalation scheme with the primary endpoint of identifying the recommended expansion dose. To confirm the acceptable tolerability of the recommended expansion dose, patients will subsequently enroll onto 1 of 4 expansion cohorts (n = 14 per cohort): (1) LSCC harboring NFE2L2 or (2) KEAP1 mutations, or (3) LUAD harboring KRAS/(KEAP1 or NFE2L2) coalterations, or (4) LSCC wild type for NFE2L2 and KEAP1. The primary endpoint of the dose expansion is to determine the preliminary efficacy of MLN0128/CB-839 combination therapy. Conclusion: This phase 1 study will determine the recommended expansion dose and preliminary efficacy of MLN0128 and CB-839 in advanced non-small-cell lung cancer with a focus on subsets of LSCC and KRAS-mutant LUAD harboring NFE2L2 or KEAP1 mutations. (C) 2020 Elsevier Inc. All rights reserved.
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