@article{208f665496e741f29d70aed63d6b0b96,
title = "Phase 1 Trial of MLN0128 (Sapanisertib) and CB-839 HCl (Telaglenastat) in Patients With Advanced NSCLC (NCI 10327): Rationale and Study Design",
abstract = "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 HCl. 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.",
keywords = "Glutaminolysis, Glycolysis, KEAP1, NRF2, Squamous-cell lung cancer",
author = "Riess, {Jonathan W.} and Paul Frankel and David Shackelford and Mark Dunphy and Badawi, {Ramsey D.} and Lorenzo Nardo and Cherry, {Simon R.} and Ian Lanza and Joel Reid and Gonsalves, {Wilson I.} and Charles Kunos and Gandara, {David R.} and Lara, {Primo N.} and Edward Newman and Paik, {Paul K.}",
note = "Funding Information: Sponsored by the NCI Cancer Therapy Evaluation Program (CTEP) under grant UM1-CA186717 . Funding Information: J.R. reports personal fees from Blueprint, personal fees and nonfinancial support from Novartis, personal fees and nonfinancial support from Boehringer Ingelheim, personal fees from Celgene, nonfinancial support from AstraZeneca, personal fees and nonfinancial support from Spectrum, personal fees from Loxo Oncology, personal fees from Genentech, personal fees from Medtronic, nonfinancial support from Merck, and nonfinancial support from Revolution Medicines, outside the submitted work. P.P. reports personal fees outside the submitted work from the following: Boehringer Ingelheim, Takeda, Celgene, EMD Serono, Calithera, AstraZeneca, AbbVie, and Lilly Oncology. D.G. reports grants from Amgen, other from AstraZeneca, other from Guardant, from Oncocyte, from IO Biotech, from Ocean Genomics, and personal fees and other from Roche-Genentech, outside the submitted work. L.N. is principal investigator of a service agreement with United Imaging Healthcare. The other authors have stated that they have no conflict of interest.Sponsored by the NCI Cancer Therapy Evaluation Program (CTEP) under grant UM1-CA186717. Funding Information: J.R. reports personal fees from Blueprint, personal fees and nonfinancial support from Novartis, personal fees and nonfinancial support from Boehringer Ingelheim, personal fees from Celgene, nonfinancial support from AstraZeneca, personal fees and nonfinancial support from Spectrum, personal fees from Loxo Oncology, personal fees from Genentech, personal fees from Medtronic, nonfinancial support from Merck, and nonfinancial support from Revolution Medicines, outside the submitted work. P.P. reports personal fees outside the submitted work from the following: Boehringer Ingelheim, Takeda, Celgene, EMD Serono, Calithera, AstraZeneca, AbbVie, and Lilly Oncology. D.G. reports grants from Amgen , other from AstraZeneca , other from Guardant , from Oncocyte , from IO Biotech , from Ocean Genomics , and personal fees and other from Roche-Genentech, outside the submitted work. L.N. is principal investigator of a service agreement with United Imaging Healthcare. The other authors have stated that they have no conflict of interest. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",
year = "2021",
month = jan,
doi = "10.1016/j.cllc.2020.10.006",
language = "English (US)",
volume = "22",
pages = "67--70",
journal = "Clinical Lung Cancer",
issn = "1525-7304",
publisher = "Elsevier",
number = "1",
}