Phase 1 Trial of MLN0128 (Sapanisertib) and CB-839 HCl (Telaglenastat) in Patients With Advanced NSCLC (NCI 10327): Rationale and Study Design
Autor: | Edward M. Newman, David R. Gandara, Paul K. Paik, Ramsey D. Badawi, Ian Lanza, Jonathan W. Riess, Wilson I. Gonsalves, Primo N. Lara, Mark Dunphy, Lorenzo Nardo, David Shackelford, Simon R. Cherry, Paul Frankel, Joel Reid, Charles A. Kunos |
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Rok vydání: | 2021 |
Předmět: |
0301 basic medicine
Oncology Cancer Research Lung Neoplasms Benzeneacetamides Squamous-cell lung cancer medicine.disease_cause 0302 clinical medicine Antineoplastic Combined Chemotherapy Protocols Clinical endpoint Non-Small-Cell Lung Lung Sapanisertib Cancer Benzoxazoles Lung Cancer Prognosis Tolerability 5.1 Pharmaceuticals 6.1 Pharmaceuticals 030220 oncology & carcinogenesis Adenocarcinoma KRAS Development of treatments and therapeutic interventions Glycolysis Pulmonary and Respiratory Medicine medicine.medical_specialty Combination therapy Clinical Sciences Oncology and Carcinogenesis Adenocarcinoma of Lung Phase I as Topic NRF2 03 medical and health sciences Rare Diseases Clinical Research Internal medicine Thiadiazoles medicine Carcinoma Humans Clinical Trials Oncology & Carcinogenesis Lung cancer Glutaminolysis business.industry Evaluation of treatments and therapeutic interventions medicine.disease KEAP1 Pyrimidines 030104 developmental biology business |
Zdroj: | Clinical lung cancer, vol 22, iss 1 |
ISSN: | 1525-7304 |
Popis: | 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. |
Databáze: | OpenAIRE |
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