Phase 1 trial of MLN0128 (sapanisertib) and CB-839 HCl (telaglenastat) in patients with advanced NSCLC (NCI 10327): Rationale and study design Journal Article
| Authors: | Riess, J. W.; Frankel, P.; Shackelford, D.; Dunphy, M.; Badawi, R. D.; Nardo, L.; Cherry, S. R.; Lanza, I.; Reid, J.; Gonsalves, W. I.; Kunos, C.; Gandara, D. R.; Lara, P. N.; Newman, E.; Paik, P. K. |
| Article 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. © 2020 Elsevier Inc. |
| Keywords: | clinical article; controlled study; gene mutation; drug activity; drug tolerability; advanced cancer; cancer combination chemotherapy; diarrhea; drug efficacy; drug safety; cancer patient; multiple cycle treatment; anemia; bleeding; thrombocytopenia; cohort analysis; steroid; drug dose escalation; febrile neutropenia; hyperglycemia; rash; fluorodeoxyglucose f 18; nausea and vomiting; insulin; antiemetic agent; phase 1 clinical trial; glycolysis; glutamine; antihistaminic agent; antidiarrheal agent; non small cell lung cancer; transcription factor nrf2; glutaminolysis; kelch like ech associated protein 1; human; male; female; article; nrf2; keap1; squamous-cell lung cancer; sapanisertib; telaglenastat |
| Journal Title: | Clinical Lung Cancer |
| Volume: | 22 |
| Issue: | 1 |
| ISSN: | 1525-7304 |
| Publisher: | Elsevier Inc. |
| Date Published: | 2021-01-01 |
| Start Page: | 67 |
| End Page: | 70 |
| Language: | English |
| DOI: | 10.1016/j.cllc.2020.10.006 |
| PUBMED: | 33229301 |
| PROVIDER: | scopus |
| PMCID: | PMC7834952 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 February 2021 -- Source: Scopus |
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