A Phase 1 Trial of MLN0128 (sapanisertib) and CB-839 HCl (telaglenastat) in Advanced NSCLC Patients (NCI 10327): Rationale and Study Design

Abstract Introduction There are currently no approved targeted therapies for squamous cell lung cancer (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 mTOR and glutaminase inhibitors. This phase 1 study was designed to assess safety and preliminary activity of the mTOR inhibitor sapanisertib (MLN0128) in combination with the glutaminase inhibitor, CB-839. 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. Subsequently, patients will enroll into four expansion cohorts (N=14 per cohort): 1) LSCC harboring NFE2L2 or 2) KEAP1 mutations or 3) LUAD harboring KRAS/(KEAP1 or NFE2L2) co-alterations, or 4) LSCC WT for NFE2L2 and KEAP1 to confirm acceptable tolerability of the RED. 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 RED and preliminary efficacy of sapanisertib (MLN0128) and CB-839 in advanced NSCLC with a focus on subsets of LSCC and KRAS mutant LUAD harboring NFE2L2 or KEAP1 mutations.