Telaglenastat Hydrochloride and Osimertinib in Treating Patients With EGFR-Mutated Stage IV Non-small Cell Lung Cancer

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PRIMARY OBJECTIVE: I. To assess the safety and tolerability of osimertinib (AZD9291) and CB-839 hydrochloride (HCl) (telaglenastat) and determine the recommended phase II dose (RP2D) in patients with metastatic, EGFR activating mutation-positive non-small cell lung cancer (NSCLC). SECONDARY OBJECTIV...

PRIMARY OBJECTIVE: I. To assess the safety and tolerability of osimertinib (AZD9291) and CB-839 hydrochloride (HCl) (telaglenastat) and determine the recommended phase II dose (RP2D) in patients with metastatic, EGFR activating mutation-positive non-small cell lung cancer (NSCLC). SECONDARY OBJECTIVES: I. To determine toxicity profile of the combination of AZD9291 and CB-839 HCl (telaglenastat) in patients with metastatic EGFR activating mutation positive NSCLC. II. To assess the pharmacokinetics (PK) of CB-839 HCl (telaglenastat) and AZD9291 in patients with metastatic EGFR activating mutation positive NSCLC. EXPLORATORY/CORRELATIVE OBJECTIVES: I. To determine the progression free survival (PFS) of AZD9291 and CB-839 HCl (telaglenastat) in patients with EGFR mutation positive NSCLC who have developed progressive disease (PD) on front-line EGFR inhibitor therapy. II. To determine the overall survival (OS) of AZD9291 and CB-839 HCl (telaglenastat) in patients with EGFR mutation positive NSCLC who have developed PD on front-line EGFR inhibitor therapy. III. To assess cell-free deoxyribonucleic acid (DNA) (cfDNA) and measure changes with response to treatment as well as disease progression (EGFR sensitizing mutations, T790M resistance mutation, recognized bypass mechanisms). IV. To assess circulating levels of glutamine, glutamate, aspartate and asparagine, and measure changes with response to treatment as well as disease progression. V. To assess 18F-fluorodeoxyglucose (18F-FDG)-positron emission tomography (PET) parameters at baseline and after treatment to evaluate changes with response to treatment as well as emergence of disease resistance or progression. (Expansion cohort, select patients only) VI. To perform molecular profiling assays on malignant and normal tissues, including, but not limited to, whole exome sequencing (WES) and ribonucleic acid (RNA) sequencing (RNAseq), in order to: VIa. To identify potential predictive and prognostic biomarkers beyond any genomic alteration by which treatment may be assigned. VIb. To identify resistance mechanisms using genomic DNA- and RNA-based assessment platforms. OUTLINE: This is a phase I, dose-escalation study of telaglenastat hydrochloride followed by a dose-expansion study. Patients receive telaglenastat hydrochloride orally (PO) twice daily (BID) and osimertinib PO once daily (QD) (starting cycle 1 day 16 of phase I). Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days.

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