PURPOSE: Glutamine is a critical fuel for solid tumors. Interference with glutamine metabolism is deleterious to neoplasia in preclinical models. A Phase 1 study of the oral, first-in-class, glutaminase inhibitor telaglenastat was conducted in treatment-refractory solid tumor patients to define recommended phase 2 dose (RP2D) and evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity.EXPERIMENTAL DESIGN: Dose escalation by 3 +3 design was followed by exploratory tumor-/biomarker-specific cohorts.RESULTS: Among 120 patients, fatigue (23%) and nausea (19%) were the most common toxicity. Maximum tolerated dose was not reached. Correlative analysis indicated >90% glutaminase inhibition in platelets at plasma exposures >300 nM; >75% tumoral glutaminase inhibition; and significant increase in circulating glutamine. RP2D was defined at 800mg twice-daily. Disease control rate (DCR) was 43% across expansion cohorts (overall response rate 5%, DCR 50% in renal cell carcinoma).CONCLUSIONS: Telaglenastatis safe with a favorable PK/PD profile and signal of antitumor activity supporting further clinical development.
View details for DOI 10.1158/1078-0432.CCR-21-1204
View details for PubMedID 34285061