Clinical cancer research : an official journal of the American Association for Cancer Research · 2021
A Phase I Dose-Escalation and Expansion Study of Telaglenastat in Patients with Advanced or Metastatic Solid Tumors.
СтатьяПоддержка исследования: вне правительства СШАКомментарийНазвание и аннотация: Перевод в очереди
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Harding James J, Telli Melinda, Munster Pamela, Voss Martin H, Infante Jeffrey R, DeMichele Angela, Dunphy Mark, Le Mai H, Molineaux Chris, Orford Keith, Parlati Frank, Whiting Sam H, Bennett Mark K, Tannir Nizar M, Meric-Bernstam Funda
Аннотация
PURPOSE: Glutamine is a critical fuel for solid tumors. Interference with glutamine metabolism is deleterious to neoplasia in preclinical models. A phase I study of the oral, first-in-class, glutaminase (GLS) inhibitor telaglenastat was conducted in treatment-refractory solid tumor patients to define recommended phase II dose (RP2D) and evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity.
PATIENTS AND METHODS: 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% GLS inhibition in platelets at plasma exposures >300 nmol/L, >75% tumoral GLS inhibition, and significant increase in circulating glutamine. RP2D was defined at 800 mg twice-daily. Disease control rate (DCR) was 43% across expansion cohorts (overall response rate 5%, DCR 50% in renal cell carcinoma).
CONCLUSIONS: Telaglenastat is safe, with a favorable PK/PD profile and signal of antitumor activity, supporting further clinical development.
PATIENTS AND METHODS: 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% GLS inhibition in platelets at plasma exposures >300 nmol/L, >75% tumoral GLS inhibition, and significant increase in circulating glutamine. RP2D was defined at 800 mg twice-daily. Disease control rate (DCR) was 43% across expansion cohorts (overall response rate 5%, DCR 50% in renal cell carcinoma).
CONCLUSIONS: Telaglenastat is safe, with a favorable PK/PD profile and signal of antitumor activity, supporting further clinical development.