TY - JOUR
T1 - A phase I dose-escalation and expansion study of telaglenastat in patients with advanced or metastatic solid tumors
AU - Harding, James J.
AU - Telli, Melinda
AU - Munster, Pamela
AU - Voss, Martin H.
AU - Infante, Jeffrey R.
AU - DeMichele, Angela
AU - Dunphy, Mark
AU - Le, Mai H.
AU - Molineaux, Chris
AU - Orford, Keith
AU - Parlati, Frank
AU - Whiting, Sam H.
AU - Bennett, Mark K.
AU - Tannir, Nizar M.
AU - Meric-Bernstam, Funda
N1 - Publisher Copyright:
2021 The Authors; Published by the American Association for Cancer Research
PY - 2021/9/15
Y1 - 2021/9/15
N2 - 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 þ 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.
AB - 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 þ 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.
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U2 - 10.1158/1078-0432.CCR-21-1204
DO - 10.1158/1078-0432.CCR-21-1204
M3 - Article
C2 - 34285061
AN - SCOPUS:85115009730
SN - 1078-0432
VL - 27
SP - 4994
EP - 5003
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 18
ER -