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A Phase I Dose-Escalation and Expansion Study of Telaglenastat in Patients with Advanced or Metastatic Solid Tumors
James J Harding1, Melinda Telli2, Pamela Munster3
1Memorial Sloan Kettering Cancer Center and Weill Medical College, New York, New York. hardinj1@mskcc.org.
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.
Insights
Telaglenastat, a glutaminase inhibitor, showed safety and antitumor activity in patients with solid tumors. This first-in-class drug warrants further clinical development for cancer treatment.
Area of Science:
- Oncology
- Cancer Metabolism
- Pharmacology
Background:
- Glutamine is a vital nutrient for solid tumor growth.
- Targeting glutamine metabolism shows promise in preclinical cancer models.
- Telaglenastat is an oral, first-in-class glutaminase inhibitor.
Purpose of the Study:
- To determine the recommended Phase II dose (RP2D) of telaglenastat.
- To evaluate the safety, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of telaglenastat.
- To investigate telaglenastat in treatment-refractory solid tumor patients.
Main Methods:
- A Phase I, 3+3 dose escalation study.
- Exploratory tumor- and biomarker-specific expansion cohorts.
- Evaluation of safety, PK, PD, and antitumor response in 120 patients.
Main Results:
- Fatigue and nausea were the most common toxicities; maximum tolerated dose was not reached.
- Telaglenastat achieved >90% GLS inhibition in platelets and >75% in tumors at target exposures.
- The RP2D was established at 800 mg twice daily, with a 43% disease control rate in expansion cohorts.
Conclusions:
- Telaglenastat is safe and well-tolerated in patients with solid tumors.
- The drug demonstrates a favorable PK/PD profile and a signal of antitumor activity.
- These findings support the continued clinical development of telaglenastat for cancer therapy.
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