In:
Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 27, No. 18 ( 2021-09-15), p. 4994-5003
Abstract:
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 & gt;90% GLS inhibition in platelets at plasma exposures & gt;300 nmol/L, & gt;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.
Type of Medium:
Online Resource
ISSN:
1078-0432
,
1557-3265
DOI:
10.1158/1078-0432.CCR-21-1204
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2021
detail.hit.zdb_id:
1225457-5
detail.hit.zdb_id:
2036787-9