A Phase I Dose-Escalation and Expansion Study of Telaglenastat in Patients with Advanced or Metastatic Solid Tumors

Overview

Journal Clin Cancer Res

Specialty Oncology

Date 2021 Jul 21

PMID 34285061

Citations 30

Authors

James J Harding

Melinda Telli

Pamela Munster

Martin H Voss

Jeffrey R Infante

Angela DeMichele

Mark Dunphy

Mai H Le

Chris Molineaux

Keith Orford

Frank Parlati

Sam H Whiting

Mark K Bennett

Nizar M Tannir

Funda Meric-Bernstam

Affiliations

Soon will be listed here.

Abstract

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.

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