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

Abstract

Purpose: Glutamine is a critical fuel for solid tumors. Interference with glutamine metabolism is deleterious to neoplasia in preclinical models. A Phase 1 study of the oral, first-in-class, glutaminase inhibitor telaglenastat was conducted in treatment-refractory solid tumor patients to define recommended phase 2 dose (RP2D) and evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity.Experimental Design: Dose escalation by 3 +3 design was followed by exploratory tumor-/biomarkerspecific 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% glutaminase inhibition in platelets at plasma exposures >300 nM; >75% tumoral glutaminase inhibition; and significant increase in circulating glutamine. RP2D was defined at 800mg 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.Statement of Significance (50/50-word limit): Dependency of tumors on glutamine may be targeted by inhibition of glutaminase, an enzyme that catalyzes the first dedicated step in glutamine metabolism. This phase 1 study of the novel glutaminase inhibitor, telaglenastat, demonstrated safety, robust glutaminase inhibition with favorable PK and signal of antitumor activity.Research.

Decrease of Intracellular Glutamine by STF-62247 Results in the Accumulation of Lipid Droplets in von Hippel-Lindau Deficient Cells

“…The drop of glutamate and glutamine observed in VHL- ccRCC cells in response to STF-62247 was particularly interesting since these tumors rely on glutamine for growth and proliferation. In fact, glutaminase inhibitors showed anti-proliferative activity in vitro and in vivo in mice in a wide range of cancer models including RCC ( 33 , 58 , 59 ). However, clinical trials using GLS inhibitor Telaglenastat (CB-839) combined with the mTOR inhibitor everolimus showed a modest improvement of progression-free survival (PFS) from 1.9 months to 3.8 months while it fails to increase PFS in advanced ccRCC in combination with cabozantinib ( 33 ).…”

Metabolic adaptations in cancers expressing isocitrate dehydrogenase mutations

“…GLS inhibitors have received attention as an adjuvant drug to more traditional chemotherapy in other cancers too, and telaglenastat is generally well tolerated. 265 , 266 , 267 , 268 In advanced/metastatic renal cell carcinoma (RCC), telaglenastat in combination with everolimus (a mammalian target of rapamycin[mTOR] inhibitor 269 ) improved PFS 268 , but did not have a similar effect when paired with cabozantinib (a tyrosine kinase inhibitor 270 ). As a single-agent treatment, it appears that telaglenastat stabilizes disease rather than being cytotoxic.…”

“…As a single-agent treatment, it appears that telaglenastat stabilizes disease rather than being cytotoxic. 265 Finally, the use of GLS inhibitors in general would benefit from stratification of affected individuals to ensure that genetic mutations that confer vulnerability to glutamine starvation are present. 271 , 272 …”

Next Wave of Targets in the Treatment of Advanced Renal Cell Carcinoma

“…Glutamine is, therefore, an essential source of energy, carbon and nitrogen, which are crucial for biosynthesis and cellular growth [ 49 ]. The first step in glutamine metabolism is the transformation of glutamine into glutamate by the enzyme glutaminase, which is often upregulated in ccRCC [ 50 ]. In preclinical models, glutaminase inhibition has suppressed cancer cell growth [ 51 , 52 , 53 ].…”

“…In preclinical models, glutaminase inhibition has suppressed cancer cell growth [ 51 , 52 , 53 ]. Due to their variable pharmacokinetics and toxicity, the clinical utilization of non-selective glutamine metabolism inhibitors has been limited [ 50 ]. Telaglenastat is the first small-molecule, selective glutaminase inhibitor that demonstrated a safe toxicity profile [ 50 ].…”