ENTRATA: Randomized, double-blind, phase II study of telaglenastat (tela; CB-839) + everolimus (E) vs placebo (pbo) + E in patients (pts) with advanced/metastatic renal cell carcinoma (mRCC)

Motzer, Robert J.; Lee, C.-H.; Emamekhoo, Hamid; Matrana, Marc; Percent, Ivor; Hsieh, James J.; Hussain, Arif; Vaishampayan, Ulka N.; Graham, Robert; Liu, S.; McCune, Steven L.; Shaheen, Montaser; Parmar, Hema; Shen, Yijing; Whiting, Sam; Tannir, Nizar M.

doi:10.1093/annonc/mdz394.048

Cited by 24 publications

(17 citation statements)

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“…The randomised, double-blind, placebo-controlled phase 2 trial is approaching completion (National Institute of Health 2017 ). However, initial results from the trial are promising, with a median progression-free survival of 3.8 months when patients were treated with telaglenastat and everolimus, compared to 1.9 months for those who received the placebo and everolimus (Motzer et al 2019 ). This promising initial data, along with the progression of other studies to phase 2 clinical trials, provides support for the use of telaglenastat as a successful glutaminase inhibitor.…”

Section: Enzymatic Inhibition Of Amino Acid Metabolismmentioning

confidence: 99%

Amino acid metabolism as a therapeutic target in cancer: a review

2021

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Malignant cells often demonstrate a proliferative advantage when compared to non-malignant cells. However, the rapid growth and metabolism required for survival can also highlight vulnerabilities specific to these malignant cells. One such vulnerability exhibited by cancer is an increased demand for amino acids (AAs), which often results in a dependency on exogenous sources of AAs or requires upregulation of de novo synthesis. These metabolic alterations can be exploited by therapy, which aims to improve treatment outcome and decrease relapse and reoccurrence. One clinically utilised strategy targeting AA dependency is the use of asparaginase in the treatment of acute lymphoblastic leukaemia (ALL), which results in a depletion of exogenous asparagine and subsequent cancer cell death. Examples of other successful strategies include the exploitation of arginine deiminase and methioninase, nutrient restriction of methionine and the inhibition of glutaminase. In this review, we summarise these treatment strategies into three promising avenues: AA restriction, enzymatic depletion and inhibition of metabolism. This review provides an insight into the complexity of metabolism in cancer, whilst highlighting these three current research avenues that have support in both preclinical and clinical settings.

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Section: Enzymatic Inhibition Of Amino Acid Metabolismmentioning

confidence: 99%

Amino acid metabolism as a therapeutic target in cancer: a review

2021

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“…These preclinical data supported the initiation of ENTRATA, a phase 2, double-blind, randomized, placebo-controlled trial of telaglenastat plus everolimus in patients with RCC, which showed encouraging efficacy and safety data [ 71 ]. Data within also supported CANTATA, a double-blind, randomized, placebo-controlled trial of telaglenastat plus cabozantinib in patients with advanced/metastatic clear cell RCC.…”

Section: Discussionmentioning

confidence: 73%

The glutaminase inhibitor telaglenastat enhances the antitumor activity of signal transduction inhibitors everolimus and cabozantinib in models of renal cell carcinoma

et al. 2021

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Dysregulated metabolism is a hallmark of cancer that manifests through alterations in bioenergetic and biosynthetic pathways to enable tumor cell proliferation and survival. Tumor cells exhibit high rates of glycolysis, a phenomenon known as the Warburg effect, and an increase in glutamine consumption to support the tricarboxylic acid (TCA) cycle. Renal cell carcinoma (RCC) tumors express high levels of glutaminase (GLS), the enzyme required for the first step in metabolic conversion of glutamine to glutamate and the entry of glutamine into the TCA cycle. We found that RCC cells are highly dependent on glutamine for proliferation, and this dependence strongly correlated with sensitivity to telaglenstat (CB-839), an investigational, first-in-class, selective, orally bioavailable GLS inhibitor. Metabolic profiling of RCC cell lines treated with telaglenastat revealed a decrease in glutamine consumption, which was concomitant with a decrease in the production of glutamate and other glutamine-derived metabolites, consistent with GLS inhibition. Treatment of RCC cells with signal transduction inhibitors everolimus (mTOR inhibitor) or cabozantinib (VEGFR/MET/AXL inhibitor) in combination with telaglenastat resulted in decreased consumption of both glucose and glutamine and synergistic anti-proliferative effects. Treatment of mice bearing Caki-1 RCC xenograft tumors with cabozantinib plus telaglenastat resulted in reduced tumor growth compared to either agent alone. Enhanced anti-tumor activity was also observed with the combination of everolimus plus telaglenastat. Collectively, our results demonstrate potent, synergistic, anti-tumor activity of telaglenastat plus signal transduction inhibitors cabozantinib or everolimus via a mechanism involving dual inhibition of glucose and glutamine consumption.

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“…Dual inhibition of glucose and glutamine metabolism in preclinical models augments anticancer activity over monotherapy and a recent phase 1b study of telaglenastat plus everolimus or cabozantinib in treatment refractory renal cell carcinoma exhibited favorable results. Data from these studies prompted two proof-of-concept, phase 2 randomized trials, ENTRATA (NCT03163667), and CANTATA (NCT03428217), evaluating the addition telaglenastat to cabozantinib in patient with RCC (37,38). Results from these studies will be described separately.…”

Section: Discussionmentioning

confidence: 99%

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

Harding

Telli

Münster

et al. 2021

Clinical Cancer Research

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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.

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ENTRATA: Randomized, double-blind, phase II study of telaglenastat (tela; CB-839) + everolimus (E) vs placebo (pbo) + E in patients (pts) with advanced/metastatic renal cell carcinoma (mRCC)

Cited by 24 publications

References 0 publications

Amino acid metabolism as a therapeutic target in cancer: a review

Amino acid metabolism as a therapeutic target in cancer: a review

The glutaminase inhibitor telaglenastat enhances the antitumor activity of signal transduction inhibitors everolimus and cabozantinib in models of renal cell carcinoma

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

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