Cargando…

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

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 defin...

Descripción completa

Detalles Bibliográficos
Autores principales: Harding, James J., Telli, Melinda, Munster, Pamela, Voss, Martin H., Infante, Jeffrey R., DeMichele, Angela, Dunphy, Mark, Le, Mai H., Molineaux, Chris, Orford, Keith, Parlati, Frank, Whiting, Sam H., Bennett, Mark K., Tannir, Nizar M., Meric-Bernstam, Funda
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for Cancer Research 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9401498/
https://www.ncbi.nlm.nih.gov/pubmed/34285061
http://dx.doi.org/10.1158/1078-0432.CCR-21-1204
_version_ 1784772980338851840
author Harding, James J.
Telli, Melinda
Munster, Pamela
Voss, Martin H.
Infante, Jeffrey R.
DeMichele, Angela
Dunphy, Mark
Le, Mai H.
Molineaux, Chris
Orford, Keith
Parlati, Frank
Whiting, Sam H.
Bennett, Mark K.
Tannir, Nizar M.
Meric-Bernstam, Funda
author_facet Harding, James J.
Telli, Melinda
Munster, Pamela
Voss, Martin H.
Infante, Jeffrey R.
DeMichele, Angela
Dunphy, Mark
Le, Mai H.
Molineaux, Chris
Orford, Keith
Parlati, Frank
Whiting, Sam H.
Bennett, Mark K.
Tannir, Nizar M.
Meric-Bernstam, Funda
author_sort Harding, James J.
collection PubMed
description 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.
format Online
Article
Text
id pubmed-9401498
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher American Association for Cancer Research
record_format MEDLINE/PubMed
spelling pubmed-94014982023-01-05 A Phase I Dose-Escalation and Expansion Study of Telaglenastat in Patients with Advanced or Metastatic Solid Tumors Harding, James J. Telli, Melinda Munster, Pamela Voss, Martin H. Infante, Jeffrey R. DeMichele, Angela Dunphy, Mark Le, Mai H. Molineaux, Chris Orford, Keith Parlati, Frank Whiting, Sam H. Bennett, Mark K. Tannir, Nizar M. Meric-Bernstam, Funda Clin Cancer Res Clinical Trials: Targeted Therapy 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. American Association for Cancer Research 2021-09-15 2021-07-20 /pmc/articles/PMC9401498/ /pubmed/34285061 http://dx.doi.org/10.1158/1078-0432.CCR-21-1204 Text en ©2021 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.
spellingShingle Clinical Trials: Targeted Therapy
Harding, James J.
Telli, Melinda
Munster, Pamela
Voss, Martin H.
Infante, Jeffrey R.
DeMichele, Angela
Dunphy, Mark
Le, Mai H.
Molineaux, Chris
Orford, Keith
Parlati, Frank
Whiting, Sam H.
Bennett, Mark K.
Tannir, Nizar M.
Meric-Bernstam, Funda
A Phase I Dose-Escalation and Expansion Study of Telaglenastat in Patients with Advanced or Metastatic Solid Tumors
title A Phase I Dose-Escalation and Expansion Study of Telaglenastat in Patients with Advanced or Metastatic Solid Tumors
title_full A Phase I Dose-Escalation and Expansion Study of Telaglenastat in Patients with Advanced or Metastatic Solid Tumors
title_fullStr A Phase I Dose-Escalation and Expansion Study of Telaglenastat in Patients with Advanced or Metastatic Solid Tumors
title_full_unstemmed A Phase I Dose-Escalation and Expansion Study of Telaglenastat in Patients with Advanced or Metastatic Solid Tumors
title_short A Phase I Dose-Escalation and Expansion Study of Telaglenastat in Patients with Advanced or Metastatic Solid Tumors
title_sort phase i dose-escalation and expansion study of telaglenastat in patients with advanced or metastatic solid tumors
topic Clinical Trials: Targeted Therapy
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9401498/
https://www.ncbi.nlm.nih.gov/pubmed/34285061
http://dx.doi.org/10.1158/1078-0432.CCR-21-1204
work_keys_str_mv AT hardingjamesj aphaseidoseescalationandexpansionstudyoftelaglenastatinpatientswithadvancedormetastaticsolidtumors
AT tellimelinda aphaseidoseescalationandexpansionstudyoftelaglenastatinpatientswithadvancedormetastaticsolidtumors
AT munsterpamela aphaseidoseescalationandexpansionstudyoftelaglenastatinpatientswithadvancedormetastaticsolidtumors
AT vossmartinh aphaseidoseescalationandexpansionstudyoftelaglenastatinpatientswithadvancedormetastaticsolidtumors
AT infantejeffreyr aphaseidoseescalationandexpansionstudyoftelaglenastatinpatientswithadvancedormetastaticsolidtumors
AT demicheleangela aphaseidoseescalationandexpansionstudyoftelaglenastatinpatientswithadvancedormetastaticsolidtumors
AT dunphymark aphaseidoseescalationandexpansionstudyoftelaglenastatinpatientswithadvancedormetastaticsolidtumors
AT lemaih aphaseidoseescalationandexpansionstudyoftelaglenastatinpatientswithadvancedormetastaticsolidtumors
AT molineauxchris aphaseidoseescalationandexpansionstudyoftelaglenastatinpatientswithadvancedormetastaticsolidtumors
AT orfordkeith aphaseidoseescalationandexpansionstudyoftelaglenastatinpatientswithadvancedormetastaticsolidtumors
AT parlatifrank aphaseidoseescalationandexpansionstudyoftelaglenastatinpatientswithadvancedormetastaticsolidtumors
AT whitingsamh aphaseidoseescalationandexpansionstudyoftelaglenastatinpatientswithadvancedormetastaticsolidtumors
AT bennettmarkk aphaseidoseescalationandexpansionstudyoftelaglenastatinpatientswithadvancedormetastaticsolidtumors
AT tannirnizarm aphaseidoseescalationandexpansionstudyoftelaglenastatinpatientswithadvancedormetastaticsolidtumors
AT mericbernstamfunda aphaseidoseescalationandexpansionstudyoftelaglenastatinpatientswithadvancedormetastaticsolidtumors
AT hardingjamesj phaseidoseescalationandexpansionstudyoftelaglenastatinpatientswithadvancedormetastaticsolidtumors
AT tellimelinda phaseidoseescalationandexpansionstudyoftelaglenastatinpatientswithadvancedormetastaticsolidtumors
AT munsterpamela phaseidoseescalationandexpansionstudyoftelaglenastatinpatientswithadvancedormetastaticsolidtumors
AT vossmartinh phaseidoseescalationandexpansionstudyoftelaglenastatinpatientswithadvancedormetastaticsolidtumors
AT infantejeffreyr phaseidoseescalationandexpansionstudyoftelaglenastatinpatientswithadvancedormetastaticsolidtumors
AT demicheleangela phaseidoseescalationandexpansionstudyoftelaglenastatinpatientswithadvancedormetastaticsolidtumors
AT dunphymark phaseidoseescalationandexpansionstudyoftelaglenastatinpatientswithadvancedormetastaticsolidtumors
AT lemaih phaseidoseescalationandexpansionstudyoftelaglenastatinpatientswithadvancedormetastaticsolidtumors
AT molineauxchris phaseidoseescalationandexpansionstudyoftelaglenastatinpatientswithadvancedormetastaticsolidtumors
AT orfordkeith phaseidoseescalationandexpansionstudyoftelaglenastatinpatientswithadvancedormetastaticsolidtumors
AT parlatifrank phaseidoseescalationandexpansionstudyoftelaglenastatinpatientswithadvancedormetastaticsolidtumors
AT whitingsamh phaseidoseescalationandexpansionstudyoftelaglenastatinpatientswithadvancedormetastaticsolidtumors
AT bennettmarkk phaseidoseescalationandexpansionstudyoftelaglenastatinpatientswithadvancedormetastaticsolidtumors
AT tannirnizarm phaseidoseescalationandexpansionstudyoftelaglenastatinpatientswithadvancedormetastaticsolidtumors
AT mericbernstamfunda phaseidoseescalationandexpansionstudyoftelaglenastatinpatientswithadvancedormetastaticsolidtumors