telaglenastat (CB-839) / Cornerstone Pharma, Synhale Therapeutics - LARVOL DELTA

BEGIN: A Basket Trial of Glutaminase inhibition with Telaglenastat in NF1, KEAP1/NRF2, and STK11/LKB1-Altered Tumors (AACR-NCI-EORTC 2025) - P2 | "While the clinical development of the agent was discontinued, these findings demonstrate preliminary clinical activity of GLS inhibition in NF1-mutant melanoma and MPNST, providing proof-of-concept and supporting further investigation with biomarker-driven combination strategies."

IO biomarker • Late-breaking abstract • Pan tumor • Brain Cancer • Melanoma • Neurofibrosarcoma • Oncology • Sarcoma • Solid Tumor • KEAP1 • NF1 • NFE2L2 • STK11

TEPH: Telaglenastat Efficacy in Pulmonary Hypertension (clinicaltrials.gov) - P1/2 | N=28 | Not yet recruiting | Sponsor: Chan, Stephen, MD, PhD | Initiation date: Aug 2026 ➔ Nov 2026

Trial initiation date • Cardiovascular • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

Telaglenastat Plus Everolimus in Advanced Renal Cell Carcinoma: A Randomized, Double-Blinded, Placebo-Controlled, Phase 2 ENTRATA Trial. (PubMed, Clin Cancer Res) - P2 | "TelaE was well tolerated and improved PFS vs PboE in patients with mRCC previously treated with TKIs and checkpoint inhibitors."

Clinical • Journal • P2 data • Cough • Fatigue • Genito-urinary Cancer • Hematological Disorders • Oncology • Pulmonary Disease • Renal Cell Carcinoma • Respiratory Diseases • Solid Tumor

Targeting glutamine metabolism and EGFR in RAS wildtype colorectal cancer (ESMO-GI 2023) - P1/2 | "We would also like to acknowledge support from Calithera Biosciences who supplied CB-839 for the study.Background: Alterations in glutamine metabolism have been proposed to play critical roles in cancer cell growth and survival. Panitumumab and CB-389 was very tolerable with some efficacy in heavily pre-treated patients. Early analysis of PET imaging data suggests a potential relationship between 18F-FSPG uptake and response, but additional studies are needed. It is anticipated that RNA-seq will identify genes that are related to glutamine avidity and represent a key determinate of response to inhibitors of glutamine metabolism."

Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • EGFR • RAS

NCI-2018-00876: Telaglenastat With Radiation Therapy and Temozolomide in Treating Patients With IDH-Mutated Diffuse Astrocytoma or Anaplastic Astrocytoma (clinicaltrials.gov) - P1 | N=23 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | N=40 ➔ 23 | Trial completion date: Dec 2026 ➔ Sep 2027

Enrollment change • Trial completion date • Anaplastic Astrocytoma • Astrocytoma • Brain Cancer • Oncology • Solid Tumor • IDH1 • IDH2

NUFIP1 gain of function promotes fibrotic remodeling and reveals a ZNHIT3-linked metabolic vulnerability in idiopathic pulmonary fibrosis models. (PubMed, Front Immunol) - "ZNHIT3 is a candidate binding partner, and CB-839 reduced NUFIP1-associated fibrotic readouts at the tested dose. Pathway specificity, endogenous necessity, and clinical relevance remain to be established."

Journal • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases • TGFB1 • VIM

Efficacy and Safety of Telaglenastat Plus Cabozantinib vs Placebo Plus Cabozantinib in Patients With Advanced Renal Cell Carcinoma: The CANTATA Randomized Clinical Trial. (PubMed, JAMA Oncol) - P2 | "A total of 276 (62%) patients had received prior immune checkpoint inhibitors, including 128 with prior nivolumab plus ipilimumab, 93 of whom had not received prior antiangiogenic therapy...Tela + Cabo was well tolerated with AEs consistent with the known risks of both agents. ClinicalTrials.gov Identifier: NCT03428217."

Clinical • Journal • Cardiovascular • Genito-urinary Cancer • Hypertension • Immune Modulation • Inflammation • Oncology • Renal Cell Carcinoma • Solid Tumor

A phase I/II study of the safety and efficacy of telaglenastat (CB-839) in combination with nivolumab in patients with metastatic melanoma, renal cell carcinoma, and non-small-cell lung cancer. (PubMed, ESMO Open) - "Telaglenastat in combination with nivolumab was generally well tolerated. The combination did not show a pattern of efficacy across different study cohorts."

Journal • P1/2 data • Clear Cell Renal Cell Carcinoma • Fatigue • Genito-urinary Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

Metabolic reprogramming-related drug resistance in osteosarcoma: from molecular mechanisms to therapeutic translation. (PubMed, Front Mol Biosci) - "Triple combination strategies (metabolic inhibitors + immunotherapy + chemotherapy) represent a mechanistically attractive but clinically untested hypothesis. Telaglenastat (CB-839), a glutaminase inhibitor, has been prioritized for osteosarcoma clinical trials but efficacy data in osteosarcoma patients remain pending."

Journal • Review • Metabolic Disorders • Oncology • Osteosarcoma • Sarcoma • Solid Tumor

Glutaminase Inhibition and Chemoradiation in Advanced Cervical Cancer (clinicaltrials.gov) - P2 | N=42 | Not yet recruiting | Sponsor: Washington University School of Medicine | Trial completion date: Oct 2032 ➔ Mar 2033 | Trial primary completion date: Oct 2032 ➔ Mar 2033

Trial completion date • Trial primary completion date • Cervical Cancer • Oncology • Solid Tumor

Targeting microglial glutaminase 1 protects against ferroptosis-driven cognitive impairment in perioperative neurocognitive disorders. (PubMed, Cell Death Differ) - "Pharmacological inhibition of GLS1 with the selective inhibitors CB839 and BPTES suppressed ferroptosis, preserved synaptic plasticity, and improved cognitive performance in PND mice, indicating GLS1 as a potential therapeutic target of PND. Notably, elevated plasma GLS1 levels in PND patients correlated negatively with cognitive test scores (R2 = 0.479, p < 0.001) and exhibited moderate diagnostic value across two independent cohorts (AUCs = 0.77 and 0.84), underscoring its clinical relevance as a potential biomarker. Collectively, our findings establish microglial GLS1 as a critical mediator of ferroptosis in PND and highlight its dual promise as a therapeutic target and diagnostic indicator."

Journal • Alzheimer's Disease • Anesthesia • CNS Disorders • Cognitive Disorders • Developmental Disorders • SLC7A11 • STAT1

YTHDC1 Orchestrates Glucose and Glutamate Rewiring to Overcome Lethal Metabolic Stress in Triple-Negative Breast Cancer. (PubMed, Adv Sci (Weinh)) - "By promoting SLC7A11 expression, therapeutic overexpression of ATF4 sensitizes TNBC cells to disulfidptosis upon GLUT inhibitor BAY-876 treatment, and to glutamate deprivation-induced cell death upon GLS inhibitor CB-839 treatment. Collectively, this work reveals YTHDC1 as a pivotal coordinator of the glucose-glutamine-cystine metabolic network and provides ATF4 mRNA nanomedicine-based combination strategies to improve TNBC therapeutic efficacy."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ATF4 • SLC2A3 • SLC7A11 • YTHDC1

Targeting Kupffer Cell CD44-Mediated Ammonia Death via the ELAVL1-GLS Metabolic Circuit in Radiation-Induced Liver Disease. (PubMed, Int J Biol Sci) - "Pharmacological inhibition of GLS with CB-839 rescued the injurious phenotype, while exogenous NH4Cl supplementation confirmed the ammonia dependence of the downstream phenotypes. Our findings reveal a CD44-ELAVL1-GLS immunometabolic circuit that links radiation stress to ammonia dysregulation in KCs and subsequent liver injury, suggesting a potential therapeutic target for RILD."

Journal • Hepatology • Liver Cancer • Liver Failure • Oncology • Solid Tumor • CD44 • ELAVL1

70 Years of DON and Beyond: Glutaminase Inhibition as a Synergistic Strategy in Cancer Combination Therapy. (PubMed, Pharmaceutics) - "This review provides a historical-to-translational overview of glutamine-targeted therapies, with particular emphasis on glutaminase inhibitors, including compound 968, BPTES, CB-839, and next-generation inhibitors, as well as DON-derived prodrugs. We discuss their mechanisms of action and their integration with chemotherapy, targeted therapies, radiotherapy, and immunotherapy, highlighting how glutamine metabolism targeting influences tumor metabolic adaptation, redox homeostasis, therapy resistance, and tumor-immune interactions. Finally, we examine current clinical developments, emerging therapeutic combinations, and the challenges that must be addressed for the incorporation of glutamine metabolism targeting into precision oncology."

Journal • Review • Oncology

CB-839 HCl in Combination With Carfilzomib and Dexamethasone in Treating Patients With Recurrent or Refractory Multiple Myeloma (clinicaltrials.gov) - P1 | N=19 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | N=36 ➔ 19 | Trial completion date: Sep 2026 ➔ Jul 2027

Enrollment change • Trial completion date • Hematological Malignancies • Multiple Myeloma • Oncology

KEAPSAKE: A Study of Telaglenastat (CB-839) With Standard-of-Care Chemoimmunotherapy in 1L KEAP1/NRF2-Mutated, Nonsquamous NSCLC (clinicaltrials.gov) - P2; N=120; Not yet recruiting; Sponsor: Calithera Biosciences, Inc

Clinical • New P2 trial • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thoracic Cancer • ALK • BRAF • KEAP1 • NTRK • ROS1 • STK11

KEAPSAKE: A Study of Telaglenastat (CB-839) With Standard-of-Care Chemoimmunotherapy in 1L KEAP1/NRF2-Mutated, Nonsquamous NSCLC (clinicaltrials.gov) - P2; N=120; Recruiting; Sponsor: Calithera Biosciences, Inc; Not yet recruiting ➔ Recruiting; Initiation date: Apr 2020 ➔ Jul 2020; Trial primary completion date: Apr 2022 ➔ Jul 2022

Clinical • Enrollment open • Trial initiation date • Trial primary completion date • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • BRAF • KEAP1 • NTRK • ROS1 • STK11

TARGETING GLUTAMINE METABOLISM AS A NEW STRATEGY TO IMPROVE ANTI-BCMA T CELL ENGAGER ACTIVITY IN MYELOMA CELLS. (EHA 2026) - "Results We found that elranatamab induced strong anti-HMCLs cytotoxicity and robust T-cell activation, which were preserved under Gln restriction; moreover, combined treatment with elranatamab and CB-839 further enhanced anti-MM cytotoxicity without affecting T-cell activation. Lastly, T cells exposed to the combination displayed increased expression of enzymes involved in alternative Gln- utilization pathways (ASNS and O-GlcNAc). . Summary/Conclusion Overall, these data suggest a rationale to integrate targeting Gln metabolisms with the use of BCMA/CD3 TCE as a novel strategy to overcome metabolic immunosuppression and enhance immunotherapeutic responses in MM patients."

IO biomarker • Hematological Malignancies • Multiple Myeloma • CD4 • CD69 • CD8 • IL2RA • SDC1 • SLC1A5

Glutamine Metabolism Supports Glucagon Secretion and Alpha-Cell Mass (ENDO 2026) - "Pharmacological inhibition of glutaminase via CB-839 in isolated islets reduced α-cell proliferation (DMSO: 6.773±1.361% Ki67+ α cells, CB-839: 0.1141±0.05521% Ki67+ α cells), mimicking results from glutamine deprivation (high glutamine: 7.457±1.052% Ki67+ α cells, low glutamine: 0.3231±0.1752% Ki67+ α cells). In vivo, tamoxifen-inducible, α-cell-specific glutaminase knockout mice (αGlsKO) had reduced glutaminase activity by ~3.25-fold in isolated islets compared to control mice (αGlsWT)...Notably, loss of glutaminase activity impaired glucagon secretion in response to low glucose, arginine, and glutamine in both mouse and human isolated islets, indicating a fundamental role for glutamine metabolism in α-cell secretory competence. Together, these findings identify glutaminase as a central metabolic regulator of α-cell growth and glucagon secretion and highlight glutamine metabolism as a key driver of α-cell adaptation under metabolic stress."

Diabetes • Metabolic Disorders • AMPK • SLC38A5 • TSC2

Targeting Glutamine Metabolism: Antitumor Effects of the Glutaminase Inhibitor CB-839 in Prostate Cancer Cells (EACR 2026) - "Taken together, our findings indicate that glutaminase inhibition by CB-839 suppresses proliferation, migration, and clonogenic potential of prostate cancer cells while promoting apoptotic cell death. These results support the potential of targeting glutamine metabolism as a therapeutic strategy in prostate cancer and highlight CB-839 as a promising candidate for further investigation."

Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CASP3

METABOLIC REWIRING BY ONCOGENIC JAK2V617F CREATES A GLUCOSE TRANSPORT VULNERABILITY IN MYELOPROLIFERATIVE NEOPLASMS (EHA 2026) - "Interestingly, co-treatment with the glutaminase inhibitor CB-839 provided no further benefit...These data provide a mechanistic rationale for further investigation of HIF-1 or GLUT inhibitors. By targeting this fundamental metabolic requirement, such agents may help overcome clinical limitations to achieve disease modification and eradicate the malignant MPN clone."

Hematological Malignancies • Myeloproliferative Neoplasm • CALR • HIF1A • JAK2 • SLC2A1 • SLC2A3

Synergistic dual targeting of mTOR and GLS1 overcomes glutamine-driven resistance in triple-negative breast cancer. (PubMed, Pharmacol Res) - "The combined treatment with rapamycin (an mTOR inhibitor) and CB839 (a GLS1 inhibitor) elicited synergistic anti-tumor effects in diverse TNBC cell lines...Furthermore, ‌synergistic‌ pharmacological inhibition of mTOR and GLS1 ‌significantly suppressed‌ in vivo tumor growth and metastasis ‌in murine models‌, ‌with no overt toxic effects observed‌. Overall, our findings indicate dual inhibition of mTOR and GLS1 as a promising clinical strategy to counteract glutamine-driven resistance, enhancing therapeutic efficacy in TNBC."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

CB-839 HCl in Combination With Carfilzomib and Dexamethasone in Treating Patients With Recurrent or Refractory Multiple Myeloma (clinicaltrials.gov) - P1 | N=36 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Terminated ➔ Active, not recruiting | N=19 ➔ 36 | Trial completion date: Nov 2023 ➔ Sep 2026 | Trial primary completion date: Nov 2023 ➔ Sep 2026

Enrollment change • Enrollment closed • Trial completion date • Trial primary completion date • Hematological Malignancies • Multiple Myeloma • Oncology

Characterizing the intracellular compartmentation of glutaminolysis in TNBC to facilitate molecular tracer development (SNMMI 2026) - "The subcellular glutamate pool sizes studies support a mitochondrial glutamate "buffer" hypothesis in TNBC [8], which we are currently further pursuing, including the link between mitochondrial compartmentation of the glutaminase reaction and the effects of mitochondrial glutamate pool sizes on mitochondrial membrane potential."

Breast Cancer • CNS Disorders • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Solid Tumor • Triple Negative Breast Cancer • ER • GAPDH • GLS1

L-5-[11C]-glutamine PET of Breast Cancer: Kinetic Analysis in Mouse Models to Evaluate Biologic Features of Glutamine Metabolism (SNMMI 2026) - "GLS1 inhibitor CB-839 did not show universal anti-tumor efficacy in clinical trials, highlighting the need for biomarkers to identify patients with the metabolic phenotype likely to respond to GLS1 inhibitor therapy [1]... Kinetic insights with [11C]glutamine PET reveal distinct metabolic behavior of highly glutaminolytic TNBC tumors and poorly glutaminolytic ER+ tumors. Despite effective glutaminase inhibition, TNBC tumors maintain residual glutaminolytic flux- a potential contributing factor for why glutaminase inhibitors failed in clinic. In contrast, ER+ tumors show low glutaminolytic flux and utilize glutamine synthetase to recycle glutamate and sustain high cellular glutamine concentrations."

Preclinical • Breast Cancer • CNS Disorders • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Metabolic Disorders • Oncology • Solid Tumor • Triple Negative Breast Cancer