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 Journal Article
| Authors: | Gouda, M. A.; Voss, M. H.; Tawbi, H.; Gordon, M.; Tykodi, S. S.; Lam, E. T.; Vaishampayan, U.; Tannir, N. M.; Chaves, J.; Nikolinakos, P.; Fan, A.; Lee, R.; McDermott, D.; Shapiro, G. I.; Gandhi, L.; Bhatia, S.; Katragadda, V.; Meric-Bernstam, F. |
| Article Title: | 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 |
| Abstract: | Background: Telaglenastat (CB-839) is a glutaminase 1 inhibitor that targets the dysregulation in glutamine metabolism in cancer cells and the tumor microenvironment. Preclinical data suggested that the combination of telaglenastat with programmed cell death protein 1 (PD-1) or programmed cell death-ligand 1 (PD-L1) antibodies can lead to enhanced immune response against cancer. Patients and methods: We designed a phase I/II trial to investigate the safety and efficacy of telaglenastat combined with nivolumab in patients with advanced solid tumors. Dose escalation was carried out using a 3 + 3 design with two dose levels for telaglenastat (600 mg and 800 mg twice daily). Nivolumab was given at a fixed dose of 240 mg by intravenous infusion on days 1 and 15 of a 28-day cycle in all patients. Expansion in phase II was planned using Simon's two-stage design in disease- and prior therapy-specific cohorts. Results: We included a total of 118 patients across different cohorts. The most frequently reported adverse events were fatigue (42.4%; n = 50), nausea (39%; n = 46), and photophobia (32.2%; n = 38). In the response-assessable analysis set (including 107 patients in dose expansion and recommended phase II dose of dose escalation), the overall response rate (ORR) was 8.4% (n = 9). The ORR was 24% in 25 patients with clear-cell renal cell carcinoma (ccRCC) who were checkpoint inhibitor-naïve, 5.9% in 17 patients with ccRCC after nivolumab, 0% in 9 patients with ccRCC after other prior anti-PD-1/PD-L1, 5.4% in 37 patients with melanoma after anti-PD-1/PD-L1, and 0% in 19 patients with non-small-cell lung cancer after anti-PD-1/PD-L1. Conclusions: Telaglenastat in combination with nivolumab was generally well tolerated. The combination did not show a pattern of efficacy across different study cohorts. © 2025 The Authors |
| Keywords: | adult; cancer survival; treatment outcome; aged; middle aged; major clinical study; overall survival; constipation; drug tolerability; fatigue; advanced cancer; diarrhea; drug efficacy; drug safety; drug withdrawal; side effect; solid tumor; cancer patient; ipilimumab; progression free survival; apoptosis; multiple cycle treatment; phase 2 clinical trial; anemia; nausea; vomiting; incidence; cohort analysis; abdominal pain; arthralgia; backache; coughing; drug dose escalation; pruritus; alanine aminotransferase; aspartate aminotransferase; hyponatremia; headache; phase 1 clinical trial; dry skin; photophobia; clinical trials; programmed death 1 ligand 1; programmed death 1 receptor; clear cell renal cell carcinoma; non small cell lung cancer; metastatic melanoma; tumor microenvironment; decreased appetite; overall response rate; nivolumab; human; male; female; article; pembrolizumab; telaglenastat; cb-839; glutaminase inhibitor |
| Journal Title: | ESMO Open |
| Volume: | 10 |
| Issue: | 5 |
| ISSN: | 2059-7029 |
| Publisher: | European Society for Medical Oncology |
| Date Published: | 2025-05-01 |
| Start Page: | 104536 |
| Language: | English |
| DOI: | 10.1016/j.esmoop.2025.104536 |
| PUBMED: | 40359708 |
| PROVIDER: | scopus |
| PMCID: | PMC12141888 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
