Telaglenastat Plus Cabozantinib or Everolimus for Advanced or Metastatic Renal Cell Carcinoma: An Open-Label Phase I Trial.

Abstract

PURPOSE:

Dual inhibition of glucose and glutamine metabolism results in synergistic anticancer effects in solid tumor models. Telaglenastat, an investigational, small-molecule, glutaminase inhibitor, exhibits modest single-agent activity in renal cell carcinoma (RCC) patients. This phase Ib trial evaluated telaglenastat plus cabozantinib or everolimus, agents known to impair glucose metabolism in patients with metastatic RCC (mRCC).

PATIENTS AND METHODS:

mRCC patients received escalating doses of telaglenastat [400-800 mg per os (p.o.) twice daily] in a 3 + 3 design, plus either everolimus (10 mg daily p.o.; TelaE) or cabozantinib (60 mg daily p.o.; TelaC). Tumor response (RECISTv1.1) was assessed every 8 weeks. Endpoints included safety (primary) and antitumor activity.

RESULTS:

Twenty-seven patients received TelaE, 13 received TelaC, with median 2 and 3 prior therapies, respectively. Treatment-related adverse events were mostly grades 1 to 2, most common including decreased appetite, anemia, elevated transaminases, and diarrhea with TelaE, and diarrhea, decreased appetite, elevated transaminases, and fatigue with TelaC. One dose-limiting toxicity occurred per cohort: grade 3 pruritic rash with TelaE and thrombocytopenia with TelaC. No maximum tolerated dose (MTD) was reached for either combination, leading to a recommended phase II dose of 800-mg telaglenastat twice daily with standard doses of E or C. TelaE disease control rate (DCR; response rate + stable disease) was 95.2% [20/21, including 1 partial response (PR)] among 21 patients with clear cell histology and 66.7% (2/3) for papillary. TelaC DCR was 100% (12/12) for both histologies [5/10 PRs as best response (3 confirmed) in clear cell].

CONCLUSIONS:

TelaE and TelaC showed encouraging clinical activity and tolerability in heavily pretreated mRCC patients.

• Authors: Funda Meric-Bernstam, Nizar M Tannir, Othon Iliopoulos, Richard J Lee, Melinda L Telli, Alice C Fan, Angela DeMichele, Naomi B Haas, Manish R Patel, James J Harding, Martin H Voss, Taofeek K Owonikoko, Bradley Carthon, Ramaprasad Srinivasan, Johanna C Bendell, Yonchu Jenkins, Sam H Whiting, Keith Orford, Mark K Bennett, Todd M Bauer
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 28 Issue 8 Pg. 1540-1548 (04 14 2022) ISSN: 1557-3265 [Electronic] United States
• PMID: 35140121 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)
• Copyright: ©2022 American Association for Cancer Research.

Chemical References

• Anilides
• Enzyme Inhibitors
• Pyridines
• cabozantinib
• Everolimus
• Transaminases

Topics

• Anilides
• Antineoplastic Combined Chemotherapy Protocols (adverse effects)
• Carcinoma, Renal Cell (drug therapy, metabolism)
• Diarrhea (drug therapy)
• Enzyme Inhibitors (therapeutic use)
• Everolimus
• Female
• Humans
• Kidney Neoplasms (pathology)
• Male
• Pyridines
• Transaminases