Telaglenastat Plus Cabozantinib or Everolimus For Advanced or Metastatic Renal Cell Carcinoma: an Open-Label Phase 1 Trial
Mené sur 40 patients atteints d'un carcinome à cellules rénales de stade avancé ou métastatique, cet essai de phase I détermine la dose maximale tolérée du télaglénastat (un inhibiteur de la gutaminase) en combinaison avec le cabozantinib ou l'évérolimus, et évalue l'efficacité des deux combinaisons, du point de vue du taux de contrôle de la maladie
Purpose: Dual inhibition of glucose and glutamine metabolism results in synergistic anti-cancer effects in solid tumor models. Telaglenastat, an investigational, small molecule, glutaminase inhibitor, exhibits modest single agent activity in RCC patients. This phase 1b trial evaluated telaglenastat plus cabozantinib or everolimus, agents known to impair glucose metabolism in patients with metastatic RCC (mRCC). Experimental Design: mRCC patients received escalating doses of telaglenastat (400-800mg per os [PO] twice daily) in a 3+3 design, plus either everolimus (10mg daily PO; TelaE) or cabozantinib (60mg daily PO; TelaC). Tumor response (RECISTv1.1) was assessed every 8 weeks. Endpoints included safety (primary) and anti-tumor activity. Results: 27 patients received TelaE, 13 received TelaC, with median 2 and 3 prior therapies, respectively. Treatment-related adverse events were mostly grade 1-2, 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 MTD was reached for either combination, leading to a recommended phase 2 dose of 800mg telaglenastat BID 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 pre-treated mRCC patients.