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

Author:

Meric-Bernstam Funda1ORCID,Tannir Nizar M.1,Iliopoulos Othon2,Lee Richard J.2ORCID,Telli Melinda L.3,Fan Alice C.3ORCID,DeMichele Angela4ORCID,Haas Naomi B.4ORCID,Patel Manish R.5ORCID,Harding James J.6ORCID,Voss Martin H.6ORCID,Owonikoko Taofeek K.7ORCID,Carthon Bradley7,Srinivasan Ramaprasad8,Bendell Johanna C.9,Jenkins Yonchu10,Whiting Sam H.10,Orford Keith10,Bennett Mark K.10,Bauer Todd M.9

Affiliation:

1. The University of Texas MD Anderson Cancer Center, Houston, Texas.

2. Massachusetts General Hospital Cancer Center, Boston, Massachusetts.

3. Stanford University School of Medicine, Stanford, California.

4. Penn Medicine Abramson Cancer Center, Philadelphia, Pennsylvania.

5. Florida Cancer Specialists/Sarah Cannon Research Institute, Sarasota, Florida.

6. Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York.

7. Emory University Winship Cancer Center, Atlanta, Georgia.

8. National Cancer Institute at the NIH, Bethesda, Maryland.

9. Sarah Cannon Research Institute/Tennessee Oncology, Nashville, Tennessee.

10. Calithera Biosciences, Inc., South San Francisco, California.

Abstract

AbstractPurpose: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.

Funder

NIH

MD Anderson Cancer Center

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

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