About this item:

65 Views | 13 Downloads

Author Notes:

Funda Meric-Bernstam, MD, Department of Investigational Cancer Therapeutics, UT MD Anderson Cancer Center, 1400 Holcombe Boulevard, Unit 455, Houston, TX 77030, USA, Phone: +1-713-794-1226, Fax: +1-713-563-0566. Email: fmeric@mdanderson.org

We thank the investigators and site staff and patients and their families for their participation in the study. Editorial support was provided by Ingrid Koo, PhD, and funded by Calithera Biosciences, Inc. This study was funded by Calithera. Additional support was obtained by the NIH Clinical Translational Science Award 1UL1TR003167, and MD Anderson Cancer Center support grant P30 CA016672. This study was also supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research

FMB has received consulting fees for Aduro BioTech Inc., Alkermes, AstraZeneca, DebioPharm, eFFECTOR Therapeutics, F. Hoffman-La Roche Ltd., Genentech Inc., IBM Watson, Jackson Laboratory, Kolon Life Science, OrigiMed, PACT Pharma, Parexel International, Pfizer Inc., Samsung Bioepis, Seattle Genetics Inc., Tyra Biosciences, Xencor, Zymeworks; participated on advisory committees for Immunomedics, Inflection Biosciences, Mersana Therapeutics, Puma Biotechnology Inc., Seattle Genetics, Silverback Therapeutics, Spectrum Pharmaceuticals, Zentalis; received research grants from Aileron Therapeutics, Inc. AstraZeneca, Bayer Healthcare Pharmaceutical, Calithera Biosciences Inc., Curis Inc., CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., Debiopharm International, eFFECTOR Therapeutics, Genentech Inc., Guardant Health Inc., Klus Pharma, Millennium Pharmaceuticals Inc., Novartis, Puma Biotechnology Inc., Taiho Pharmaceutical Co., honoraria from Chugai Biopharmaceuticals, Mayo Clinic, Rutgers Cancer Institute of New Jersey; and travel-related expenses from Beth Israel Deaconess Medical Center

NMT has consulted for Novartis, Exelixis, Bristol-Myers Squibb, Nektar, Pfizer, Eisai Medical Research, Ono Pharmaceutical, Oncorena, Surface Oncology, Neoleukin Therapeutics, Ipsen, Merck Sharp & Dohme, Calithera Biosciences; research funding from Bristol-Myers Squibb, Exelixis, Pfizer, Nektar Therapeutics, Calithera Biosciences, Lilly, Mirati Therapeutics, Arrowhead Pharmaceuticals, Takeda, Epizyme, Eisai; received honoraria from Pfizer, Novartis, Bristol-Myers Squibb, Exelixis, Nektar, Eisai Medical Research, Ono Pharmaceutical, Eli Lilly, Oncorena, Ipsen, Surface Oncology, Neoleukin Therapeutics, Merck Sharp & Dohme, Calithera Biosciences; and travel-related expenses from Pfizer, Nektar, Bristol-Myers Squibb, Eisai, Medical Research, Surface Oncology, Lilly Oncology, Ipsen, Calithera Biosciences.

OI has consulted for Merck. RJL has received research funding from Janssen and has consulted for Bayer, Dendreon, Exelixis, and Janssen. MT reports an advisory role for AbbVie, Aduro, AstraZeneca, Blueprint Medicines, Celgene, Daiichi Sankyo, Guardant, Genentech, G1 Therapeutics, Immunomedics, Lilly, Merck & Co.., Natera, OncoSec Medical, and Pfizer; institutional research funding from AbbVie, AstraZeneca, Bayer, Biothera, Calithera, EMD Serono, Genentech, Merck & Co., OncoSec Medical, Pfizer, PharmaMar, Tesaro, Vertex. ACF has consulted for Duke Clinical Research Institute (Verily Baseline Study), research funding from NCI, DOD, Conquer Cancer Foundation, Calithera Biosciences, Filtricine Inc., Earli Inc, Vortex Biosciences, advisory board for Dendreon Inc, honoraria from the Medical Educator Consortium, and has founder’s equity in Molecular Decisions, Inc. NH has consulted with Eisai, Aveo and Genentech. MRP has served on advisory boards for Genentech, Exelixis, Pfizer,EMD serono, Bayer, Celgene, Pharmacyclics, Janssen, and Abbvie; and received institutional research funding from Acerta Pharma, ADC Therapeutics, Agenus, Aileron Therapeutics, Artios Pharma, AstraZeneca, Bicycle Therapeutics, BioNTech, Boehringer Ingelheim, Calithera, Celgene, Checkpoint Therapeutics, Ciclomed, Clovis, Curis, Cyteir Therapeutics, Daiichi Sankyo, Effector Therapeutics, Eli Lilly, EMD Serono, Evelo Biosciences, Forma Therapeutics, Genentech/Roche, Gilead, GlaxoSmithKline, H3 Biomedicine, Hengrui, Hutchinson MediPharma, Ignyta, Incyte, Jacobio, Janssen, Jounce Therapeutics, Klus Pharma, Kymab, Loxo Oncology, LSK Biopartners, Lycera, Mabspace,Macrogenics, Merck, Millennium Pharmaceuticals, Mirati Therapeutics, ModernaTX, ORIC Pharmaceuticals, Pfizer, Phoenix Molecular Designs, Placon Therapeutics, Portola Pharmaceuticals, Prelude Therapeutics, Qilu Puget Sound Biotherapeutics, Revolution Medicines, Ribon Therapeutics, Seven and Eight Biopharmaceuticals, Syndax, Synthorx, Stemline Therapeutics, Taiho, Takeda, Tesaro, TopAlliance, Vedanta, Verastem, Vigeo, and Xencor JJH has received research funding from Bristol Myers Squibb and has consulted for Bristol Myers Squib, Merck, Eisai, Exelexis, Eli Lilly, QED, Zymework, ImVax, and Cytomx. MHV has received commercial research grants from Bristol-Myers Squibb, Pfizer and Genentech/Roche; honoraria from Novartis and Bristol-Myers Squibb; travel/accommodation fees from AstraZeneca, Eisai, Novartis, and Takeda; and has served as a consultant/advisory board member for Alexion Pharmaceuticals, Aveo, Bayer, Calithera Biosciences, Corvus Pharmaceuticals, Exelixis, Eisai, GlaxoSmithKline, Merck, Natera; Onquality Pharmaceuticals; Novartis, and Pfizer. TKO serves on the Data Safety Monitoring Committee for a Calithera-sponsored trial. He received payment for advisory board participation for Novartis Oncology, AstraZeneca, Bayer, Eisai, Amgen, Takeda, Debiopharma, Ipsen, Beigene, Lilly, Jannssen, Genentech, Merck, EMD Serono and Exelixis. BC has no conflicts of interests to declare. RS reports funding to CCR, NCI by Calithera Biosciences, Peloton/Merck partly defrayed the costs of clinical studies conducted in collaboration with these entities. JCB has received institutional research funding from Gilead, Genentech/Roche, BMS, Five Prime, Lilly, Merck, MedImmune, Celgene, EMD Serono, Taiho, Macrogenics, GSK, Novartis, OncoMed, LEAP, TG Therapeutics, AstraZeneca, BI, Daiichi Sankyo, Bayer, Incyte, Apexigen, Koltan, SynDevRex, Forty Seven, AbbVie, Array, Onyx, Sanofi, Takeda, Eisai, Celldex, Agios, Cytomx, Nektar, ARMO, Boston Biomedical, Ipsen, Merrimack, Tarveda, Tyrogenex, Oncogenex, Marshall Edwards, Pieris, Mersana, Calithera, Blueprint, Evelo, FORMA, Merus, Jacobio, Effector, Novocare, Arrys, Tracon, Sierra, Innate, Arch Oncology, Prelude Oncology, Unum Therapeutics, Vyriad, Harpoon, ADC, Amgen, Pfizer, Millennium, Imclone, Acerta Pharma, Rgenix, Bellicum, Gossamer Bio, Arcus Bio, Seattle Genetics, TempestTx, Shattuck Labs, Synthorx, Inc, Revolution Medicines, Inc., Bicycle Therapeutics, Zymeworks, Relay Therapeutics, Scholar Rock, NGM Biopharma, Stemcentrx, Beigene, CALGB, Cyteir Therapeutics, Foundation Bio, Innate Pharma, Morphotex, OncXerna, NuMab, AtlasMedx, Treadwell Therapeutics, IGM Biosciences, Mabspace, Hutchinson MediPharma, REPARE Therapeutics, NeoImmune Tech, Regeneron, and PureTech Health; consulting/advisory roles (institutional) for Gilead, Genentech / Roche, BMS, Five Prime, Lilly, Merck, MedImmune, Celgene, Taiho, Macrogenics, GSK, Novartis, OncoMed, LEAP, TG Therapeutics, AstraZeneca, BI, Daiichi Sankyo, Bayer, Incyte, Apexigen, Array, Sanofi, ARMO, Ipsen, Merrimack, Oncogenex, FORMA, Arch Oncology, Prelude Therapeutics, Phoenix Bio, Cyteir, Molecular Partners, Innate, Torque, Tizona, Janssen, Tolero, Amgen, Seattle Genetics, Moderna Therapeutics, Tanabe Research Laboratories, Beigene, Continuum Clinical, Agios, Bicycle Therapeutics, Relay Therapeutics, Evelo, Pfizer, Samsung Bioepios, Fusion Therapeutics; and travel/food/beverage from Gilead, Genentech/Roche, BMS, Lilly, Merck, MedImmune, Celgene, Taiho, Novartis, OncoMed, BI, ARMO, Ipsen, Oncogenex, FORMA YJ, SW, KO, and the late MKB are current or former employees and have held or currently hold ownership interest in Calithera Biosciences, Inc. TMB has held consulting or advisory roles for Guardant Health, Loxo, Pfizer, Exelixis, Blueprint Medicines, Foundation Medicine, Bayer, AstraZeneca; has served on Speakers’ Bureaus for Bayer, Bristol-Myers Squibb, and Lilly; travel/accommodations/expenses from Astellas Pharma, AstraZeneca, celgene, Clovis Oncology, EMD Serono, Genentech, Lilly, Merck, Novartis, Pharmacyclics, Sysmex, and Pfizer. TMB reports institutional research funding from Daiichi Sankyo, Medpacto, Inc., Incyte, Mirati Therapeutics, MedImmune, Abbvie, AstraZeneca, Leap Therapeutics, MabVax, Stemline Therapeutics, Merck, Lilly, GlaxoSmithKline, Novartis, Pfizer, Genetech/Roche, Deciphera, Merrimack, Immunogen, Millennium, Ignyta, Calithera Biosciences, Koltan Pharmaceuticals, Principa Biopharma, Peleton, Immunocore, Roche, Aileron, Bristol-Myers Squibb, Amgen, Moderna Therapeutics, Sanofi, Boehringer Ingelheim, Astellas Pharma, Five Prime Therapeutics, Jacobio, Top Alliance BioScience, Loxo, Janssen, Clovis Oncology, Takeda, Karyopharm Therapeutics, Onyx, Phosplatin Therapeutics, Foundation Medicine, and ARMO Biosciences; and consulting/advisory roles (institutional) for Ignyta, Moderna Therapeutics, and Pfizer.

Subjects:

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Oncology
  • GLUTAMINASE
  • DIAGNOSIS

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

Show all authors Show less authors

Tools:

Journal Title:

CLINICAL CANCER RESEARCH

Volume:

Volume 28, Number 8

Publisher:

, Pages 1540-1548

Type of Work:

Article | Post-print: After Peer Review

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.
Export to EndNote