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.
Original language | English (US) |
---|---|
Pages (from-to) | 1540-1548 |
Number of pages | 9 |
Journal | Clinical Cancer Research |
Volume | 28 |
Issue number | 8 |
DOIs | |
State | Published - Apr 15 2022 |
ASJC Scopus subject areas
- Oncology
- Cancer Research
MD Anderson CCSG core facilities
- Clinical and Translational Research Center
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In: Clinical Cancer Research, Vol. 28, No. 8, 15.04.2022, p. 1540-1548.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Telaglenastat Plus Cabozantinib or Everolimus for Advanced or Metastatic Renal Cell Carcinoma
T2 - An Open-Label Phase I Trial
AU - Meric-Bernstam, Funda
AU - Tannir, Nizar M.
AU - Iliopoulos, Othon
AU - Lee, Richard J.
AU - Telli, Melinda L.
AU - Fan, Alice C.
AU - DeMichele, Angela
AU - Haas, Naomi B.
AU - Patel, Manish R.
AU - Harding, James J.
AU - Voss, Martin H.
AU - Owonikoko, Taofeek K.
AU - Carthon, Bradley
AU - Srinivasan, Ramaprasad
AU - Bendell, Johanna C.
AU - Jenkins, Yonchu
AU - Whiting, Sam H.
AU - Orford, Keith
AU - Bennett, Mark K.
AU - Bauer, Todd M.
N1 - Funding Information: K. Orford has a patent for US 10,278,968 issued. T.M. Bauer reports grants from sponsor during the conduct of the study; personal fees from Pfizer, Lilly, BMS, AZ, GuardantHealth, Foundation Medicine, and Bayer outside the submitted work. No disclosures were reported by the other authors. Funding Information: F. Meric-Bernstam reports grants from Calithera Biosciences and Novartis during the conduct of the study; personal fees from AbbVie, Aduro BioTech Inc., Alkermes, AstraZeneca, DebioPharm, eFFECTOR Therapeutics, F. Hoffman-La Roche Ltd., Genentech Inc., IBM Watson, Infinity Pharmaceuticals, Jackson Laboratory, Kolon Life Science, Lengo Therapeutics, OrigiMed, PACT Pharma, Parexel International, Pfizer Inc., Samsung Bioepis, Seattle Genetics Inc., Tallac Therapeutics, Tyra Biosciences, Xencor, Zymeworks, Black Diamond, Biovica, Eisai, Immunomedics, Inflection Biosciences, Karyopharm Therapeutics, Loxo Oncology, Mersana Therapeutics, OnCusp Therapeutics, Puma Biotechnology Inc., Seattle Genetics, Silverback Therapeutics, Spectrum Pharmaceuticals, and Zentalis, and grants from Aileron Therapeutics, Inc. AstraZeneca, Bayer Healthcare Pharmaceutical, Curis Inc., Cytomx Therapeutics Inc., Daiichi Sankyo Co. Ltd., Debiopharm International, eFFECTOR Therapeutics, Genentech Inc., Guardant Health Inc., Klus Pharma, Takeda Pharmaceutical, Puma Biotechnology Inc., and Taiho Pharmaceutical Co. outside the submitted work. N.M. Tannir reports grants from Calithera Bioscience during the conduct of the study; grants and personal fees from Eisai Medical Research, Bristol-Myers Squibb, Nektar Therapeutics, Exelisis, Inc., and Novartis, personal fees from Pfizer, Ili Lilly, Oncorena, Surface Oncology, Ipsen, and MSD, and grants from Arrowhead, Mirati Therapeutics, and Takeda outside the submitted work. R.J. Lee reports personal fees from Bayer, Dendreon, Exelixis, and GE and grants from Janssen outside the submitted work. M.L. Telli reports grants from Calithera during the conduct of the study; grants and personal fees from Merck, Genentech, AbbVie, OncoSec Medical, Novartis, AstraZeneca, and Pfizer; personal fees from Sanofi Aventis, Immunomedics, G1 Therapeutics, Guardant, Aduro, Natera, Blueprint Medicines, Lilly, and Celgene; and grants from Bayer, Biothera, EMD Serono, and Vertex outside the submitted work. A.C. Fan reports other support from Calithera during the conduct of the study; other support from Molecular Decisions Inc., grants from Earli, personal fees from Dendreon, Tempus, Duke Clinical Research Institute, and Medical Educator Consortium outside the submitted work. A. DeMichele reports grants from Calithera during the conduct of the study; grants from Pfizer, Novartis, and Genentech outside the submitted work. N.B. Haas reports personal fees from Exilexis outside the submitted work. M.R. Patel reports other support from Calithera outside the submitted work. J.J. Harding reports grants and personal fees from BMS, personal fees from CytomX, Eli Lilly, Eisai, Exelexis, Imvax, Merck, Adaptii-mune, QED, Zymeworks, HCC Connect, Research to Practice, and MORE Health, and nonfinancial support and other support from Genoscience outside the submitted work. M.H. Voss reports personal fees from Calithera and grants from BMS during the conduct of the study; personal fees from Aveo, Eisai, Exelixis, Novartis, Natera, Merck, and Onquality, grants and personal fees from Pfizer, and nonfinancial support from AstraZeneca and Takeda outside the submitted work. T.K. Owonikoko reports grants from Calithera and personal fees from Calithera during the conduct of the study. R. Srinivasan reports nonfinancial support and other support from Calithera Biosciences during the conduct of the study; nonfinancial support and other support from Merck, Novartis, and Genentech Roche outside the submitted work. J.C. Bendell reports grants from Gilead, Genentech/Roche, 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, Ipsen, Boston Biomedical, Tarveda, Merrimack, Tyro-genex, Oncogenex, Marshall Edwards, Pieris, Mersana, Blueprint, Evelo, Calithera, FORMA, Merus, Effector, Jacobio, Arrys, Tracon, Sierra, Novocare, Innate, Arch Oncology, Prelude Oncology, Unum Therapeutics, Vyriad, Harpoon, ADC, Amgen, Pfizer, ImClone, Millennium, Rgenix, Bellicum, Acerta Pharma, Arcus Bio, Seattle Genetics, Shattuck Labs, TempestTx, Synthorx Inc., Revolution Medicines, Inc., Zymeworks, Bicycle Therapeutics, Relay Therapeutics, Scholar Rock, NGM Biopharma, Beigene, CALGB, Stemcentrx, Foundation Bio, Cyteir Therapeutics, Morphotex, Innate Pharma, OncXerna, NuMab, AtlasMedx, IGM Biosciences, Mabspace, Treadwell Therapeutics, REPARE Therapeutics, Hutchinson Medi-Pharma, Regeneron, NeoImmune Tech, PureTech Health, Cyteir, Molecular Partners, Phoenix Bio, Innate, Torque, Tizona, Janssen, Tolero, Amgen, Continuum Clinical, Moderna Therapeutics, Agios, Samsung Bioepios, Pfizer, and Fusion Therapeutics during the conduct of the study; grants from Genentech/Roche, Gilead, BMS, Five Prime, Lilly, Merck, Celgene, MedImmune, Taiho, Macrogenics, GSK, EMD Serono, Novartis, OncoMed, LEAP, AstraZeneca, BI, TG Therapeutics, Bayer, Incyte, Apexigen, Daiichi Sankyo, Koltan, Forty Seven, AbbVie, SynDevRex, Array, Onyx, Sanofi, Takeda, Eisai, Celldex, Agios, Nektar, ARMO, Cytomx, Ipsen, Merrimack, Tarveda, Boston Biomedical, Oncogenex, Pieris, Tyrogenex, Mersana, Calithera, Marshall Edwards, Blueprint, Evelo, FORMA, Merus, Jacobio, Effector, Arrys, Tracon, Sierra, Novocare, Innate, Arch Oncology, Prelude Oncology, Unum Therapeutics, Harpoon, ADC, Amgen, Pfizer, ImClone, Millennium, Rgenix, Bellicum, Acerta Pharma, Arcus Bio, Seattle Therapeutics, Gossamer Bio, TempestTx, Shattuck Labs, Synthorx, Inc., Bicycle Therapeutics, Revolution Medicines, Inc., Zymeworks, Relay Therapeutics, Scholar Rock, Stemcentrx, NGM Biopharma, Beigene, CALGB, Cyteir Therapeutics, Foundation Bio, Morphotex, NuMab, Innate Pharma, Onc-Xerna, AtlasMedx, Treadwell Therapeutics, IGM Biosciences, Mabspace, REPARE Therapeutics, Hutchinson MediPharma, Regeneron, PureTech Health, NeoImmune Tech, Cyteir, Molecular Partners, Phoenix Bio, Innate, Torque, Tizona, Janssen, Tolero, Amgen, Moderna Therapeutics, Agios, Continuum Clinical, Pfizer, Fusion Therapeutics, and Samsung Bioepios outside the submitted work. Y. Jenkins reports other support from Calithera Biosciences outside the submitted work. K. Orford reports personal fees from Calithera Biosciences during the conduct of the study; personal fees from Calithera Biosciences outside the submitted work; in addition, Funding Information: 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, NCI, Center for Cancer Research. Publisher Copyright: © 2022 American Association for Cancer Research Inc.. All rights reserved.
PY - 2022/4/15
Y1 - 2022/4/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85128334650&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85128334650&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-21-2972
DO - 10.1158/1078-0432.CCR-21-2972
M3 - Article
C2 - 35140121
AN - SCOPUS:85128334650
SN - 1078-0432
VL - 28
SP - 1540
EP - 1548
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 8
ER -