A Phase Ib/II Randomized Study of RO4929097, a Gamma-Secretase or Notch Inhibitor with or without Vismodegib, a Hedgehog Inhibitor, in Advanced Sarcoma.

Autor:	Gounder MM; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.; Department of Medicine, Weill Cornell Medical College, New York, New York., Rosenbaum E; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.; Department of Medicine, Weill Cornell Medical College, New York, New York., Wu N; Analytical Pharmacology Core, Memorial Sloan Kettering Cancer Center, New York, New York., Dickson MA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.; Department of Medicine, Weill Cornell Medical College, New York, New York., Sheikh TN; Department of Medicine, Columbia University Irving Medical Center, New York, New York., D'Angelo SP; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.; Department of Medicine, Weill Cornell Medical College, New York, New York., Chi P; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.; Department of Medicine, Weill Cornell Medical College, New York, New York., Keohan ML; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.; Department of Medicine, Weill Cornell Medical College, New York, New York., Erinjeri JP; Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York., Antonescu CR; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York., Agaram N; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York., Hameed MR; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York., Martindale M; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York., Lefkowitz RA; Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York., Crago AM; Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York., Singer S; Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York., Tap WD; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.; Department of Medicine, Weill Cornell Medical College, New York, New York., Takebe N; Cancer Therapy Evaluation Program, National Cancer Institute, Rockville, Maryland., Qin LX; Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York., Schwartz GK; Department of Medicine, Columbia University Irving Medical Center, New York, New York.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2022 Apr 14; Vol. 28 (8), pp. 1586-1594.
DOI:	10.1158/1078-0432.CCR-21-3874
Abstrakt:	Purpose: Because the Hedgehog and Notch pathways are often overexpressed in mesenchymal malignancies, we evaluated the efficacy of concurrent inhibition of Notch and Hedgehog signaling using the gamma-secretase inhibitor (GSI) RO4929097 and the smoothened antagonist vismodegib in unresectable or metastatic sarcoma. Patients and Methods: In this investigator-initiated trial, phase Ib used standard 3+3 dose escalation in which patients first received vismodegib once daily for 21 days, followed by the combination of RO4929097 concurrently with vismodegib in 21-day cycles. In phase II, patients were randomized to RO4929097 alone or in combination with vismodegib. Results: Nine patients were treated in phase Ib with no dose-limiting toxicities. RO4929097 at 15 mg daily in combination with 150 mg daily of vismodegib was declared the recommended phase II dose. Most adverse events were grade ≤ 2. In phase II (closed early due to discontinuation of RO4929097 evaluation), 34 patients were randomized to RO4929097 alone and 33 to RO4929097 plus vismodegib. RO4929097 did not interfere with the steady-state concentration of vismodegib, while vismodegib reduced the plasma concentration of RO492909. No patients had an objective response. Neither progression-free nor overall survival differed significantly between treatment arms. Paired tumor biopsies from a subset of patients demonstrated inhibition of cleaved Notch. Conclusions: The combination of RO4929097 plus vismodegib was generally well tolerated. Although accrual to this study was not completed, vismodegib did not meaningfully enhance the clinical efficacy of RO4929097 in an unplanned analysis. GSIs and GSIs plus vismodegib can inhibit intratumoral Notch and downstream phosphorylated Akt signaling. (©2022 American Association for Cancer Research.)
Databáze:	MEDLINE
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