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Background: We carried out a phase I trial of the vascular endothelial growth factor inhibitor pazopanib and the histone deacetylase inhibitor vorinostat to determine the safety and efficacy. Because these agents are known to target factors activated by TP53 mutation and facilitate mutant p53 degradation, a subgroup analysis may be interesting in patients with TP53 mutant malignancies.

Patients and Methods: Patients with advanced solid tumors (n = 78) were enrolled following a 3 + 3 design, with dose expansion for those with responsive tumors. Hotspot TP53 mutations were tested when tumor specimens were available.

Results: Adverse events of ≥grade 3 included thrombocytopenia, neutropenia, fatigue, hypertension, diarrhea and vomiting. Overall, the treatment produced stable disease for at least 6 months or partial response (SD ≥6 months/PR) in 19% of the patients, median progression-free survival (PFS) of 2.2 months, and median overall survival (OS) of 8.9 months. In patients with detected hotspot TP53 mutant advanced solid tumors (n = 11), the treatment led to a 45% rate of SD ≥6 months/PR (1 PR and 3 SD ≥6 months), median PFS of 3.5 months, and median OS of 12.7 months, compared favorably with the results for patients with undetected hotspot TP53 mutations (n = 25): 16% (1 PR and 3 SD ≥6 months, P = 0.096), 2.0 months (P = 0.042), and 7.4 months (P = 0.1), respectively.

Conclusion: The recommended phase II dosage was oral pazopanib at 600 mg daily plus oral vorinostat at 300 mg daily. The preliminary evidence supports further evaluation of the combination in cancer patients with mutated TP53, especially in those with metastatic sarcoma or metastatic colorectal cancer.

Clinical Trial Registration: www.clinicaltrials.gov, NCT01339871.

Titel:	Phase I study of pazopanib and vorinostat: a therapeutic approach for inhibiting mutant p53-mediated angiogenesis and facilitating mutant p53 degradation.
Autor/in / Beteiligte Person:	Fu, S ; Hou, MM ; Naing, A ; Janku, F ; Hess, K ; Zinner, R ; Subbiah, V ; Hong, D ; Wheler, J ; Piha-Paul, S ; Tsimberidou, A ; Karp, D ; Araujo, D ; Kee, B ; Hwu, P ; Wolff, R ; Kurzrock, R ; Meric-Bernstam, F
Link:	Full Text Finder (Volltext)
Zeitschrift:	Annals of oncology : official journal of the European Society for Medical Oncology, Jg. 26 (2015-05-01), Heft 5, S. 1012-1018
Veröffentlichung:	2020- : London : Elsevier ; <i>Original Publication</i>: Dordrecht ; Boston : Kluwer Academic Publishers, c1990-, 2015
Medientyp:	academicJournal
ISSN:	1569-8041 (electronic)
DOI:	10.1093/annonc/mdv066
Schlagwort:	Administration, Oral Adolescent Adult Aged Angiogenesis Inhibitors adverse effects Antineoplastic Combined Chemotherapy Protocols adverse effects Disease Progression Disease-Free Survival Drug Administration Schedule Female Histone Deacetylase Inhibitors adverse effects Humans Hydroxamic Acids adverse effects Indazoles Kaplan-Meier Estimate Male Middle Aged Neoplasms blood supply Neoplasms genetics Neoplasms mortality Neoplasms pathology Proportional Hazards Models Protein Stability Proteolysis Pyrimidines adverse effects Sulfonamides adverse effects Texas Time Factors Treatment Outcome Tumor Suppressor Protein p53 metabolism Vorinostat Young Adult Angiogenesis Inhibitors administration & dosage Antineoplastic Combined Chemotherapy Protocols therapeutic use Histone Deacetylase Inhibitors administration & dosage Hydroxamic Acids administration & dosage Mutation Neoplasms drug therapy Neovascularization, Pathologic Pyrimidines administration & dosage Sulfonamides administration & dosage Tumor Suppressor Protein p53 genetics
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Clinical Trial, Phase I; Journal Article Language: English [Ann Oncol] 2015 May; Vol. 26 (5), pp. 1012-1018. <i>Date of Electronic Publication: </i>2015 Feb 10. MeSH Terms: Mutation* ; Neovascularization, Pathologic* ; Angiogenesis Inhibitors / administration & dosage ; Antineoplastic Combined Chemotherapy Protocols / therapeutic use ; Histone Deacetylase Inhibitors / administration & dosage ; Hydroxamic Acids / administration & dosage ; Neoplasms / drug therapy ; Pyrimidines / administration & dosage ; Sulfonamides / administration & dosage ; Tumor Suppressor Protein p53 / genetics ; Administration, Oral ; Adolescent ; Adult ; Aged ; Angiogenesis Inhibitors / adverse effects ; Antineoplastic Combined Chemotherapy Protocols / adverse effects ; Disease Progression ; Disease-Free Survival ; Drug Administration Schedule ; Female ; Histone Deacetylase Inhibitors / adverse effects ; Humans ; Hydroxamic Acids / adverse effects ; Indazoles ; Kaplan-Meier Estimate ; Male ; Middle Aged ; Neoplasms / blood supply ; Neoplasms / genetics ; Neoplasms / mortality ; Neoplasms / pathology ; Proportional Hazards Models ; Protein Stability ; Proteolysis ; Pyrimidines / adverse effects ; Sulfonamides / adverse effects ; Texas ; Time Factors ; Treatment Outcome ; Tumor Suppressor Protein p53 / metabolism ; Vorinostat ; Young Adult References: J Clin Oncol. 2013 May 20;31(15):1815-24. (PMID: 23589546) ; J Cancer Res Clin Oncol. 2008 Feb;134(2):193-201. (PMID: 17636327) ; Cancer Lett. 2009 Aug 8;280(2):145-53. (PMID: 19111391) ; Clin Cancer Res. 2012 Oct 15;18(20):5796-805. (PMID: 22927482) ; Adv Cancer Res. 2004;91:137-68. (PMID: 15327890) ; J Biol Chem. 2006 May 12;281(19):13612-9. (PMID: 16543236) ; Nat Med. 1998 Dec;4(12):1371-6. (PMID: 9846573) ; Cancer Biol Ther. 2014 May;15(5):578-85. (PMID: 24556916) ; Mol Cell. 2013 Nov 7;52(3):406-20. (PMID: 24120667) ; Nat Rev Cancer. 2014 May;14(5):359-70. (PMID: 24739573) ; J Mol Diagn. 2013 Sep;15(5):607-22. (PMID: 23810757) ; Cancer Cell. 2009 Mar 3;15(3):167-70. (PMID: 19249675) ; Genes Dev. 2000 Jan 1;14(1):34-44. (PMID: 10640274) ; Br J Cancer. 2012 Nov 6;107(10):1722-8. (PMID: 23079576) ; Oncogene. 2013 Jan 31;32(5):599-609. (PMID: 22391568) ; Eur J Cancer. 2009 Jan;45(2):228-47. (PMID: 19097774) ; Oncol Rep. 2007 Mar;17(3):647-51. (PMID: 17273746) ; Nat Biotechnol. 2013 Nov;31(11):1023-31. (PMID: 24142049) ; Int J Radiat Oncol Biol Phys. 2010 Mar 1;76(3):879-88. (PMID: 20159362) ; Cancer Cell. 2009 Mar 3;15(3):232-9. (PMID: 19249681) ; Cancer Res. 2005 Aug 15;65(16):7386-92. (PMID: 16103091) ; Am J Clin Oncol. 1982 Dec;5(6):649-55. (PMID: 7165009) ; Cell. 2007 May 4;129(3):465-72. (PMID: 17482542) ; Blood. 2007 Jan 1;109(1):31-9. (PMID: 16960145) ; Lancet. 2012 May 19;379(9829):1879-86. (PMID: 22595799) ; Cell Death Differ. 2011 Dec;18(12):1904-13. (PMID: 21637290) ; Cancer Cell. 2014 Mar 17;25(3):304-17. (PMID: 24651012) ; Biometrics. 2007 Jun;63(2):429-36. (PMID: 17688495) Grant Information: P30 CA016672 United States CA NCI NIH HHS Contributed Indexing: Keywords: TP53 mutation; colorectal cancer; pazopanib; sarcoma; vorinostat Molecular Sequence: ClinicalTrials.gov NCT01339871 Substance Nomenclature: 0 (Angiogenesis Inhibitors) ; 0 (Histone Deacetylase Inhibitors) ; 0 (Hydroxamic Acids) ; 0 (Indazoles) ; 0 (Pyrimidines) ; 0 (Sulfonamides) ; 0 (TP53 protein, human) ; 0 (Tumor Suppressor Protein p53) ; 58IFB293JI (Vorinostat) ; 7RN5DR86CK (pazopanib) Entry Date(s): Date Created: 20150212 Date Completed: 20160519 Latest Revision: 20211203 Update Code: 20240513 PubMed Central ID: PMC6279067

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Phase I study of pazopanib and vorinostat: a therapeutic approach for inhibiting mutant p53-mediated angiogenesis and facilitating mutant p53 degradation.