1. Phase I study of pazopanib and vorinostat: a therapeutic approach for inhibiting mutant p53-mediated angiogenesis and facilitating mutant p53 degradation.
- Author
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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, and Meric-Bernstam F
- Subjects
- 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
- Abstract
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., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2015
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