Reference Detail

Ref Type Journal Article
PMID (25669829)
Authors 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
Title Phase I study of pazopanib and vorinostat: a therapeutic approach for inhibiting mutant p53-mediated angiogenesis and facilitating mutant p53 degradation.
Journal Annals of oncology : official journal of the European Society for Medical Oncology
Vol 26
Issue 5
Date 2015 May
URL
Abstract Text 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 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.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.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.www.clinicaltrials.gov, NCT01339871.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
TP53 mutant sarcoma sensitive Pazopanib + Vorinostat Phase I Actionable In a Phase I trial, the combination of Votrient (pazopanib) and Zolinza (vorinostat) resulted in improved progression-free survival and overall survival in metastatic sarcoma and colorectal cancer patients harboring TP53 hotspot mutations, and resulted in a stable disease rate of 83% (5/6), compared to a stable disease rate of 9% (1/11) in patients without detected TP53 mutations (PMID: 25669829). 25669829
TP53 mutant Advanced Solid Tumor sensitive Pazopanib + Vorinostat Phase I Actionable In a Phase I trial, the combination of Votrient (pazopanib) and Zolinza (vorinostat) improved progression-free survival and overall survival in advanced solid tumor patients harboring TP53 hotspot mutations, and resulted in an increased stable disease rate of 45% (5/11), compared to a stable disease rate of 16% (4/25) in patients without detected TP53 mutations (PMID: 25669829). 25669829
TP53 mutant colorectal cancer sensitive Pazopanib + Vorinostat Phase I Actionable In a Phase I trial, the combination of Votrient (pazopanib) and Zolinza (vorinostat) resulted in improved progression-free survival and overall survival in metastatic sarcoma and colorectal cancer patients harboring TP53 hotspot mutations, and resulted in a stable disease rate of 83% (5/6), compared to a stable disease rate of 9% (1/11) in patients without detected TP53 mutations (PMID: 25669829). 25669829