TY - JOUR
T1 - Phase I study of pazopanib and vorinostat
T2 - A therapeutic approach for inhibiting mutant p53-mediated angiogenesis and facilitating mutant p53 degradation
AU - Fu, Siqing
AU - Hou, M. M.
AU - Naing, A.
AU - Janku, F.
AU - Hess, K.
AU - Zinner, R.
AU - Subbiah, V.
AU - Hong, D.
AU - Wheler, J.
AU - Piha-Paul, S.
AU - Tsimberidou, A.
AU - Karp, D.
AU - Araujo, D.
AU - Kee, B.
AU - Hwu, P.
AU - Wolff, R.
AU - Kurzrock, R.
AU - Meric-Bernstam, F.
N1 - Publisher Copyright:
© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.
PY - 2015/5/1
Y1 - 2015/5/1
N2 - 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.
AB - 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.
KW - Colorectal cancer
KW - Pazopanib
KW - Sarcoma
KW - TP53 mutation
KW - Vorinostat
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U2 - 10.1093/annonc/mdv066
DO - 10.1093/annonc/mdv066
M3 - Article
C2 - 25669829
AN - SCOPUS:84929089379
SN - 0923-7534
VL - 26
SP - 1012
EP - 1018
JO - Annals of Oncology
JF - Annals of Oncology
IS - 5
ER -