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

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.

Keywords: TP53 mutation; colorectal cancer; pazopanib; sarcoma; vorinostat.

© 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.

Figures

Figure 1.

Kaplan–Meier plots of the rates of progression-free (PFS; A) and overall (OS; B) survival in 36 cancer patients tested for TP53 mutation and treated with pazopanib and vorinostat. Ninety-five percent confidence intervals are indicated in parentheses.

Figure 2.

Kaplan–Meier plots of the rates of progression-free (PFS; A) and overall (OS; B) survival in patients with metastatic sarcoma or metastatic colorectal cancer who were tested for TP53 mutation and treated with pazopanib and vorinostat. Ninety-five percent confidence intervals are indicated in parentheses.