Phase I study of pazopanib and vorinostat: a therapeutic approach for inhibiting mutant p53-mediated angiogenesis and facilitating mutant p53 degradation |
| |
| Affiliation: | 1. Departments of Investigational Cancer Therapeutics;2. Biostatistics;3. Sarcoma;4. GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston;5. University of California San Diego, Moores Cancer Center, La Jolla, USA;6. Division of Hematology-Oncology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan |
| |
| Abstract: | TP53 mutation enhances vascular endothelial growth factor overexpression, rendering cancer cells sensitive to pazopanib. Furthermore, treatment with vorinostat facilitates mutant p53 degradation and downregulates hypoxia-mediated resistant pathways. The preliminary clinical evidence we reported here supports the use of pazopanib and vorinostat in patients with TP53-mutated advanced malignancies.BackgroundWe 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 methodsPatients 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.ResultsAdverse 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.ConclusionThe 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 registrationwww.clinicaltrials.gov, NCT01339871 |
| |
| Keywords: | |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
