title: 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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  www.clinicaltrials.gov, NCT01339871.
authors: Departments of Investigational Cancer Therapeutics. Electronic address: siqingfu@mdanderson.org.
authors: S
authors: S
authors: Fu
authors: Departments of Investigational Cancer Therapeutics; Division of Hematology-Oncology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan.
authors: M M
authors: MM
authors: Hou
authors: Departments of Investigational Cancer Therapeutics.
authors: A
authors: A
authors: Naing
authors: Departments of Investigational Cancer Therapeutics.
authors: F
authors: F
authors: Janku
authors: Biostatistics.
authors: K
authors: K
authors: Hess
authors: Departments of Investigational Cancer Therapeutics.
authors: R
authors: R
authors: Zinner
authors: Departments of Investigational Cancer Therapeutics.
authors: V
authors: V
authors: Subbiah
authors: Departments of Investigational Cancer Therapeutics.
authors: D
authors: D
authors: Hong
authors: Departments of Investigational Cancer Therapeutics.
authors: J
authors: J
authors: Wheler
authors: Departments of Investigational Cancer Therapeutics.
authors: S
authors: S
authors: Piha-Paul
authors: Departments of Investigational Cancer Therapeutics.
authors: A
authors: A
authors: Tsimberidou
authors: Departments of Investigational Cancer Therapeutics.
authors: D
authors: D
authors: Karp
authors: Sarcoma.
authors: D
authors: D
authors: Araujo
authors: GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston.
authors: B
authors: B
authors: Kee
authors: Sarcoma.
authors: P
authors: P
authors: Hwu
authors: GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston.
authors: R
authors: R
authors: Wolff
authors: University of California San Diego, Moores Cancer Center, La Jolla, USA.
authors: R
authors: R
authors: Kurzrock
authors: Departments of Investigational Cancer Therapeutics.
authors: F
authors: F
authors: Meric-Bernstam
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D018450:Disease Progression; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage* / Q000009:adverse effects; D007191:Indazoles; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D009389:Neovascularization, Pathologic; D016016:Proportional Hazards Models; D055550:Protein Stability; D059748:Proteolysis; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects; D013449:Sulfonamides / Q000008:administration & dosage* / Q000009:adverse effects; D013781:Texas; D013997:Time Factors; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D000077337:Vorinostat; D055815:Young Adult
chemical_list: D020533:Angiogenesis Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007191:Indazoles; D011743:Pyrimidines; D013449:Sulfonamides; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000077337:Vorinostat; C516667:pazopanib
keywords: TP53 mutation; colorectal cancer; pazopanib; sarcoma; vorinostat