S Fu1, M M Hou2, A Naing3, F Janku3, K Hess4, R Zinner3, V Subbiah3, D Hong3, J Wheler3, S Piha-Paul3, A Tsimberidou3, D Karp3, D Araujo5, B Kee6, P Hwu5, R Wolff6, R Kurzrock7, F Meric-Bernstam3. 1. Departments of Investigational Cancer Therapeutics. Electronic address: siqingfu@mdanderson.org. 2. Departments of Investigational Cancer Therapeutics; Division of Hematology-Oncology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan. 3. Departments of Investigational Cancer Therapeutics. 4. Biostatistics. 5. Sarcoma. 6. GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston. 7. University of California San Diego, Moores Cancer Center, La Jolla, USA.
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.
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 cancerpatients with mutated TP53, especially in those with metastatic sarcoma or metastatic colorectal cancer. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov, NCT01339871.
Authors: Zhijie Wang; Naiyi Shi; Aung Naing; Filip Janku; Vivek Subbiah; Dejka M Araujo; Shreyaskumar R Patel; Joseph A Ludwig; Lois M Ramondetta; Charles F Levenback; Pedro T Ramirez; Sarina A Piha-Paul; David Hong; Daniel D Karp; Apostolia M Tsimberidou; Funda Meric-Bernstam; Siqing Fu Journal: Cancer Med Date: 2016-11-23 Impact factor: 4.452
Authors: Roberto Pili; Glenn Liu; Sreenivasulu Chintala; Hendrick Verheul; Shabnam Rehman; Kristopher Attwood; Martin A Lodge; Richard Wahl; James I Martin; Kiersten Marie Miles; Silvia Paesante; Remi Adelaiye; Alejandro Godoy; Serina King; James Zwiebel; Michael A Carducci Journal: Br J Cancer Date: 2017-02-21 Impact factor: 7.640
Authors: Ming-Mo Hou; Zhijie Wang; Filip Janku; Sarina Piha-Paul; Aung Naing; David Hong; Shannon Westin; Robert L Coleman; Anil K Sood; Apostolia M Tsimberidou; Vivek Subbiah; Jennifer Wheler; Ralph Zinner; Karen Lu; Funda Meric-Bernstam; Siqing Fu Journal: Oncotarget Date: 2016-06-07