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Inhibiting Histone Deacetylase as a Means to Reverse Resistance to Angiogenesis Inhibitors: Phase I Study of Abexinostat Plus Pazopanib in Advanced Solid Tumor Malignancies
- Source :
- Journal of clinical oncology : official journal of the American Society of Clinical Oncology, vol 35, iss 11, Aggarwal, R, Thomas, S, Pawlowska, N, Bartelink, I, Grabowsky, J, Jahan, T, Cripps, A, Harb, A, Leng, J, Reinert, A, Mastroserio, I, Truong, T G, Ryan, C J & Munster, P N 2017, ' Inhibiting histone deacetylase as a means to reverse resistance to angiogenesis inhibitors : Phase i study of abexinostat plus pazopanib in advanced solid tumor malignancies ', Journal of Clinical Oncology, vol. 35, no. 11, pp. 1231-1238 . https://doi.org/10.1200/JCO.2016.70.5350, Journal of Clinical Oncology, 35(11), 1231-1238. American Society of Clinical Oncology
- Publication Year :
- 2017
- Publisher :
- American Society of Clinical Oncology, 2017.
-
Abstract
- Purpose This phase I trial evaluated epigenetic modulation of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor by using a histone deacetylase abexinostat in combination with pazopanib to enhance response and reverse resistance. Patients and Methods Pazopanib was administered once a day on days 1 to 28 and abexinostat was administered orally twice a day on days 1 to 5, 8 to 12, and 15 to 19 (schedule A) or on days 1 to 4, 8 to 11, and 15 to 18 (schedule B). Dose escalation (3 + 3 design) in all solid tumors was followed by dose expansion in renal cell carcinoma (RCC). Results Fifty-one patients with RCC (N = 22) were enrolled, including 30 (59%) with one or more lines of prior VEGF-targeting therapy. Five dose-limiting toxicities, including fatigue (n = 2), thrombocytopenia (n = 2), and elevated AST/ALT (n = 1), were observed with schedule A; one dose-limiting toxicity was observed (elevated AST/ALT) was observed with schedule B. Grade ≥ 3 related adverse events included fatigue (16%), thrombocytopenia (16%), and neutropenia (10%). The recommended phase II dose was established as abexinostat 45 mg/m2 twice a day administered per schedule B plus pazopanib 800 mg/d. Objective response rate was 21% overall and 27% in the RCC subset. Median duration of response was 9.1 months (1.2 to > 49 months). Eight patients (16%) had durable control of disease for > 12 months. Durable tumor regressions were observed in seven (70%) of 10 patients with pazopanib-refractory disease, including one patients with RCC with ongoing response > 3.5 years. Peripheral blood histone acetylation and HDAC2 gene expression were associated with durable response to treatment. Conclusion Abexinostat is well tolerated in combination with pazopanib, allowing prolonged exposure and promising durable responses in pazopanib- and other VEGF inhibitor-refractory tumors, which supports epigenetically mediated reversal of treatment resistance.
- Subjects :
- 0301 basic medicine
Male
Vascular Endothelial Growth Factor A
Cancer Research
Kidney Disease
Angiogenesis
Abexinostat
Drug Resistance
Gene Expression
Histone Deacetylase 2
Angiogenesis Inhibitors
Pharmacology
Hydroxamic Acids
Epigenesis, Genetic
Histones
chemistry.chemical_compound
0302 clinical medicine
Renal cell carcinoma
Antineoplastic Combined Chemotherapy Protocols
Medicine
6.2 Cellular and gene therapies
Fatigue
Cancer
Sulfonamides
Acetylation
Alanine Transaminase
ORIGINAL REPORTS
Middle Aged
Kidney Neoplasms
Vascular endothelial growth factor
Treatment Outcome
Oncology
6.1 Pharmaceuticals
030220 oncology & carcinogenesis
Toxicity
Disease Progression
Female
medicine.drug
Adult
Neutropenia
Indazoles
Maximum Tolerated Dose
Clinical Trials and Supportive Activities
Clinical Sciences
Oncology and Carcinogenesis
Disease-Free Survival
Histone Deacetylases
Pazopanib
03 medical and health sciences
Young Adult
Genetic
Clinical Research
Genetics
Humans
Oncology & Carcinogenesis
Aspartate Aminotransferases
Adverse effect
Carcinoma, Renal Cell
Aged
Benzofurans
business.industry
Carcinoma
Renal Cell
Evaluation of treatments and therapeutic interventions
medicine.disease
Thrombocytopenia
Histone Deacetylase Inhibitors
030104 developmental biology
Pyrimidines
chemistry
Drug Resistance, Neoplasm
Neoplasm
Histone deacetylase
business
Epigenesis
Subjects
Details
- Language :
- English
- ISSN :
- 0732183X
- Database :
- OpenAIRE
- Journal :
- Journal of clinical oncology : official journal of the American Society of Clinical Oncology, vol 35, iss 11, Aggarwal, R, Thomas, S, Pawlowska, N, Bartelink, I, Grabowsky, J, Jahan, T, Cripps, A, Harb, A, Leng, J, Reinert, A, Mastroserio, I, Truong, T G, Ryan, C J & Munster, P N 2017, ' Inhibiting histone deacetylase as a means to reverse resistance to angiogenesis inhibitors : Phase i study of abexinostat plus pazopanib in advanced solid tumor malignancies ', Journal of Clinical Oncology, vol. 35, no. 11, pp. 1231-1238 . https://doi.org/10.1200/JCO.2016.70.5350, Journal of Clinical Oncology, 35(11), 1231-1238. American Society of Clinical Oncology
- Accession number :
- edsair.doi.dedup.....620df736eb6c7871f46eac309fbf5547