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|Ref Type||Journal Article|
|Authors||Aggarwal R, Thomas S, Pawlowska N, Bartelink I, Grabowsky J, Jahan T, Cripps A, Harb A, Leng J, Reinert A, Mastroserio I, Truong TG, Ryan CJ, Munster PN|
|Title||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||Journal of clinical oncology : official journal of the American Society of Clinical Oncology|
|Date||2017 Apr 10|
|Abstract Text||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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||renal cell carcinoma||not applicable||Abexinostat + Pazopanib||Phase Ib/II||Actionable||In a Phase Ib/II trial, 27% (6/22) of renal cell carcinoma patients demonstrated a response when treated with a combination of Abexinostat (PCI-24781) and Votrient (pazopanib) (PMID: 28221861).||28221861|
|Unknown unknown||clear cell renal cell carcinoma||not applicable||Abexinostat + Pazopanib||Phase Ib/II||Actionable||In a Phase Ib/II trial, 31% (5/16) of renal clear cell carcinoma patients demonstrated a response to the combination of Abexinostat (PCI-24781) and Votrient (pazopanib) (PMID: 28221861).||28221861|
|Unknown unknown||papillary renal cell carcinoma||not applicable||Abexinostat + Pazopanib||Phase Ib/II||Actionable||In a Phase Ib/II trial, 17% (1/6) of patients with papillary renal cell carcinoma demonstrated a response to the combination of Abexinostat (PCI-24781) and Votrient (pazopanib) (PMID: 28221861).||28221861|
|Unknown unknown||Advanced Solid Tumor||not applicable||Abexinostat + Pazopanib||Phase Ib/II||Actionable||In a Phase Ib/II trial, the combination of Abexinostat (PCI-24781) and Votrient (pazopanib) in advanced solid tumor patients resulted in a clinical benefit rate of 37% (16/43), a median response duration of 9.1 months, and 8 patients of 43 achieved stable disease or durable response for greater than 12 months (PMID: 28221861).||28221861|