Κυριακή, 12 Μαρτίου 2017

HISTONE DEACETYLASE INHIBITORS REVERSE RESISTANCE TO ANTIANGIOGENIC TREATMENT

In a phase I study reported in the Journal of Clinical Oncology, Aggarwal et al found evidence that the histone deacetylase (HDAC) inhibitor abexinostat may act to reverse resistance to the vascular endothelial growth factor (VEGF) inhibitor pazopanib (Votrient) via epigenetic modulation of VEGF in advanced solid tumors, including renal cell carcinoma.
Study Details
In the trial, 51 patients with advanced solid tumors, including 22 with renal cell carcinoma, received pazopanib at 400 to 800 mg once a day on days 1 to 28 and abexinostat orally twice a day at 30 or 45 mg/m2 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 (in 3 + 3 design) in all solid tumors was followed by dose expansion in patients with renal cell carcinoma. Among all patients, 59% had received at least one line of prior VEGF-targeting therapy.
Dose-Limiting Toxicity
Five dose-limiting toxicities, including fatigue (n = 2), thrombocytopenia (n = 2), and elevated aspartate transaminase/alanine transaminase (AST/ALT; n = 1), were observed with schedule A, whereas one toxicity (elevated AST/ALT) was observed with schedule B. Grade ≥ 3 treatment-related adverse events included fatigue (16%), thrombocytopenia (16%), neutropenia (10%), and diarrhea (10%). The recommended phase II dose was identified as abexinostat at 45 mg/m2 twice a day administered on schedule B plus pazopanib at 800 mg/d.
Responses
Objective response was observed in 21% of patients overall and in 27% of those with renal cell carcinoma. Median duration of response was 9.1 months, with a range of 1.2 to more than 49 months. Durable control of disease for more than 12 months was observed in 8 patients (16%). Durable tumor regression was seen in 7 of 10 patients (70%) with pazopanib-refractory disease, including 1 patient with renal cell carcinoma, with an ongoing response at more than 3.5 years.
Greater time to disease progression was significantly associated with higher baseline peripheral blood HDAC2 expression level (P = .0019), the strongest predictor of prolonged response, and with fold change in peripheral blood peripheral blood mononuclear cell histone H4 acetylation (P = .003).
The investigators concluded: “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.”
The study was supported by GlaxoSmithKline.

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