Inhibiting Histone Deacetylase as a Means to Reverse Resistance to Angiogenesis Inhibitors: Phase I Study of Abexinostat Plus Pazopanib in Advanced Solid Tumor Malignancies

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/m 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.

[18F]Fluciclatide PET as a biomarker of response to combination therapy of pazopanib and paclitaxel in platinum-resistant/refractory ovarian cancer

“…While only in a small number of patients, we also show an increase in [ 18 F]fluciclatide uptake in those lesions that progressed on CT imaging following pazopanib therapy. Resistance to VEGF inhibitors is inevitable, the mechanism of which is postulated to be the overexpression and stabilization of hypoxia-inducible factor (HIF)-1α that directly regulates VEGF expression, and our results clearly illustrate this failure of functional blockade [58]. Taken together, the [ 18 F]fluciclatide-PET data suggest that the PET parameters obtained are consistent with the PD endpoint of pazopanib.…”

Therapeutic applications of histone deacetylase inhibitors in sarcoma

“…In a latest reported phase I trial, the addition of HDI abexinostat to pazopanib is well tolerated and resulted in durable responses in patients who experienced prior progression during treatment with VEGF inhibitors. Peripheral blood histone acetylation and HDAC2 gene expression were associated with durable response to treatment, which supports epigenetically mediated reversal of treatment resistance 116 . In a phase I dose-escalation study of the mTOR inhibitor sirolimus and the HDI vorinostat in patients with advanced malignancy, stable disease was observed in patient with fibromyxoid sarcoma 117 .…”

Chimeric HDAC inhibitors: Comprehensive review on the HDAC‐based strategies developed to combat cancer

“…In addition, there are FDA‐approved small‐molecule VEGFR‐2 inhibitors such as sunitinib ( 13 ), sorafenib ( 11 ), and vandetanib ( 38 ), which were approved for the treatment of various types of cancers including renal cell carcinoma, gastrointestinal stromal tumor, hepatocellular carcinoma, and thyroid cancer . Unfortunately, the increased resistance rates against VEGR inhibitors terminated their success, so many strategies to overcome this resistance were adopted, one of them is to develop chimeric VEGFR/HDAC inhibitors, especially when there is great synergy between RTK and HDAC inhibitors as previously mentioned . Peng et al .…”

“…45 Unfortunately, the increased resistance rates against VEGR inhibitors terminated their success, so many strategies to overcome this resistance were adopted, 46 one of them is to develop chimeric VEGFR/HDAC inhibitors, especially when there is great synergy between RTK and HDAC inhibitors as previously mentioned. 47 Peng et al 48 in 2015 developed a dual VEGFR/HDAC inhibitor by combining pharmacophores of two reference drugs, vandetanib (38), which acts as a VEGFR inhibitor, and SAHA, which acts as an HDAC inhibitor, to yield series of chimeric compounds with the most potent compound 38a ( Figure 10). Hybrid 38a showed HDAC isoform and kinase selectivity as well as improving its physiochemical properties.…”