Abstract A173: Long-term responders to epigenetic modulators: abexinostat and pazopanib
2018
Characterization of long-term responders in a phase I trial evaluating the role of epigenetic modulation of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor by using a histone deacetylase
abexinostatin combination with
pazopanibto enhance response and reverse resistance. Patients and Methods:
Pazopanibwas administered once a day on days 1 to 28 and
abexinostatwas 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
allsolid tumors was followed by dose expansion in renal cell carcinoma (RCC). Histone acetylation and HDAC2 expression were correlated long-term responders, >1y). Results: Fifty-one patients including RCC (N = 22) were enrolled, including 30 (59%) with one or more lines of prior VEGF-targeting therapy. Toxicities and PK studies were reported previously. 7 pts had response > 23 months (23-60+), including 5/22 patients with RCC, and one patient with medullary thyroid and thymic neurondocrine cancer. Long-term response was associated with high HDAC2 expression in PBMCs, increased histone acetylation, and modulation of VEGF level. Conclusion: Epigenetic modulation with
HDAC inhibitorsis strongly dependent on
host factorsto promote long-term benefit to
abexinostatand
pazopanibin pretreated patients. Citation Format:
RahulAggarwal, Nela Pawlowsk, Jennifer Grabowsky, Armand Harb, Kamran Abri-Lavasani, Scott Thomas, Pamela N. Munster. Long-term responders to epigenetic modulators:
abexinostatand
pazopanib[abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A173.
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