Updated survival follow-up for phase I study of abexinostat with pazopanib in patients with solid tumor malignancies.

Abstract

3150 Background: Histone deacetylase (HDAC) inhibition downregulates HIF-1a, which may be effective in overcoming resistance to VEGF-targeting tyrosine kinase inhibitors. We report the updated survival follow-up for patients treated with abexinostat and pazopanib in a phase Ib trial. Methods: Patients with solid tumor malignancies were enrolled in this phase Ib, open-label trial (NCT01543763) of abexinostat in combination with pazopanib (3+3 design), with a dose expansion restricted to renal cell carcinoma (RCC). Patients received a 1-week run-in period with abexinostat alone, and then combination abexinostat with pazopanib during a 28-day treatment cycle until disease progression, unacceptable toxicity or study withdrawal. Plasma samples from 29 patients were sent for metabolomics analysis. Results: 51 patients were enrolled: N = 36 patients in dose escalation, N = 15 in dose expansion. At the time of last report in 2017, 5 patients remained on study treatment: N = 4 with RCC, and N = 1 with thymic neuroendocrine carcinoma. 4 of these patients have now had disease progression. Median duration of therapy measured 44.9 months (range 39.8-102.2). One patient with metastatic RCC (patient 1) remains on study treatment, after progression on 5 prior lines of systemic therapy. With updated survival follow-up, median OS measured 12.4 months in the dose escalation arm and 27.65 months in the RCC dose expansion cohort. Overall median duration of therapy in all 51 patients measured 5.6 months (range 1-103 months). Progression-free survival among patients with high PBMC HDAC2 expression (> 0.4) remains longer compared to those with low expression (median 6.3 vs. 3.7 months, p = 0.0041). Metabolomics analysis demonstrated a negative correlation between HDAC2 and N6-acetyllysine, suggesting that baseline HDAC2 may impact efficacy of HDAC inhibition. Conclusions: The combination of abexinostat with pazopanib appears promising, with the potential for long-term responses particularly in patients with metastatic RCC. This has led to an ongoing phase III trial examining this combination in RCC. Clinical trial information: NCT01543763. [Table: see text]