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/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.

Fig 1.

Summary of efficacy in dose escalation and expansion cohorts. (A) Maximal percent change from baseline in tumor-measurement-evaluable patients (n = 43). Confirmed objective responses were observed in 9 (21%) of 43 evaluable patients, including six patients with prior progresssion receiving one or more VEGF-targeting therapies. (B) Duration of response in the dose escalation and renal cell expansion cohorts. Median duration of response was 9.1 months (range, 1.2 to ≥ 44 months) and clinical benefit rate (partial response plus stable disease > 6 months) was observed in 16 (37%) of 43 patients. Eight patients achieved exceptional response defined as response duration of > 12 months. Adr CC, adrenocortical carcinoma; HNSCC, head and neck squamous cell carcinoma; Meso, mesothelioma; NET, neuroendocrine tumor; RCC, renal cell carcinoma; TNBC, triple-negative breast cancer; VEGF, vascular endothelial growth factor.

Fig 2.

Durable response in patient with treatment-refractory clear cell renal cell carcinoma. Patient had previously experienced progression receiving five systemic lines of therapy for kidney cancer, including four prior VEGF-targeting therapies. His cancer was primary refractory to prior pazopanib monotherapy. Upon initiation of study treatment with pazopanib in combination with abexinostat in December 2012, the patient experienced a rapid and deep response to treatment with ongoing response for > 3.5 years. B, bevacizumab; E, everolimus; P, pazopanib monotherapy; S, sorafenib.

Fig 3.

Summary of abexinostat pharmacokinetics. (A) Raw plasma concentrations of abexinostat by dose level. Median and interquartile range of observed concentrations presented by occasion and dose level is shown. Abexinostat concentrations at first dose without pazopanib (C1D-7, blue triangles, dotted blue line); at steady state concentration (Css) without pazopanib (C1D-4, gold circles, gold line); at Css with pazopanib (C1D + 4 gray squares, dashed gray line). (B) Estimated pharmacokinetic parameters of abexinostat. Median area under the concentration-time curve (AUC; ng*h/L) and median maximum serum concentration (C_max; ng/mL) and 95% CIs are presented. (*)Individual pharmacokinetic parameters AUC and C_max were estimated by using the population pharmacokinetic parameters of abexinostat as previously described. C_max, maximum serum concentration.

Fig 4.

Biomarkers predictive of response to therapy. (A) Peripheral blood mononuclear cell (PBMC) histone deacetylase 2 (HDAC2) expression levels by subgroups of patients categorized by duration of response. Kruskal-Wallis test for comparison across three groups: P = .0025. Mean (± standard error of the mean [SEM]) values are as follows: > 12 months, 1.1 (± 0.19); 6 to 12 months, 0.63 (± 0.18); and < 6 months, 0.41 (± 0.08). (*)Mann-Whitney test to compare > 12 months versus < 6 months: P = .0019. (†)Mann-Whitney test to compare 6 to 12 month versus < 6 months: P = .0129. (B) PBMC HDAC6 expression levels and duration of response. Kruskal-Wallis test for three-way comparison, P = .39. Mann-Whitney test for pairwise comparisons: < 6 months v > 6 to < 12 months, P = .23; < 6 months and > 12 months, P = .59. (C) Progression-free survival according to HDAC2 expression in PBMCs. Kaplan-Meier curve for patients (n = 43) according to HDAC2 expression in PBMCs: low HDAC2 expression (< 0.4; 3.5 months) versus high HDAC2 expression (> 0.4; 5.9 months); hazard ratio (95% CI) by log rank: 0.41 (0.17 to 0.67); P = .0034. (D) Change in WBC count and duration of response. Effects of abexinostat without effects of pazopanib on patients’ WBC count on cycle one, day 8 (depicted as ratio of day 1 to day 8) by response duration: > 6 versus < 6 months. Means (± standard error of the mean), 0.84 (± 0.04) versus 1.13 (± 0.06); P = .0029.

Fig A1.

Correlation between induction in peripheral blood mononuclear cell (PBMC) histone acetylation with exposure to abexinostat on day −4. Correlation between induction of PBMC histone acetylation at 4 hours postdose and abexinostat concentration on day −4 (R² = 0.45; P = .0094). AcH4, acetylated H4 expression relative to pan H3 expression; C_max, serum concentration of abexinostat 4 hours postdose. C_max, maximum serum concentration.

Fig A2.

Correlation between induction in peripheral blood mononuclear cell (PBMC) histone acetylation with plasma vascular endothelial growth factor (VEGF) levels in patients with renal cell carcinoma. Correlation between fold increase in PBMC histone acetylation and ratio of post-treatment to pretreatment plasma VEGF levels among patients with renal cell carcinoma (Pearson’s r = −0.59; P = .01).