Background: PAZ is a tyrosine kinase inhibitor of VEGFR, PDGFR, and c-KIT approved for use in renal cell carcinoma (RCC). ABX is a potent pan-HDAC inhibitor (HDACi). Pre-clinical models suggest that HDACi-mediated epigenetic modulation of VEGF expression prevents PAZ resistance and potentiates efficacy. We therefore designed a Phase I clinical trial combining ABX with PAZ in pts with advanced solid tumors with an expansion cohort in RCC.
Methods: The primary endpoint was the maximal tolerated dose (MTD) of PAZ plus ABX. Secondary endpoints included pharmacokinetics (PK) and efficacy. PAZ was dosed days 1-28 and ABX days 1-5, 8-12, and 15-19 of 28-day cycle (schedule A) with at a starting dose of 400 mg/day and 45 mg/m2 orally twice daily respectively. An alternate ABX dosing schedule days 1-4, 8-11, and 15-18 was investigated (schedule B) due to toxicity of Schedule A.
Results: 52 patients (pts) (RCC; N = 23) with advanced solid tumors were enrolled (N = 22 schedule A; N = 30 schedule B). There were six dose-limiting toxicities including fatigue (N = 2), thrombocytopenia (N = 2), and elevated AST/ALT (N = 2). The most common grade ? 3 related adverse events observed were fatigue (13%), thrombocytopenia (12%), and diarrhea (10%). The MTD was PAZ 800 mg/day + ABX 45 mg/m2 BID on schedule B. 8 evaluable pts (19%) (N = 6 RCC; 2 thyroid; median number of prior lines of therapy = 3) achieved partial tumor response (PR), with median duration of response of 9.2 months (1-33.2+). 7/9 (78%) of pts with prior disease progression on PAZ monotherapy had reduction in tumor burden on study. 15 out of 48 evaluable pts (31%) experienced stable disease or better for ? 6 months, and two previously PAZ-refractory pts with PRs remain on study for > 20 and 37 mos respectively. PK analyses did not reveal drug-drug interaction. Degree of histone acetylation and metabolomic profile are being evaluated.
Conclusion: The combination of PAZ + ABX was well tolerated and durable tumor control (> 3 yrs) was observed in RCC and thyroid cancer. Tumor regressions observed in majority of PAZ-refractory tumors preliminarily support the potential of ABX to reverse therapeutic resistance. A randomized phase 2 study with cross-over design is planned to further evaluate the combination of PAZ + HDACi.
Citation Format: Rahul Aggarwal, Scott Thomas, Jennifer Grabowsky, Armand Harb, Jim Leng, Anne Reinert, Ilaria Mastroserio, Thach-Giao Truong, Pamela N. Munster. Abexinostat (ABX) as a means to reverse pazopanib (PAZ) resistance: a phase I study in advanced solid tumor malignancies. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT016.