A. K. Goey, T. M. Sissung, C. J. Peer, S. Ehrlich, S. Balasubramaniam, C. Bryla, S. E. Bates, W. D. Figg; National Cancer Institute, Bethesda, MD
BACKGROUND: The histone deacetylase inhibitor belinostat (BEL), recently approved for peripheral T-cell lymphoma, is extensively glucuronidated by UGT1A1; polymorphic variants with reduced function could lead to higher BEL exposure and toxicity.
METHODS: In a Phase I trial, BEL (400-800 mg/m2/24 h) was administered as a 48 h continuous IV infusion in combination with cisplatin (CIS) and etoposide (ETO): 25 patients with advanced or recurrent cancer were genotyped for 3 UGT1A1 variants associated with reduced function: UGT1A1*6, UGT1A1*28 and UGT1A1*60. In Cycle 1, non-compartmental PK analysis of BEL was carried out and clinical outcomes were monitored.
RESULTS: Pts carrying 1 or 2 UGT1A1*60 variants (n = 18) had significantly higher BEL AUCs than pts carrying wild-type alleles (n = 5): median 11.4 vs 8.3 ng/mL*h/mg, P = 0.043. Consistent with greater exposure, pts carrying at least 1 variant UGT1A1*60 allele (n = 18) were at significantly higher risk for developing Gr 3-4 thrombocytopenia vs. pts with wild-type alleles (n = 5): OR (95%CI) = 21.2 (1.01-445.30, P = 0.014). A trend towards increased risk of Gr 3-4 thrombocytopenia (P = 0.023) and neutropenia (P = 0.036) was observed for UGT1A1*28. A marginal trend for Gr 3-4 neutropenia was also seen in *60 carriers (P = 0.066).
CONCLUSION: Here we report the first clinical effects of UGT1A1 genetic variants on the PK and toxicities of BEL in combination with CIS and ETO. UGT1A1*60 genotype status was significantly associated with increased systemic exposure to BEL. A significant increase in hematological toxicities was also observed with UGT1A1 genotype status, potentially an on-target toxicity due to BEL-enhanced CIS- and ETO-induced DNA damage. A population PK model accounting for genotype has been developed to titrate BEL dose based on UGT1A1 genotype.