Abstract 5480: Effects of UGT1A1 genotype on pharmacokinetics and toxicities of belinostat administered by continuous infusion in two clinical trials
Authors: Goey Andrew K.L. , Sissung Tristan M. , Peer Cody J. , Ehrlich Sheryl , Bryla Christina , Berman Arlene W. , Balasubramaniam Sanjeeve , Rajan Arun , Giaccone Giuseppe , Bates Susan E. , Figg William D. 
Published: August 2015

Background: Belinostat (B), a histone deacetylase inhibitor recently approved for peripheral T-cell lymphoma, is extensively glucuronidated by UGT1A1. Genotypes with reduced UGT1A1 function could lead to higher B exposure and toxicities (tox).

Methods: In a Phase I (BPE) and Phase I/II trial (BPAC), B (400-1000 mg/m2/24 h) was administered as a 48 h continuous infusion in combination with either cisplatin (P) and etoposide (E), or P, doxorubicin (A) and cyclophosphamide (C), respectively. Pts with small cell lung cancer and other cancers of neuroendrocrine origin (n = 25 in BPE) or advanced or unresectable thymic epithelial tumors (n = 26 in BPAC) underwent genotyping for UGT1A1 variants associated with reduced function: UGT1A1*6, *28 and *60. In both trials PK of B was analyzed and during Cycle 1 clinical outcomes were monitored. In 9 pts the Drug Metabolizing Enzymes and Transporter (DMET) genotyping array was carried out to study relationships between drug metabolizing enzymes and transporters with B PK or tox.

Results: Pts carrying 1 or 2 UGT1A1*60 variants (n = 18) in BPE, had significantly higher B AUCs than WT pts (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. WT pts (n = 5): OR (95%CI) = 21.2 (1.01-445.30), P = 0.014. A trend towards an increased risk of Gr 3-4 thrombocytopenia (P = 0.038), Gr 3-4 neutropenia (P = 0.045) and QTc prolongation (P = 0.030) was observed for UGT1A1*28. For Gr 3-4 neutropenia a marginal trend was also seen in *60 carriers (P = 0.088).

In the BPAC trial UGT1A1*28 and UGT1A1*60 status did not significantly affect B PK (AUC, Cmax and CL, P&gt;0.05) nor the incidence of most tox (P&gt;0.05). Only Gr 3-4 thrombocytopenia occurred more frequently in *28 carriers (n = 11) than in WTs (n = 15): OR (95%CI) = 18.6 (0.88-392.7), P = 0.022.

The DMET array revealed significant associations between SNPs in SLC15A1 and CYP24A1 and B PK (P&lt;0.01). SNPs in SLCO1B3, SLCO1B1 and ABCB4 were significantly associated with the incidence of lymphocytopenia (P&lt;0.01). Significant trends were observed between SNPs in UGT1A1, CYP2C19, CHST7, ABCB7 and ATP7A and the incidence of neutropenia. A SNP in XDH significantly trended with the incidence of thrombocytopenia (P&lt;0.01).

Conclusion: This is the first report of UGT1A1 polymorphisms effect on the PK and tox of B in combination with PE or PAC. In the BPE trial UGT1A1 status was associated with the extent of systemic exposure to B and the incidence of hematological tox. These associations were less profound in the BPAC trial and possible explanations are still under investigation. The DMET results indicate that besides UGT1A1 other drug transporters or enzymes could affect B PK and tox. Based on these findings, a population PK model accounting for genotype has been developed to titrate B dose based on UGT1A1 genotype.

Citation Format: Andrew K.L. Goey, Tristan M. Sissung, Cody J. Peer, Sheryl Ehrlich, Christina Bryla, Arlene W. Berman, Sanjeeve Balasubramaniam, Arun Rajan, Giuseppe Giaccone, Susan E. Bates, William D. Figg. Effects of UGT1A1 genotype on pharmacokinetics and toxicities of belinostat administered by continuous infusion in two clinical trials. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5480. doi:10.1158/1538-7445.AM2015-5480