UGT1A1 genotype effects on PK, PD and toxicities of belinostat administered by 48 h continuous infusion.

e13581 Background: UGT1A1 plays a major role in the glucuronidation of the histone deacetylase inhibitor belinostat (BEL). Polymorphisms with reduced UGT1A1 function could result in increased BEL exposure, global protein lysine acetylation (AcK) and toxicities (tox). Methods: In a Phase I (BPE) and Phase I/II trial (BPAC), BEL (400-1000 mg/m2/24 h) was administered by 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 neuroendocrine origin (n = 25 in BPE) or thymic epithelial tumors (n = 26 in BPAC) were genotyped for UGT1A1 variants associated with reduced function: UGT1A1*6, UGT1A1*28 and UGT1A1*60. In both trials PK BEL parameters and clinical outcomes were monitored during cycle 1. Endpoints were associations between UGT1A1 genotype and BEL PK, AcK, and tox. Results: Carriers of UGT1A1*60 variants in BPE, had progressively higher BEL t1/2 than WTs: P= 0.0...