A pharmacokinetic (PK) dose escalation study of DX-8951f (DX) in adult cancer patients with hepatic dysfunction: A comparison of the NCI hepatic dysfunction criteria and the Child-Pugh classification

Abstract

2017 Background: DX-8951f (exatecan mesylate) is a novel camptothecin analog active in GI tumors such as pancreatic cancer. Its dose limiting toxicities (DLT) include neutropenia and thrombocytopenia. Because of its hepatic metabolism, a dose escalation study was performed in liver dysfunction patients (pts). Methods: Pts were classified in hepatic dysfunction cohorts defined by a modified NCI Organ Dysfunction Working Group (NCI) schema. Once a DLT was observed, pts were divided into minimally pretreated (MP) and heavily pretreated (HP) groups. Both the NCI and the FDA-recommended Child-Pugh classifications were used for data analysis. Results: Overall, 42 pts received 0.1–0.5 mg/m2/d DX x 5 q3 wks and 33 pts had PK data available. Dose escalation reached 0.5, 0.5, 0.4, and 0.2 mg/m2 for MP pts and 0.4, 0.4, 0.2, 0.1 mg/m2 for HP pts in Groups A, B, C and D, respectively. DLT's were neutropenia and low platelets, observed at 0.4 and 0.2 mg/m2 for MP and HP in group C, respectively. The MTD and drug clearance (CL) strongly correlated with liver dysfunction. Using the NCI criteria, DX CL was 1.43, 1.43, 0.7 and 0.32 L/h/m2 in Groups A, B, C, and D, respectively, resulting in recommended dose reductions of 50% and 80% in Group C and D pts. Using the FDA criteria, the DX CL decreased from 1.32, to 0.42, and 0.25 L/h/m2 in Class A, B, and C, respectively, corresponding to 66% and 80% dose reductions in Class B and C pts. Conclusions: DX dose reduction is required in liver dysfunction pts. Stratification by NCI criteria results in recommended dose reductions in 23 pts, compared to 17 pts using FDA criteria. Ongoing PK simulations will determine which approach optimally minimizes interpatient variability. This comparison of FDA and NCI classification schemes may assist in the design of future hepatic dysfunction trials in oncology. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Daiichi Daiichi Daiichi Corp.