Final results of a phase I study of liposome encapsulated SN-38 (LE-SN38): Safety, pharmacogenomics, pharmacokinetics, and tumor response

Abstract

2017 Background: The prodrug irinotecan is converted into its active moiety, SN-38, with wide interpatient variability, due in part to differential expression of cellular carboxylesterases responsible for prodrug hydrolysis. The enzyme UDP-glucuronosyltransferase 1A1 (UGT1A1) detoxifies SN-38 by metabolizing it to SN-38 glucuronide. Polymorphisms in the UGT1A1 promoter lead to decreased expression of the enzyme and are associated with increased risk of irinotecan toxicity. Methods: This was a multi-center, dose-escalation study of Liposome Encapsulated SN-38 (LE-SN38) in patients with advanced cancer. To examine whether toxicities and appropriate dose levels might differ with UGT1A1*28 genotype, patients were stratified prospectively. LE-SN38 was infused intravenously over 90 minutes every 21 days until disease progression or unacceptable toxicity occurred. Tumor progression was monitored radiographically after every 2 cycles. Results: Enrollment is complete; 75 patients were treated with LE-SN38. Screened patients had genotype frequencies of 42.4% homozygous wild-type (WT/WT), 45.1% heterozygous (WT/*28), 10.9% homozygous variant (*28/*28), and 1.6% other. Across all genotypes the most frequent adverse events were fatigue, nausea, anorexia, diarrhea, and vomiting. Importantly, diarrhea was generally mild and self-limiting, and no late onset diarrhea was reported. DLTs of neutropenia/febrile neutropenia in WT/WT patients at 40 mg/m2 resulted in an MTD of 35 mg/m2. No DLTs occurred in *28/*28 patients; accrual was halted at 20 mg/m2 before the MTD was reached. PK results showed that *28/*28 patients had 2- to 3-fold greater drug exposure than WT/*28 or WT/WT patients at the same doses. Stable disease (≥4 cycles) was observed in 37% of patients. Conclusions: LE-SN38 was well tolerated in all patients, with no reported acute/delayed diarrhea. The MTD was not reached for *28/*28 patients. An MTD of 35 mg/m2 LE-SN38 was found for WT/WT patients. Since WT/WT and WT/*28 patients did not appear to exhibit clinically significant differences in safety or PK profiles, this dose will be evaluated in both groups in a Phase II study of patients with colon cancer. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration NeoPharm