Phase I and pharmacokinetic (PK) study of IHL-305 (pegylated liposomal irinotecan) in patients with advanced solid tumors

Autor: J. R. Infante, Mace L. Rothenberg, Vicki L. Keedy, S. Ikeda, H. A. Burris, Emily Chan, William C. Zamboni, W. Lee, Siân Jones, Johanna C. Bendell
Rok vydání: 2009
Předmět:
Zdroj: Journal of Clinical Oncology. 27:2547-2547
ISSN: 1527-7755
0732-183X
DOI: 10.1200/jco.2009.27.15_suppl.2547
Popis: 2547 Background: Irinotecan (CPT-11) is a prodrug of SN-38 that has antitumor activity in a wide range of solid tumors. IHL- 305 is a PEGylated-liposomal formulation of irinotecan designed to increase the therapeutic index by prolonging the duration of exposure in both plasma and tumors. IHL-305 demonstrates superior anti-tumor activity in preclinical models. Methods: Eligible patients (pts) had advanced solid tumors, ECOG ≤2, adequate organ function and no prior exposure to CPT-11. In a standard 3+3 escalation, IHL-305 was infused over 60 minutes q 28 days. UGT1A1*28 genotyping was performed with the homozygous (*28/*28) variants treated at 50% of current dose (subsequent escalation allowed). The area under the plasma concentration- time curve (AUC) of sum total (encapsulated + released) CPT-11, released CPT-11, SN-38, and SN-38 glucuronide (SN-38G) was calculated. The % CPT-11 released was calculated as the ratio of released CPT-11 AUC to sum total CPT-11 AUC x 100. The primary objectives were to determine the dose limiting toxicities (DLTs), phase II recommended dose (P2RD), and clinical pharmacology of IHL- 305. Results: 42 pts treated; homozygous wild-type (wt/wt; n=23), heterozygous (wt/*28; n=13) and homozygous variants (*28/*28; n= 6). 10 dose levels explored; 7, 14, 28, 37, 50, 67, 88, 120, 160 and 210 mg/m2. DLTs included: 1 Gr 3 acute nausea/vomiting at 67 mg/ m2 (subsequent pts received premedication), 1 Gr 3 delayed-onset diarrhea at 160 mg/m2, and 1 Gr 3 delayed nausea/vomiting and one Gr 3 febrile neutropenia at 210mg/m2. Pts received repeated courses of IHL-305 with no delays for myelosuppression or diarrhea. 7 pts had stable disease ≥ 6 cycles. The mean ± SD PK parameters are summarized in the table below. Conclusions: The MTD and P2RD of IHL-305 is 160 mg/m2 IV q 28 days. IHL-305 shows a high and prolonged exposure of sum total and released CPT-11 and SN-38. [Table: see text] [Table: see text]
Databáze: OpenAIRE
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