Phase I study of nanoliposomal irinotecan PEP02 in advanced solid tumor patientsReport as inadecuate




Phase I study of nanoliposomal irinotecan PEP02 in advanced solid tumor patients - Download this document for free, or read online. Document in PDF available to download.

Cancer Chemotherapy and Pharmacology

, Volume 75, Issue 3, pp 579–586

First Online: 11 January 2015Received: 08 July 2014Accepted: 30 December 2014DOI: 10.1007-s00280-014-2671-x

Cite this article as: Chang, T.C., Shiah, H.S., Yang, C.H. et al. Cancer Chemother Pharmacol 2015 75: 579. doi:10.1007-s00280-014-2671-x

Abstract

PurposeTo define the dose-limiting toxicity DLT, maximum tolerated dose MTD and pharmacokinetics PK of PEP02, a novel liposome-encapsulated irinotecan, in patients with advanced refractory solid tumors.

MethodsPatients were enrolled in cohorts of one to three to receive escalating dose of PEP02 in a phase I trial. PEP02, from 60 to 180 mg-m, was given as a 90-min intravenous infusion, every 3 weeks.

ResultsA total of 11 patients were enrolled into three dose levels: 60 one patient, 120 six patients and 180 mg-m four patients. DLT was observed in three patients, one at 120 mg-m grade 3 catheter-related infection and two at 180 mg-m grade 4 neutropenia lasting for >3 days in one, grade 4 hematological toxicities and grade 4 diarrhea in the other. MTD was determined as 120 mg-m. Comparing with those after free-form irinotecan in the literature, the dose-normalized PK of SN-38 the active metabolite after PEP02 was characterized by lower Cmax, prolonged terminal half-life and higher AUC but with significant inter-individual variation. One patient who died of treatment-related toxicity had significantly higher Cmax and AUC levels of SN-38 than those of the other three patients at 180 mg-m. Post hoc pharmacogenetic study showed that the patient had a combined heterozygosity genotype of UGT1A1*6-*28. Two patients had objective tumor response.

ConclusionsPEP02 apparently modified the PK parameters of irinotecan and SN-38 by liposome encapsulation. The MTD of PEP02 monotherapy at 3-week interval is 120 mg-m, which will be the recommended dose for future studies.

KeywordsIrinotecan sucrosofate Liposome PEP02 MM-398 Pharmacokinetics UGT1A1 gene T. C. Chang and H. S. Shiah have contributed equally to this work.

PEP02 is designated as MM-398 by Merrimack Pharmaceuticals, Inc. Cambridge, MA, USA.

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Author: T. C. Chang - H. S. Shiah - C. H. Yang - K. H. Yeh - A. L. Cheng - B. N. Shen - Y. W. Wang - C. G. Yeh - N. J. C

Source: https://link.springer.com/







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