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A phase I dose-escalation study of PEP02 (irinotecan liposome injection) in combination with 5-fluorouracil and leucovorin in advanced solid tumors

BACKGROUND: PEP02 (also known as MM-398, nal-IRI) is a novel nanoparticle formulation of irinotecan encapsulated in liposomes. The aims of this study were to investigate the dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and pharmacokinetics (PK) of PEP02 in combination with 5-FU and LV,...

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Autores principales: Chiang, Nai-Jung, Chao, Tsu-Yi, Hsieh, Ruey-Kuen, Wang, Cheng-Hsu, Wang, Yi-Wen, Yeh, C. Grace, Chen, Li-Tzong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5117585/
https://www.ncbi.nlm.nih.gov/pubmed/27871319
http://dx.doi.org/10.1186/s12885-016-2933-6
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author Chiang, Nai-Jung
Chao, Tsu-Yi
Hsieh, Ruey-Kuen
Wang, Cheng-Hsu
Wang, Yi-Wen
Yeh, C. Grace
Chen, Li-Tzong
author_facet Chiang, Nai-Jung
Chao, Tsu-Yi
Hsieh, Ruey-Kuen
Wang, Cheng-Hsu
Wang, Yi-Wen
Yeh, C. Grace
Chen, Li-Tzong
author_sort Chiang, Nai-Jung
collection PubMed
description BACKGROUND: PEP02 (also known as MM-398, nal-IRI) is a novel nanoparticle formulation of irinotecan encapsulated in liposomes. The aims of this study were to investigate the dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and pharmacokinetics (PK) of PEP02 in combination with 5-FU and LV, in patients with advanced refractory solid tumors. METHODS: Patients were enrolled in cohorts to receive PEP02 from 60 to 120 mg/m(2) (dose expressed as the irinotecan hydrochloride trihydrate salt) as a 90-min intravenous infusion on day 1, followed by 24 h infusion of 5-FU 2,000 mg/m(2) and LV 200 mg/m(2) on days 1 and 8, every 3 weeks. RESULTS: A total of 16 patients were assigned to four dose levels, 60 (three patients), 80 (six patients), 100 (five patients) and 120 mg/m(2) (two patients). DLT was observed in four patients, two at the 100 mg/m(2) dose level (one had grade III infection with hypotension and grade III hemorrhage; the other had grade III diarrhea and grade IV neutropenia), and two at the 120 mg/m(2) dose level (one had grade III diarrhea and grade IV neutropenia; the other had grade III diarrhea). The MTD of PEP02 was determined as 80 mg/m(2). The most common treatment-related adverse events were nausea (81%), diarrhea (75%) and vomiting (69%). Among the six patients who received the MTD, one patient exhibited partial response, four patients had stable disease and one showed progressive disease. Pharmacokinetic data showed that PEP02 had a lower peak plasma concentration, longer half-life, and increased area under the plasma concentration-time curve from zero to time t of SN-38 than irinotecan at similar dose level. CONCLUSIONS: The MTD of PEP02 on day 1 in combination with 24-h infusion of 5-FU and LV on days 1 and 8, every 3 weeks was 80 mg/m(2), which will be the recommended dose for future studies. TRIAL REGISTRATION: The trial was retrospectively registered (NCT02884128) with date of registration: August 12, 2016. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12885-016-2933-6) contains supplementary material, which is available to authorized users.
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spelling pubmed-51175852016-11-28 A phase I dose-escalation study of PEP02 (irinotecan liposome injection) in combination with 5-fluorouracil and leucovorin in advanced solid tumors Chiang, Nai-Jung Chao, Tsu-Yi Hsieh, Ruey-Kuen Wang, Cheng-Hsu Wang, Yi-Wen Yeh, C. Grace Chen, Li-Tzong BMC Cancer Research Article BACKGROUND: PEP02 (also known as MM-398, nal-IRI) is a novel nanoparticle formulation of irinotecan encapsulated in liposomes. The aims of this study were to investigate the dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and pharmacokinetics (PK) of PEP02 in combination with 5-FU and LV, in patients with advanced refractory solid tumors. METHODS: Patients were enrolled in cohorts to receive PEP02 from 60 to 120 mg/m(2) (dose expressed as the irinotecan hydrochloride trihydrate salt) as a 90-min intravenous infusion on day 1, followed by 24 h infusion of 5-FU 2,000 mg/m(2) and LV 200 mg/m(2) on days 1 and 8, every 3 weeks. RESULTS: A total of 16 patients were assigned to four dose levels, 60 (three patients), 80 (six patients), 100 (five patients) and 120 mg/m(2) (two patients). DLT was observed in four patients, two at the 100 mg/m(2) dose level (one had grade III infection with hypotension and grade III hemorrhage; the other had grade III diarrhea and grade IV neutropenia), and two at the 120 mg/m(2) dose level (one had grade III diarrhea and grade IV neutropenia; the other had grade III diarrhea). The MTD of PEP02 was determined as 80 mg/m(2). The most common treatment-related adverse events were nausea (81%), diarrhea (75%) and vomiting (69%). Among the six patients who received the MTD, one patient exhibited partial response, four patients had stable disease and one showed progressive disease. Pharmacokinetic data showed that PEP02 had a lower peak plasma concentration, longer half-life, and increased area under the plasma concentration-time curve from zero to time t of SN-38 than irinotecan at similar dose level. CONCLUSIONS: The MTD of PEP02 on day 1 in combination with 24-h infusion of 5-FU and LV on days 1 and 8, every 3 weeks was 80 mg/m(2), which will be the recommended dose for future studies. TRIAL REGISTRATION: The trial was retrospectively registered (NCT02884128) with date of registration: August 12, 2016. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12885-016-2933-6) contains supplementary material, which is available to authorized users. BioMed Central 2016-11-21 /pmc/articles/PMC5117585/ /pubmed/27871319 http://dx.doi.org/10.1186/s12885-016-2933-6 Text en © The Author(s). 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Chiang, Nai-Jung
Chao, Tsu-Yi
Hsieh, Ruey-Kuen
Wang, Cheng-Hsu
Wang, Yi-Wen
Yeh, C. Grace
Chen, Li-Tzong
A phase I dose-escalation study of PEP02 (irinotecan liposome injection) in combination with 5-fluorouracil and leucovorin in advanced solid tumors
title A phase I dose-escalation study of PEP02 (irinotecan liposome injection) in combination with 5-fluorouracil and leucovorin in advanced solid tumors
title_full A phase I dose-escalation study of PEP02 (irinotecan liposome injection) in combination with 5-fluorouracil and leucovorin in advanced solid tumors
title_fullStr A phase I dose-escalation study of PEP02 (irinotecan liposome injection) in combination with 5-fluorouracil and leucovorin in advanced solid tumors
title_full_unstemmed A phase I dose-escalation study of PEP02 (irinotecan liposome injection) in combination with 5-fluorouracil and leucovorin in advanced solid tumors
title_short A phase I dose-escalation study of PEP02 (irinotecan liposome injection) in combination with 5-fluorouracil and leucovorin in advanced solid tumors
title_sort phase i dose-escalation study of pep02 (irinotecan liposome injection) in combination with 5-fluorouracil and leucovorin in advanced solid tumors
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5117585/
https://www.ncbi.nlm.nih.gov/pubmed/27871319
http://dx.doi.org/10.1186/s12885-016-2933-6
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