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

Nai Jung Chiang, Tsu Yi Chao, Ruey Kuen Hsieh, Cheng Hsu Wang, Yi Wen Wang, C. Grace Yeh, Li Tzong Chen

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

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/m2 (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/m2 and LV 200 mg/m2 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/m2 (two patients). DLT was observed in four patients, two at the 100 mg/m2 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/m2 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/m2. 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/m2, which will be the recommended dose for future studies. Trial registration: The trial was retrospectively registered (NCT02884128) with date of registration: August 12, 2016.

Original languageEnglish
Article number907
JournalBMC Cancer
Volume16
Issue number1
DOIs
Publication statusPublished - Nov 21 2016

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irinotecan
Leucovorin
Liposomes
Fluorouracil
Injections
Maximum Tolerated Dose
Neoplasms
Diarrhea
Neutropenia
Pharmacokinetics

Keywords

  • 5-fluorouracil
  • Dose-limiting toxicity
  • Liposomal irinotecan
  • Maximum tolerated dose

ASJC Scopus subject areas

  • Oncology
  • Genetics
  • Cancer Research

Cite this

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.

In: BMC Cancer, Vol. 16, No. 1, 907, 21.11.2016.

Research output: Contribution to journalArticle

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. In: BMC Cancer. 2016 ; Vol. 16, No. 1.
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abstract = "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/m2 (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/m2 and LV 200 mg/m2 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/m2 (two patients). DLT was observed in four patients, two at the 100 mg/m2 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/m2 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/m2. 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/m2, which will be the recommended dose for future studies. Trial registration: The trial was retrospectively registered (NCT02884128) with date of registration: August 12, 2016.",
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AU - Hsieh, Ruey Kuen

AU - Wang, Cheng Hsu

AU - Wang, Yi Wen

AU - Yeh, C. Grace

AU - Chen, Li Tzong

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N2 - 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/m2 (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/m2 and LV 200 mg/m2 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/m2 (two patients). DLT was observed in four patients, two at the 100 mg/m2 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/m2 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/m2. 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/m2, which will be the recommended dose for future studies. Trial registration: The trial was retrospectively registered (NCT02884128) with date of registration: August 12, 2016.

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KW - 5-fluorouracil

KW - Dose-limiting toxicity

KW - Liposomal irinotecan

KW - Maximum tolerated dose

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