Journal Article

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

2016

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V
• Subject: Adult / Aged / Antineoplastic Combined Chemotherapy Protocols - adverse effects / Antineoplastic Combined Chemotherapy Protocols - therapeutic use / Biomedical and Life Sciences / Biomedicine / Blood platelets / Blood tests / Brain cancer / Camptothecin - administration & dosage / Camptothecin - analogs & derivatives / Camptothecin - pharmacokinetics / Cancer / Cancer Research / Cancer therapies / Care and treatment / Chemotherapy / Creatinine / Cytotoxicity / Diarrhea / Dosage and administration / Drug Administration Schedule / Drug Combinations / Drug dosages / Drug Monitoring / Female / Fluorouracil / Fluorouracil - administration & dosage / Fluorouracil - pharmacokinetics / Health Promotion and Disease Prevention / Hematology / Humans / Leucovorin / Leucovorin - administration & dosage / Leucovorin - pharmacokinetics / Liposomes / Male / Medical and radiation oncology / Medicine/Public Health / Middle Aged / Neoplasm Grading / Neoplasm Staging / Neoplasms - drug therapy / Neoplasms - genetics / Neoplasms - pathology / Neutrophils / Oncology / Patients / Pharmacogenomic Variants / Pharmacokinetics / Research Article / Sucrose - administration & dosage / Sucrose - analogs & derivatives / Sucrose - pharmacokinetics / Surgical Oncology / Toxicity / Treatment Outcome / Tumors