Chang T.C.Shiah H.S.CHIH-HSIN YANGKUN-HUEI YEHANN-LII CHENGShen B.N.Wang Y.W.Yeh C.G.Chiang N.J.Chang J.Y.Chen L.T.2020-05-262020-05-2620150344-5704https://www.scopus.com/inward/record.uri?eid=2-s2.0-84923651982&doi=10.1007%2fs00280-014-2671-x&partnerID=40&md5=a8413d5d03a4662865c9f9ae91ea5570https://scholars.lib.ntu.edu.tw/handle/123456789/495017Purpose: To 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. Methods: Patients 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/m2, was given as a 90-min intravenous infusion, every 3 weeks. Results: A total of 11 patients were enrolled into three dose levels: 60 (one patient), 120 (six patients) and 180 mg/m2 (four patients). DLT was observed in three patients, one at 120 mg/m2 (grade 3 catheter-related infection) and two at 180 mg/m2 (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/m2. 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 C max, prolonged terminal half-life and higher AUC but with significant inter-individual variation. One patient who died of treatment-related toxicity had significantly higher C max and AUC levels of SN-38 than those of the other three patients at 180 mg/m2. Post hoc pharmacogenetic study showed that the patient had a combined heterozygosity genotype of UGT1A1?6/?28. Two patients had objective tumor response. Conclusions: PEP02 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/m2, which will be the recommended dose for future studies. ? 2015 The Author(s).[SDGs]SDG3antineoplastic agent; firtecan; fluorouracil; folinic acid; gemcitabine; glucuronosyltransferase 1A1; irinotecan; irinotecan sucrosofate; oxaliplatin; antineoplastic agent; camptothecin; glucuronosyltransferase; irinotecan; liposome; nanoparticle; UGT1A1 enzyme; adult; advanced cancer; aged; alopecia; anorexia; area under the curve; Article; breast cancer; cancer chemotherapy; cancer radiotherapy; cancer surgery; chemotherapy induced anemia; chemotherapy induced emesis; chest tightness; clinical article; computer assisted tomography; diarrhea; drug clearance; drug dose increase; drug dose titration; drug elimination; drug fatality; drug half life; drug safety; electrolyte disturbance; fatigue; febrile neutropenia; female; genetic polymorphism; genotype; heterozygosity; human; leukopenia; male; maximum plasma concentration; maximum tolerated dose; mean residence time; multicenter study; neuroendocrine tumor; neutropenia; non small cell lung cancer; pancreas cancer; phase 1 clinical trial; plasma concentration-time curve; priority journal; solid tumor; thymus cancer; time to maximum plasma concentration; uterine cervix cancer; volume of distribution at steady-state; analogs and derivatives; clinical trial; comparative study; dose response; genetics; half life time; intravenous drug administration; middle aged; Neoplasms; pathology; pharmacogenetics; treatment outcome; Adult; Antineoplastic Agents, Phytogenic; Area Under Curve; Camptothecin; Dose-Response Relationship, Drug; Female; Genotype; Glucuronosyltransferase; Half-Life; Humans; Infusions, Intravenous; Liposomes; Male; Maximum Tolerated Dose; Middle Aged; Nanoparticles; Neoplasms; Pharmacogenetics; Treatment Outcomejournal article10.1007/s00280-014-2671-x255771332-s2.0-84923651982