Phase I study of liposome irinotecan (PEP02) in combination with weekly infusion of 5-FU/LV in advanced solid tumors

[[abstract]]Background: PEP02 is a novel nanoparticle liposome formulation of irinotecan (CPT-11) that has improved PK and tumor biodistribution of CPT-11 and its active metabolite-SN38 with encouraging safety and tumor response in preclinical studies and a single-agent phase I study. The study is to define the DLT, MTD, and PK of PEP02 when in combination with high-dose fluorouracil/leucovorin (HDFL) in patients (pt) with advanced solid tumors. Methods: Pts who had failed to standard chemotherapy, ECOG PS 0-1 and adequate organ functions, no prior CPT-11, were eligible. PEP02 was given as 90 mins i.v. infusion on D1 in combination with 24-hr infusion of 5FU (2,000 mg/m2)/ LV (200 mg/m2) on D1 and D8, every 3 weeks. Cohorts of 3-6 pts were treated at 60, 80, 100, and 120 mg/m2. PK and PGx samples were collected. Results: A total of 16 pts were enrolled, with 3, 6, 5, and 2 at 60, 80, 100, and 120 mg/m2. DLTs were observed in 4 pts, including 2 each at 100 and 120 mg/m2 dose levels. DLTs were mainly G3 diarrhea and G4 hematologic toxicities. MTD was determined as 80 mg/m2. Grade 3 or above adverse events at the MTD dose and all dose levels were 10.6% and 18.4%, respectively. The PK of total CPT-11 after PEP02 (at 80 mg/m2) in combination with HDFL was characterized by low clearance (mean = 116.4 mL/m2/hr) and small volume of distribution (mean = 2.93 L/m2, similar to plasma volume) as did of PEP02 monotherapy study. Compared to the PK of SN-38 after 250 mg/m2 of CPT-11 (in combination with capecitabine, Ann Oncol 2005; 16: 1123-32), the Cmax after 80 mg/m2 of PEP02 was lower (7.98 ± 4.39 vs 62.0 ± 37.4 ng/mL), but the AUC0 t was similar (354.77 ± 145.35 vs 396 ± 247 ngxh/mL). The correlation of UGT1A family with PK and toxicity was not observed. However, the only subject with the coexistence of two variants of UGT1A1*6 and *28 had higher dose-normalized AUCSN-38and experienced DLT. The best response of 15 evaluable pts was PR in 2 (gastric cancer and breast cancer) and SD in 9. Conclusions: The MTD of PEP02 in combination with HDFL given every-3-week is 80 mg/m2. The observation of tumor response in two heavily pre-treated patients suggests the combination deserves further exploration in advanced solid tumor patients who are refractory to standard therapy