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

e13024 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 ng×h/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. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration PharmaEngine PharmaEngine PharmaEngine PharmaEngine