Background: PEP02 is a highly stable nanoliposomal irinotecan. This randomized non-comparative phase II (PEPCOL) study evaluated the efficacy and safety of PEP02 (MM-398) or irinotecan in combination with LV/5-FU in the second-line treatment of metastatic colorectal cancer (mCRC). (EudraCT 2010-020468-39A, NCT01375816). Methods: Patients with unresectable mCRC who had failed one prior oxaliplatin-based first-line therapy were randomly assigned to FUPEP (PEP02 80 mg/m² d1, folinic acid (FA) 400 mg/m² d1, 5-FU 2,400 mg/m² d1-2) or FOLFIRI (FOLFIRI1: irinotecan 180 mg/m² d1, FA 400 mg/m² d1, 5-FU bolus 400 mg/m² d1, 5-FU infusion 2,400 mg/m² d1-2; or modified FOLFIRI3: irinotecan 90 mg/m² d1 and 3, FA 400 mg/m² d1, 5-FU infusion 2,400 mg/m² d1-2). Bevacizumab q2w (5 mg/kg) was allowed in both arms as of June 2012 (TML study report). The primary endpoint was the objective tumor response (OR). Results: Fifty-five patients were randomized (FUPEP, n=28; FOLFIRI, n=27). In the evaluable population (n=50), OR rate were 16.7% (n=4/24) and 11.5% (n=3/26) in the FUPEP and the FOLFIRI arms, respectively. Most common grade 3-4 adverse events reported in the respective FUPEP and the FOLFIRI arms were diarrhea (21% vs 33%), neutropenia (11% vs 30%), mucositis (11% vs 11%), and alopecia (G2: 25% vs 26%). Conclusions: FUPEP regimen exhibits promising tumor response and safety profile, and can be combined with bevacizumab, for oxaliplatin-pretreated patients. Hence PEP02 (MM-398) may provide a new second-line treatment option for mCRC. Based on the safety profile of the FUPEP regimen in this PEPCOL study, it was added as the third arm to the positive phase III metastatic pancreatic cancer (NAPOLI-1) study. Clinical trial information: NCT01375816