Background: Simtuzumab (SIM) is a humanized antibody that inhibits lysyl oxidase-like molecule 2 (LOXL2), a matrix enzyme that catalyzes the cross-linking of collagen and is widely expressed across desmoplastic tumors. Inhibiting LOXL2 is expected to block formation of desmoplasia, which is thought to play an important role in tumor progression and metastasis. In Phase I, SIM was safe in patients (pts) with advanced solid tumors and showed early evidence of efficacy. Based on these results, a randomized, double-blind, placebo-controlled phase II study of SIM+5-fluorouracil, leucovorin and irinotecan (FOLFIRI) vs. placebo (pbo)+FOLFIRI as second line therapy in pts with metastatic KRAS mutant colorectal adenocarcinoma (CRC) was conducted. Methods: Enrolled pts had advanced KRAS mutated CRC that had progressed on first-line oxaliplatin-based chemotherapy. Pts were ECOG performance status (PS) ≤ 2. Subjects were randomized in a 1:1:1 ratio to receive SIM 200 mg, SIM 700 mg, or pbo in combination with FOLFIRI every 2 weeks, and the randomization was stratified according to ECOG PS (0 or > 0). The primary endpoint was progression free survival (PFS) and the secondary endpoints were overall survival (OS) and objective response rate (ORR). Results: Between April, 2012 and December, 2014, 249 pts were randomized and treated; 85 pts (200 mg SIM/FOLFIRI), 84 pts (700 mg SIM/FOLFIRI), and 80 pts (pbo/FOLFIRI). Median PFS was 5.4 months (HR 1.45; 95% CI 1.01 to 2.06; p = 0.04 vs pbo), 5.5 months (HR 1.32; 95% CI 0.92 to 1.89; p = 0.10 vs pbo), and 5.8 months for the 200 mg SIM/FOLFIRI, 700 mg SIM/FOLFIRI, and pbo/FOLFIRI arms, respectively. Median OS was 10.5 (HR 1.50; 95% CI 0.98 to 2.30; p = 0.06 vs pbo), 11.4 (HR 1.23; 95% CI 0.80 to 1.91; p = 0.25 vs pbo), and 16.3 months, respectively. ORR was 5.9%, 11.9%, and 10%, respectively. There were no differences in the safety profile of the SIM/FOLFIRI groups versus pbo/FOLFIRI group. Conclusions: The addition of SIM to FOLFIRI does not improve PFS or OS in advanced KRAS mutant CRC pts. Exploratory analyses to investigate the potential prognostic factors influencing PFS or OS are being conducted. Clinical trial information: NCT01479465