Background: The insulin growth factor (IGF) pathway is activated in hepatocarcinogenesis. C is a monoclonal antibody against insulin-like growth factor-1 receptor (IGF-1R). In vivo HCC models showed activated IGF signaling and antitumor effects due to C. Given the cross-talk between the IGF and VEGF pathways, the combination of C and S was chosen. Methods: This study evaluated the safety of C (2, 4 or 6 mg/kg) IV weekly with standard doses of S (400 mg po bid) in patients (pts) with HCC. Eligibility criteria included: no prior systemic therapy for HCC, Child-Pugh score of A or B7, ECOG 0 or 1, platelets > 75,000/mm3, and albumin > 2.8 g/dl. The study used a standard 3+3 design. One cycle was 28 days. Results: A total of 21 pts (17 males and 4 females) were enrolled; mean age was 63 years (43-85); 10 Asian, 4 Hispanic, 5 White, 1 Black, and 1 Native American. There were 3 dose limiting toxicities (DLTs); grade 3 hyperglycemia, grade 3 hypophosphatemia, and grade 5 peritonitis (see table). The maximum tolerated dose (MTD) was C 4 mg/Kg and S 400 mg BID. 18 of 21 (86%) pts had ≥grade 3 toxicities attributable to treatment. Grade 3 adverse events that occurred in ≥ 2 pts were: diarrhea (4; 19%), hypertension (4; 19%), thrombocytopenia (3; 14%), palmar-plantar erythrodysesthesia (2; 10%), hyperglycemia (2; 10%), and fatigue (2; 10%). There was 1 grade 4 colonic perforation and 1 grade 5 peritoneal infection in the same pt. The median number of cycles was 4 (0-19 cycles). Sixteen of the 21 pts completed 2 cycles and were evaluated for response. 13 of the 16 (81%) (95% CI: 54%-96%) achieved stable disease. The median event free survival was 3.8 months (95%CI: 1.9, 11.3). The median OS was 13.1 months (95% CI: 7.6, undefined). An increase of 0.5 in baseline natural log of hepatocyte growth factor and insulin growth factor binding protein 3 were associated with risk of death (log rank p value 0.01 and 0.03). Conclusions: The majority of adverse events in pts treated with the combination of C and S were typical of sorafenib toxicity. There was preliminary evidence of efficacy as seen in the median OS. Clinical trial information: NCT01008566.