Tolerance of full-dose sorafenib (S) combined with irinotecan (I; weekly, two on, one off) and cetuximab (C) in previously treated patients with advanced colorectal cancer (CRC)

522 Background: The epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) pathways are qualified targets in CRC, and are both inhibited by S. Preclinical evidence suggests S may also overcome cetuximab resistance. We previously reported (2008 GI Symposium, abstr#435) excessive toxicity of this combination with I 120 mg/m2 days (d) 1,8,15,22 every 42 d; the study was amended with an alternative I dose/schedule and the phase I results are presented. Methods: Patients (pts) with advanced, pretreated CRC irrespective of KRAS mutation status with ECOG PS 0-2 and good organ function were eligible. The original dose/schedule of I was combined with C 400 mg/m2 IV d1 and 250 mg/m2 weekly; and S PO daily with dose level (DL) 1 = 200mg QD, DL2=200 mg BID and DL 3=400 mg BID. 2/4 pts had DLTs: grade (g) 3 fatigue and febrile neutropenia. The dose/schedule were amended to I 100 mg/m2 d1, 8 of 21d cycles (c) without changing S or C. As with the original design, there was a C/S lead-in for 2 weeks in c1, thus c1 (DLT window) was 5 weeks (w). Results: In the original design, 5 subjects were recruited; after the study amendment, 13 additional pts were recruited (3, 3 and 7 pts respectively at amended DL1, DL2 and DL3). Overall, median age was 56.5 yrs, M: F 12:6 and colon: rectal cancer 16:2. All patients are evaluable and 3 are still on treatment (10+ - 20+ w). At the amended I dose/schedule, there were no further DLTs. Any c g3 toxicities included constitutional (fatigue:2, dehydration:1), gastrointestinal (nausea:1, vomiting:2, diarrhea:1), metabolic (hypomagnesemia:2 including one with tetany; hypokalemia:3), elevated ALT:1 and neutropenia:1. G 4 toxicities included neutropenia:1, thrombocytopenia:1. Two pts (one KRAS MT) had partial response with one pt (KRAS WT) on treatment for >44 w. 10 pts had stable disease (5–20+ w). PK/PD analysis is ongoing. Conclusions: The recommended phase II dose is I 100 mg/m2d1,8; C 400 mg/m2 IV d1 and 250 mg/m2 weekly; and S 400 mg PO BID. The regimen is tolerable in advanced, pretreated CRC. Due to the limited responses and current phase III studies with S in CRC, there are no plans to open the phase II portion at this time. No significant financial relationships to disclose.