3605 Background: Vascular endothelial growth factors (VEGF-A, -B, -C, D and -E) are potent angiogenesis factors secreted by many solid tumors. PTK/ZK is a novel, oral, small molecule angiogenesis inhibitor that blocks all known VEGF receptor tyrosine kinases, important mediators in the formation of new blood and lymph vessels that contribute to tumor growth and metastasis. Method: The goal of this trial is to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of once-daily oral PTK/ZK in combination with infusional 5-fluorouracil (5-FU)/leucovorin (LV) plus irinotecan (FOLFIRI) as first-line treatment in patients (Pts) with metastatic CRC. PTK/ZK was administered in doses of 500, 1,000, 1,250, and 1,500 mg/day (d) to cohorts of 3 to 7 Pts. FOLFIRI was administered every 2 weeks (wks) as irinotecan (180 mg/m2, day 1) plus LV (200 mg/m2, 2-hour infusion) and 5-FU (400 mg/m2 bolus followed by 600 mg/m2 as a 22-hour infusion) on days 1 and 2. Results: To date, 21 Pts are enrolled; 6 at the 500 mg/d dose, 7 at 1,000 mg/d, 5 at 1,250 mg/d, and 3 at 1,500 mg/d. PTK/ZK was well tolerated. There was 1 DLT at 500 mg/d (grade [Gr] 3 fatigue) and 1 at 1,000 mg/d (Gr 3 hypertension); both resolved within 2 wks of PTK/ZK discontinuation. The pharmacokinetics of PTK/ZK was unaffected by FOLFIRI. Coadministration of 1,250 mg/d PTK/ZK with FOLFIRI had minor effects on irinotecan exposure but lowered the AUC of SN38 in serum by ∼40%; clinical relevance is under investigation. Best response by SWOG criteria for 17 evaluable Pts include 7 (41%) partial responses, 8 (47%) with stable disease, and 2 (12%) with progressive disease. Median PFS for 17 Pts was 7.1 months (95% CI = 6.2, 11.7 months). Median OS for 19 intent-to-treat Pts was 24.3 months (95% CI = 18.0, unknown months). Conclusion: The results suggest that the combination of PTK/ZK with FOLFIRI is safe, well tolerated, and has activity in Pts with metastatic CRC. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis, Schering AG