Phase I/II study of PTK787/ZK 222584 (PTK/ZK), a novel, oral angiogenesis inhibitor in combination with FOLFIRI as first-line treatment for patients with metastatic colorectal cancer

3558 Background: Increased angiogenesis is correlated with poor prognosis in patients with advanced metastatic colorectal cancer (CRC). PTK/ZK is a novel, oral angiogenesis inhibitor that potently inhibits all known VEGF receptor tyrosine kinases, important mediators in the formation of new blood vessels that contribute to tumor growth and metastasis. Methods: This trial determined the MTD and 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 with metastatic CRC. PTK/ZK was administered orally once daily in escalating doses of 500, 1,000, and 1,250 mg/day to cohorts of 3–7 patients. FOLFIRI was administered q 2 weeks 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, 16 patients have been enrolled at 500 (n = 6), 1,000 (n = 7), and 1,250 (n = 3) mg/day. PTK/ZK was well tolerated; commonly reported grade 1/2 adverse events were nausea, fatigue, vomiting, epistaxis, diarrhea, and dizziness. There was 1 DLT at 500 mg/day (grade 3 fatigue) and 1 at 1,000 mg/day of PTK/ZK (grade 3 hypertension); both resolved uneventfully within 2 weeks of PTK/ZK discontinuation, and no other PTK/ZK-related severe toxicities have been observed. The pharmacokinetics of PTK/ZK was unaffected by FOLFIRI. Coadministration of 1,250 mg/day PTK/ZK with FOLFIRI had minimal effect on irinotecan exposure but lowered the AUC of SN38 in serum by ∼40%; the clinical relevance is under investigation. Preliminary efficacy results (by SWOG criteria) for 12 evaluable patients included 4 partial responses (33%) and 5 (42%) patients had stable disease. Median time to progression for 11 evaluable patients was 6.7 months (95% CI = 6.1, 7.1 months). At a median follow-up of 9.0 months, all 16 patients are alive. Conclusions: These preliminary results suggest that the combination of PTK/ZK with FOLFIRI is safe, well tolerated, and has activity in patients with metastatic CRC. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Pharmaceuticals Corp.; Schering AG Novartis Pharmaceuticals Corp.