Expanded phase I/II study of PTK787/ZK 222584 (PTK/ZK), a novel, oral angiogenesis inhibitor, in combination with FOLFOX-4 as first-line treatment for patients with metastatic colorectal cancer

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Abstract
3556 Background: Increased angiogenesis correlates with poor prognosis in patients with metastatic colorectal cancer (CRC). PTK/ZK is a novel, oral angiogenesis inhibitor that potently inhibits all known VEGF receptor tyrosine kinases, which are important mediators of the formation of new blood vessels that contribute to tumor growth and metastasis. Methods: This phase I/II study assessed the safety and preliminary response profile of oral PTK/ZK in combination with chemotherapy. Previously untreated patients (N = 35) with advanced CRC were treated with escalating doses of PTK/ZK plus oxaliplatin/5-fluorouracil (5-FU)/leucovorin (FOLFOX4). PTK/ZK was administered once daily at doses of 500 mg (n = 4), 1,000 mg (n = 3), 1,250 mg (n = 23), 1,500 mg (n = 3), and 2,000 mg (n = 2). FOLFOX-4 was administered q 2 weeks, and consisted of oxaliplatin (85 mg/m2) infusion on day 1, leucovorin (200 mg/m2 via 2-hour infusion) on days 1 and 2, and 5-FU (400 mg/m2 bolus followed by 600 mg/m2 over 22 hours) on days 1 and 2. Results: The pharmacokinetics and toxicity profiles of both PTK/ZK and FOLFOX4 were unaffected by coadministration. PTK/ZK was well tolerated at doses ≤ 1,250 mg/day; no DLTs occurred at 1,250 mg/day in the first 6 patients evaluated for MTD. Adverse events at 1,250 mg/day included ataxia (grade [G] 3), neutropenia (G4), thrombocytopenia (G3), and 2 episodes of dizziness (G3). CNS adverse events (G3/4) were dose-limiting in 2 patients at 2,000 mg/day, and expressive dysphasia (G3) and intermittent dizziness (G3) were dose-limiting at 1,500 mg/day. Best response data by SWOG criteria for 28 evaluable patients to date showed 1 (4%) CR, 14 (50%) PR, and 9 (32%) patients had SD. For 34 evaluable patients, median PFS is 11 months (95% CI = 6.8, 12.0 months). Estimated median overall survival for 35 patients is 16.6 months (95% CI = 12.9, 21.0 months). Conclusions: The early efficacy and safety of PTK/ZK+FOLFOX4 for metastatic CRC has been encouraging, and phase III randomized controlled trials of PTK/ZK+FOLFOX4 in metastatic CRC (CONFIRM-1 & -2) are ongoing.

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