PTK 787/ZK 222584: Clinical results with a novel angiogenesis inhibitor in colorectal cancer

Ryan Smith, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: November 12, 2003

Faculty Disclosure: Peter J. O'Dwyer, M.D.
This presentation by Dr. O'Dwyer contains a discussion on the use of PTK 787/ZK 222584 for the treatment of colorectal cancer which has not been approved by the FDA.

Presenter: Peter J. O'Dwyer, M.D.
Affiliation: University of Pennsylvania

Angiogenesis has been shown to be a critical determinant of tumor growth, as tumors are dependent on their vascular supply for nutrition, oxygen, etc. Vascular endothelial growth factor (VEGF) appears to be the critical component in angiogenesis. Tumor cells produce VEGF when induced by hypoxia, COX-2, NO, EGF, TGF-B, etc. VEGF binds to endothelial cells via one of the three types of VEGF receptors. The tyrosine kinase portion of the VEGF receptors start a signal transduction pathway which results in endothelial cell proliferation. Hence, targets of angiogenesis inhibition are VEGF itself, the VEGF recptor(s), or the signal transduction pathways induced by the binding event.

PTK 787 is a selective inhibitor of all three types of the VEGF receptors. It has been shown to reduce the number of tumor microvessels with resultant dilation of the remaining vessels. It has also been shown to inhibit VEGF receptors and has been effective in animal tumor models. In addition, dynamic contrast-enhanced MRI (DCE-MRI) and PET imaging have shown a reduction in blood flow to tumors after the administration of PTK 787.

PTK 787 has been tested in a phase I study in 35 patients with previously untreated metastatic colorectal (CR) cancer. Escalating doses of PTK 787 were combined with FOLFOX4 chemotherapy. In the 28 patients available for response, there was a response rate of 54% and an additional 29% with stable disease. Median time to progression was an impressive 11 months with a median overall survival of 16 months. More importantly in the phase I setting, toxicity profiles were very similar to treatment with FOLFOX4 alone.

This has led to the planning of two phase III studies using PTK 787 at a dose of 1250 mg per day. One is for patients with previously untreated metastatic CR cancer, randomizing between FOLFOX4 + PTK 787 vs. FOLFOX4 alone. The other study has the same design, for patients who have failed 5FU based chemotherapy.

In summary, PTK 787/ZK 222584 is a novel angiogenesis inhibitor, blocking all three VEGF receptors. Its once per day oral dosing is convenient with demonstrated inhibition of angiogenesis as measured by many means, including DCE-MRI and PET imaging. It is well-tolerated with phase I data showing response rates and low toxicity. As the side effects were similar to FOLFOX4 alone with a long time to progression, the phase III study should be supported in hopes of increasing the efficacy of the treatment of metastatic CR cancer.