Surrogate End Points

The corneal assay is a powerful tool that provides a means to assess the in vivo biologic activity of a systemically administered AI (22). Obviously, such an approach is not

Fig. 1. Hypothetical difference between ideal dose of a cytotoxic drug and the OBD of an angio-genesis inhibitor, in relation to MTD.

appropriate in human subjects (23). Surrogate end points need to be incorporated into clinical trial design of AIs, but surrogate end points that truly correlate with the biologic activity of the AI, and would be feasible to assess in patients, have proven difficult to identify.

If the presumed mechanism of action of a particular AI is the inhibition of an enzyme (i.e., matrix metalloproteinases [MMP]) that controls a step in the angiogenesis cascade, then a more relevant end point in a phase I trial may be to determine the dose of AI that will inhibit the activity of that enzyme to a certain degree. A corollary of that example is the presumption that preclinical data will help predetermine what degree of enzyme inhibition (i.e., 25 vs 50 vs 90% inhibition) is biologically relevant to achieve the desired effect. A more significant challenge will involve the identification of surrogate end points that correlate with the desired biologic effect at the target-tissue level.

Considering the example of matrix metalloproteinase inhibitors (MMPI), several issues need to be considered. MMPs are a family of structurally related zinc-containing enzymes involved in the degradation of extracellular matrix proteins during tumor growth and progression, as well as normal tissue remodeling, such as wound healing and bone fracture repair (24). The MMP family includes collagenases, stromelysins, matrilysin, gelatinases, and metalloelastase (24). The MMPI agents in development include those with broad inhibitory activity against several enzymes, as well as agents with more selective inhibitory activity. In addition, certain tumor types preferentially overexpress one or more MMPs (25,26). This knowledge may influence trial design. One could determine if patients with tumors that strongly overexpress a certain MMP are more likely to benefit from treatment with a particular MMPI, compared to patients who weakly express that MMP. If sensitive assays are available, changes in the circulating serum concentration of the MMP target could be determined before therapy, and over the course of treatment. S imilarly, zymographic determination of intratumor ratios of the activated proenzymatic forms of MMPs, or urinary products of bone turnover, could be determined (27). A recent report also suggests that circulating MMP-2:TIMP-2 ratios provide useful information regarding prognosis in patients with urothelial tumors after complete resection (28). One could speculate that this analysis could be applied to patients while they undergo active therapy with an MMPI targeting MMP-2. This information may provide an insight into which patients are most likely to benefit from this form of therapy.

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