Abstract

The development of cytotoxic agents is based on the paradigm of a single direct dose–response relationship, i.e. the greater the dose, the greater the effect. The effect of decreasing tumour burden is, however, accompanied by a greater degree of toxicity. Targeted agents, in contrast, are framed differently. The specificity of a given effect may, in fact, be lost at high doses while not achieving greater benefit after a given biologically effective dose. Although contemporary early drug development has shifted away from cytotoxics and it is primarily focused upon molecularly targeted agents, the paradigm of drug development has only been partially modified.

In this talk we will first address how targeted therapies have transformed phase I trials in an arena for hypothesis testing (proof of concept), and how this has changed not only the objectives and methods of these trials, but also the patient population and expectations of efficacy. This raises some practical, logistical and ethical concerns. We will, then, use three scenarios (molecularly selected patient populations, the development of a TGFbeta inhibitor and of a Sonic Hedgehog inhibitor) to depict how modern phase I trials, molecular biology and translational medicine are connected.