How to design a phase I trial of an anticancer botanical

Abstract

Phase I trials are an important part of traditional drug development in oncology. Such trials address two key issues: safety and dose. Currently, there is a dearth of phase I trials of anticancer botanicals. This may result from the apparently widespread view that a history of human use precludes the need for early-phase study. However, the safe use of a botanical by the population at large does not guarantee safety when the botanical is used in combination with other agents in the complex medical setting of oncology. Several cases of unpredictable adverse events have been recorded following the use of botanicals by cancer patients. We propose a simple, robust design for phase I trials of anticancer botanicals. This design incorporates important characteristics of botanical medicines including low toxicity, prior data on a likely safe dose, a limit on the highest dose it is feasible to administer, and the unknown relationship between dose-toxicity and dose-response curves. Two principal design features are the use of predetermined dose levels and the direct measurement of a response endpoint such as survival or immunity. This response end point can be used to determine the optimal dose if toxicity is acceptable at all dose levels. Increasing the use of phase I methodology would ensure a more systematic development of botanicals as anticancer agents. This would likely increase the chance that at least one such agent would be proven to extend lives.

Figure 1

Dose-response (solid line) and dose-toxicity (dotted line) curves for a typical cytotoxic drug. The arrows show the maximum tolerated dose (MTD); small reductions in the dose below the MTD lead to large decreases in effectiveness (response).

Figure 2

Results of a typical phase I dose-escalation trial for a chemotherapy agent.

Figure 3

Theoretic dose-response (solid line) and dose-toxicity (dotted line) curves for a low-toxicity agent. The arrows show the maximum tolerated dose (MTD): reductions in the dose below the MTD lead do not have a marked impact on therapeutic effectiveness (response).

Figure 4

Theoretic dose-response (solid line) and dose-toxicity (dotted line) curves for an agent with a “non-monotone” dose response. The arrows show maximum tolerated dose (MTD): the agent is less effective at the MTD than at a lower dose.

Figure 5

Study design for determining whether a botanical affects pharmacokinetics (PK) of a chemotherapy agent.