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• Design
• Clinical trials: an overview
• Trial definitions
• Phase I trials
• Phase II trials
• Phase III trials
• Sample size
• Reference texts

Phase I Trials

Phase I trials are the first to take place and are primarily concerned with the saftey of the treatment. In drug development trials the main objective is to estimate the maximum tolerated dose (MTD) and investigate drug toxicity.

Phase I trials for cytostatic drugs

The aims of such trials are typically to:

• Estimate the maximum tolerated dose (MTD)
• Determine the extent, duration and reversibility of toxicity
• Observe any anti-tumour activity

The criteria for patient entry is often very broad.

Small groups of patients are treated with gradually escalating doeses. This continues until a number of patients experience a pre-determines degree of toxicity. The MTD is sometimes taken to be the dose given prior to the dose which caused toxic effects. Data collection is intensive per patient.

An appropriate does escalating regime and subsequent estimate for the MTD should be chosen carefully. It is both desirable and ethical to use a design and dose escalating regime which allows the MTD to be determined with the minimum number of patients in the shortest time possible.

The choice of MTD for a combination of drugs is a more complex issue than for a single drug. Tolerable-dose diagrams which display toxicities at various dose combinations have been shown to be a useful aid when planning a phase I trial involving combination treatments (see E.L.Korn).

One of the most widely accepted dose escalating regimes, which is a modified Fibonaachi series, can be seen in Table 1 (EORTC, Von Hoff).

A standard design is to give the starting dose (d) to a group of three patients (see Table 1). If toxic effects do not reach pre-determined levels then another series of three patients are given 2.od. This process is continued until toxic levels are observed in the patients. Possible values for d are 0.1*LD10 in mice. Designs for several phase I trials are investigated by Storer and Gordon & Wilson.