THE PRE-CLINICAL PHASE AND THE NEED FOR CANCER PATIENTS
The main problem with phase 1 trials relates to the needs of the patients. Mostly, these studies are happening in patients who have exhausted all standard therapy options and who are clearly desperate for further viable therapies. By its very nature, the phase 1 trial is mostly delivering drug below the likely therapeutic range with a consequent low chance of benefit. Furthermore, at least two of the last six patients entered in a study will receive too high a dose and will experience a high level of side effects. Finally, most drugs entering phase 1 will actually turn out to be of little therapeutic value due to either unforeseen problems preventing delivery of sufficient drug or simply a lack of efficacy against the target cancers. For most patients, therefore, entering a phase 1 trial needs to be seen largely as an act of altruism, and it is indeed true that many patients entering trials will say things like ‘well if it helps people after me, it will be worth it’. Nonetheless, ethics committees and doctors must be careful to protect vulnerable and desperate patients from harm in these trials.
If an agent performs well in phase 1 – in other words, side effects are manageable and acceptable, usually with some evidence of a positive effect on cancer, then a phase 2 trials will follow. The aim of phase 2 studies is to study the efficacy of the drug in more detail. The drug will be tested at the optimal dose defined in phase 1 in a group of patients assessed as likely to benefit from the drug. This is clearly different to phase 1 as the risk of under- or overdosing is much reduced, though it still remains, due to the limitations of the dose-finding mechanisms in phase 1 discussed above. Furthermore, as the patients are selected on the basis of likely benefit, the risk/benefit ratio for participants is much better. Typically, up to 40 or 50 patients will enter a phase 2 trials, and the endpoints will be efficacy, and of course safety, in the more defined, usually somewhat fitter, patient population.
Defining efficacy is a major problem. Generally, agents that produce tumour shrinkage are defined as active, and this has led to standardized ways of defining how much shrinkage constitutes a worthwhile response. The most widely used method is the RECIST (Response Evaluation Criteria in Solid Tumors) system, first published in 2000 and updated in January 2009. Disease responses are broadly classified as follows:
- Complete response: all assessable disease disappeared;
- Partial response: reduction in size by the pre-specified amount of all assessable disease;
- Stable disease: insufficient change to be put in another category;
- Progressive disease: worsening of disease by pre-specified amount or appearance of new cancer deposits.
The principle underlying this system of assessment is simple; the application in practice is complex. As with many things, the devil is in the detail – the following is a list of tricky issues (not comprehensive) to illustrate the difficulties:
- How much should a tumour grow before it counts as progression?
- How much should it shrink to count as a response to treatment?
- What if some lumps shrink but not others?
- When should you carry out the response measurements (too early and you may under-report; too late and patients may have started relapsing)?
- How do you assess tumour deposits in tissues such as bone or pleura (the lining around the lung) where there is no discrete lump that can be measured?
This last point is a particular problem with certain diseases such as prostate cancer that mainly affect bone. Therefore, while the response to treatment remains an important test of drug activity, the second set of measures based on how long a patient takes to start getting worse – termed the ‘time to progression’ – is increasingly used. This has proved particularly important with the new targeted molecular therapies for diseases like renal cancer. With this disease, large masses often shrink but by less than the standard RECIST criteria. On review of the scans in these patients, it became obvious that the tumours changed in appearance, with the centre appearing to be less ‘active’ than before – borne out when lumps were removed and found to have dead tissue in the middle. In parallel, tumour-related symptoms often improved. For these patients, therefore, prolonged ‘stable’ disease becomes a very worthwhile outcome. Improved time to progression is therefore frequently used as a means of assessing the activity of an agent. Finally, of course, agents can be assessed for their effect on overall survival times. This is not frequently used in phase 2 as the principal outcome for a variety of reasons, mainly time – the aim is to establish as quickly as possible which agents to take forward for phase 3 licensing trials.