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New drugs need new trials

by Kat Arney | Analysis

29 June 2009

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New cancer drugs may mean new ways of doing clinical trials

New cancer drugs may mean new ways of doing clinical trials

Clinical trials are an essential part of cancer research. Only by testing new treatments in patients can we truly know if they are effective, find out what dose to use, and check for side effects.

In a recent study published in the British Journal of Cancer, Cancer Research UK-funded scientists have found that traditionally designed clinical trials may not be suitable for testing the next generation of cancer drugs – a discovery that has big implications for trials, and for the patients involved.

To understand why, we first need to look in a bit more detail at the scientific rationale behind early-stage trials.

About clinical trials – “More is better”?
Mention the words ‘clinical trials’, and people probably think of large studies involving hundreds or thousands of patients, testing new treatments against the current ‘gold standard’ (or a placebo,  if no standard treatment exists).  Such trials are known as ‘phase 3 trials’, and they provide important information about the effectiveness of cancer treatments.

But there are other, equally important, types of trial. Known as phase 1 and phase 2 trials, these are much smaller – often involving fewer than twenty people. These trials aim to find out what dose of a new drug to use, study how it is broken down by the body, and check for any unacceptable side effects.  Cancer Research UK is one of the world’s leading funders of such early-stage trials of new cancer treatments.

One of the key aims of a phase 1 trial is to discover the ‘maximum tolerated dose’ or MTD, of a new drug. This is the largest dose that can be given before the patient experiences unacceptable side effects. It’s usually found by giving a small dose to a few patients – and monitoring them carefully –  then gradually increasing the dose for the next handful of patients, and so on. The MTD is then used to work out the best dose of the drug that should be used in further trials.

It’s important to point out that phase 1 trials don’t usually aim to successfully treat a person’s cancer.  The volunteers on the trials are usually patients who have reached the end of all the available treatment options, and are unlikely to survive for more than a few months.

However, because of improvements in drug development – as can be heard in this interview from the 2007 NCRI conference –  we are starting to see patients surviving much longer on early-stage trials. As a result, the ethics of finding the MTD in this way has been hotly debated.  Are patients who come onto a trial in the first, low-dose stages of a phase 1 trial at a disadvantage, compared with people who get higher doses later on?

Conventional wisdom suggests that “more is better”, and that we should be aiming to give the highest possible tolerated doses in order to treat cancer effectively. But in a recent paper, Cancer Research UK-funded scientists at The Institute of Cancer Research and the Royal Marsden Hospital have discovered that this maxim may not hold true for the new generation of cancer drugs.

The next generation of cancer drugs
Conventional chemotherapy drugs, like cisplatin or Taxol, are known as cytotoxic (cell-killing) agents. They are relatively crude drugs that block the division of rapidly-growing cells. Unfortunately for patients, these drugs can’t tell the difference between fast-growing cancer cells and rapidly multiplying cells in the hair follicles, gut or bone marrow, so they cause side effects such as hair loss, fatigue and sickness.

But in recent years, we’ve seen the development of a new generation of cancer drugs, as a result of research into fundamental cancer biology.  These are so-called ‘smart drugs’ – specifically designed to target faulty molecules in cancer cells. Examples include the breast cancer drug Herceptin and the experimental lung cancer treatment Tarceva.

So far, these smart drugs have been tested in clinical trials in the same way as traditional cytotoxic drugs – increasing the dose in phase 1 trials to reach the MTD, then using this to calculate the dose for further trials.  But is this the best way to test them?

Trials on trial
To find out, Professor Stan Kaye and his colleagues studied the combined results of phase 1 clinical trials of a range of targeted drugs that had been carried out at the Marsden in 2005 and 2006.

The researchers grouped 135 patients into three sets, depending on the dose of drug they had received, relative to the final MTD that was calculated at the end of the trial – 0-33 per cent of the MTD, 34-65 per cent and 66-100 per cent.  Then they looked at how well the patients had responded to treatment, and how long they had survived.

If survival was dependent on the dose of drug that a patient received (as seen for conventional cancer drugs), we would expect the patients in the 66-100 per cent MTD group to do best, and those in the 0-33 per cent group to do worst. But that wasn’t what the scientists found.

Instead, they discovered that average survival, and other measures of progress, were not strongly related to the amount of drug someone received. In fact, there was no statistical difference in survival between the three groups.  An intriguing – and important – result.

What does it mean for future trials?

The results mean that patients on relatively low doses of targeted drugs are still getting a significant benefit – and probably as much as people on higher doses. Although this is a small study, and needs repeating in larger groups of patients, the researchers think their findings could influence future trials in a number of ways.

For a start, it can be difficult to recruit patients on to trials, particularly if the trial is in its early stages and doses are low.   But knowing that being one of the first people on a trial isn’t necessarily a disadvantage might help to boost recruitment.

The results also have an important clinical impact, as they show that the most effective dose of a targeted drug isn’t necessarily the biggest possible dose. This is to be expected, as targeted agents are designed to work in a different way to standard cytotoxic drugs. So researchers might need to come up with alternative ways to measure the effectiveness of these new treatments in trials.

Finally, there is an alternative, less rosy, conclusion that could be drawn from data – the drugs make no impact on a patient’s cancer, and for that reason, don’t affect survival.  But by looking at scans, the scientists found that patients’ tumours were shrinking, even at doses below the MTD.

This suggests that even at low doses, the drugs were having a measurable biological effect on the cancer.  So researchers also need to find better ways to measure patient progress, such as routinely using imaging techniques to find out if tumours are shrinking.

So in the future, as well as seeing a new generation of cancer drugs, we could be seeing a new generation of trials for testing them.



Postel-Vinay, S. et al (2009). Clinical benefit in Phase-I trials of novel molecularly targeted agents: does dose matter? British Journal of Cancer, 100 (9), 1373-1378 DOI: 10.1038/sj.bjc.6605030