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Skip to 0 minutes and 14 seconds Most cancer drugs used date back to the 1970s and ’80s. These cytotoxic chemotherapy drugs work in various ways, but by and large, work by stopping cells from dividing, uncontrolled cell division being just one of the hallmarks of cancer. They do this in various ways, for example, by preventing DNA replication or preventing chromosomes from separating during mitosis. Such drugs are crude tools, often having minimal and unpredictable effects on the tumours– the benefits– but also on the normal tissues– the side effects. With the explosion in our understanding of the fundamental biology of cancer has come a similar explosion in the list of known molecular defects which can cause cancer.

Skip to 1 minute and 0 seconds Some of these molecular defects are known to be absolutely critical for individual cancers to continue to grow and survive. These critical defects can sometimes be switched off directly using drugs, which may thereby kill cancers or limit their growth and survival. Such drugs are sometimes known as molecularly targeted therapy or biological therapy. Furthermore, these defects may enable us to develop a test, or biomarker, which enables us to specifically select the right drug for the right patient. This approach is sometimes known as precision medicine or personalised medicine. However, this new way of treating cancer requires new approaches to the way in which we conduct research in patients.

Skip to 1 minute and 44 seconds In particular, it demands a much closer working relationship between the clinical researchers and the laboratory researchers who are engaged in what is often referred to as translational research.

Skip to 1 minute and 58 seconds So what do we have to do before we can start using a new cancer drug in routine clinical practise? All drugs are to a degree poisons, so it’s vitally important that they are used in as safe a manner as possible. But it’s equally important that we don’t start routinely using drugs, which in reality offer little or no benefit. Therefore, it’s vital that clinical researchers demonstrate that a drug is both safe and effective. In particular, it’s important that the new drug is more effective, and or, safer than the existing treatment for that group of patients. It doesn’t matter how clever the science is. If it’s not improving care for patients, then it shouldn’t be used.

Skip to 2 minutes and 38 seconds Each country has a complex set of rules and regulations, which must be satisfied before it is legal to market a new drug. And without such marketing approval, it’s not legal to prescribe new drugs, except in very specific circumstances. These regulations are overseen by the regulatory authorities, and probably the best example is the Food and Drugs Administration in the United States of America. When we first start using a new drug in man, we have only limited information from the laboratory. In particular, we do not know how much needs to be given to be effective, and equally important, how much is sufficient to cause unacceptable side effects.

Skip to 3 minutes and 17 seconds So initial trials are generally conducted under very closely monitored conditions, using very cautious initial doses of a drug. If the initial dose is found to be safe i.e. there are few significant side effects, then the next group of patients will be given a higher dose and so on and so forth until we begin to see significant side effects. With molecularly targeted therapies, of course, it’s often possible to take samples from the patient, for example, samples of blood, saliva, skin, or hair follicles, or even samples from the tumour itself whilst they’re taking the drug. We can then take these samples back to the laboratory and measure whether or not the drug is hitting its target.

Skip to 3 minutes and 56 seconds Though this isn’t quite the same thing as the drug working, this information can be really helpful in understanding whether a particular drug is worth taking forwards into further trials and at what dose. So, if we know what dose to use, a dose that is safe enough but ideally one which is known to be hitting the target in humans, then we can start doing trials to see whether or not it’s actually tackling the cancer. The next trial would generally be limited to patients with the disease of interest. In a precision medicine trial, we’ll probably want to include only patients where we can show that the molecular defect that we are targeting is present.

Skip to 4 minutes and 37 seconds Once we have identified the patient group of interest, we then need to measure the effects of the new drug on the disease. We may do this by taking accurate measurements of the tumour, for example, using CT scans before and after treatment and seeing whether or not the tumour has shrunk or stopped growing. Sometimes we need to include a control group, ie a group of similar patients who are not receiving the new drug but maybe a matching dummy drug, known as a placebo. Of course, simply knowing that a drug slows or reverses tumour growth doesn’t necessarily mean that it’s helpful. We must now show two things.

Skip to 5 minutes and 13 seconds First, that the drug actually improves things that patients care about, for example, by extending survival or improving symptom control. And second, that it is doing this better than the normal treatment for these patients. Phase three trials take a large group of patients, usually 100s, but sometimes 1000s, and randomly allocate them to receive either the new treatment or the old treatment. Great care is taken to avoid bias in the results. For example, wherever possible, the study is double blinded. This means that neither the patient nor the doctor knows whether the patient is receiving the new treatment or the old treatment.

Skip to 5 minutes and 51 seconds This is usually done by using placebos and avoids people assuming that the patients are getting better because they’re on the new treatment. They are also designed to minimise the risk of drawing the wrong conclusion due to chance. This is why they have to include so many patients.

Skip to 6 minutes and 9 seconds With precision medicine, it’s also really important that the tests used to identify patients is practical, accurate, and reliable. The test may be very easy to carry out in cancer cells in a laboratory flask or in laboratory mice, but it may be much more difficult to extend this testing to samples taken from patients who may live many miles from the laboratory. Often, tumours are very difficult and uncomfortable to access, and samples are easily contaminated, or may contain a mixture of cancer cells and normal cells. If the test goes wrong, you may not be able to get a second test sample.

Skip to 6 minutes and 42 seconds And very often, a patient needs to start treatment within days of diagnosis, so it’s important that the test can be conducted quickly and accurately whenever and wherever it is needed. Many research organisations, such as universities, hospitals, and drug companies will build specialised laboratories designed to carry out these molecular pathology tests to standards which are agreed and consistent across the world. In fact, getting the test right is often more challenging than getting the drug right. Very often when we start doing phase three trials with new drugs, we don’t actually know how to select the right patients for the drugs.

Skip to 7 minutes and 18 seconds So increasingly, even in trials which are not designed as precision medicine trials, we will try and collect tumour samples from all the patients entering the trial. We can then do molecular tests, for example, looking for common gene mutations associated with the drug to see if we can define a subgroup of patients who do or, equally importantly, who do not benefit from the new treatment. These types of experiments can often be instrumental in developing the next treatment and trials.

Cancer clinical trials: the post genomic era

Dr Rob Jones discusses targeted therapies and companion diagnostics. Learn how a drug makes it from the laboratory into clinical practice.

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This video is from the free online course:

Cancer in the 21st Century: the Genomic Revolution

The University of Glasgow