Lecture 10 Designer drugs and clinical cancer trials

How are clinical trials performed?

A
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protocol is written
Includes reasons for conducting trial
How many people are needed
Who is eligible
What treatments will be used, what information will be collected

Statics very important must have statistical power (statistically

significant)
- Enough patients used to reject the null hypothesis which states that
the difference in benefits of the new therapy is no better than the
existing treatment adopted
- Not too many patients otherwise it will slow development or expose too
many patients to ineffective therapy
An ethic committee reviews it to ensure the safety and scientific validity of
the drug tested and the trial that is to be conducted. It is unethical to
approve rubbish science subjecting patients to poor science
Suitable patients are invited to participate
Patients are treated according to the a preset plan this is what the
protocol states, not what the doctor thinks is best or the accepted
treatment
When the required number of people have been treated for a specified
time, the results are collected and analysed
If a new treatment is seen to be better than the trial is stopped once the
null hypothesis is rejected, the trial should be stopped. It is unethical to
continue if one treatment is shown to be better
Maximum Tolerated Dose
Maximum tolerated dose (MTD) refers to the highest dose of a radiological or
pharmacological treatment that will produce the desired effect without
unacceptable toxicity [1]. The purpose of administering MTD is to determine
whether long-term exposure to a chemical might lead to unacceptable adverse
health effects in a population, when the level of exposure is not sufficient to
cause premature mortality due to short-term toxic effects. The maximum dose is
used, rather than a lower dose, to reduce the number of test subjects (and,
among other things, the cost of testing), in order to detect an effect that might
occur only rarely.

Clinical trial 3 phases

PHASE I

Safety
Determine a phase II dose &
schedule
Determine the maximum tolerated
dose (MTD)
Determine the optimal biological
dose (OBD)
Target modulation
Pharmacokinetics (what the body
does to the drug, how it is
distributed)

Initially we start by giving patients low

dose and then gradually escalate the
dose. As we increase the dose, we record
the severity of drug side effects (1-5 scale
where 3 is severe).
Through this, we determine the dose
limiting toxicity (grade 3, severe side
effects) and in turn the maximum
tolerated dose which is one dose level
below the dose DLT.
We also aim to determine the optimal
biologic dose which is: the quantity of a
radiological or pharmacological treatment
that will produce the desired effect with
acceptable toxicity.
Often, we now tend to define the MTD,
see whether it is effective without severe
side effects, if so, we continue the trial as
this dosage for reasons outlined in
paragraph above.

PHASE II

Efficacy
Response rate (>30% reduction in
sum of tumour diameters) as well
as time to progression, some
cancer therapies ac to arrest
tumour growth rather than kill cells.
Predictive markers
safety

From phase I to phase II, we expand

patient numbers to achieve more robust
idea about efficacy of the drug.

PHASE III

efficacy compared to standard of

care
Overall survival, not only tumour
shrinkage, were now considering
long term outcomes of the drug
treatment. Time to progression as
well as quality of life in patients on
the drug
predictive markers
safety

Phase III trials may be carried out by

pharmaceutical companies who are
developing drugs.
This phase involves randomly assigning
patients into each group, one on the new
drug (vemurafenib) and the second group
on the existing approved treatment:
(dacarbazine)