Phase I trials

Question 1

What is an issue with the short duration of phase I trials? (For secondary outcomes like efficacy)

Answer 1

Long term endpoints can’t be documented so surrogate markers of efficacy have to be used instead.

Question 2

How many participants are there usually in a phase I trial? Why?

Answer 2

Few participants (Around 30) - first in man trial so it would be unethical to give lots of participants the drug without knowing the toxicity they will experience. Also it saves on costs.

Question 3

What is the primary outcome of a phase I trial?

Answer 3

Dose limiting toxicity (DLT)

Question 4

Why might an adverse event not be classified as a DLT?

Answer 4

If the subjects are already ill, some adverse events would be expected to occur naturally, so would not be counted as a DLT

Question 5

What is the maximal tolerated dose?

Answer 5

A primary outcome measure for a phase I trial. It is the dose that has an acceptable number of side-effects and therefore can be used in further studies.
OR a dose at which a pre-specified number of individuals suffer a severe adverse event indicating that this dose may be too unsafe so the next lowest dose would be investigated further.

Question 6

What are 4 secondary outcomes of phase I trials?

Answer 6

Drug uptake
Metabolism
Excretion
Surrogate markers

Question 7

What are 5 examples of the series in which phase I trials are conducted

Answer 7

1. Dose escalation
2. Expansion cohort studies
3. Interaction studies with food/ other drugs
4. Multiple dose studies
5. Pharmacokinetics/ Pharmacodynamics

Question 8

What is pharmacodynamics referring to?

Answer 8

The physical or biological measures that show the effect of the new drug on the body (could include efficacy).

Question 9

What is an example of pharmacodynamic effects to be looked at during a phase I study?

Answer 9

Does it make you drowsy - so you can’t take the drug when driving

Question 10

What is pharmacokinetics referring to?

Answer 10

Physical or biological measures that show how the body deals with the new drug. Eg absorption, metabolism or elimination

Question 11

What is Cmax?

Answer 11

The max concentration that a drug is found at in the plasma following administration.

Question 12

What is AUC?

Answer 12

Area under the curve - the measure of the total plasma exposure to the drug over a given time period and is determined by the dose and clearance of the drug.

Question 13

What are examples of preclinical information that could help determine the starting dose for first in human studies?

Answer 13

Toxicology data
Novelty of the agent
Biological potency
Mechanism of action
Degree of species-specificity of the agent
Dose response curves of biological effects in human and animal cells
Pharmacokinetic and pharmacodynamic modelling

Question 14

What are the common starting doses compared to preclinical ones?

Answer 14

1/10th of the lethal dose in 10% of rodents

1/3 or 1/6th of lowest dose that results in any adverse event in other animals

Question 15

What methods are used to decide what the subsequent dosage should be following the initial dose?

Answer 15

Fibonacci sequence

Evidence from other studies or previous experience

Question 16

What is the 3+3 phase I trial design?

Answer 16

Give a dose to 3 patients. If 0 have a DLT go to the next, higher dose and give it to three new patients. If 1 patient in the original group had a DLT, treat a new set of 3 patients with the same dose. If any of them experience a DLT then the previous dose is the MTD. If in the original group 2 or 3 of the patients experienced a LTD then the previous dose is the MTD.

Question 17

What are some advantages to the 3+3 trial design

Answer 17

Simple, easy to implement, it’s conservative in escalation so is safe, clear decision making for stopping or escalating.

Question 18

What are some disadvantages of the 3+3 design?

Answer 18

Trial can take longer due to slow dose escalation, may require a large number of patients, several subjects may be treated without providing much information about the MTD (patients treated at subtherapeutic doses as a result), design has a high probability of recommending a dose below the MTD for phase II trials.

Question 19

How does the 3+3 design variation differ to the original?

Answer 19

Dose escalation is only stopped if all three of the patients experience a LTD

Question 20

What are more efficient methods of dose escalation?

Answer 20

Continuous reassessment method and Bayesian methods (both are based on statistical modelling - often a sigmoid curve)

Question 21

What are key pharmacokinetic parameters of interest

Answer 21

AUC - area under the curve
Cmax - maximum plasma concentration
Tmax - Time to reach Cmax
T1/2 - Terminal half life
Clearance - removal of the drug from the body mediated by metabolism and excretion

Question 22

How is the Fibonacci sequence used for dose escalation?

Answer 22

While the numbers appear to increase quickly, the relative increase is roughly constant. In practice, the doses are rounded down or up - this is modified Fibonacci