This transcript has been edited for clarity.
I'm David Kerr, professor of cancer medicine at the University of Oxford. I've just come back from lecturing in China with some fantastic collaborators of ours at Huaxi Hospital of Sichuan University. One of my lectures was on innovative trial design, thinking a little about how we bring medicines into the clinic from the laboratory bench to the patient's bedside.
I'd like to bring to your attention a fantastic review published in Annals of Oncology looking at some of the recommendations from a task force that was set up by the FDA, the Methodology for the Development of Innovative Cancer Therapies Taskforce.
I've been a cancer doctor for 40 years, though that may be hard to believe, looking at my relatively youthful potato head. In that time, I have seen some very interesting ideas as to how we take new agents forward into phase 1 trials.
In terms of targeted therapies, they're not quite fit for purpose. The classical aim is to define the maximum tolerated dose, giving us a feel for what the pattern of side effects and toxicity of the drug and perhaps link that to pharmacokinetic endpoints or, increasingly, pharmacodynamic endpoints in which we're using biopsies or taking normal tissue surrogates to see whether we can demonstrate that the drug hits its target.
With targeted therapies, we quite often get toxicities wrong in terms of defining a biologically optimal dose: the dose of drug that inhibits a target in the tissue — in our case, the tumor — as effectively as is necessary to change the phenotype of the cancer cell and usually induce cancer cell death.
We've seen innovations in which we've looked at pharmacokinetic dose escalations. These have failed, generally speaking, because when we look at the pharmacokinetics of a drug in cancer patients, certainly the interindividual variation, the difference in dosing between you and I is very large. It makes it really hard to come up with that target pharmacokinetic parameter, for example, steady-state concentration and area under the plasma concentration-time curve, that allows us to dose escalate rationally and safely.
I'm a bit of a pharmacokinetic nerd, which is why I really would have loved that to have worked. There are other scales and schedules like intrapatient dose escalation, which are sort of good. We've looked at truncated methods and different statistical methods.
The statistical underpinning of phase 1 trials has always been threadbare to say the very least. We've used various other statistical models to try and speed things up. They weren't very impactful, one would have to say.
For those of you who are interested in new anticancer drug development, which should be the whole oncology community, it's worthwhile having a look at this paper. I actually found the recommendations rather thoughtful in this review.
I guess the main idea really was that rather than being able to define a single dose to go forward to the phase 2 trials, perhaps we should try to recommend a range of doses that we might be able to test in a rather more adaptive or even randomized phase 2 trial design.
I've said this many times before: As oncologists, the single most important thing that we can control about the treatment that we deliver to our patients is not their germline genetics or the somatic tumoral mutational landscape; it's the drug dose and schedule that we give. We can control this.
We need to put more thought into it. We need to think more strongly about the statistical underpinning of phase 1 trials. I agree with the authors of this report, with the general thrust of the task force, that looking at a range of different doses will give us better options about defining, particularly with targeted therapies, a more rational dose schedule to go forward into phase 2 or emerge from phase 2 into phase 3 trials.
Have a look at the review. Tell me what your own thoughts are. For those of you who are interested in the tricky methodology of phase 1 trials, I'd be very interested in your comments.
For the wider oncology community, you must see how important it is. I'd like all of you to think about dose and think, every time we treat a patient, whether with drugs relatively rarely in single dose or in combination; are we certain that we've got the optimal drug dose schedule?
Have a think about it. Any comments would be most welcome.
For the time being, Medscapers, as always, thanks for listening. Over and out. Thank you.
David J. Kerr, CBE, MD, DSc, is a professor of cancer medicine at the University of Oxford. He is recognized internationally for his work in the research and treatment of colorectal cancer and has founded three university spin-out companies: COBRA Therapeutics, Celleron Therapeutics, and Oxford Cancer Biomarkers. In 2002, he was appointed Commander of the British Empire by Queen Elizabeth II.
Medscape Oncology © 2023
Cite this: David J. Kerr. Phase 1 Trials: Are We Using Optimal Drug Dose Schedules? - Medscape - Dec 28, 2023.
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