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May 21, 2024 • 19 mins

How can phase I studies with ATMPs address unmet needs in oncology and what are the challenges? In this episode of Conversations in Drug Development, Dr Katherine Bowen is joined by Pharmaceutical Physician, Dr Harriet Gray Stephens, to delve into the complexities of phase I oncology studies involving advanced therapy medicinal products (ATMPs). Join us as we discuss the unique challenges of ATMPs, such as their different benefit-risk profiles compared to traditional therapies, and the need for innovative dose escalation and efficacy evaluation methods as well as the potential of ATMPs to meet unmet needs in cancer treatment.

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(00:00):
Music.

(00:05):
Hello, and a warm welcome to the latest edition of Conversations in Drug Development,
brought to you by the team at Boyds.
This podcast is for our fellow community of scientists and clinicians working
in the wonderful world of cell and gene therapy and drug development.
Thank you for tuning in, and we hope you enjoy the conversation.
Music.

(00:29):
Conversation. Hello and welcome. My name is Dr.
Catherine Bowen. I'm a Senior Director in Regulatory Affairs at Boyd's and I'm
absolutely delighted to be joined in the studio today by one of our pharmaceutical
physicians, Dr. Harriet Gray-Stevens.
Welcome, Harriet. Thank you, Catherine, for the invite. That is quite all right.
It's lovely to have you. So I think we've got a really interesting topic today.

(00:51):
Julie Warner and I have spoken previously on our podcasts about just generally
oncology development with a particular focus on regulatory affairs.
But today we're going to take a bit more of a deep dive into one particular
element of that, which is the challenges associated with doing phase one studies
in the oncology space, particularly with advanced therapies.

(01:12):
And today, since we've got Harriet with us, we're going to focus a little bit
on some of the elements that are really relevant for the pharmaceutical physician
in terms of the patient perspective on things,
as well as some of the considerations for the practicalities of actually designing
and running those trials.
So perhaps we can start a little bit by setting the scene and talking about

(01:33):
why this is such an important and very relevant topic in where we are in terms
of drug development in the oncology space.
Yeah, and thanks Catherine for that introduction. So ATMPs, Advanced Therapy
for Medicinal Products, are increasingly being used and developed in the oncology space.
It's a really exciting time for drug development.
Advanced therapies, ATMPs, provide significant advantages over traditional chemotherapy

(01:57):
agents, what we'd call cytotoxics, that act to kill cancer, but in the nature
of the product, also cause some toxicity.
There's been a vast expansion within the market, and particularly in the last
five years, both within the solid cancer and the hematological space,
with equal numbers of therapies within both areas.
But as we're probably aware, the oncology space is dominated by solid tumours,

(02:19):
and there really is a significant unmet need currently.
What we want to be able to do is offer cancer patients a variety of individualised
treatment options with a minimal burden of side effects, so that we can effectively
cure their cancers without making them really stick.
And these treatment options don't really exist at the moment.
But ATMPs are going to be the future of bringing these treatment options to patients.

(02:42):
Okay, great introduction there. And it's interesting, there was a review from
last year, about 45% of ATMPs in development are in the oncology space,
which I think might actually be a reduction in some respects.
I feel like ATMPs are making a resurgence in other areas as well.
And of course, some areas are already quite clouded. There's quite a few CAR
T's around now, particularly the CD19 CAR T's.

(03:06):
So more and more, I'm starting to see other targets coming through where perhaps
the knowledge base isn't quite the same.
So particularly today, we're going to be talking about the challenges in the
phase one space, those first in human trials where you're trying to get the
initial information about dosing.
And to me, that is one of the most important bits to get right, isn't it?

(03:28):
Yeah. So just to be really clear when we're talking about phase one studies,
so particularly in the non-oncology space, we talk about phase one studies as
being in healthy volunteers.
And this population isn't generally healthy volunteers. We're talking about
patients with cancer in these studies here, which is what sets these trials
apart from the majority of other clinical development programs.

(03:48):
What's the reason for this? Well, that's because these agents have generally
got a different benefit-risk profile.
And that's a point we'll come back to in multiple points today,
it's really important that we carefully evaluate the benefits to individuals versus the risks.
And within the oncology space, those risks are generally a little bit higher.
Patients are willing to tolerate a little bit more morbidity,

(04:09):
so side effects and adverse events than the general population.
And that's why our phase one clinical trials within the oncology space are a little bit different.
What's really interesting in the oncology space is that that benefit-risk needle
sits in a slightly different space.
We've got to remember at the end of the day, these are...
Not just healthy volunteers, as in a lot of early phase clinical trials,

(04:32):
but these are real patients with a real need.
Often they've come to the end of the line in terms of standard of care treatment options.
It'd be nice for them to be able to derive some benefit from an early phase trial.
And that's where looking at dose selection from a benefit risk profile,
maybe erring towards a slightly more risk might be acceptable with some ATMPs,

(04:54):
simply because it's nice to be able to derive some patient benefit in these
situations whilst accepting there might be a little bit more toxicity.
However, on the counter argument here, we've got to remember often these cellular
therapies are completely new and we've got very poor preclinical understanding
and so weighing up these two countering arguments can be quite difficult and

(05:16):
that's where careful dose selection is just really important.
Yeah, absolutely. So you've mentioned safety a few times.
And I know that perhaps we're less likely to get some of the toxicities that
we would generally see with cytotoxics or with some of the targeted small molecule
therapies, you know, nausea, vomiting, fatigue, neutropenia.

(05:40):
But obviously, we are dealing with a different safety profile.
And we can't just stop dosing patients with an ATMP and switch it off like we
we can with the small molecules.
So what are those risks and how in reality do you start dealing with those in
the context of designing a phase one trial?
First of all, let's talk about the safety profile of ATMPs. And then let's talk

(06:03):
about how we manage those risks or how we address it.
So you correctly said ATMPs got a very different safety profile in terms of
not being cytotoxics by their name. So we don't see the same cellular effects.
GI-associated, everything that's associated with killing cells,
which are rapidly dividing.

(06:24):
So hair loss, GI side effects, as well as low platelets and other cytopenias.
So we see other things. And this is what's been really interesting going forward,
is we don't really understand the other toxicities completely associated with ATMPs.
These toxicities can be generally classified into acute, subacute, and then delayed.

(06:45):
And it's the delayed ones which are really interesting. So the acute ones appear
to have a variety of acute effects, including cytokine release syndrome,
which can make patients really sick, and other weird, wonderful things such as neurotoxicity.
Some patients develop subacute problems such as graft-versus-host disease.
But the real problem is understanding the delayed effects. There's increasing

(07:07):
knowledge coming out of the anti-CD19 CAR-T space of incidents of secondary
malignancies, for example. Yeah, new FDA labelling around those black boxed warnings.
Yeah, so you might be cured from your primary cancer, but suffer with secondary
cancers, as well as other long term problems, which we really need to think about.

(07:27):
And the problem is within clinical development, how do you evaluate for these?
So within early phase clinical development, our patients are generally pretty sick.
As we mentioned earlier, they're at the the end of their standard of care treatments
and often have a poor prognosis or overall survival and for these reasons we
don't see patients living long enough to develop these secondary complications

(07:49):
and then the question is so how can we look at these problems or understand risks and,
early on during clinical development and currently with the populations that
we're generally investigating that just isn't a possibility.
The key for this however is for those patients who do live long enough to enroll
them on ongoing trials or keep them within registries or surveillance studies

(08:12):
to be able to see what happens to them in terms of the long-term side effect
profile and to be able to understand those risks as soon as possible.
Yeah and it's It's interesting what you say about the patients being really
sick. I think we have to remember this.
Generally speaking, we're in last line with a lot of these therapies.
How does that also play into how you're designing the trials in terms of sampling

(08:36):
burden, how you get them where?
Is there a big element of that when you're designing just that patient experience of the trial?
Yeah, I mean, we are so fortunate to have patients who are willing to contribute.
As you say, remember, these patients are often exceptionally frail.
Have been through multiple rounds of other cytotoxic agents their immune system
as well as the whole bodies are often shot.

(08:58):
As a physician it's really important to make patient experience central to the
clinical development process.
It causes lots of problems both in terms of the burden of visits for patients
having to come in for multiple extra blood tests or images and this often leads
to a high dropout rate which can become difficult for drug developers to manage

(09:19):
to interpret what this means.
It also can mean that recruitment rates for patients are a lot lower than we
do participate because patients are either unwilling or unable to commit to
the burden or don't meet the really strict criteria which are required for their
participation in the trial.
And this leads to general problems with the data that we're generating.
We're not getting the real patients in this study. We're getting patients who

(09:42):
are really sick and who don't represent the
average population it's interesting though isn't it that we
start off with these patients who are real yeah it is
it is and i've spoken before about fda's project
front runner which i think is a great idea it's all
about trying to get promising new therapies coming through into earlier lines

(10:03):
of therapy sooner in development so you're not always starting at the end and
kind of depriving the patients who are probably going to receive the most benefit
from getting that product until quite a long way through the development pathway.
But it is difficult, isn't it, with ATMPs when there is so little knowledge
sometimes, particularly with the potential for longer term side effects.

(10:28):
It all comes down again to the benefit-risk profile. Until we don't know what
the benefits are and we don't know what the risks are, people are less willing
to take the risk in otherwise healthy population.
But I think really in the ATMP space, we are shooting ourselves in the foot.
A lot of the ATMPs require patients to have competent immune systems,
be able to get cellular reconstitution or good activity from their cellular gene therapy.

(10:51):
But by the time that immune system and the whole physiological reserves have
been absolutely ruined by multiple lines of first,
maybe second, sometimes even third line chemotherapies, we don't see the same
effectiveness of the ATMPs as we would do in a relatively healthier population.
And this can lead to developers underestimating the treatment benefit size of

(11:12):
their asset and thus not expediting the development, which is really required.
But it's really a difficult thing to do, isn't it? to take the risk of giving
these therapies to individuals who are less sick.
And that's where careful consideration and discussion to regulators is required,
and to see if we can, in certain small populations, try expediting ATMPs to

(11:38):
be part of first or second line therapies.
In some cases, it can be used as add-ons to standard of care,
which is actually a really interesting way of looking at options.
And that's where expedited development is primarily sitting at the moment but
there are going to need to be extra ways in the future to try and expedite development
in first or second line treatments.

(11:58):
And it's always tricky when we start talking about adding on to other products
just in terms of understanding the contribution of various components it's certainly
something that we talk a lot about for combination clinical trials in the small
molecule and biologic space.
Yeah, I mean, there have to definitely be some synergies there.
So the question is, is there an additive or synergistic effect?

(12:20):
And the problem with a lot of cellular therapies is that there won't be from
a mechanistic, from a scientific perspective, particularly cytotoxics.
They work in completely different ways.
And theoretically, there might not be any benefit of the two being given together.
And that makes it very difficult to do these add-on trials in the oncology space. Yeah.
So there are some other challenges that I think are quite specific to ATMPs,

(12:43):
not least the thing themselves and how you go about making it.
So I'm not expecting you to be an expert in manufacturing of cell and gene therapies
today, Harriet, don't worry.
But from a clinical trial design, what kind of challenges does that pose for you?
Yeah i mean manufacturing of cell and gene therapies is

(13:03):
very complex and for me there's two main factors here
one what's in the cell and gene therapy and two
how on earth we're going to give it to a patient so with
regards to what's in it often these therapies rely on
cultural feeder lines and have got lots
of other bits and pieces in the potion these can
be problematic in terms of allergic reactions everything from

(13:25):
anaphylaxis down to small more minor cutaneous so
skin reactions and this can be problematic because
how do we tell what's the actual therapy causing
the problems versus all these impurities all these
additives which are absolutely necessary for the
stability of the of the cellular therapy and
then to my second point as well talking about actually giving it

(13:47):
to the patient that can be really quite difficult these cells
often have to be supplied as frozen suspensions the cold chain supply chain
is really important to ensure that products arrive in optimal conditions and
then they require specialist facilities to reconstitute or to make them up into
a formulation which is suitable to be given to patients.

(14:09):
This in addition to manufacturing problems particularly when the autologous
space so that's where patients have their own cells taken through a conditioning
regime or other that are manipulated and given back to the patients can mean
that it takes a fair bit of time to make these treatments.
So all these complications mean that actually scheduling the patient dosing
and their participation in the clinical trial can be quite difficult.

(14:32):
Patients may relapse before they actually become eligible or the product is
ready for them to be given.
Or they have to travel a long distance to go to a centre where they're used
to or they have facilities to manage and to handle these cellular therapies,
which can be quite inconvenient if you're quite unwell anyway.
I was going to say, if you're really sick and you've already been through multiple

(14:54):
lines of treatment, then you've got to drag your backside out multiple times
for all of these processes.
It makes it really hard for patients to actually contribute.
And that's where extra facilities are really required to help patients access
these experimental cellular therapies and support as well for their participation
within clinical trials.

(15:14):
Yeah, and absolutely. I think that's really good points.
But we also sometimes have issues that, But I mean, occasionally,
for example, we might have to administer some therapies before we've got all
the batch data, particularly if they've got a short shelf life and sterility
testing isn't complete at the time of administration.
So even that requires potentially some really strong clinical mitigations in

(15:38):
the protocol to cover those situations.
So, for example, checking for infections due to limited sterility data at the
time of administration,
all of those challenges that are additional to the normal, we get some pills
in a vial and give them to the patient on site, does add an extra level of complexity.
And those things have to be thought about and talked about in the protocol and

(16:02):
justified to avoid getting perfectly reasonable questions from the regulators.
Regulators I like what you said earlier you've mentioned
a couple of times about the importance of speaking to
the regulators and I think that goes throughout all
of this from how you're thinking about your dose finding the
overall design of the trial where you know the risks are and how you're intending

(16:25):
to mitigate them and I think with an awful lot of these particularly very innovative
therapies in general the companies are absolutely the experts aren't they.
Yes, you're right, they are the experts.
The only treatment reality out there is persuading the regulators of that data
and the validity of your often limited preclinical models.

(16:49):
I'd also like to touch on your prior point about the manufacturing process and
the sterility perspective, if that's okay.
So there's so many different variables when it comes to cellular therapies and
giving them to patients.
Imagine if you're a patient, you know, you've gone through a regime where you've
had some conditioning treatments to harvest your own cells which makes you a
little bit sick in itself and then you're told that you can't have your own

(17:10):
treatment back there are no other options for you.
It's an absolutely heartbreaking situation to be left in, whether it be because
of the batch release criteria, impurities, or even because there weren't enough
cells to give yourself a full batch.
This can be really difficult for patients. That's, I think, why a good clinical development,
discussions with regulators, flexible protocols is really required,

(17:34):
even through the use of other protocols, which would accept patients who would
be eligible for the treatment but wouldn't meet the specifics of that full main protocol,
so that we can still give these patients the cellular therapies in certain situations
where other batch release criteria have been met and were okay with the benefit-risk protocol.

(17:57):
File just to be able to give them a
chance but also to generate some initial
safety and efficacy data that would otherwise just be lost through patients
not receiving these treatments and that that's what it keeps coming back to
it's the patients yeah isn't it it is the patients this has been an absolutely
fascinating discussion harriet i've got one final question for you and I'm not going to time you.

(18:22):
But if I said to you in one minute, summarise your advice for conducting phase
one trials in oncology with a new ATMP, what would you say?
For me, there's four main considerations to think. One, early discussions with the regulators.
Two, think about the real scientific justification and the rationale for what

(18:43):
you are doing and really bring that out both during the preclinical and clinical development.
Development and thirdly my piece of advice would be patients are at the centre
of everything but remember we need to consider how they are as individuals but
also how long it may take for them to be able to access this novel treatment.
Things always take a lot longer both during the pre-clinical and the clinical

(19:07):
phases and allow for this extra time during your scheduling for your clinical
development programmes.
Thank you, thank you so much for an incredibly informative discussion today, Harriet.
I've thoroughly enjoyed myself and I hope we can have you back for another discussion
soon. That sounds brilliant. Thank you very much. All right. Thank you.

(19:28):
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the podcast series brought to you by the team at Boyce.
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