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The SUB-urothelial DUrvalumab InjEction-1 (SUBDUE-1) trial

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Dickon Hayne discusses the safety of sub-urothelial injection of durvalumab and examine the impact on tissue and circulating immune cell populations.

Image courtesy of interviewee. May 29, 2024

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This video discusses a study exploring the use of checkpoint inhibitor therapy, specifically durvalumab, for treating bladder cancer, particularly in earlier stages. The aim is to integrate checkpoint inhibitors into the treatment paradigm for non-muscle invasive bladder cancer to potentially avoid the need for cystectomy (bladder removal).

Historically, such therapies have been used effectively for metastatic malignancies, but there is limited research on their application in earlier stages of bladder cancer. Researchers propose a novel method of directly injecting the drug into the bladder to achieve more effective local delivery, addressing challenges with absorption through the bladder lining.

The study focused on safety and feasibility, given that this is a first-in-human trial. Results showed that the administration of the drug was well tolerated, with no significant systemic immune-related side effects observed, which are common in systemic immunotherapy. Immune responses were noted in the bladder tissue, and one patient showed no evidence of carcinoma in situ following treatment, indicating potential effectiveness.

Overall, the findings suggest that direct bladder injection of checkpoint inhibitors like durvalumab is safe and could elicit local immune responses, warranting further studies to refine this approach and explore its use with other checkpoint inhibitors for bladder cancer patients who might benefit from therapy without requiring bladder removal.

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00:00.000 --> 00:01.725
Really, we were trying to look at a way

00:01.825 --> 00:05.685
to bring checkpoint inhibitor therapy earlier on in the

00:05.685 --> 00:07.765
bladder cancer, treatment paradigm.

00:08.105 --> 00:10.045
Um, so these drugs are well known

00:10.105 --> 00:13.205
to be very effective in treating,

00:13.205 --> 00:14.405
metastatic malignancy

00:14.405 --> 00:16.965
and certainly urothelial cancer checkpoint inhibitors

00:17.025 --> 00:18.085
are well known to be active.

00:18.705 --> 00:21.565
Um, but there was a desire to bring them earlier on in, in,

00:21.565 --> 00:23.045
in the treatment process for so

00:23.045 --> 00:24.685
that they could potentially be used in the future

00:24.795 --> 00:26.845
with non-muscle invasive bladder cancer

00:27.025 --> 00:30.285
and hopefully prevent people from requiring cystectomy

00:30.285 --> 00:32.165
with the removal of the bladder for bladder cancer.

00:32.345 --> 00:34.005
That's an interesting point because there are very,

00:34.005 --> 00:38.365
there are virtually no, recorded, studies.

00:38.365 --> 00:41.485
There's one study which is still, unreported.

00:41.485 --> 00:44.165
There was just a protocol paper about using potentially

00:44.165 --> 00:47.325
direct injection of the drug durvalumab into the cervix,

00:47.325 --> 00:49.685
as a potential treatment for spike cancer, but no results.

00:50.225 --> 00:52.725
Um, so it really is a, it really is quite a novel approach.

00:53.385 --> 00:55.085
Um, the thing about the bladder is it's very

00:55.085 --> 00:56.725
accessible to urologists.

00:57.025 --> 01:00.205
Um, now you can put drugs into the bladder down a catheter,

01:00.425 --> 01:02.685
and there are indeed, there are, there have been ongoing,

01:02.815 --> 01:05.085
there are ongoing studies where they've done exactly that

01:05.085 --> 01:07.245
with the same drug that we use in our study

01:07.345 --> 01:09.485
and durvalumab, which is the PD L one inhibitor.

01:09.785 --> 01:11.845
But the, the, these drugs are antibodies.

01:11.845 --> 01:13.165
They're very big molecules,

01:13.185 --> 01:15.005
and the lining of the bladder is designed

01:15.105 --> 01:16.685
to stop stuff getting out through it.

01:16.785 --> 01:19.805
Um, so it's a, it's a fairly impenetrable, beast.

01:20.465 --> 01:23.405
Um, and it may be that it's very difficult to absorb,

01:23.685 --> 01:25.565
a checkpoint inhibitor through the urothelium.

01:25.565 --> 01:26.725
We certainly don't know that you can,

01:26.905 --> 01:28.645
and to my mind, there's no good evidence

01:28.715 --> 01:30.925
that it is well absorbed, certainly,

01:30.925 --> 01:32.405
when administered on its own.

01:32.625 --> 01:34.845
So the, the idea was to circumvent that

01:34.845 --> 01:37.965
by literally injecting the, the drug past the, the barrier

01:37.965 --> 01:39.605
of the urothelium into the, into the,

01:39.605 --> 01:41.245
essentially the lamina propria and the,

01:41.245 --> 01:43.165
and the detrusor muscle of the bladder itself.

01:43.225 --> 01:46.525
So literally way of getting, infiltrating the drug directly

01:46.525 --> 01:48.525
around the bladder and getting it in that way.

01:48.825 --> 01:51.525
The potential advantage of that being, if I carry on

01:52.145 --> 01:54.085
the potential advantages of that being,

01:54.155 --> 01:55.965
with systemic administration, we know

01:55.965 --> 01:57.045
that these drugs are very toxic.

01:57.045 --> 01:58.965
They have a lot of immune related side effects.

01:59.505 --> 02:02.925
Um, and the whole idea of there is a precedent

02:02.945 --> 02:04.925
for giving systemic checkpoint inhibitor

02:04.925 --> 02:06.325
therapy for bladder cancer.

02:06.465 --> 02:09.525
So there's a study using pembrolizumab called Keynote,

02:09.525 --> 02:12.645
57, where people with who didn't respond

02:12.645 --> 02:13.725
to the standard treatment

02:13.725 --> 02:17.285
for bladder ca non loss invasive bladder cancer, BCG,

02:17.595 --> 02:20.965
were given, systemic, immunotherapy

02:21.075 --> 02:24.845
with pembrolizumab, with some, degree of,

02:25.235 --> 02:26.605
success, but,

02:26.705 --> 02:28.525
but a, a systemic therapy

02:28.835 --> 02:31.085
with all the associated toxicities of that therapy.

02:31.585 --> 02:33.765
Um, and obviously if you can just give the drug to the area

02:33.895 --> 02:35.525
where it's gonna be most effective

02:35.525 --> 02:37.365
and reduce the side effects, not to mention costs

02:37.365 --> 02:39.965
of the drug, et cetera, that would be advantageous.

02:39.985 --> 02:42.645
So that was the, that was the idea behind the study.

02:42.965 --> 02:46.165
I think that really you're trying to de I mean, the problem

02:46.165 --> 02:48.805
with, checkpoint inhibitors is

02:48.805 --> 02:49.925
that the actual dose required

02:49.925 --> 02:51.405
for an effect is, is very unclear.

02:51.425 --> 02:53.085
And indeed a lot of the industry studies

02:53.435 --> 02:55.365
with systemic checkpoint inhibitors, it's,

02:55.365 --> 02:57.285
it's highly likely that far more

02:57.285 --> 02:58.565
of these drug is being given

02:58.715 --> 03:01.725
Than, than perhaps, is actually required to,

03:01.785 --> 03:03.325
to stimulate the immune response,

03:03.345 --> 03:06.005
the desirable immune response in the bladder.

03:06.425 --> 03:09.565
Um, if you take the sort of volume of the bladder compared

03:09.565 --> 03:12.325
to the volume of a person, it's probably less than 5%

03:12.505 --> 03:15.045
of the, of the, of the volume of tissue

03:15.045 --> 03:16.325
that's in a human body.

03:16.825 --> 03:20.845
Um, so we worked, around that, supposition

03:20.845 --> 03:24.205
that if we got the dose up to 10% of the systemic dose,

03:24.345 --> 03:25.885
giving it directly into the bladder,

03:26.235 --> 03:29.085
then we would be more than exceeding the likely amount

03:29.085 --> 03:30.805
of drug that you would administer to the bladder

03:30.805 --> 03:32.005
with systemic administration.

03:32.065 --> 03:35.765
So that's how we designed our, our dose escalation schedule.

03:36.465 --> 03:38.205
Um, because it was a,

03:38.235 --> 03:42.165
because it was a first in world, sort of first in human,

03:42.465 --> 03:44.365
trial,

03:44.505 --> 03:46.445
we really were just looking mainly at s

03:46.505 --> 03:47.805
safety and feasibility.

03:48.385 --> 03:51.005
Um, and of course, though these doses,

03:51.095 --> 03:54.125
these drugs are very safe in high dose systemically,

03:54.545 --> 03:56.605
but we didn't know for certain that it would be all right

03:56.605 --> 03:58.605
to give them injected directly into the bladder.

03:59.065 --> 04:02.125
Um, and for that reason, we chose a population of patients

04:02.125 --> 04:03.325
who were, who were volunteers.

04:03.325 --> 04:05.565
They were very carefully counseled into the fact

04:05.565 --> 04:07.005
that they were, they were,

04:07.005 --> 04:08.765
volunteering, to this study.

04:09.305 --> 04:12.725
Um, and we really chose patients who were scheduled

04:12.725 --> 04:16.045
to have the bladder remove a bladder cancer in any case,

04:16.065 --> 04:19.245
so that if there were to un unrealized toxicities

04:19.265 --> 04:21.765
or issues, then those, patients wouldn't be left,

04:21.765 --> 04:22.765
suffering for very long.

04:22.795 --> 04:24.765
Well, I think the first thing was that we got up

04:24.765 --> 04:27.325
to our target dose, without any,

04:27.685 --> 04:29.445
systemic immune related adverse effects.

04:29.465 --> 04:32.645
So by that I mean there was no, dermatitis,

04:32.945 --> 04:36.045
no bowel related, you know, colitis

04:36.185 --> 04:39.365
or hepatitis, all the other various inflammatory conditions

04:39.365 --> 04:42.765
that are well recognized side effects of, immunotherapy.

04:42.945 --> 04:44.005
Now, this is a, we have

04:44.005 --> 04:46.845
to remember it's an 11 patient study, so that doesn't mean

04:46.845 --> 04:49.525
that somebody couldn't have a systemic immune response in

04:49.525 --> 04:52.365
the future, where we got safely up to the target dose,

04:52.365 --> 04:55.245
which is a very large dose, we believe, for the bladder.

04:55.825 --> 04:57.885
Um, so that was the, the, that was the first point.

04:58.265 --> 05:01.885
Um, it was very well tolerated, by the patients.

05:01.885 --> 05:03.245
We did give the drug,

05:03.505 --> 05:05.845
to patients under general anesthetic,

05:06.075 --> 05:08.645
because again, it was a first in human study,

05:08.865 --> 05:11.045
but there's no real reason why these drugs couldn't be

05:11.045 --> 05:12.925
administered down a flexible cystoscope

05:12.925 --> 05:14.045
under local anesthetic.

05:14.185 --> 05:15.325
And the other main finding was

05:15.325 --> 05:18.045
that we did see immune related effects in the bladder.

05:18.185 --> 05:20.885
So we looked at various immune cell populations in the

05:20.885 --> 05:23.245
bladder and saw how they changed before and

05:23.245 --> 05:25.085
after the administration of the durvalumab.

05:25.705 --> 05:28.165
Um, so this was only a single dose of the drug

05:28.165 --> 05:30.805
that was given, and we'd taken biopsies from the bladder

05:30.805 --> 05:33.565
immediately before the drug was given into the bladder,

05:34.145 --> 05:37.005
and then at least, at least two weeks later,

05:37.005 --> 05:38.765
sometimes longer, when the patient came back

05:38.765 --> 05:41.325
for their scheduled surgery to remove the whole bladder,

05:41.585 --> 05:43.285
we took more biopsies again, first,

05:43.705 --> 05:45.285
and of course we also had the whole bladder

05:45.305 --> 05:46.805
to look at under the microscope

05:46.905 --> 05:48.165
so we could look at these various

05:48.165 --> 05:49.525
populations of immune cells.

05:49.905 --> 05:51.285
And they did change,

05:51.285 --> 05:53.085
following the durvalumab administration.

05:53.505 --> 05:54.765
The, the other, I mean,

05:54.765 --> 05:56.765
potentially exciting issue with, with

05:56.865 --> 05:57.925
One particular patient

05:58.025 --> 05:59.965
who had something called carcinoma in situ you

05:59.965 --> 06:02.085
of the bladder, which was proven on the biopsies

06:02.085 --> 06:04.045
before the durvalumab administration.

06:04.505 --> 06:07.205
Uh, there was no carcinoma of situ in the bladder at all,

06:07.205 --> 06:09.405
subsequently after they'd been given the drug.

06:09.585 --> 06:12.605
Now it's obviously one patient in a, in a, in a small study,

06:12.605 --> 06:14.045
so we can't read too much into that,

06:14.045 --> 06:16.965
but it's certainly an encouraging start in conclusion, it's,

06:16.965 --> 06:18.085
it's safe,

06:18.505 --> 06:21.675
and there are immune related,

06:21.915 --> 06:23.355
consequences of doing this.

06:23.355 --> 06:25.675
So it seems to be active in, in, in the sense

06:25.675 --> 06:29.835
of it's an immune, it's a, it's a immune stimulating drug,

06:29.835 --> 06:30.955
which has an immune effect when

06:30.955 --> 06:32.275
injected directly into the bladder.

06:32.775 --> 06:34.835
Um, and that we didn't see any systemic

06:34.975 --> 06:36.275
immune related side effects.

06:36.275 --> 06:38.035
So those are really our main conclusions.

06:38.535 --> 06:40.035
Uh, clearly now we'd be interested

06:40.035 --> 06:42.155
to do further studies both with durvalumab

06:42.155 --> 06:44.315
or potentially with other checkpoint inhibitors such

06:44.315 --> 06:46.275
as pembrolizumab or others,

06:46.275 --> 06:48.795
where we are giving repeated, injections,

06:48.795 --> 06:50.155
into the bladder, similarly to

06:50.155 --> 06:51.635
how you would give the immune therapy

06:52.715 --> 06:55.235
repeatedly into a vein, when treating patients.

06:55.535 --> 06:58.395
Um, and actually, look at the longer term of it as,

06:58.415 --> 06:59.635
as a treatment for patients

06:59.635 --> 07:01.395
who already have established bladder cancer,

07:01.415 --> 07:04.075
but aren't necessarily going to require cystectomy.

00:00 - Really, we were trying to look at a way to bring checkpoint inhibitor therapy earlier on in the bladder cancer, treatment paradigm. so these drugs are well known to be very effective in treating, metastatic malignancy

00:14 - and certainly urothelial cancer checkpoint inhibitors are well known to be active. but there was a desire to bring them earlier on in, in, in the treatment process for so that they could potentially be used in the future with non-muscle invasive bladder cancer and hopefully prevent people from requiring cystectomy with the removal of the bladder for bladder cancer. That's an interesting point because there are very, there are virtually no, recorded, studies.

00:38 - There's one study which is still, unreported. There was just a protocol paper about using potentially direct injection of the drug durvalumab into the cervix, as a potential treatment for spike cancer, but no results. so it really is a, it really is quite a novel approach. the thing about the bladder is it's very accessible to urologists. now you can put drugs into the bladder down a catheter, and there are indeed, there are, there have been ongoing, there are ongoing studies where they've done exactly that

01:05 - with the same drug that we use in our study and durvalumab, which is the PD L one inhibitor. But the, the, these drugs are antibodies. They're very big molecules, and the lining of the bladder is designed to stop stuff getting out through it. so it's a, it's a fairly impenetrable, beast. and it may be that it's very difficult to absorb, a checkpoint inhibitor through the urothelium. We certainly don't know that you can,

01:26 - and to my mind, there's no good evidence that it is well absorbed, certainly, when administered on its own. So the, the idea was to circumvent that by literally injecting the, the drug past the, the barrier of the urothelium into the, into the, essentially the lamina propria and the, and the detrusor muscle of the bladder itself. So literally way of getting, infiltrating the drug directly around the bladder and getting it in that way.

01:48 - The potential advantage of that being, if I carry on the potential advantages of that being, with systemic administration, we know that these drugs are very toxic. They have a lot of immune related side effects. and the whole idea of there is a precedent for giving systemic checkpoint inhibitor therapy for bladder cancer. So there's a study using pembrolizumab called Keynote, 57, where people with who didn't respond

02:12 - to the standard treatment for bladder ca non loss invasive bladder cancer, BCG, were given, systemic, immunotherapy with pembrolizumab, with some, degree of, success, but, but a, a systemic therapy with all the associated toxicities of that therapy. and obviously if you can just give the drug to the area where it's gonna be most effective and reduce the side effects, not to mention costs

02:37 - of the drug, et cetera, that would be advantageous. So that was the, that was the idea behind the study. I think that really you're trying to de I mean, the problem with, checkpoint inhibitors is that the actual dose required for an effect is, is very unclear. And indeed a lot of the industry studies with systemic checkpoint inhibitors, it's, it's highly likely that far more of these drug is being given

02:58 - Than, than perhaps, is actually required to, to stimulate the immune response, the desirable immune response in the bladder. if you take the sort of volume of the bladder compared to the volume of a person, it's probably less than 5% of the, of the, of the volume of tissue that's in a human body. so we worked, around that, supposition that if we got the dose up to 10% of the systemic dose, giving it directly into the bladder,

03:26 - then we would be more than exceeding the likely amount of drug that you would administer to the bladder with systemic administration. So that's how we designed our, our dose escalation schedule. because it was a, because it was a first in world, sort of first in human, trial, we really were just looking mainly at s safety and feasibility. and of course, though these doses,

03:51 - these drugs are very safe in high dose systemically, but we didn't know for certain that it would be all right to give them injected directly into the bladder. and for that reason, we chose a population of patients who were, who were volunteers. They were very carefully counseled into the fact that they were, they were, volunteering, to this study. and we really chose patients who were scheduled to have the bladder remove a bladder cancer in any case,

04:16 - so that if there were to un unrealized toxicities or issues, then those, patients wouldn't be left, suffering for very long. Well, I think the first thing was that we got up to our target dose, without any, systemic immune related adverse effects. So by that I mean there was no, dermatitis, no bowel related, you know, colitis or hepatitis, all the other various inflammatory conditions that are well recognized side effects of, immunotherapy.

04:42 - Now, this is a, we have to remember it's an 11 patient study, so that doesn't mean that somebody couldn't have a systemic immune response in the future, where we got safely up to the target dose, which is a very large dose, we believe, for the bladder. so that was the, the, that was the first point. it was very well tolerated, by the patients. We did give the drug, to patients under general anesthetic, because again, it was a first in human study,

05:08 - but there's no real reason why these drugs couldn't be administered down a flexible cystoscope under local anesthetic. And the other main finding was that we did see immune related effects in the bladder. So we looked at various immune cell populations in the bladder and saw how they changed before and after the administration of the durvalumab. so this was only a single dose of the drug that was given, and we'd taken biopsies from the bladder

05:30 - immediately before the drug was given into the bladder, and then at least, at least two weeks later, sometimes longer, when the patient came back for their scheduled surgery to remove the whole bladder, we took more biopsies again, first, and of course we also had the whole bladder to look at under the microscope so we could look at these various populations of immune cells. And they did change,

05:51 - following the durvalumab administration. The, the other, I mean, potentially exciting issue with, with One particular patient who had something called carcinoma in situ you of the bladder, which was proven on the biopsies before the durvalumab administration. there was no carcinoma of situ in the bladder at all, subsequently after they'd been given the drug. Now it's obviously one patient in a, in a, in a small study,

06:12 - so we can't read too much into that, but it's certainly an encouraging start in conclusion, it's, it's safe, and there are immune related, consequences of doing this. So it seems to be active in, in, in the sense of it's an immune, it's a, it's a immune stimulating drug, which has an immune effect when injected directly into the bladder. and that we didn't see any systemic

06:34 - immune related side effects. So those are really our main conclusions. clearly now we'd be interested to do further studies both with durvalumab or potentially with other checkpoint inhibitors such as pembrolizumab or others, where we are giving repeated, injections, into the bladder, similarly to how you would give the immune therapy repeatedly into a vein, when treating patients.

06:55 - and actually, look at the longer term of it as, as a treatment for patients who already have established bladder cancer, but aren't necessarily going to require cystectomy.

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