Ashish Kamat: Hello everybody and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, Urologic Oncologist in Houston, Texas, and I'm joined in the forum today by a dear friend, a true expert in bladder cancer, and someone who's really pioneered the way when it comes to the surgeon-scientist field and really that the platform. And it's a pleasure to welcome John Taylor to the Forum. Welcome, John.

John A. Taylor III: Thank you. Thank you for the overzealous introduction. Appreciate it.

Ashish Kamat: John, you've been part of this UroToday forum for many years, and today it's really nice to have you here to tell us a little bit about your trial that got funded, and kudos to you, right, because this is a large amount of money coming from the DOD for a true surgeon-scientist project. So share with us a little bit through your PowerPoint presentation, exactly what the trial is, and at the end of it, I'd love to pick your brains on your advice to young investigators moving forward, trying to emulate things that you've done. So with that first, the stage is yours.

John A. Taylor III: Yeah, no, thank you. And I think that as long as you and I have been doing this, Ashish, it's really exciting to see the changes in bladder cancer. I mean, there were so few options for patients just a decade ago, and we're just having an explosion of novel drugs and trials. And for this grant, it's really exciting that bladder cancer is getting the national recognition that deserves. I'll just jump right into it. Our trial is entitled IVC or Intravenous Vitamin C with chemotherapy or Cisplatin-Ineligible and or Cisplatin-Refused Patients with Muscle-Invasive bladder Cancer. A little bit that I think most of us understand about the disease and we'll cover the disease-specific needs will go into the background on intravenous vitamin C. I'll review the early phase trial results and then the current phase two trial that was funded by the Department of Defense. So I think as I was saying, things that we all know about bladder cancer, which are unfortunate until recently, about 40 to 50% of patients with muscle-invasive disease are actually cisplatin-ineligible and they're unable to receive standard of care neoadjuvant cisplatin-based chemotherapy.

We also know that alternate regimens up to this point, and there's some exciting data coming out of some newer trials, but up until this point, alternate regimens have proven to be inferior. Most of these patients have proceeded straight to cystectomy and or been enrolled in clinical trials. But even in this space, I think there's been a dearth of opportunities for them. And one of the problems that we've seen is concern for delay is we know that if we put cystectomy off for too long, we can see changing outcomes in patients. So just a little bit of a background on vitamin C, and our group has done some groundbreaking work that led to some of the trials that are on this slide as well as help develop the trial that was funded. But vitamin C, or ascorbate is known to cause cell-mediated death by superoxide formation.

It's cytotoxic to cancer cells versus normal cells due to the abnormal energy and metabolism found in cancer cells. The difference that we're always asked is, well, why not just give it orally? There's an absorption saturation limitation when it's taken orally and we can only see serum levels around 70 to 80 micromolar. If we bypass that mechanism and give it intravenously, we can get serum levels up to 25 to 30 millimolar. And these are pharmacological levels that are cytotoxic to cells. There have been a plethora of preclinical models showing that vitamin C is efficacious and has synergy with multiple chemotherapeutics that are used in bladder cancer. And at the time that this presentation was made, and it might be updated at this point, there have been a lot of early phase clinical trials showing efficacy and safety of vitamin C. 18 trials in advanced disease to greater than 12 early phase trials and multiple cancers.

Again showing the safety, feasibility and potential efficacy of vitamin C. Most importantly, two of the earlier trials in solid tumors such as pancreatic and ovarian, showed that vitamin C is synergistic with gemcitabine and carboplatin as well as some immunotherapeutics, and it's led to improved tolerance of chemotherapeutics stable disease if not prolonged survival. So we embarked on a phase one trial that was funded by NCATS, and this was really exploratory in nature. It was a single-center, single-arm Simon two-stage study design where we give a single cycle of intravenous vitamin C plus a single cycle... I'm sorry, a single cycle of gemcitabine carboplatin with high-dose intravenous vitamin C. And it was a small study that was just aimed at showing that this was safe, patients tolerated it, and to see if we had any significant pathological downstaging, which has been our primary outcome metric. And in this early phase trial, and we've reported this before, we saw a 33% pathological downstaging to less than YpT2.

Interestingly, three out of four of those patients, or 25% overall, 75% of responders had a pathological complete response, and that included a patient with advanced plasmacytoid disease. One of our secondary outcomes was quality of life metrics across the duration of treatment, and we use the FACT-Bl questionnaire, and as you know, when patients get chemotherapy, we see significant dips in quality of life scores in the FACT-Bl, and we saw no change in the FACT-Bl scores from these patients either at termination of the cycle of chemotherapy and vitamin C or after surgery. So based on that trial, we applied to a new granting mechanism from the DOD, it's called Advancing Cancer Care through Clinical Trial Award. And this is a $4 million award that required early phase trial results that directly led to a larger phase trial. This was designed as a multi-center. Iowa is our second site, Mike O'Donnell is the Site PI there single arm again Simon two stage phase two trial.

Our planned enrollment is 39 patients in phase one with nine additional patients if we meet our criteria for continuation after phase one and the scheme is pretty simple, we're just doubling up on the cycles of IVC with Gem/Carbo. And this was the predominant feedback we got when we presented the first stage results or the first trial results at national meetings. So we're doubling up. So patients will get two cycles of Gem/Carbo with intravenous vitamin C. The vitamin C is given on a dose escalating scale in the first week. So patients will receive up to three doses and then once we get steady state serum levels at the appropriate dose, we'll continue that out for twice a week for the ensuing seven weeks. And during that timeframe, they'll get two cycles of Gem/Carbo as a standard dosing and days of treatment. At completion, patients go to cystectomy within two weeks of completion of chemotherapy and intravenous vitamin C.

What we're trying to do here is stay within the window that is deemed acceptable for delay of cystectomy, particularly if we thought that this wasn't going to work for patients. A primary outcome metric we're looking at is pathological downstaging and complete response rates. Secondary outcomes or quality of life with the FACT-Bl as well as ctDNA results. And then we have exploratory outcomes looking at single cell sequencing and mechanisms of vitamin C activity within patients. So this trial is open and enrolling. We are accruing on schedule and we anticipate that it'll take us about three years to reach our goals. So just in a quick summary, the first trial is funded by NCATS. Single cycle of Gem/Carbo with high dose intravenous. Vitamin C was extremely well tolerated. We had no treatment related AEs or SAEs, and it appears to have activity in a very difficult to treat population of patients with muscle invasive disease who are cisplatin-ineligible and potentially an alternative for patients who would otherwise not realize the benefits of neoadjuvant chemotherapy.

The current open enrolling trial, again funded by the Department of Defense is two cycles of the same. Hoping to confirm and expand on our earlier findings. Our take-home message from this is that intravenous vitamin C has shown efficacy as a cancer therapeutic in multiple early phase trials. It improves clinical parameters, including most importantly, disease-free survival. None of the trials have shown significant drug-related AEs or SAEs suggesting that vitamin C has the potential to increase our options for patients with bladder cancer on a cost-effective unit.

And that's really the crux of the prior study and the current study. I think it's really exciting and I think it's too early to say, but we're seeing similar results in the patients that have completed trial so far.

Ashish Kamat: Great. Thank you so much, John, for sharing that. And I think one of the critical things that you highlighted of course, is the cost-effectiveness, right? Because we all understand in the field there are many new regimens and drugs and paradigms coming down the pike, but they're going to be expensive and they are expensive. And if you can take something like ascorbic acid and reinvent it or reuse it, essentially, I think that's a really innovative, novel way to improve the care of patients, not just in the US but globally, where access to these expensive drugs is often a problem. And of course, something that's cheap and readily available should be repurposed and used. So kudos to that, to you and your group.

John A. Taylor III: I was just going to say, you and I talk about this all the time, there's some really, really exciting novel therapies coming down the pike, but antibody drug conjugates can cost up to $450,000 a year. So we're really excited about this novel. I mean, this is pennies on the dollar and it's translatable globally.

Ashish Kamat: Absolutely. John, I want to take a few minutes to actually talk to you about something that I think many of our listeners and audience that are in their phases of career where they're looking for guidance would find helpful. Again, you and I have talked offline, I have taken part in DOD review panels, I've even shared DOD review panels, and it really, it is not appreciated by many, I'm sure, how much of an achievement this grant award to you is. In short, because I know you could have a whole seminar on this, if somebody is listening to this and saying, oh my God, it's been frustrating. I just can't get funding for bladder trials. I've applied. I've applied, it hasn't worked. What are your take home messages when it comes to someone for that purpose, like career guidance advice?

John A. Taylor III: And before we go there, just back to the importance of this work, this award, I think it's the bladder cancer community. We all work together. We support each other, and that's what allows investigators like you or me to just keep beating our heads against the wall until we get funding. But I think there's been a sea change in the recognition of bladder cancer and such as this award. So there are five major academic sites that received this award. The other four sites are bloodborne malignancies. So not only is this the only solid tumor, but it's bladder cancer. And I think that speaks to the recognition that yeah, entities, the IBCG, the IBCN, BCAN, the Albert, I think we're all doing our fair share to make sure that this disease is getting recognized. And I think that this is a kudos to our community, that we as a group have brought bladder cancer to the level of recognition where we can be rubbing shoulders with big academic centers that are getting funded for bloodborne malignancies.

I think that comes from all of us doing this and persisting at it. But you struggled with the same thing that I have in the past, and that's getting funding. And I think that you just don't quit. You have to stick with your morals and stay after it and look at the critiques. Take the critiques that you get with a grain of salt, go back and just keep trying. I mean, one of the first things that I was ever taught in academic medicine was the only grant that will never get funded is the one you don't submit. And I think that thick skin, perseverance and accommodation. So listen to what people have to say and make changes and talk to your colleagues. It's a group effort. I mean, at the end of the day, it's a group effort. How many times have you and I talked about the research I'm doing and you've given me some great ideas that have changed the direction of the route or even just small changes in grants. So use your colleagues, use the community. Don't give up and just persevere. It happens.

Ashish Kamat: Yeah. And again, just to summarize what you said, it really is a community effort. Obviously we have leaders within the community such as yourself, but for folks out there that are looking to connect with anyone that is doing bladder cancer research, clearly the think tank, the Albert Institute, IBCN, IBCG, any place, AUA, EAU, wherever you can approach folks that are in your field that you feel are not approachable, we are. We love to hear from you. We love to hear from the younger faculty, younger residents, trainees, and welcome you to the group. So again, with that, John, in the interest of time, we'll close here. But thank you again for taking the time and joining us, and congratulations once again.

John A. Taylor III: Yeah, thank you for having me, Ashish. It's been a pleasure. And as I said, it's a great kudos for the community itself.