CORE-008 Cohort A: Cretostimogene in BCG-Naïve High-Risk NMIBC – Trial Design & Update - Trinity Bivalacqua
May 6, 2025
Sam Chang speaks with Trinity Bivalacqua about the CORE-008 trial for non-muscle invasive bladder cancer. Dr. Bivalacqua explains that CORE-008 is a multi-cohort, multicenter trial similar to STAMPEDE, with different cohorts investigating cretostimogene grenadenorepvec, an oncolytic immunotherapy with a dual mechanism of action. Cohort A, which has completed enrollment of 150 patients, focuses on BCG-naïve high-risk patients with either CIS (with or without papillary disease) or papillary-only disease. Cohort B targets BCG-exposed patients who developed recurrence after initially responding to BCG - a common but understudied clinical scenario. Cohort CX examines combination therapy with cretostimogene and gemcitabine in BCG-unresponsive and BCG-exposed patients, testing both sequential and concurrent administration approaches. All cohorts include provisions for re-induction and maintenance therapy, with endpoints measuring complete response and recurrence-free survival at 12 months.
Biographies:
Trinity Bivalacqua, MD, PhD, Director of Urologic Oncology, Co-Director of the Genitourinary Cancer Service Line, Abramson Cancer Center, Professor of Surgery at the Hospital of the University of Pennsylvania, Philadelphia, PA
Sam S. Chang, MD, MBA, Urologist, Patricia and Rodes Hart Professor of Urologic Surgery, Vanderbilt University Medical Center, Chief Surgical Officer, Vanderbilt-Ingram Cancer Center, Nashville, TN
Biographies:
Trinity Bivalacqua, MD, PhD, Director of Urologic Oncology, Co-Director of the Genitourinary Cancer Service Line, Abramson Cancer Center, Professor of Surgery at the Hospital of the University of Pennsylvania, Philadelphia, PA
Sam S. Chang, MD, MBA, Urologist, Patricia and Rodes Hart Professor of Urologic Surgery, Vanderbilt University Medical Center, Chief Surgical Officer, Vanderbilt-Ingram Cancer Center, Nashville, TN
Related Content:
AUA 2025: Updates to the CORE-008 Trial Protocol: A Phase 2 Multi-Arm, Multi-Cohort Study to Evaluate Intravesical Cretostimogene Grenadenorepvec in Patients with High-Risk Non-Muscle Invasive Bladder Cancer
ASCO GU 2025: CORE-008: A Phase 2, Multi-Arm, Multi-Cohort, Open-Label Study To Evaluate Intravesical Cretostimogene Grenadenorepvec in Participants With High-Risk NMIBC
SUO 2024: CORE-008: A Phase 2, Multi-Arm, Multi-Cohort, Open-Label Study to Evaluate the Safety and Efficacy of Cretostimogene Grenadenorepvec in Participants with High-Risk NMIBC
AUA 2025: Updates to the CORE-008 Trial Protocol: A Phase 2 Multi-Arm, Multi-Cohort Study to Evaluate Intravesical Cretostimogene Grenadenorepvec in Patients with High-Risk Non-Muscle Invasive Bladder Cancer
ASCO GU 2025: CORE-008: A Phase 2, Multi-Arm, Multi-Cohort, Open-Label Study To Evaluate Intravesical Cretostimogene Grenadenorepvec in Participants With High-Risk NMIBC
SUO 2024: CORE-008: A Phase 2, Multi-Arm, Multi-Cohort, Open-Label Study to Evaluate the Safety and Efficacy of Cretostimogene Grenadenorepvec in Participants with High-Risk NMIBC
Read the Full Video Transcript
Sam Chang: Hi, I'm Sam Chang. I'm a urologist in Nashville, Tennessee, at Vanderbilt University Medical Center, and we are with one of the true stars in urologic oncology. Dr. Trinity Bivalacqua has been now at the University of Pennsylvania for a few years now, and has been quite influential in translational work as well as clinical trials focusing on bladder cancer. And so, at this year's AUA 2025, we've got some trials in progress, we've got different things.
But I wanted to focus on an update on the overall CORE-008 trial regimen, which looks at cretostimogene and different patient populations, along with other medications. So I wanted you to give us an outline of what CORE-008 involves.
Trinity Bivalacqua: Sure. Thanks, Sam, for having me here and letting me talk about the CORE-008 trial. So CORE-008 is a multi‑cohort, multicenter trial. Think about it like STAMPEDE.
Sam Chang: OK.
Trinity Bivalacqua: So where you have STAMPEDE, where they have different agents or different disease states, you can pop it into the trial.
Sam Chang: Right.
Trinity Bivalacqua: That's exactly what CORE-008 is. So the first cohort was looking at patients that were BCG naïve. OK, so high‑risk, non‑muscle‑invasive bladder cancer. Never treated with any intravesical agent. Looking at the role of cretostimogene in patients with BCG‑naïve disease. And actually, cohort A has CIS patients. Patients that have CIS. And then patients that have papillary‑only disease. So CIS plus or minus papillary as well as papillary only.
Sam Chang: I think that's really important because so many of the early trials that we've had more recently in non‑muscle‑invasive disease have focused on BCG‑unresponsive. So this is a change. This is a BCG‑naïve population. And really, for FDA approval, really, it focused on CIS patients with or without papillary disease. So by enrolling these, you're actually then having a larger patient population that you're studying. Is that right?
Trinity Bivalacqua: Essentially, two disease states. At least that's kind of the way I think about it.
Sam Chang: Right.
Trinity Bivalacqua: And currently, cohort A, which is the CIS plus or minus papillary, has actually finished enrolling. So we'll actually have data for that towards the end of the year. So we'll see if cretostimogene, as you know, it's an oncolytic immunotherapy, which is given intravenously weekly for six weeks. And then there's the possibility to give another induction course if patients have high‑grade disease at that first three‑month assessment, and then they're put on maintenance therapy. Just like BCG maintenance from the SWOG protocol.
Sam Chang: So intravesical, adenoviral therapy, focusing on RB‑deficient cancer cells. And then also there's a GM‑CSF component as well.
Trinity Bivalacqua: Right. So it essentially has a dual mechanism of action. RB/E2F‑deficient alterations, actually, in the tumor. So you're able to effectively see tumor lysis in those tumors or CIS lesions that are in the bladder. And then you've also got the GM‑CSF, which has more lysis. So tumor lysis. And it also induces the immune system to activate.
Sam Chang: So a two‑pronged attack.
Trinity Bivalacqua: Two‑pronged attack. Two‑pronged attack.
Sam Chang: And looking in then, in cohort A for BCG‑naïve patients that have high‑risk non‑muscle‑invasive bladder cancer. So looking at CIS, looking at papillary. So a very important trial in terms of patient population.
Trinity Bivalacqua: Right.
Sam Chang: These are, in terms of your n, your patient population pool. This is a big patient population pool for sure.
Trinity Bivalacqua: And actually, the trial has-- is enrolling-- will have 150 patients. So this is not a small trial. This is a good‑sized trial. I mean, we've seen agents with registration for FDA approval with that amount.
Sam Chang: Absolutely. And then if you-- are the endpoints then different for the two, for CIS versus papillary or are there different primary endpoints?
Trinity Bivalacqua: Yeah, so your primary endpoint is what you're used to, right? So 12‑month, a complete response, recurrence‑free survival. Importantly, high‑grade recurrence, not low‑grade. And then disease‑free interval. So a CIS assessment as you pointed out, you have to have no evidence of CIS.
Sam Chang: Sure.
Trinity Bivalacqua: Whereas with the papillary, it's more event‑free survival.
Sam Chang: Disease‑free, yeah, in that time period. So that is cohort A. Other cohorts.
Trinity Bivalacqua: Yeah, so cohort B is actually looking at the role of cretostimogene in BCG‑exposed patients. So as you know, this is sort of a newer definition. So these are patients-- we'll make it simple, patients that have had a history of high‑risk disease treated with BCG, effectively treated. But then, approximately 12 months later, there's other subsets. But the way we should think about it is, at about 12 months or more, they then develop a high‑grade recurrence.
So what do we do there? As you know, as being the chair of the guidelines, we either give more BCG or we give intravesical chemo. But we actually don't know what's the best agent in this disease space. So cohort B is assessing, does cretostimogene have effectiveness in this disease state?
Sam Chang: Really an enigma. And again, how many patients do we see in this? A large, large number for different reasons. Patients, ourselves, that we've treated that perhaps had difficulty with that induction BCG that haven't had BCG. Patients referred to us, who have been referred to us because they think, well, BCG hasn't worked, we thought it worked, et cetera.
And so having that BCG‑exposed state with disease that then develops within this time period will give us an idea of, OK, do we try another type of therapy? Is it effective Yes or no?
Trinity Bivalacqua: Right.
Sam Chang: So having that patient population-- and how is that trial doing so far?
Trinity Bivalacqua: So cohort B is the BCG‑exposed. Just started enrolling, April 21. So what are we, four days?
Sam Chang: Yeah.
Trinity Bivalacqua: So we'll actually start enrolling our first patients in that. I suspect that we should be able to enroll enough patients here. Because as you pointed out, this is a very common scenario that we see.
Sam Chang: But unique in trial situations.
Trinity Bivalacqua: Absolutely. Yeah, absolutely.
Sam Chang: So really, to have that offered to patients is fantastic.
Trinity Bivalacqua: And I'm sure you've seen this in your practice. Patients come and see you with the diagnosis of BCG‑unresponsive disease. And you look at it and you're like, wait a minute, I mean, you actually--
Sam Chang: Exactly.
Trinity Bivalacqua: You've actually-- BCG was highly effective for you. You just recurred. I saw a patient literally Tuesday that was like five years. And they came to me for BCG‑unresponsive disease. And I'm like, hey listen you--
Sam Chang: We got some good news.
Trinity Bivalacqua: Yeah.
Sam Chang: Yeah, we've got some--
Trinity Bivalacqua: You actually responded to BCG. So these are new disease states that we are currently investigating in agents and it's exciting.
Sam Chang: Yeah, no, it'll be really fascinating because as that trial gathers data, you'll be able to, hopefully, help determine, hey, which of the patients, really, are going to get benefit from this type of therapy? And then tell me about the last cohort so far in CORE-008?
Trinity Bivalacqua: So cohort CX is actually the newest concept. So it's the newest arm of CORE-008. And CORE-008 is-- I'm sorry, cohort CX is looking at two different disease states. BCG‑unresponsive as well as BCG‑exposed. So it's a little bit more of a heterogeneous group of patients.
Sam Chang: Sure.
Trinity Bivalacqua: But these are all high‑risk patients. Obviously, BCG‑unresponsive, the concern there is that they may develop progression. They want to preserve their bladder. And what cohort CX is doing is actually looking at the combination of cretostimogene with gemcitabine.
Sam Chang: With the chemotherapeutic agent?
Trinity Bivalacqua: With a chemotherapeutic agent. So that's what the CX is for. And really, what it-- it has actually two arms. And the two arms are actually looking at either sequential creto with gemcitabine or given together. So sequentially or given together. So sequentially, you get creto for two weeks, gem, creto for two weeks, gem. Or you are given the combination of creto with gemcitabine weekly for six weeks.
Sam Chang: And is that in actually one instillation or is that--
Trinity Bivalacqua: No, they're given--
Sam Chang: It's sequential on the same day, as opposed to, here are two rounds of creto, followed by, a week later with a-- interesting, interesting.
Trinity Bivalacqua: Yeah, and then same protocol as we have in cohort A and B. The ability to give re‑induction if there's no signs of any-- if there's evidence of high‑grade disease at that first assessment, and then with maintenance therapy. And so these are going to be patients, once again, BCG‑unresponsive, CIS plus or minus papillary disease or BCG‑exposed.
Sam Chang: Yeah. I mean, I think, within that CORE-008, to have these different arms, just as you said, analogous to the STAMPEDE type of regimen for prostate cancer, we've got, actually, information that we're going to gain with multiple different patient populations with different regimens.
Trinity Bivalacqua: Right.
Sam Chang: So all of us in urologic oncology are looking forward to the results of these trials. And we really appreciate all your efforts to help lead them, Trinity. So kudos to you and all your efforts, and we look forward to hearing the results as results come in for these trials.
Trinity Bivalacqua: Thanks, Sam. Appreciate it.
Sam Chang: Hi, I'm Sam Chang. I'm a urologist in Nashville, Tennessee, at Vanderbilt University Medical Center, and we are with one of the true stars in urologic oncology. Dr. Trinity Bivalacqua has been now at the University of Pennsylvania for a few years now, and has been quite influential in translational work as well as clinical trials focusing on bladder cancer. And so, at this year's AUA 2025, we've got some trials in progress, we've got different things.
But I wanted to focus on an update on the overall CORE-008 trial regimen, which looks at cretostimogene and different patient populations, along with other medications. So I wanted you to give us an outline of what CORE-008 involves.
Trinity Bivalacqua: Sure. Thanks, Sam, for having me here and letting me talk about the CORE-008 trial. So CORE-008 is a multi‑cohort, multicenter trial. Think about it like STAMPEDE.
Sam Chang: OK.
Trinity Bivalacqua: So where you have STAMPEDE, where they have different agents or different disease states, you can pop it into the trial.
Sam Chang: Right.
Trinity Bivalacqua: That's exactly what CORE-008 is. So the first cohort was looking at patients that were BCG naïve. OK, so high‑risk, non‑muscle‑invasive bladder cancer. Never treated with any intravesical agent. Looking at the role of cretostimogene in patients with BCG‑naïve disease. And actually, cohort A has CIS patients. Patients that have CIS. And then patients that have papillary‑only disease. So CIS plus or minus papillary as well as papillary only.
Sam Chang: I think that's really important because so many of the early trials that we've had more recently in non‑muscle‑invasive disease have focused on BCG‑unresponsive. So this is a change. This is a BCG‑naïve population. And really, for FDA approval, really, it focused on CIS patients with or without papillary disease. So by enrolling these, you're actually then having a larger patient population that you're studying. Is that right?
Trinity Bivalacqua: Essentially, two disease states. At least that's kind of the way I think about it.
Sam Chang: Right.
Trinity Bivalacqua: And currently, cohort A, which is the CIS plus or minus papillary, has actually finished enrolling. So we'll actually have data for that towards the end of the year. So we'll see if cretostimogene, as you know, it's an oncolytic immunotherapy, which is given intravenously weekly for six weeks. And then there's the possibility to give another induction course if patients have high‑grade disease at that first three‑month assessment, and then they're put on maintenance therapy. Just like BCG maintenance from the SWOG protocol.
Sam Chang: So intravesical, adenoviral therapy, focusing on RB‑deficient cancer cells. And then also there's a GM‑CSF component as well.
Trinity Bivalacqua: Right. So it essentially has a dual mechanism of action. RB/E2F‑deficient alterations, actually, in the tumor. So you're able to effectively see tumor lysis in those tumors or CIS lesions that are in the bladder. And then you've also got the GM‑CSF, which has more lysis. So tumor lysis. And it also induces the immune system to activate.
Sam Chang: So a two‑pronged attack.
Trinity Bivalacqua: Two‑pronged attack. Two‑pronged attack.
Sam Chang: And looking in then, in cohort A for BCG‑naïve patients that have high‑risk non‑muscle‑invasive bladder cancer. So looking at CIS, looking at papillary. So a very important trial in terms of patient population.
Trinity Bivalacqua: Right.
Sam Chang: These are, in terms of your n, your patient population pool. This is a big patient population pool for sure.
Trinity Bivalacqua: And actually, the trial has-- is enrolling-- will have 150 patients. So this is not a small trial. This is a good‑sized trial. I mean, we've seen agents with registration for FDA approval with that amount.
Sam Chang: Absolutely. And then if you-- are the endpoints then different for the two, for CIS versus papillary or are there different primary endpoints?
Trinity Bivalacqua: Yeah, so your primary endpoint is what you're used to, right? So 12‑month, a complete response, recurrence‑free survival. Importantly, high‑grade recurrence, not low‑grade. And then disease‑free interval. So a CIS assessment as you pointed out, you have to have no evidence of CIS.
Sam Chang: Sure.
Trinity Bivalacqua: Whereas with the papillary, it's more event‑free survival.
Sam Chang: Disease‑free, yeah, in that time period. So that is cohort A. Other cohorts.
Trinity Bivalacqua: Yeah, so cohort B is actually looking at the role of cretostimogene in BCG‑exposed patients. So as you know, this is sort of a newer definition. So these are patients-- we'll make it simple, patients that have had a history of high‑risk disease treated with BCG, effectively treated. But then, approximately 12 months later, there's other subsets. But the way we should think about it is, at about 12 months or more, they then develop a high‑grade recurrence.
So what do we do there? As you know, as being the chair of the guidelines, we either give more BCG or we give intravesical chemo. But we actually don't know what's the best agent in this disease space. So cohort B is assessing, does cretostimogene have effectiveness in this disease state?
Sam Chang: Really an enigma. And again, how many patients do we see in this? A large, large number for different reasons. Patients, ourselves, that we've treated that perhaps had difficulty with that induction BCG that haven't had BCG. Patients referred to us, who have been referred to us because they think, well, BCG hasn't worked, we thought it worked, et cetera.
And so having that BCG‑exposed state with disease that then develops within this time period will give us an idea of, OK, do we try another type of therapy? Is it effective Yes or no?
Trinity Bivalacqua: Right.
Sam Chang: So having that patient population-- and how is that trial doing so far?
Trinity Bivalacqua: So cohort B is the BCG‑exposed. Just started enrolling, April 21. So what are we, four days?
Sam Chang: Yeah.
Trinity Bivalacqua: So we'll actually start enrolling our first patients in that. I suspect that we should be able to enroll enough patients here. Because as you pointed out, this is a very common scenario that we see.
Sam Chang: But unique in trial situations.
Trinity Bivalacqua: Absolutely. Yeah, absolutely.
Sam Chang: So really, to have that offered to patients is fantastic.
Trinity Bivalacqua: And I'm sure you've seen this in your practice. Patients come and see you with the diagnosis of BCG‑unresponsive disease. And you look at it and you're like, wait a minute, I mean, you actually--
Sam Chang: Exactly.
Trinity Bivalacqua: You've actually-- BCG was highly effective for you. You just recurred. I saw a patient literally Tuesday that was like five years. And they came to me for BCG‑unresponsive disease. And I'm like, hey listen you--
Sam Chang: We got some good news.
Trinity Bivalacqua: Yeah.
Sam Chang: Yeah, we've got some--
Trinity Bivalacqua: You actually responded to BCG. So these are new disease states that we are currently investigating in agents and it's exciting.
Sam Chang: Yeah, no, it'll be really fascinating because as that trial gathers data, you'll be able to, hopefully, help determine, hey, which of the patients, really, are going to get benefit from this type of therapy? And then tell me about the last cohort so far in CORE-008?
Trinity Bivalacqua: So cohort CX is actually the newest concept. So it's the newest arm of CORE-008. And CORE-008 is-- I'm sorry, cohort CX is looking at two different disease states. BCG‑unresponsive as well as BCG‑exposed. So it's a little bit more of a heterogeneous group of patients.
Sam Chang: Sure.
Trinity Bivalacqua: But these are all high‑risk patients. Obviously, BCG‑unresponsive, the concern there is that they may develop progression. They want to preserve their bladder. And what cohort CX is doing is actually looking at the combination of cretostimogene with gemcitabine.
Sam Chang: With the chemotherapeutic agent?
Trinity Bivalacqua: With a chemotherapeutic agent. So that's what the CX is for. And really, what it-- it has actually two arms. And the two arms are actually looking at either sequential creto with gemcitabine or given together. So sequentially or given together. So sequentially, you get creto for two weeks, gem, creto for two weeks, gem. Or you are given the combination of creto with gemcitabine weekly for six weeks.
Sam Chang: And is that in actually one instillation or is that--
Trinity Bivalacqua: No, they're given--
Sam Chang: It's sequential on the same day, as opposed to, here are two rounds of creto, followed by, a week later with a-- interesting, interesting.
Trinity Bivalacqua: Yeah, and then same protocol as we have in cohort A and B. The ability to give re‑induction if there's no signs of any-- if there's evidence of high‑grade disease at that first assessment, and then with maintenance therapy. And so these are going to be patients, once again, BCG‑unresponsive, CIS plus or minus papillary disease or BCG‑exposed.
Sam Chang: Yeah. I mean, I think, within that CORE-008, to have these different arms, just as you said, analogous to the STAMPEDE type of regimen for prostate cancer, we've got, actually, information that we're going to gain with multiple different patient populations with different regimens.
Trinity Bivalacqua: Right.
Sam Chang: So all of us in urologic oncology are looking forward to the results of these trials. And we really appreciate all your efforts to help lead them, Trinity. So kudos to you and all your efforts, and we look forward to hearing the results as results come in for these trials.
Trinity Bivalacqua: Thanks, Sam. Appreciate it.