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CORE-008 Cohort B Investigates Cretostimogene Grenadenorepvec for BCG-Exposed High-Risk NMIBC - Trinity Bivalacqua

December 4, 2025

Zachary Klaassen speaks with Trinity Bivalacqua about CORE-008 Cohort B, investigating cretostimogene grenadenorepvec in BCG-exposed high-risk non-muscle invasive bladder cancer. Dr. Bivalacqua explains that cretostimogene is an oncolytic immunotherapy with dual mechanism through viral replication causing tumor lysis and GM-CSF encoding that stimulates immune response. Primary endpoints include complete response for CIS and high grade event-free survival for papillary disease, with reinduction allowed at three months. Dr. Bivalacqua notes the pragmatic inclusion criteria address real-world clinical scenarios including BCG shortages, and previous BOND-003 data showed 84% complete response rate in BCG-unresponsive disease.

Biographies:

Trinity Bivalacqua, MD, PhD, Director of Urologic Oncology, Co-Director of the Genitourinary Cancer Service Line, Abramson Cancer Center, Professor of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA

Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor of Surgery/Urology at the Medical College of Georgia at Augusta University, Wellstar MCG, Georgia Cancer Center, Augusta, GA



Related Content:

 SUO 2025: Trials in Progress - CORE-008 Cohort B: Evaluating Intravesical Cretostimogene Grenadenorepvec in Patients with High Risk, BCG-Exposed NMIBC

CORE-008 Cohort B: Cretostimogene for BCG-Exposed NMIBC – Trial Activation & Clinical Goals - Trinity Bivalacqua

CORE-008 Cohort A: Cretostimogene in BCG-Naïve High-Risk NMIBC – Trial Design & Update - Trinity Bivalacqua

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

EAU 2025: Updated Clinical & Translational Results: BOND-003 Cohort C: A Phase 3, Single-Arm Study of Intravesical Cretostimogene Grenadenorepvec for High-Risk BCG-Unresponsive NMIBC with CIS
Read the Full Video Transcript

Zachary Klaassen: Hi, my name is Zach Klaassen, urologic oncologist at the Georgia Cancer Center. I'm joined on UroToday by Dr. Trinity Bivalacqua, who is a urologist and urologic oncologist at Penn Medicine up in Pennsylvania. Today, we're going to be discussing SUO 2025 trials in progress, looking specifically at the CORE-008 Cohort B. Trinity, thanks so much as always for joining us on UroToday.

Trinity Bivalacqua: Thanks, Zach. Appreciate the opportunity to talk about our most recent trial and progress that was presented at the SUO. These are my disclosures as it relates to the topic of bladder cancer. I think first, I'll talk a little bit about the mechanism of action of this novel oncolytic immunotherapy. It actually has a dual mechanism of action for cretostimogene. It's viral replication that occurs in the bladder with tumor lysis and stimulation of the immune response. And the way that works is this is an adenovirus. It's conditionally replicating highly immunogenic, under the regulation of the human E2F-1 promoter. So this selectively selects for RB-E2F pathway alterations.

In tumors with this alteration, you get viral replication, and this lyses cancer cells. But importantly, it also encodes, the adenovirus also encodes for GM-CSF, which induces a robust immune response, which is anti-tumor in effect as well. So this really causes activation of the immune system as another primary mechanism of action for which we see tumor oncogenesis and tumor control. So, when we look at the CORE-008 trial, it's actually a multi-arm, multi-cohort, open-label trial in high-risk non-muscle-invasive bladder cancer. So what that essentially means is, we have multiple cohorts. And the best way to think about it is, everybody in urologic oncology understands STAMPEDE and the STAMPEDE-like approach. And that's kind of what we have here. We presented data on the cohort A, which is actually in BCG-naive patients that received cretostimogene. That was actually presented on Friday.

I presented as a late-breaking abstract. But what we're here today to talk about is the Cohort B, which is in the BCG-exposed disease space. As you know, this is sort of a newly defined space in high-risk non-muscle-invasive bladder cancer for which we see patients get BCG induction and develop a high-grade papillary or CIS recurrence at its first evaluation. Essentially, this is BCG-resistant disease, which falls under the BCG-exposed. But really, another way that we see patients in this disease space is if you see adequate BCG or inadequate BCG is given, so essentially six out of six or five out of six induction course. And then you see any high-risk recurrence either at 12 to 24 months after the last BCG treatment, especially for patients with CIS, or we see TA or T1 after adequate BCG induction at between six to 24 months after receiving adequate BCG induction, which is, as I said, five out of six plus two out of three for maintenance or even a full dose of maintenance that develop a late recurrence, so late relapse essentially. So, this also falls under BCG-exposed definition.

And then also patients that receive inadequate BCG. So those are people that either couldn't tolerate BCG or didn't have it available, right, because of the shortage, where we see a high-grade recurrence less than 24 months after last BCG treatment. So that's our cohort that we're investigating where we're seeing a treatment where you get induction, cretostimogene, with our primary endpoint for CIS as a complete response at any time. And as you know, for high-grade papillary disease-only patients, where we're seeing a primary endpoint of high-grade event-free survival in those patients. So, as seen in the BOND-003 cohort, we allow for reinduction of cretostimogene at that three-month time point for patients with high-grade TA and/or CIS at month three. And our response assessments in this group include cystoscopy, biopsy as indicated, if this could be as seen by a high-grade cytology or papillary disease is seen at our three-month evaluation for the first two years. And then we obviously evaluate every six months for year three, and we allow for maintenance upwards of three years. Key trial features are, as I pointed out, are really a broad inclusive population.

These are patients that we oftentimes in the past would've potentially given BCG. We do require a mandatory biopsy at 51 weeks, and we have central pathology review. Now, when we look at additional endpoints of this trial, we look at the duration of response, we look at a complete response as well as high-grade event-free survival at 12 months for all patients. As you know, in order to get a new agent approved in high-risk non-muscle-invasive bladder cancer, we need to document the complete response at 12 months. We also look at all-cause event-free survival, cancer-specific survival, cystectomy-free survival, progression-free survival, and then safety. I suspect in this patient cohort, we're going to have very little progression events. However, that remains to be seen. Exploratory endpoints include overall survival, patient reported outcomes. And then we have embedded in this trial a lot of correlative sciences looking at tissue-based markers as well as looking at urinary minimal residual disease as determined by molecular analysis. So, in summary, this trial may be able to identify patients that have met the criteria for BCG-exposed, where we currently don't have a specific agent that we're going to use in these patients.

Like I said, in the past, we've used BCG, but currently it's unknown if an alternative agent, intravesical agent could be utilized. And I think that results from this trial may inform additional intravesical treatment options, which would include cretostimogene. The trial is currently open for enrollment. It actually opened this week. So, this trial is also being run through the SUO-CTC, so I suspect that enrollment should proceed rather quickly as we've been able to enroll a lot of our non-muscle-invasive bladder cancer through the SUO-CTC and the large group of our investigators in the clinical trials consortium. It is open in the United States and Canada, and I'd like to thank my key investigators who obviously are critically and thoughtfully looking for patients and were involved in protocol design and obviously thank all of our bladder cancer patients and study coordinators and nurses. So that's all I have for you right now, Zach. I'm happy to answer any additional questions that you may have related to the trial.

Zachary Klaassen: Yeah, thanks so much, Trinity. Great timing. As you mentioned, the trials open this week. And if we look at the previous success, as you mentioned through SUO-CTC, PIVOT-006 accruing really quickly. I think you're absolutely right. This will probably accrue quickly as well. I just want to get your take, and I think it's important to point out, just to reiterate for our listeners, this is a really pragmatic inclusion criteria in terms of the BCG-exposed, which I think is important. You touched on BCG shortages. We start BCG, we can't get it anymore. Now what do we do? That patient who has had BCG maybe somewhat inadequately have a recurrence later on. Just speak to how this fits in with clinical practice in general that we see on a day-to-day basis.

Trinity Bivalacqua: Yeah. I mean, I think that's the million-dollar question, right Zach? So how do we choose an intravesical agent in this disease space? I mean, we know from the BOND-003 trial and the BCG-unresponsive that we had a really robust complete response rate at any time of 84% using cretostimogene, right?

Zachary Klaassen: Yeah.

Trinity Bivalacqua: So, we know that we have activity in this disease space. A lot of these patients in the BCG-exposed group are frankly very similar to our BCG-unresponsive patients, right?

Zachary Klaassen: Surely.

Trinity Bivalacqua: I mean, there is some overlap when you look at it. So I think that this is something that will likely be utilized if there's activity. I've got to believe that there will be activity. And everybody, at least one of the reasons why I like cretostimogene for my patients is the fact that we get to have the ability to use reinduction in the BOND-003 trial, 50% of patients that were reinduced had a response. So, this trial and this design fits into our practices. So I think it's something that we're all very comfortable doing, intravesical treatment, the SWOG BCG protocol. I mean, it follows it to the T. So I think that this is something that I'm hopeful we'll have activity so we could utilize it for our patients.

Zachary Klaassen: Absolutely. No, we'll definitely keep an eye on this cohort as we move forward and likely have you back on to discuss. Any take-home points or final thoughts for our listeners?

Trinity Bivalacqua: Yeah, I mean, I think this is a new disease space. We don't have any FDA-approved agents here because we've essentially just established this cohort of patients that we see. So, this trial will allow us to be able to hopefully identify an intravesical agent that works, that works well, and as you know, the safety profile for this for cretostimogene is excellent. So, I'm hopeful we'll get some good results.

Zachary Klaassen: Awesome. So to our listeners, join the SUO-CTC. This is definitely going to be enrolling quickly. Trinity, thanks so much for your valuable time as always.

Trinity Bivalacqua: Thank you.