CORE-008 Trial Cohort CX: Combining Cretostimogene Grenadenorepvec and Gemcitabine for Bladder Cancer - Trinity Bivalacqua
May 8, 2025
Sam Chang interviews Trinity Bivalacqua about a presentation on the latest arm of the CORE-008 study for non-muscle invasive bladder cancer. Dr. Bivalacqua explains that CORE-008 is a multi-cohort trial similar to STAMPEDE, with different treatment arms that can be added as research evolves. While Cohort A studies cretostimogene grenadenorepvec in BCG-naïve patients and Cohort B examines it in BCG-exposed patients, Dr. Bivalacqua highlights the new Cohort CX which investigates combination therapy of cretostimogene plus gemcitabine in both BCG-unresponsive and BCG-exposed patients. This approach tests two distinct administration methods - concurrent weekly combination for six weeks versus sequential administration alternating the agents. Both physicians note the potential for synergy between the immune-stimulating effects of cretostimogene and the cytotoxic action of gemcitabine, hoping this combination might improve upon the approximately 30% twelve-month response rates currently seen with monotherapies.
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
CORE-008 Trial Explores Cretostimogene Grenadenorepvec for Multiple Bladder Cancer Patient Groups - Trinity Bivalacqua
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
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
CORE-008 Trial Explores Cretostimogene Grenadenorepvec for Multiple Bladder Cancer Patient Groups - Trinity Bivalacqua
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
Read the Full Video Transcript
Sam Chang: Hi, I'm Sam Chang. I'm a urologic oncologist in Nashville, Tennessee, and I'm actually in Las Vegas, Nevada. We've just finished up AUA 2025, and one of the stars there, and one of the stars always, is Dr. Trinity Bivalacqua.
Trinity Bivalacqua: Thank you.
Sam Chang: Trinity, thank you so much for spending some time with us. The AUA has actually attempted to add some more exciting different formats to its sessions. And one of the key sessions is the Trials in Progress, one of the most popular ones in looking at different trials and different disease states, giving, I think, clinicians an idea of what's out there, what may be exciting, what may be occurring. And so you presented a trial in progress looking at one of the new arms in CORE‑008. So I'll stop with that. And basically, tell us about CORE‑008 and tell us about what you presented at the Trials in Progress session.
Trinity Bivalacqua: Thanks, Sam. Yeah, the Trials in Progress allows investigators to be able to essentially introduce new trials and actually provide the rationale of why we did it. Dr. Penson has asked us that we put specifically what are the inclusion criteria? What are the exclusion? How do we come up with the experimental design for that trial? So we were tasked to do that. So the presentation that I gave on CORE‑008 was to discuss the trial in general. It's a multicenter, multi‑cohort trial.
It's kind of like STAMPEDE where you have the ability to introduce a new agent or a new disease state and place it into the trial format. So there's three cohorts currently. The first cohort is looking at the role of cretostimogene, which is an oncolytic immunotherapy given intravesically to patients with high‑risk non‑muscle‑invasive bladder cancer. So cohort A is looking at this in BCG‑naïve patients.
Sam Chang: OK.
Trinity Bivalacqua: And actually, the CIS arm—the CIS plus or minus papillary disease—has already finished enrolling. There's also a papillary‑only disease. Cohort B is actually looking at a new disease state, which is the BCG‑exposed patients. These are patients that have had previous BCG exposure, adequate BCG response, but then, unfortunately, developed a recurrence.
But the reason why we presented this trial at the Trials in Progress is because we actually have a new arm, which is cohort CX.
Sam Chang: OK.
Trinity Bivalacqua: And this is actually looking at two disease states, looking at BCG‑unresponsive disease as well as BCG‑exposed patients. These are patients with high‑risk disease at risk of progression/recurrence. And now we're looking at cretostimogene in combination with gemcitabine, both given intravesically.
So intravesical cretostimogene plus intravesical chemotherapy, that chemotherapy being gemcitabine.
Trinity Bivalacqua: Correct.
Sam Chang: OK.
Trinity Bivalacqua: And there are two arms. So the first arm is actually looking at giving it in combination weekly for six weeks. And then also a second arm, which is looking at sequential administration, where you give cretostimogene for two weeks as a solo agent, then gemcitabine, creto for two weeks, and then gemcitabine. And the goal here is to determine, number one, is there activity? Is it safe?
Remember, this is now—we're introducing another element here, right?
Sam Chang: Right, right.
Trinity Bivalacqua: We're introducing another agent that's given intravenously.
Sam Chang: Very different mechanisms of action.
Trinity Bivalacqua: Very different mechanisms of action.
Sam Chang: Perhaps symbiotic.
Trinity Bivalacqua: Right.
Sam Chang: --but also may result in significant side effects.
Trinity Bivalacqua: Correct
Sam Chang: But could really change our treatment algorithm if we see this combination of a chemotherapy versus a therapeutic agent being beneficial.
Trinity Bivalacqua: Right.
Sam Chang: Really an important study.
Trinity Bivalacqua: Yeah. And I think what it will tell us is that if this—because we've looked at monotherapy, right, and we've actually seen some trials that have looked at systemic combined with intravesical. This will be one of the first trials that will be looking at a combination therapy with two intravesical agents. Now, we can't—we've got to acknowledge those ahead of us, right?
Sam Chang: Sure.
Trinity Bivalacqua: Our forefathers that looked at BCG with mitomycin, BCG with gemcitabine, and actually showed that that's safe.
Sam Chang: Right.
Trinity Bivalacqua: But the activity probably wasn't what we wanted.
Sam Chang: Right.
Trinity Bivalacqua: So the question that we're asking is, can we give this combination therapy? And as you pointed out, potential synergism--
Sam Chang: Sure.
Trinity Bivalacqua: --or is it going to be additive, or is it just going to be a bust?
Sam Chang: Yeah.
Trinity Bivalacqua: Right?
Sam Chang: Right.
Trinity Bivalacqua: We don't know, and that's the goal of this trial. I mean, I've got to say, I'm excited because right now we've got a number of agents that we're using in the BCG‑unresponsive state, but we've got to do better than response rates at 12 months that are, at best, 30%. So this is that attempt to be able to improve upon the response rates and durability of response for many years.
Sam Chang: Yeah, I think that obviously it's appealing to have the different mechanisms' stimulation of the immune system for individual patients, perhaps focused on that individual tumor, but then also tumor death by the chemotherapeutic—the cytotoxic effect of chemotherapy. We have seen gemcitabine effectiveness. We're learning about cretostimogene and its effectiveness, and it just makes sense to have that combination. And I think you're right, historically, the combination never really took off with BCG plus an intravesical therapy.
And a lot of the early data was on mitomycin and it wasn't that great, and there were side effects, et cetera. But better tolerance of gemcitabine, I think, has been understood. And having that combination therapy really is promising. So are we yet enrolling patients? Where are we at in terms of logistics here in early May 2025?
Trinity Bivalacqua: I mean, currently it is being activated. So we haven't started enrolling patients just yet. But it will be activated shortly. Obviously, it's going through the regulatory approvals and whatnot, but this is clearly going to happen, and we're all looking forward to putting our patients into this trial. At least I am.
Sam Chang: Yeah, I mean, the take‑home message is, obviously, a combination—chemotherapy plus cretostimogene—in a patient population that we have some, obviously, FDA‑approved agents, some that we're studying, but uniquely having this combination therapy being presented, and then being able to hopefully see some type of advantage. And I love the dual‑arm of the different treatment schedules.
Trinity Bivalacqua: Right.
Sam Chang: Trying to determine if the timing really does make a difference—that combination, giving the body a little bit of a break, turning on the immune system, then hitting it with chemo. All these questions will, hopefully, be answered by this trial, and I hope and look forward to you presenting, as this trial progresses, what the data look like and what we're learning from it.
Trinity Bivalacqua: Great. Thank you so much.
Sam Chang: Hi, I'm Sam Chang. I'm a urologic oncologist in Nashville, Tennessee, and I'm actually in Las Vegas, Nevada. We've just finished up AUA 2025, and one of the stars there, and one of the stars always, is Dr. Trinity Bivalacqua.
Trinity Bivalacqua: Thank you.
Sam Chang: Trinity, thank you so much for spending some time with us. The AUA has actually attempted to add some more exciting different formats to its sessions. And one of the key sessions is the Trials in Progress, one of the most popular ones in looking at different trials and different disease states, giving, I think, clinicians an idea of what's out there, what may be exciting, what may be occurring. And so you presented a trial in progress looking at one of the new arms in CORE‑008. So I'll stop with that. And basically, tell us about CORE‑008 and tell us about what you presented at the Trials in Progress session.
Trinity Bivalacqua: Thanks, Sam. Yeah, the Trials in Progress allows investigators to be able to essentially introduce new trials and actually provide the rationale of why we did it. Dr. Penson has asked us that we put specifically what are the inclusion criteria? What are the exclusion? How do we come up with the experimental design for that trial? So we were tasked to do that. So the presentation that I gave on CORE‑008 was to discuss the trial in general. It's a multicenter, multi‑cohort trial.
It's kind of like STAMPEDE where you have the ability to introduce a new agent or a new disease state and place it into the trial format. So there's three cohorts currently. The first cohort is looking at the role of cretostimogene, which is an oncolytic immunotherapy given intravesically to patients with high‑risk non‑muscle‑invasive bladder cancer. So cohort A is looking at this in BCG‑naïve patients.
Sam Chang: OK.
Trinity Bivalacqua: And actually, the CIS arm—the CIS plus or minus papillary disease—has already finished enrolling. There's also a papillary‑only disease. Cohort B is actually looking at a new disease state, which is the BCG‑exposed patients. These are patients that have had previous BCG exposure, adequate BCG response, but then, unfortunately, developed a recurrence.
But the reason why we presented this trial at the Trials in Progress is because we actually have a new arm, which is cohort CX.
Sam Chang: OK.
Trinity Bivalacqua: And this is actually looking at two disease states, looking at BCG‑unresponsive disease as well as BCG‑exposed patients. These are patients with high‑risk disease at risk of progression/recurrence. And now we're looking at cretostimogene in combination with gemcitabine, both given intravesically.
So intravesical cretostimogene plus intravesical chemotherapy, that chemotherapy being gemcitabine.
Trinity Bivalacqua: Correct.
Sam Chang: OK.
Trinity Bivalacqua: And there are two arms. So the first arm is actually looking at giving it in combination weekly for six weeks. And then also a second arm, which is looking at sequential administration, where you give cretostimogene for two weeks as a solo agent, then gemcitabine, creto for two weeks, and then gemcitabine. And the goal here is to determine, number one, is there activity? Is it safe?
Remember, this is now—we're introducing another element here, right?
Sam Chang: Right, right.
Trinity Bivalacqua: We're introducing another agent that's given intravenously.
Sam Chang: Very different mechanisms of action.
Trinity Bivalacqua: Very different mechanisms of action.
Sam Chang: Perhaps symbiotic.
Trinity Bivalacqua: Right.
Sam Chang: --but also may result in significant side effects.
Trinity Bivalacqua: Correct
Sam Chang: But could really change our treatment algorithm if we see this combination of a chemotherapy versus a therapeutic agent being beneficial.
Trinity Bivalacqua: Right.
Sam Chang: Really an important study.
Trinity Bivalacqua: Yeah. And I think what it will tell us is that if this—because we've looked at monotherapy, right, and we've actually seen some trials that have looked at systemic combined with intravesical. This will be one of the first trials that will be looking at a combination therapy with two intravesical agents. Now, we can't—we've got to acknowledge those ahead of us, right?
Sam Chang: Sure.
Trinity Bivalacqua: Our forefathers that looked at BCG with mitomycin, BCG with gemcitabine, and actually showed that that's safe.
Sam Chang: Right.
Trinity Bivalacqua: But the activity probably wasn't what we wanted.
Sam Chang: Right.
Trinity Bivalacqua: So the question that we're asking is, can we give this combination therapy? And as you pointed out, potential synergism--
Sam Chang: Sure.
Trinity Bivalacqua: --or is it going to be additive, or is it just going to be a bust?
Sam Chang: Yeah.
Trinity Bivalacqua: Right?
Sam Chang: Right.
Trinity Bivalacqua: We don't know, and that's the goal of this trial. I mean, I've got to say, I'm excited because right now we've got a number of agents that we're using in the BCG‑unresponsive state, but we've got to do better than response rates at 12 months that are, at best, 30%. So this is that attempt to be able to improve upon the response rates and durability of response for many years.
Sam Chang: Yeah, I think that obviously it's appealing to have the different mechanisms' stimulation of the immune system for individual patients, perhaps focused on that individual tumor, but then also tumor death by the chemotherapeutic—the cytotoxic effect of chemotherapy. We have seen gemcitabine effectiveness. We're learning about cretostimogene and its effectiveness, and it just makes sense to have that combination. And I think you're right, historically, the combination never really took off with BCG plus an intravesical therapy.
And a lot of the early data was on mitomycin and it wasn't that great, and there were side effects, et cetera. But better tolerance of gemcitabine, I think, has been understood. And having that combination therapy really is promising. So are we yet enrolling patients? Where are we at in terms of logistics here in early May 2025?
Trinity Bivalacqua: I mean, currently it is being activated. So we haven't started enrolling patients just yet. But it will be activated shortly. Obviously, it's going through the regulatory approvals and whatnot, but this is clearly going to happen, and we're all looking forward to putting our patients into this trial. At least I am.
Sam Chang: Yeah, I mean, the take‑home message is, obviously, a combination—chemotherapy plus cretostimogene—in a patient population that we have some, obviously, FDA‑approved agents, some that we're studying, but uniquely having this combination therapy being presented, and then being able to hopefully see some type of advantage. And I love the dual‑arm of the different treatment schedules.
Trinity Bivalacqua: Right.
Sam Chang: Trying to determine if the timing really does make a difference—that combination, giving the body a little bit of a break, turning on the immune system, then hitting it with chemo. All these questions will, hopefully, be answered by this trial, and I hope and look forward to you presenting, as this trial progresses, what the data look like and what we're learning from it.
Trinity Bivalacqua: Great. Thank you so much.