portal on your screen, or you can email me directly at mark.frahm@tdsecurities.com, and then I will add those questions into the list as well and hopefully try to get them answered with Mark. With that, maybe, Mark, do you want to just kind of level set people, give a brief kind of state of the company and maybe lay out, like, what the major events over the next 12 months or so that investors should be looking towards?
Yeah. Thank you, Mark. I really really appreciate this opportunity at your summit to be able to talk about Cardiff Oncology and what we're doing here. High level, Cardiff Oncology has an investigative drug called onvansertib. It's highly selective, it's a highly selective inhibitor of PLK1. Tumors, in essence, they hijack, they overexpress PLK1, and PLK1 basically enables uncontrolled growth. Onvansertib is very well-tolerated. It's been demonstrated by seven clinical trials across multiple cancer types with more than 300 patients to be, as I said, well-tolerated. Our lead program, as Mark mentioned, is our RAS mutated metastatic colorectal cancer. And we're currently in the randomized trial and first line, and we expect to have a significant inflection point in H2 of 2024, this year.
Now, in addition to this program, Mark did also touch on it, we do have other exploratory clinical programs in small cell lung cancer, triple-negative breast cancer, and also pancreatic through investigator-initiated trials. For example, in our small cell lung cancer trial, we have shown single-agent activity of onvansertib, that is to say, onvansertib monotherapy, with one confirmed PR with a -50% reduction in tumor from seven initial small cell lung cancer patients. So at a high level, that's really what Cardiff Oncology is doing.
Okay. Thanks for that, Mark. Maybe just to start diving into the KRAS positive colorectal cancer program. Over the past year, you made the decision to kind of pivot from second line into first line. Can you walk through kind of the rationale for that decision, and maybe dive in a little bit more on the mechanisms of that synergy potentially with Bev?
Yeah, absolutely. Well, there was really two major reasons why we moved the onvansertib clinical development program from the second line to the first line. First of all, was the data. So we had a discovery of what we call the Bev-naïve signal from our single-arm Phase 1b/2 trial in second-line KRAS-mutated metastatic CRC. And what I mean by that is that there was a subset of patients that had not received Bev, bevacizumab or Avastin in first line, and those patients in our trial in second line which received onvansertib and FOLFIRI plus Bev had really very high response rates, 73% response rate versus a 16% response rate in those patients had been exposed to Bev before. And so this was really the first of the two major reasons.
The second reason was our Type C meeting with the FDA. The FDA reviewed our data, and their suggestion or recommendation was that given the data, but that we pivot from a second line to a first-line clinical development path. And, you know, they were basing that on not only our data, but also the fact that in first line, all patients are Bev-naïve, and it's a much bigger population of patients in first line that are RAS mutated. And so that was really the main reasons. Now, we went on to, and I think maybe you'll ask me about this later, but also Pfizer saw the data, and they also made the... They offered to work with them in their Pfizer Ignite, their CRO program, which we can talk about later.
But that was really the two major reasons, was the data and the FDA. Now, the actual mechanism that we think onvansertib is synergizing with Bev is really through the hypoxia pathway. It's really what our data indicates is it's a one-two punch. There's really when you look at what we're doing with these patients, they're getting onvansertib, which shuts down the HIF-1 alpha inducibility of the tumor. It inhibits the ability of the tumor to induce the hypoxia pathway. And then secondly, they get Bev, which is a antibody that neutralizes VEGF, which is a growth factor for angiogenesis. So that's really how we think that things are working with onvansertib synergizing with Bev.
Okay. And you mentioned that the signal really seems to be in the Bev-naïve patients.
Right.
But, you know, everyone in that phase, in that Phase 1b was getting Bev. I guess, why does it make sense that the synergy is happening only in a Bev-naïve patient, that it doesn't kind of help resensitize people to Bev once they've already seen it?
Yeah, that's really, this is a really interesting story and a great, obviously a great question. You know, we, we obviously wondered that ourselves, and so we went on to do a relatively large study with a company called Tempus, where we examined 135 patients, in essence, their whole genome transcriptome, all their-- all the genes that they were expressing, through biopsies of these patients... and in essence, compared and exactly mimicked the type of patient, the two different types of patients coming into our trial. Those that got, in first line FOLFOX only, and those that got FOLFOX plus Bev. And so then we compared those two, and what we came out of that was the really, the, resistant mechanisms were apparent for both Bev and for onvansertib.
And the surprise was really that there were resistant mechanisms that we were seeing with the different kind of gene expression gene sets being expressed that were only expressed in those tumors that got exposed to Bev. So I, you know, clearly it's a hypothesis at this point, Mark, but what this data is suggesting is strongly suggesting is that the reason why patients did not have responses that were previously exposed to Bev was because Bev in essence induces a radical change in the biology of the tumor such that new sets of genes are being turned on that enable that tumor to be resistant to not only Bev but also to onvansertib.
Right. So now, based on that signal, you've opened a first-line trial. You wanna walk through the design of that first-line trial that's now open?
Yeah. Right now, our trial is called Cardiff-004. You know, this is a trial that is a randomized trial. It's a 90-patient trial, 30 patients per arm. There's three arms. One arm is a control arm. That is to say, those patients will receive either FOLFOX and FOLFOX plus Bev or FOLFIRI plus Bev. And then also we have two arms of the study drug, of onvansertib. So one of them is at the 20 mg and the other is at the 30 mg. So that's, in essence, the design. At its simplest, simplest, is a three-armed randomized trial, 90 patients, 30 patients per arm.
Okay. Can you provide an update on where you are in terms of site initiation? You know, how many are planned? Yeah, I know it's kind of always a bit of a moving target, but, you know, at the moment, how many sites are planned to ultimately be part of the trial?
Yeah, I mean, right now, as we sit here today, we have 29 sites across the United States. It's a U.S.-only trial. Our plan is to have up to 45 sites, but that number can be a little squishy because if a site is not really performing, that is to say they're not enrolling patients, then we have the right to remove them from the trial. But the goal right now is to get up to 45.
Yeah, I guess along that is, you know, I think early on, you had... maybe it took you a little bit longer than you were hoping to get some of the sites up and running and starting to enrollment. I guess, how has enrollment progressed, you know, now that you, I mean, obviously, you've made real progress with 29 sites open.
Right. Yeah, I mean, we, we're not, we're not giving enrollment data as we go. But what I will say, what I can say, though, is that we are on track to release initial data on about half the patients in the trial, 40-45 patients, in the H2 of this year. And what I mean by that data, it would be that these patients would have at least one post-baseline scan. So that's, that's what our plan is right now, is to release that, that initial data later this year.
Okay. And maybe we'll get, we'll come to that data update in a minute, but just more on the baseline factors. Just, you mentioned, there's gonna be a mix of FOLFIRI, FOLFOX in here. You know, what are you kind of expecting that mix to be? I think there are some some kind of limits on the upper and lower limits for it within the trial design, but kind of what should that mix be in terms of patient population?
Yeah, that's what it is actually is that, I mean, and when I mentioned the three arms, the simplistic sort of trial design of three arms, it's actually the design of the trial is actually six arms, in the sense that they're randomized. Patients are randomized to the chemo backbone. So in other words, in the control arm, there are 30 patients. And within those 30, there'll be 15 that'll get FOLFOX plus Bev, and 15 that'll get FOLFIRI plus Bev. And then likewise, in the patients who get the 20 mg of onvansertib, plus either they'll have the FOLFIRI, Bev or FOLFOX, Bev, both there, 15 and 15 as well, and so on for the 30 mg onvansertib.
At the end of the day, the way the randomization is being set up is to the chemo, so that we have-
Okay
... equal representation of chemo, both chemo backbones, FOLFOX and FOLFIRI, equal representation within each, within all the arms, within each arms.
And based on what you're seeing, kind of screening and enrollment-wise, should we expect... you know, since it's gonna be an interim look, it and maybe not all 6 of those arms are gonna enroll, at the same exact rate. Like, should we expect the population to still be about 50/50 between FOLFIRI and FOLFOX?
Um, yeah-
Or might it be biased one way or the other?
I don't think there'll be that much bias, in all honesty. But, you know, obviously, we're not there yet, as far as the, like, that data. But the expectation is that we'll be pretty close to having equal representation.
Okay, and can what do you view as the bars there? Like, what are you expecting those control arms to do for FOLFIRI, for FOLFOX? And kind of what's a meaningful delta when you start reading out response rate at first? Obviously, later it'll be PFS and other endpoints too.
Right. I mean, based on our feedback from our scientific advisory board, as well as other KOLs that are KOLs within colorectal cancer, you know, they're stating that a meaningful clinical result would be approximately a 20% delta difference between the control arm and the treatment arms. So that's kind of where it is. When you look at the clinical trials that have gone in first line, depending on which trial you look at, the ones that are in the United States, these trials in the United States, you're looking at response rates that are for KRAS mutated with FOLFIRI plus Bev, there was a 38% response rate. For FOLFOX plus Bev in RAS mutated was 44%.
Those are kind of, I'd say, in the forties, is what the expectation would be for the control arm.
So something kind of in the mid-60s or so-
Yeah.
down in surgical arm
Yeah.
Would be interesting. And I guess when you've done that analysis looking, you know, across trials in the colorectal space, you know, response rate has not traditionally been an approval endpoint here. And, you know, but how predictive do you view it as to what's going on, gonna ultimately happen on PFS? You know, is it a very strong correlation? Is it, you know, modest?
I mean, I think it's reasonably strong in the sense that when I say that is because in our meeting with the FDA, they proposed that we do, for our registrational trial, they proposed that we do a seamless trial, one trial for both, the accelerated approval and also the full approval. When we went back and proposed that registrational trial, we proposed that the accelerated approval be based on an interim analysis of ORR and in essence DOR, and they agreed to that. And they said they agreed to us using ORR as a primary endpoint for accelerated approval, with the full approval being PFS with an OS trend in the right direction.
So I think the answer I'd say is that it's been shown that there is a concordance or a correlation with ORR to PFS and OS. But more importantly for us, the FDA has agreed to us using ORR as a primary endpoint for accelerated approval. Now, importantly, that is, that's the registrational trial. That is not the trial that we're doing right now. We're doing the trial that confirms the dose, the Project Optimus, but that is... This trial will lead right into that registrational trial.
Yeah. Okay. And, I guess the triggering event to showing the data is kind of getting to that low 40s number with one scan, or, is there just kind of a hard cutoff also of, "Look, you know, if we get well into H2, we're just gonna cut the data if it's 38 patients, not 40?
Well, I mean, I think that the goal is really around 40-45, and that we think that that's the number that we would need to show the difference, but that's based on our calculations at this point.
Okay. Go ahead.
No, I mean, I think, I mean, the idea, though, you know, the thing to just make sure that we all know is that, understand as a level set, is that, you know, this trial that we're doing today, is obviously important from a point of view of showing a difference between, onvansertib with standard care versus standard care alone, but also importantly is, to be able to go back to the FDA with a dose. So that we have two doses in this trial. We have 20 mg and 30 mg onvansertib. And the goal is to go as quickly as we can back to the FDA with the dose, that is, that is to say, the, either the 20 or the 30.
Obviously, in this trial we're doing right now, we do have a lot of PK analysis as well, ongoing, so that we can make those arguments to the FDA. Because that really, in essence, in addition to the efficacy that we observe in this trial, the other is the dose and being able to, that's the real gating factor for the registrational trial.
When you get this, this data, is there kind of a formal or, or maybe not completely formal, like a futility analysis that will also be done to particularly, you know, across... Because you've got a lot of different comparisons here, right? You've got the different dosages, you've got FOLFIRI, FOLFOX, right? Like, maybe you see a signal on FOLFOX, but not FOLFIRI, or vice versa. Should we expect kind of go, no-go type of decisions to continue the rest of the, of this trial and/or the Phase 3, you know, based on those different subsets, or is that asking too much of 40-45 patients?
Yeah. I mean, at this point, we'll have to see where the data goes. But I think clearly we are de-risking our registrational trial by doing FOLFOX in addition to FOLFIRI in this trial. And the reason for that, of course, is that we wanna explore FOLFOX as a backbone now before going into the registrational because FOLFOX and FOLFIRI, as you know, are both approved for first-line chemo for metastatic colorectal cancer. So it makes sense for us to look at that prior to going into a registrational trial. But you know, these things are all on the table to look at and examine. And of course, a lot of it will depend on how strong the signal is coming from the study drug in this case.
You know, clearly we're looking at all these things.
Okay. And then, as we get through this update, what's likely to be the next update from the trial after this H2 20? Is it response rate from the full, you know, 90 patients? Is it, you know, waiting for PFS data? Just what's the next update there?
Yeah, I mean, I think, you know, what I'd say to you there is that, This trial will continue going forward. We will be looking at ORR, as well as, of course, PFS with time, you know, and, you know, when, as the data matures. And we have not made any public announcement yet of when we would make that announcement of the second announcement of the trial results. Clearly, as we get further into this trial, we'll be able to more accurately predict when we would do that. But, yeah, so that's kind of where we are right now.
Okay. Makes sense. We're running up on time, but maybe in the last few minutes, just, before we leave CRC, you want, you want to walk through what that likely Phase 3 trial design would look like for, the trial?
Yeah, absolutely. Now, what we have presented to the FDA, and they agreed to on the registrational trial, was a very simple design of two arms, onvansertib plus standard of care, versus standard care alone. The situation, depending on how things go with FOLFOX in this trial, it may be, for example, one scenario would be that it's a simple two-arm, you know, design, but with investigator choice on which chemo backbone to use. So these are kind of some of the things as we learn more about FOLFOX in this trial, we'll be able to more hone in on that. But currently, as we sit here today, this is the design that we did present to the FDA, and they liked it.
And so they obviously said, "Come back, with your dose, and, we'll go, we'll go forward from there." But they also, at that time, agreed to ORR being the primary endpoint for accelerated, and then PFS and, and, a trend in OS to be for full approval within the same trial.
Can you remind us, just around the deal with Pfizer's Ignite initiative, just what access they're getting to the data as the trial, as this trial runs, what rights they have or don't have for Phase 3, and maybe also your right to continue using Ignite if you want to, for larger trial, for additional trials?
Right. I mean, what I'd say, first of all, is that it's a great relationship that we do have with Pfizer, and specifically now with Pfizer Ignite. We're working very closely with them on the execution of this current trial, Cardiff-004, that we've been talking about. With Cardiff with the Pfizer Ignite, you know, they in essence they approached us. They approached companies that in essence have a strategic alignment with them and they wanna work with. But having said that, you know, this collaboration, I guess you'd call it, with Pfizer Ignite, they do not have any rights to the molecule. In essence, Pfizer Ignite is... if you can...
The most simplistic view, they are, in essence, our CRO for this trial. So, we pay them obviously cash, for them to execute on this trial. But they do not have. The rest of Pfizer does not have access to our data. You know, there's certainly, but they are truly-- and we've been working with them now for, you know, some time, and they truly are-- that's how it really is. It's really a CRO interaction that we're dealing with with them.
Okay. We're really running up on time, but there are a couple other trials ongoing in additional tumor types. Just can you run us just the timelines for when we might see some data out of those programs?
Yeah, we haven't made any announcements on that yet, Mark. As I did mention, we do have triple-negative, and we do have small cell lung cancer, which we have already made one announcement on. And then we also have two first-line pancreatic trials. All of these are investigator-initiated trials. And I think, as you know, they have different kinds of speed. It's not the same as a sponsored trial by us. So then we're a little bit at their mercy as far as how fast they go, 'cause they are single-site trials. But we, you know, as we get into 2024 a little bit more, I think we should be able to make some guidance on that as far as some of that data.
Okay. Unfortunately, we're out of time, so we're gonna have to cut it off there.
Okay, great.
Thanks a lot for joining, Mark.
Absolutely
... everyone on the line as well.
Thank you, Mark. Appreciate the opportunity.
... Hi, welcome in colorectal cancer, but we may touch on a few other tumor types as well, later in the conversation. So I and my associates have come up with a list of questions that I'm planning on running through with Mark. But we would like this to be as interactive as possible. So feel free for the investors on the line to submit questions, either through the portal on your screen, or you can email me directly at mark.fram@tdsecurities.com, and then I will add those questions into the list as well and hopefully try to get them answered with Mark.
With that, maybe, Mark, do you want to just kind of level set people, give a brief kind of state of the company, and maybe lay out, like, what the major events over the next 12 months or so that investors should be looking towards?
Yeah. Thank you, Mark. I really really appreciate this opportunity at your summit to be able to talk about Cardiff Oncology and what we're doing here. High level, Cardiff Oncology has an investigational drug called onvansertib. It's highly selective. It's a highly selective inhibitor of PLK1. Tumors, in essence, they hijack, they overexpress PLK1, and PLK1 basically enables uncontrolled growth. Onvansertib is very well-tolerated. It's been demonstrated by seven clinical trials across multiple cancer types with more than 300 patients to be, as I said, well-tolerated. Our lead program, as Mark mentioned, is our RAS-mutated metastatic colorectal cancer. And we're currently in the randomized trial and first line, and we expect to have a significant inflection point in H2 of 2024, this year.
Now, in addition to this program, Mark did also touch on it, we do have other exploratory clinical programs in small cell lung cancer, triple-negative breast cancer, and also pancreatic through investigator-initiated trials. For example, in our small cell lung cancer trial, we have shown single-agent activity of onvansertib, that is, that is to say, onvansertib monotherapy, with one confirmed PR, with a -50% reduction in tumor from 7 initial small cell lung cancer patients. So at a high level, that's really what Cardiff Oncology is doing.
Okay. Thanks for that, Mark. Maybe just to start diving into the KRAS-positive colorectal cancer program. Over the past year, you made the decision to kind of pivot from second line into first line. Can you walk through kind of the rationale for that decision, and maybe dive in a little bit more on the mechanisms of that synergy potentially with Bev?
Yeah, absolutely. Well, there was really two major reasons why we moved the onvansertib clinical development program from the second line to the first line. First of all, was the data. So we had a discovery of the, what we call the Bev-naïve signal from our single-arm phase 1b/2 data trial in second-line KRAS-mutated metastatic CRC. And what I mean by that is that there was a subset of patients that had not received Bev-bevacizumab or Avastin in first line, and those patients in our trial in second line, which received onvansertib and FOLFIRI plus a Bev, had really very high response rates, 73% response rate versus a 16% response rate, in those patients who had been exposed to Bev before. And so this was really the first of the two major reasons.
The second reason was our Type C meeting with the FDA. The FDA reviewed our data, and their suggestion or recommendation was that, given the data, that we pivot from a second-line to a first-line clinical development path. And, you know, they, they were basing that on not only our data but also the fact that in first line, all patients are Bev naive, and it's a much bigger population of patients in first line that are RAS mutated. And so that was really the main reasons. Now, we went on to, and I think maybe you'll ask me about this later, but also Pfizer saw the data, and they also made, they offered to work with them in their Pfizer Ignite, their CRO program, which we can talk about later.
But that was really the two major reasons, was the data and the FDA. Now, the actual mechanism that we think onvansertib is synergizing with BEV is really through the hypoxia pathway. It's really a one-two punch. Our data indicates it's a one-two punch. There's really, when you look at what we're doing with these patients, they're getting onvansertib, which shuts down the HIF-1 alpha inducibility of the tumor. It inhibits the ability of the tumor to induce the hypoxia pathway. And then, secondly, they get BEV, which is an antibody that neutralizes VEGF, which is a growth factor for angiogenesis. So that's really how we think that things are working with onvansertib synergizing with BEV.
Okay. And you mentioned that the signal really seems to be in the BEV-naive patients.
Right.
But, you know, everyone in that phase, in that Phase 1b was getting BEV. I guess, why does it make sense that the synergy is happening only in a BEV-naive patient, that it doesn't kind of help resensitize people to BEV once they've already seen it?
Yeah, that's really this is a really interesting story and a great, obviously a great question. You know, we obviously wondered that ourselves. And so we went on to do a relatively large study with a company called Tempus, where we examined 135 patients, in essence, their whole genome transcriptome, all the genes that they were expressing, through biopsies of these patients. And in essence, compared and exactly mimicked the type of patient, the two different types of patients coming into our trial: those that got in first-line FOLFOX only, and those that got FOLFOX plus BEV. And so then, we compared those two, and what we came out of that was really the resistant mechanisms were apparent for both BEV and for onvansertib.
And the surprise was really that there were resistant mechanisms that we were seeing with the different kind of gene expression gene sets being expressed that were only expressed in those tumors that got exposed to BEV. So I... You know, clearly, it's a hypothesis at this point, Mark, but what this data is suggesting is, strongly suggesting, is that the reason why patients did not have responses who were previously exposed to BEV was because BEV, in essence, induces a radical change in the biology of the tumor, such that new sets of genes are being turned on that enable that tumor to be resistant to not only BEV but also to onvansertib.
Right. So now, based on that signal, you've opened a first-line trial. You wanna walk through the design of that first-line trial that's now open?
Yeah. Right now, our trial is called Cardiff-004. And you know, this is a trial that is a randomized trial. It's a 90-patient trial, 30 patients per arm. There's 3 arms. One arm is a control arm. That is to say, those patients will receive either FOLFOX and FOLFOX plus BEV or FOLFIRI plus BEV. And then also, we have two arms of the study drug, of onvansertib. So one of them is at the 20 mg and the other is at the 30 mg. So that's, in essence, the design. At its simplest, simplest, is a 3-armed randomized trial, 90 patients, 30 patients per arm.
Okay. Can you provide an update on where you are in terms of site initiation? You know, how many are planned? Yeah, I know it's kind of always a bit of a moving target, but, you know, at the moment, how many sites are planned to ultimately be part of the trial?
Yeah, I mean, right now, as we sit here today, we have 29 sites across the United States. It's a U.S.-only trial. Our plan is to have up to 45 sites, but, that number can be, a little squishy because if a site is not really performing, that is to say, they're not enrolling patients, then we have the right to remove them, from the trial. But the goal right now is to get up to 45.
Yeah, I guess along that is, you know, I think early on, you had maybe it took you a little bit longer than you were hoping to get some of those sites get up and running and starting to enrollment. I guess, how has enrollment progressed, you know, now that you... I mean, obviously, you've made real progress with 29 sites open.
Right. Yeah, I mean, we're not, we're not giving enrollment data as we go. But what I will say, what I can say though, is that we are on track to release initial data on about half the patients in the trial, 40-45 patients in the H2 of this year. And what I mean by that data, it would be that these patients would have at least one post-baseline scan. So that's, that's what our plan is right now, is to release that initial data later this year.
... Okay. And maybe we'll come to that data update in a minute, but just more on the baseline factors. Just you mentioned, there's gonna be a mix of FOLFIRI, FOLFOX in here. You know, what are you kind of expecting that mix to be? I think there are some kind of limits on the upper and lower limits for it within the trial design, but kind of what should that mix be in terms of patient population?
Yeah, what it is actually is that, I mean, and when I mentioned the three arms, the simplistic sort of trial design of three arms, it's actually the design of the trial is actually six arms in the sense that, they're randomized, patients are randomized to the chemo backbone. So in other words, in the control arm, there are 30 patients. And within those 30, there'll be 15 that'll get FOLFOX plus BEV and 15 that'll get FOLFIRI plus BEV. Also, and likewise, in the patients who get the 20 mg of onvansertib, plus either they'll have the FOLFIRI, BEV or FOLFOX BEV, both there are 15 and 15 as well, and so on for the 30 mg onvansertib.
At the end of the day, the way the randomization is being set up is to the chemo, so that we have-
Okay
... equal representation of chemo, both chemo backbones, FOLFOX and FOLFIRI, equal representation within each, within all the arms, within each arms.
And based on what you're seeing, kind of, screening and enrollment-wise, should we expect... you know, since it's gonna be an interim look, and maybe not all six of those arms are gonna enroll, at the same exact rate. Like, should we expect the population to still be about 50/50 between FOLFIRI and FOLFOX?
Um, yeah.
Or might it be biased one way or the other?
I don't think there'll be that much bias, in all honesty, but, you know, obviously, we're not there yet, as far as the, like, that data. But the expectation is that we'll be pretty close to having equal representation.
Okay. And can... What do you view as the bars there? Like, what are you expecting those control arms to do for FOLFIRI, for FOLFOX? And kind of what's a meaningful delta, when you start reading out response rate at first? Obviously, later, it'll be PFS and other endpoints too.
Right. I mean, based on our feedback from our scientific advisory board, as well as other KOLs that are KOLs within colorectal cancer, you know, they're stating that a meaningful clinical result would be approximately a 20% delta difference between the control arm and the treatment arms. So that's kind of where it is. When you look at the clinical trials that have gone in first line, depending on which trial you look at, the ones that are in the United States, the trials in the United States, you're looking at response rates that are for KRAS mutated with FOLFIRI plus BEV, there was a 38% response rate. For FOLFOX plus BEV in RAS mutated was 44%.
Those are kind of, I'd say, in the 40s, is what the expectation would be for the control arm.
Something kind of in the mid-60s or so-
Yeah
on the onvansertib arm
Yeah.
Would be interesting. And I guess when you've done that analysis, looking at, you know, across trials in the colorectal space, you know, response rate has not traditionally been an approval endpoint here. And, you know, but how predictive do you view it as to what's gonna ultimately happen on PFS? You know, is it a very strong correlation? Is it, you know, modest?
I mean, I think it's reasonably strong in the sense that when I say that is because in our meeting with the FDA, they proposed that we do... For our registrational trial, they proposed that we do a seamless trial, one trial for both, the accelerated approval and also the full approval. When we went back and proposed that registrational trial, we proposed that the accelerated approval be based on an interim analysis of ORR and in essence DOR, and they agreed to that. And they agreed to us using ORR as a primary endpoint for accelerated approval, with the full approval being PFS with an OS trend in the right direction.
So I, I think the answer, I'd say, is that there has been—it's been shown that there is a concordance or, or a correlation with ORR to PFS and OS. But more importantly for us, the FDA has agreed to us using ORR as a primary endpoint for accelerated approval. Now, importantly, that is, that's the registrational trial. That is not the trial that we're doing right now. We're doing the trial that confirms the dose, the Project Optimus, but that is... This, this trial will lead right into that registrational trial.
Yeah. Okay. And, I guess the triggering event to showing the data is kind of getting to that low 40s number with one scan, or is there just kind of a hard cutoff also of, look, you know, if we get well into H2, we're just gonna cut the data if it's 38 patients, not 40?
Well, I mean, I think that the goal is really around 40-45, and that we think that that's the number that we would need to show the difference, but that's our based on our calculations at this point.
Okay. Go ahead.
... No, I mean, I mean, the idea though, you know, keep the thing to just make sure that we all know is that, understand as a level set, is that, you know, this trial that we're doing today, is obviously important from a point of view of showing a difference between, onvansertib with standard care versus standard care alone. But also importantly is, to be able to go back to the FDA with a dose, so that we have two doses in this trial. We have a 20 mg and a 30 mg onvansertib. And the goal is to go as quickly as we can back to the FDA with the dose, that is, that is to say, either the 20 or the 30.
Obviously, in this trial we're doing right now, we do have a lot of PK analysis as well ongoing, so that we can make those arguments to the FDA. Because that really, in essence, in addition to the efficacy that we observe in this trial, the other is the dose and being able to... That's the real gating factor for the registrational trial.
When you get this, this data, is there kind of a formal or, or maybe not completely formal, like a futility analysis that will also be done to particularly, you know, across- because you've got a lot of different comparisons here, right? You've got the different doses, you've got FOLFIRI, FOLFOX, right? Like, maybe you see a signal on FOLFOX, but not FOLFIRI, or vice versa. Should we expect kind of go, no-go type of decisions to continue the rest of the, of this trial and, or the Phase III, you know, based on those different subsets, or is that asking too much of 40-45 patients?
Yeah, I mean, at this point, we'll have to see where the data goes. But, I think clearly we're looking—we are de-risking our registrational trial by doing FOLFOX in addition to FOLFIRI in this trial. And the reason for that, of course, is that we wanna explore FOLFOX as a backbone now before going into the registrational, because FOLFOX and FOLFIRI, as you know, are both approved for first-line chemo for metastatic colorectal cancer. So it makes sense for us to look at that prior to going into a registrational trial. But, you know, these things are all on the table to look at and examine. And of course, a lot of it will depend on how strong the signal is coming from the study drug in this case.
You know, clearly, we're looking at all these things.
Okay. And then as we get through this update, what's likely to be the kind, the next update from the trial after this H2? Is it response rate from the full 90 patients? Is it, you know, waiting for PFS data? What's the next update there?
Yeah, I mean, I think, you know, what I'd say to you there is that, we will this trial will continue going forward. We will be looking at ORR as well as, of course, PFS with time, you know, you know, when as the data matures. And we have not made any, public announcement, yet of when we would make that announcement of the second announcement of the trial results. Clearly, as we get further into this trial, we'll be able to more accurately predict when we would do that. But, yeah, so that's kind of where we are right now.
Makes sense. We're running up on time, but maybe in the last few minutes, just, before we leave mCRC, you wanna walk through what that likely Phase 3 trial design would look like for-
Yeah, there-
Uh.
Yeah, absolutely. Now, what we have presented to the FDA, and they agreed to on the registrational trial, was a very simple design of two arms, the onvansertib plus standard of care, versus standard care alone. What would be the situation, depending on how things go with FOLFOX in this trial, it may be, for example, one scenario would be that it's a simple two-arm, you know, design, but with investigator choice on which chemo backbone to use. So these are kinda some of the things as we learn more about FOLFOX in this trial, we'll be able to more hone in on that. But currently, as we sit here today, this is the design that we did present to the FDA, and they liked it.
And so they obviously said, "Come back with your dose, and we'll go forward from there." But they also, at that time, agreed to ORR being the primary endpoint for accelerated, and then PFS and a trend in OS to be for full approval within the same trial.
Can you remind us, just around the deal with Pfizer's Ignite initiative, just what access they're getting to the data as the trial, as this trial runs, what rights they have or don't have for Phase 3, and maybe also your right to continue using Ignite if you want to, for larger trial, for additional trials?
Right. I mean, what I'd say, first of all, is that it's a great relationship that we do have with Pfizer, and specifically now with Pfizer Ignite. We're working very closely with them on the execution of this current trial, Cardiff-004, that we've been talking about. With the Pfizer Ignite, you know, they, in essence, they approached us. They approached companies that, in essence, have a strategic alignment with them and they wanna work with.... But having said that, this, you know, this collaboration, I guess you'd call it, with Pfizer Ignite, they do not have any rights to the molecule. In essence, Pfizer Ignite is, if you can...
The most simplistic view, they are, in essence, our CRO for this trial. And so, we pay them obviously cash for them to execute on this trial. But they do not have... The rest of Pfizer does not have access to our data. There's, you know, there's certainly, but they are truly. And we've been working with them now for, you know, some time, and they truly are. That's how it really is. It's really a CRO interaction that we're dealing with them.
We're really running up on time, but there are a couple other trials ongoing in additional tumor types. Just, can you run us just the timelines for when we might see some data out of those programs?
Yeah, we haven't made any announcements on that yet, Mark. As I did mention, we do have triple-negative, and we do have small cell lung cancer, which we have already made one announcement on, and then we also have 2 first-line pancreatic trials. All of these are investigator-initiated trials. And I think, as you know, they have different kinds of speed. It's not the same as a sponsored trial by us. So then we're a little bit at their mercy as far as how fast they go, 'cause they are single-site trials. But you know, as we get into 2024 a little bit more, I think we should be able to make some guidance on that as far as some of that data.
Okay. Unfortunately, we're out of time, so we're gonna have to cut it off there.
Okay, great.
Thanks a lot for joining, Mark.
Absolutely
... your wine as well.
Thank you, Mark. Appreciate the opportunity.