Cardiff Oncology, Inc. (CRDF) Earnings Call Transcript & Summary

Good morning, and welcome to the Cardiff Oncology KOL Call. [Operator Instructions] As a reminder, this conference is being recorded, and a replay will be made available on the Cardiff Oncology website following the event. I would now like to turn the call over to your host, Dr. Mark Erlander, Chief Executive Officer of Cardiff Oncology. Please go ahead, sir.

Thank you, Sara, and good morning to everyone, and thank you for joining us today for our key opinion leader webinar on onvansertib for the treatment of KRAS-mutated metastatic colorectal cancer. The first key opinion leader, or KOL, to be featured in today's webinar will be Dr. Daniel Ahn, a GI Medical Oncologist and Assistant Professor in the Division of Hematology/Oncology at the Mayo Clinic. He also is the lead investigator for our ongoing clinical trial in KRAS-mutated metastatic CRC. In addition to his role as an Assistant Professor, Dr. Ahn is the lead for the GI Oncology Translational Research Disease Working Group at Mayo Clinic Arizona and serves on the Board of Directors for Academic and Community Cancer Research United, a Mayo-Clinic-supported cancer research consortium. During his presentation, Dr. Ahn will provide an overview of the current treatment landscape in KRAS-mutated metastatic colorectal cancer and benchmark response rates and progression-free survival achieved with the current second-line standard of care, which we believe represents a relevant point of comparison for our ongoing trial. He will also provide an update on patients treated today in the trial. Following Dr. Ahn's presentation, we will be joined by Dr. Manish Sharma, who will review observations from the expanded access program that we initiated last June following receipt of Fast Track designation from the FDA for our clinical program in KRAS-mutated metastatic CRC. Dr. Sharma is an Associate Director of Clinical Research at START Midwest and a Medical Oncologist in Grand Rapids, Michigan. He completed his internal medicine training at the University of California, followed by a combined fellowship training in hematology/oncology and clinical pharmacology and pharmacogenomics at the University of Chicago. Following the presentations by our 2 distinguished key opinion leaders, I will give a company update and discuss our outlook for the remainder of 2021. We will then conclude the event with a Q&A session.

Great. Thanks, Mark...

I'll just...

Next slide.

Yes. Just...

We need the next slide. Put it...

Yes, Vicki.

Mark, you're on mute. Can you please unmute your audio?

All right. So I'll be presenting the results of the Phase Ib/II trial, looking at the combination of onvansertib with FOLFIRI and Avastin for second-line metastatic colorectal cancer. So in today's discussion, we'll be kind of talking about the historical landscape about -- looking at second-line treatment in metastatic colorectal cancer, looking at what we typically would expect to see based off previous clinical trials, the scientific rationale for looking at the combination of onvansertib with FOLFIRI and bevacizumab as well as looking at some of the clinical results from our ongoing clinical trial. And so when you look at historical landscape in terms of patients with advanced colorectal cancer, we know that patient outcomes are relatively poor when patients are found to have a KRAS mutation. We know that KRAS mutations portend to poor prognosis with a high degree of treatment resistance, increased risk for metastasis and worse outcomes. And so when you look historically across several clinical trials, including TRIBE2, the ML18147, we can see that historically for patients with KRAS-mutated colorectal cancer, objective response rates typically are about 5% to maybe up to 10% with a PFS less than 6 months and an overall survival less than 12 months, highlighting the need for more effective treatment option for patients with metastatic colorectal cancer, specifically in those with KRAS mutations. And so when you think about KRAS mutations, currently the only drugs that are really in development are specific for KRAS G12C where we know that the most common mutation of KRAS in colorectal cancer is K12 -- KRAS G12D. These agents are specifically targeting KRAS G12C, as we know, AMG510 as well as MRTX849. But in terms of its efficacy, we know that with monotherapy based on the results where we've seen from these early -- from the early stage of these clinical trials that the response rates are relatively modest with sotorasib having an objective response rate of about 7% and adagrasib having a response rate of 17%. But again, as we know, KRAS G12C only represents a small proportion of KRAS mutation in colorectal cancer, only about 8%, with predominant mutation again is KRAS G12D. There's currently some other interest in looking at other potential ways of targeting KRAS mutations, looking at downstream of the MAPK pathway, including looking at the combination of MEK inhibition with SHP2 inhibitors, which are currently under investigation. Another agent of interest is the SOS1 inhibitor, which they're looking in combination with MEK inhibition. But overall, there hasn't been really much headway in terms of targeting KRAS mutations in colorectal cancer. Onvansertib presents a potential strategy in terms of overcoming KRAS mutations, which will present some of our preclinical as well as clinical results. And so when you look again historically across colorectal cancer, most of our providers tend to use first-line FOLFOX plus bevacizumab, especially when you think about right-sided disease, while second-line options include FOLFIRI plus bevacizumab but in the first-line setting, either could be used in terms of use, but I think most providers tend to use FOLFOX plus bevacizumab based off their comfortability and being a more, I guess, older standard of care. But in terms of frontline therapy, either one is acceptable. But in terms of use of second-line treatment, most oncologists tend to use FOLFIRI plus bevacizumab in the setting. And so when you look at the preclinical data as well as, again, the scientific rationale, we can -- have several reasons why onvansertib may be potentially efficacious in patients with KRAS mutations. And so KRAS mutations -- KRAS-mutant colorectal cancer cells are more sensitive to onvansertib than KRAS wild-type colorectal cancer cells. And preclinical studies, they have shown -- have synthetic lethality in combination with chemotherapy. And so with some of the preclinical studies that have been done, what they've shown is that these KRAS-mutant colorectal cancer cells are not -- are more highly sensitive to PLK1 inhibition specifically with onvansertib. As you know, the MAPK pathway does activate PLK1 via CRAF through the MEK/ERK independent pathway. The downstream target of KRAS, phosphorylated CRAF, localizes to the mitotic spindle poles at mitosis, where it interacts with PLK1 and promotes PLK1 activation, leading to mitosis and tumor progression. So a preclinical data does suggest that KRAS-activated cells are dependent on PLK1 for their proliferation and survival, and innovation of PLK1 by onvansertib could inhibition -- could inhibit tumor growth. So when we look at some of the preclinical studies, we can see that onvansertib is synergistic in combination with chemotherapy with irinotecan and 5-FU. Here, we can see -- both on the left and right, we can see 2 preclinical studies, looking at a combination of onvansertib with irinotecan. And on the right, we can look at the combination of onvansertib with 5-FU compared to just the vehicle. And here, we can see the combination does lead to significant tumor growth inhibition in both treatment groups. These results from the preclinical studies provided the rationale for us to conduct a Phase Ib/II clinical trial. Looking at the combination of onvansertib with FOLFIRI plus bevacizumab in patients with treatment refractory metastatic colorectal cancer, the study did complete its initial Phase I dose escalation and is currently being conducted at these 5 sites. And so in terms of the study design and schema, the study was initially done as a dose escalation study with 3-by-3 dose escalation study where patients received a combination of FOLFIRI plus bevacizumab with onvansertib, where onvansertib was administered on days 1 through 5 of every 14 days. One cycle was determined to be every 28 days. In terms of the primary end point of study, the primary end point was to look at objective response rate in patients who received at least 1 cycle of treatment with progression-free survival and duration of response being secondary end points. And as part of the correlative work, we did look at decreasing KRAS mutation burden and response to treatment. The study was deemed to have a clinically meaningful outcome if greater than 20% of patients achieved an objective response, which was confirmed by radiographic scans and to see a median progression-free survival greater than 6 months. So in terms of our enrollment, here, we can see the total number of patients that were enrolled across the various dose levels, starting at dose level 0 at 12 milligrams per meter squared, followed by 15 milligrams per meter squared, followed by 18 milligrams per meter squared. And based off the DLTs, the confirmed dose was found to be 15 milligrams per meter squared. Here on the right, we can look at the patient demographic and characteristics. The median age of patients that were enrolled in the study were 56 years of age with the equal distribution between males and females. Performance status, the majority of the patients were to have an ECOG of 0, but about 40% of patients were to have an ECOG of 1. When you look at the median number of metastatic sites, majority of the patients have at least 2 metastatic organs involved, and approximately 55% did receive prior bevacizumab. When you look at the treatment-associated adverse effects, we can see that the treatment was relatively well tolerated, with minimal grade 3 or grade 4 adverse events. Five patients had grade 4 adverse events, with 1 patient having grade 4 neutropenia, 4 patients -- and 1 patient having grade 4 neutropenic fever and 4 patients having grade 4 neutropenia. 1 patient did experience some leukopenia, and 1 patient did have hyperphosphatemia, who also experienced neutropenia. Again, onvansertib recommended Phase II dose was confirmed at 15 milligrams per meter squared. Again, overall, the combination was well tolerated with only 11% of these patients having grade 3 or higher adverse events. In terms of the grade 3 or grade 4 adverse events, these were managed through just dose modification or dose delay or growth factor support with chemotherapy, including many patients having their 5-FU bolus discontinued, which was felt to be a major driver of the neutropenia that was observed in the study. No major unexpected toxicities were felt to be related to the investigational agent. So when you -- in terms of when you look at efficacy, here we can look at both the treatment response and duration as well as look in the tumor reduction size. So on the left here, we do have a swimmer's plot, which shows each individual patient and in terms of their response to treatment. Here, we can see that several patients did have a prolonged duration of response with 1 patient who has gone out past 64 weeks prior to disease progression. And here on the right, we can look at the percentage of tumor change for each individual patient. Of the 18 patients evaluated for efficacy, 39% of patients did achieve a partial response that represented KRAS mutations in G12D, G13D, G12B, G12A and A146T, suggesting that irrespective of the mutation at which codon, there is evidence of efficacy across all KRAS mutations. 4 patients did have a confirmed partial response with 1 patient who ended up receiving curative surgery. In terms of individual response, 1 patient with an unconfirmed PR went off study due to treatment-unrelated adverse events. That patient did just decide to come off treatment. Two patients with nonconfirmed partial response currently await results at the time of the next restaging scans. So again, when you look historically compared to an objective response rate within the second-line setting for patients with KRAS mutations which can be expected to see about 5% to 10%, here, we're observing currently 39% of partial response or better. So in terms of duration of response, the median progression-free survival that have been observed at this time was 9.4 months. Again, when you compare again historically to the benchmark of being about 4.5 months, here, you can see a near doubling in PFS in patients in the second-line setting with KRAS-mutated colorectal cancer. And again, in terms of treatment tolerability, we did see the treatment to be well tolerated as well. So in terms of the correlative work as part of the study, we did assess KRAS-mutant allelic frequency burden throughout treatment. KRAS-mutant allelic frequency was measured by digital droplet PCR at baseline and on treatment of days 1 of cycles 2 through 9. 16 of the 18 patients had KRAS mutations detected by PCR at baseline, but all patients did have KRAS mutations that were detected by NGS. And so some of the limitations that can be seen with blood-based assays could be related to the actual shedding of ctDNA into the bloodstream, which may -- which is why only 16 of the 18 patients probably did have detectable KRAS mutation by ctDNA. In terms of clinical responses, they were again observed irrespective of the KRAS mutations across -- whether -- irrespective of whether a patient had a KRAS mutation in G12D, G12D (sic) [ G12V ] or G13D. The greatest decreases in KRAS-mutant allelic frequency after one cycle of treatment were observed in patients that achieved a partial response. So all 7 patients with a PR had a greater than 75% decrease in KRAS-mutant allelic frequency, with 5 of the 7 patients with stable disease that had reduction greater than 75% or more. 2 patients who had progressed showed a modest decrease in KRAS-mutant allelic frequency, about 26% and 55%, respectively. So in conclusion, the combination of onvansertib with FOLFIRI plus bevacizumab was well tolerated in patients that experienced hematologic toxicities. Most of this stuff were felt to be attributable to chemotherapy, which were resolved after the elimination of the 5-FU bolus from the regimen. The MTD was determined to be 15 milligrams per meter squared, which is the current dose being used in the Phase II trial. In terms of the early results for efficacy, 39% of patients had an objective response of a partial response or better, including 4 confirmed PRs and 2 patients with upcoming confirmatory scans. The median PFS that was observed was 9.4 months, which is greater than twofold increase compared to what was historically observed in previous clinical trials. And 7 of the 18 patients remain on treatment to date. In terms of the correlative studies, the clinical responses were observed across different KRAS variants, including the 3 most common observed in colorectal cancer. And in patients that achieved a clinical response of stable disease or better, they showed the greatest decrease in plasma mutant KRAS after the first cycle of therapy. And so to put things into perspective to show what we've been actually observing in the clinical trial, we'll kind of review one of the patients who have been on study. And so this is a patient who was 83 years old with a KRAS G12D mutant metastatic colorectal cancer. In terms of her treatment history, here, we can see that she previously did receive FOLFOX followed by maintenance 5-FU plus bevacizumab. And while on maintenance chemotherapy, she did experience disease progression and was enrolled in a study to receive FOLFIRI plus bevacizumab in combination with onvansertib starting on November 2020. In terms of treatment, her treatment was relatively well tolerated, but she did experience grade 4 neutropenia where treatment was held and subsequently had her 5-FU bolus discontinued. On cycle 3 of treatment, she did experience neutropenia, which did lead to treatment delays and treatment reduction in her 5-FU and irinotecan. In terms of her radiographic and clinical response, here, we can see the initial restaging scans in January 2021, she did experience stable disease with the 16% reduction in her -- size of her metastatic lesions. At the time of her second restaging scans at 16 weeks, she did achieve a partial response with 39% reduction in her tumor size and her metastatic disease. So here, we can see -- on the right, we can see her baseline scans. Here, we can see these peritoneal lesions that started at 16.1 millimeters and, at 8 weeks, decreased to 12.4 millimeters. And subsequently at 16 weeks, we can see a reduction at 8.9 millimeters. And on the right, we can see the similar findings in another metastatic lesion. As part of the corollary work, when you look at the graph on the left, we can also see a nice correlation and decrease in our KRAS-mutant allelic frequency. And we can see a near threefold decrease to nearly being undetectable by the time she went on to receive cycle 1 -- cycle 5 day 1 of treatment. And so just those -- to put these things in perspective. The study is still ongoing, where we're seeing a lot of promising results. And hopefully, we continue to see these results from the study. I'm going to turn it over now to Dr. Sharma.

Thank you. Thanks for having me as part of this program. It's an honor to be able to present some of our data. These data, by the way, have been submitted as an e-poster for the American Association for Cancer Research, AACR, meeting that's actually ongoing currently. So I think they just became public, these slides did, with my verbal presentation a couple of days ago. So you can feel free to view those through the AACR website as well. But we're going to talk about the expanded access program that was opened up for onvansertib in collaboration with Cardiff Oncology. And the idea here is to talk about heavily pretreated patients that were given access to the drug in combination with FOLFIRI and bevacizumab, and we'll show some data that we've collected on those patients as well as go through a case report that highlights some of the potential for this combination. So we can go on to the next slide here. So just as a way of background, we really do need better treatment for heavily pretreated patients with metastatic colorectal cancer. What we know is that after you get through the first couple of lines of therapy, third line or later lines of treatment have quite poor outcomes. And what we know is that there's a couple of therapies that are approved in this setting. One is regorafenib, also known as Stivarga. Another one is trifluridine/tipiracil, also known as Lonsurf. These are therapies that are approved actually for KRAS-nonmutated as well as KRAS-mutated patients in the third line or greater setting. But these -- even with these agents available, we know that median progression-free survival is around 2 to 3 months and median overall survival in the range of 6 to 9 months. So there's definitely a need for better therapies in the setting for these patients. And although most patients have previously received FOLFIRI, the expanded access program was made available to provide the opportunity for these patients to receive potentially clinical benefit with the addition of onvansertib to a FOLFIRI plus bevacizumab backbone regimen. We can go on to the next slide here. So the EAP, as far as the eligibility goes, was a little bit different than the clinical trial that Dr. Ahn presented. These were patients, of course, with metastatic or unresectable colorectal cancer with confirmed KRAS mutation, and participants had to have progressed on multiple lines of prior therapy, including prior FOLFIRI. So that's one major difference. That was the Phase Ib/II trials in the second-line setting. The EAP is really more for patients in the third line or greater setting. Then participants are not eligible for the ongoing Phase Ib/II trial in order to be on the EAP. The treatment that they received was onvansertib at 15 milligrams per meter squared plus the FOLFIRI and bevacizumab backbone, and there was an option to eliminate the 5-FU bolus, which at least in our patients here, at Cancer & Hematology Centers of Western Michigan, we did eliminate that bolus in most of our patients. The aims here were to evaluate the safety of the combination as well as to have exploratory objectives around progression-free survival, changes in plasma KRAS-mutant allelic frequency that we talked about previously as well. And this, on the right side of the slide here, is just a graphic representation of the study design. The onvansertib is given on days 1 through 5 of the 14-day treatment course, whereas the chemotherapy, of course, is initiated on day 1 of each 14-day treatment course, and that's FOLFIRI and bevacizumab. As far as the enrollment goes, this was -- these data were as of now actually, April 12. But there's been 45 patients treated. 20 of them had reached the first on-treatment CT scan and had results available at the time when we kind of looked at these data for AACR cutoff. And 2 had discontinued treatment prior to the first CT scan. So we've got data from at least about half of the patients that have been treated on the EAP that we're presenting here. We can go on the next slide. So these are the safety and clinical benefit data. As far as safety goes, the onvansertib in combination with FOLFIRI and bevacizumab has been very well tolerated. No serious adverse events have been reported on any of these participants, which is great news and consistent with what we saw as well with the -- on the clinical trial. As far as clinical benefit goes, there's 20 participants that have been evaluated for clinical benefit. They had a median number of 3 lines of prior treatment. So as I said, these are a little bit more heavily pretreated patients compared to the clinical trial, and 65% of them are progressing prior to enrolling in EAP on their prior therapy. These patients, as you can see here, look somewhat similar otherwise to the ones that we saw in the clinical trial, age of a median of 50, 3 prior lines of therapy in terms of the median and in terms of -- about 75% of patients had received prior irinotecan-based regimen at their last therapy just before going on the EAP, and 65% of them were progressing just prior to enrolling. They had a -- on the study, these participants had a median PFS of about 5.6 months. And you can see the confidence interval ranging between 2.7 up to the upper bound, which has not been reached yet. And 11 of these 20 patients remain on treatment to date, which is a pretty remarkable number. So you can see we got right to the median there and that kind of stayed there flat from that point. So it will be interesting to see how these data mature as time goes by. We can go on to the next slide here. As far as changes in plasma KRAS-mutant allelic frequency, this was very interesting in that we were able to see that the changes did correlate with outcomes of the patients, the participants on the study. And you can see this was measured by ddPCR, very similar technique as to what was used in the clinical trial, both at baseline as well as at the end of cycle 1 in all the patients that were evaluated for clinical benefit. And 16 of these 20 participants had a variant that we could detect at baseline. And what we did was stratify these participants into 2 groups. So we had the group that had a greater than 50% decrease in their KRAS MAF after the first cycle and then another group that had a less than 50% decrease. And as you can see, these are small numbers. 10 participants had a greater than 50% decrease, and 6 had less than 50% decrease. But you can see the stratification here in terms of the progression-free survival with the patients who had a greater decrease in the KRAS MAF being -- having a better progression-free survival or longer progression-free survival. And the numbers are shown here on the right side of the slide, where we haven't reached the median PFS in the group that had a larger decrease, whereas the participants that had a smaller decrease had only a median PFS of about 2.6 months, which is right around what you would expect based on the data that have been collected in other third line and greater clinical trials. We can go to the next slide. So I wanted to go over a patient case report that highlights again, similar to Dr. Ahn's patient, some of the potential of this combination. This is -- we can go to the next slide here. Can we move forward on the slide, please? Here we go. I might have skipped one. Here we go. So this is our participant. This is actually my patient here at Cancer & Hematology Centers of Western Michigan. This was a 61-year-old woman with KRAS G12V metastatic sigmoid colon cancer. As you can see, she was diagnosed back in April of 2017, initially had surgery followed by adjuvant chemotherapy with FOLFOX. In 2018, she progressed to having metastatic disease and was treated with first-line therapy for metastatic disease with FOLFIRI and bevacizumab, actually had a good response to that treatment at that point but then eventually had disease progression and ended up going on a clinical trial with trastuzumab and pertuzumab because she had HER2 amplification in her tumor. And then she ended up going, subsequent to that after progressing, on a Phase I trial of a drug called zotatifin, which is a selective inhibitor of mRNA translation that's available through our Phase I program here at START Midwest. Unfortunately, she had disease progression with -- and lung metastases on that study. And so at that point, we decided to enroll her in the EAP program with onvansertib plus FOLFIRI and bev. As you can see, she received several prior lines of treatment, including FOLFIRI and bev and had progressed just prior to going on study. She received the onvansertib at the 15 milligram per meter squared, the RP2D that was determined from the Phase Ib/II trial. We can go on to the next slide here. So these are some images from our CT scans as well as data from her KRAS MAF. So what was interesting here is that at about -- at the 8-week CT scan, we started to see a decrease in the size of her numerous lung metastases. On the upper panel here, you can see a decrease in size of her lung metastases at 8 weeks; and then again at 16 weeks, further decrease. And in the lower panel here, you can see some of these lung metastases that actually became a little bit necrotic. We call it -- the appearance of these tumors is such that they look a little bit hollowed out, which is how dead tumor typically will look on a scan. And we saw that at 8 weeks as well as at 16 weeks. So this was a great response to treatment, certainly something that I would consider equivalent of a partial response on -- for this patient. And the decrease in tumor lesions were accompanied by a decrease in KRAS MAF. She had, at baseline, an MAF of about 1.4%. That decreased essentially to undetectable levels, 0%; and at the same time had a decrease in her CEA from 24.4 nanograms per milliliter at baseline to 4.6, which is essentially in the normal range for CEA. So she's doing really well. This patient actually remains on study to date. And we see her every couple of weeks, so when she comes back for treatment. She's clinically very well, living an active lifestyle and very grateful for the opportunity to have been on the study. So hopefully, this is the first of many successful cases that we'll have. So this is a summary. So treatment on the EAP has been well tolerated with no SAEs reported to date. As of the AACR cutoff date, we've had 20 participants with a median of 3 or more prior therapies evaluated for clinical benefit. And the median PFS was 5.6 months, 11 of those 20 participants remaining on treatment to date. And we think this is certainly an improvement over what would be expected in terms of historical controls for median PFS. Changes in plasma KRAS MAF have correlated with clinical benefit with patient participants who had greater than 50% decrease in the KRAS MAF having a significant increase in their PFS compared to those who had a decrease of less than 50%. So this is a promising data. And certainly, we were very grateful to have been part of the study, to be able to offer this to our patients. We're also grateful to Cardiff Oncology for selecting us as a site for the expansion of the Phase II trial that's going to be coming up. We hope to be able to contribute many, many patients to that study as well and hopefully continue to see success with this novel agent. So thanks for your attention.

Okay. Thank you very much. Thank you, Dr. Sharma, and also thank you, Dr. Ahn. Now I will turn and talk to you about really a corporate update and our outlook for 2021. Next slide, please. So really, when you look at our strategy, we're really transforming to lead the way, and we really are -- really look at corporate and clinical development and our research as we look forward into 2021. First of all, in corporate, overall, we are really undergoing a corporate transformation that's going to position Cardiff for long-term success. As some of you may know, we're accelerating our corporate governance to best practices. We started with a new CEO leadership, that is me, about a year ago. We've also had Board evolution and updated policies. Currently, we are seeking -- we're in the middle of recruiting both a CFO and a CMO and later looking for a CSO. And we are, of course, very committed to investor communication transparency and disclosure. Now in the clinical development, we are really -- we are leveraging onvansertib in combination with targeted therapeutics and chemotherapies across multiple cancer indications. We have the most advanced PLK1 inhibitor. We're developing strategies to enable the most rapid path to approval, and we are focusing on opportunities to lead the drug-ability enhancement of KRAS-mutated cancers. As well, I'll talk a little bit about our research. PLK1, as an enzyme in cell division, is a key enzyme. It's really at a unique nexus within the convergence of many tumor-promoting pathways. And really, we're also -- we're really leveraging our -- also our deep expertise in translational biomarker integration within our clinical programs. And we are focusing now, in 2021, on pipeline expansion through synergistic combinations that we find through our preclinical research. Next slide, please. This is looking at us at a glance at Cardiff. We are based in San Diego. We're a clinical-stage biotech company. You've been hearing all about what we're doing in colorectal cancer. We raised significant amount of cash in Q4 of last year. As of the end of the year, publicly, we've disclosed we have $131 million in cash. And our burn rate is around $16 million per year. Next slide. So I should just mention it's obvious that we're well-funded. We're well-funded to do the programs that we're talking about here today. This shows you really our key anticipated catalysts, which really go into 3 different buckets. One is that we will be participating throughout the year at different health care conferences. Also, we will be going to scientific and medical conferences. In particular, we will be giving an -- our next update on the colorectal cancer trial will be at ESMO in September. And also, we will give an update on our castrate-resistant prostate cancer program toward the end of October at the Prostate Cancer Foundation Retreat. We also are planning to meet with -- the end of Phase Ib meeting with the FDA in the June, July time frame. And the other thing that I should mention as well is that -- and I'll talk a little bit more about it, but we do believe that we will have our first patient enrolled in the pancreatic trial, which I will just mention right now is that Dr. Ahn is the principal investigator of that trial. Now let's talk a little bit about the Ib/II ongoing and the patient accrual anticipated timing results. We have really significantly increased the number of sites from 2 sites that we started with, which was really just USC and Mayo Clinic Arizona, now to 7. The -- our first patient enrollment in the Phase II was in early February of this year. Already to date, we have 16 patients enrolled that are either already on treatment or in screening. We do anticipate efficacy data of around -- greater than or equal to 30 patients, which would include -- including the Ibs and the IIs in that at ESMO. Next slide, please. As far as our regulatory path, there are really 2 scenarios that we're looking at as far as we're preparing to meet with the FDA. And really, the FDA Fast Track designation does provide us the opportunity to accelerate our clinical development. The scenario 1 would really be a single-arm trial, which in essence would be an expansion of our existing Phase II. Per protocol, we will have 26 patients on the Phase II part of our trial today, our current trial, and this would then be proposing that we would actually expand that to about 87. So that's really the -- this, of course, would then -- the primary end point here would be objective response rate and duration of response. The other scenarios on the next slide were -- what we'll be looking at there is a randomized trial. And you can see here that this would be a more conventional approach where we would have a randomized trial in second line with the treatment arm being the onvansertib plus FOLFIRI/bev versus the standard of care, FOLFIRI/bev. Here, the primary end points would be PFS and secondarily would be overall survival. Next slide, please. One thing I wanted to do as well, while I'm talking about what we're doing in 2021, is just talk a little bit about our metastatic castrate-resistant prostate cancer program, which is really at the 3 Harvard hospitals. The next slide really talks about the unmet need, which is really the fact that patients who are castrate-resistant -- have castrate-resistant prostate cancer do develop resistance to anti-androgens. And so really, the question is what can we do about this? And of course, what we're doing is that we have extensive amount of preclinical work in our collaboration with MIT showing that there is synergy between abiraterone, or Zytiga, and onvansertib. So briefly here, we have a Phase II ongoing trial. Arm A, B and C, as you can see, are just really, in essence, different dosing schedules where you go from Arm A to Arm C. You're increasing your dose density. Arm C is the greatest amount, which is 14 days on in a 21-day cycle. The next slide shows you the -- some of the data. So you can see here that in Arm A, B and C, if you look at disease control, which is the primary end point, we do see a significant uptick in Arm C, where we have the greatest amount of dose density. And so we're also seeing activity in the different antigen receptor alterations as well. So this is -- we're very excited about these data and particularly in the Arm C, where we are seeing even a greater amount of activity. The next slide. And with that, we've also -- at AACR, just a couple of days ago, we released a poster where we're working with MIT on. And we really are unraveling the mechanism underneath the onvansertib/abiraterone synergy. Not only that, we've identified a signature. We're working with Decipher Biosciences to really now assess that signature that we have identified with MIT to see whether or not this will track and will predict responses within our current ongoing Phase II trial. So exciting days here for this trial, and stay tuned, and we will be giving you an update on this in Q4 of this year. The next slide talks about the metastatic pancreatic ductal adenocarcinoma trial. This -- as I mentioned earlier, Dr. Ahn is our principal investigator for this trial out of Mayo Clinic. But also, we have other institutions as well involved. Shout out to the University of Kansas as well as the University of Nebraska Medical Center. Next slide. Here in second-line therapies are greatly needed, currently in second line with standard of care, irinotecan plus 5-FU. The response rate is 7.7%, and the PFS is 3.1. So we are here. What we're doing is we're leveraging that synergy that we've already observed in the colorectal cancer trial. We are looking at that synergy as well in second-line PDAC or pancreatic cancer. Next slide. And the trial here will be -- the schema here will be every 2 weeks or 14 days, will be 10 days on and 4 days off. The -- our primary end point will be ORR, objective response rate. And a clinically meaningful outcome would be greater or equal to 20% patients receiving -- or achieving an ORR. Next slide. And one thing I should mention -- I should have mentioned is that we -- I mentioned a little earlier, but we think that we will have our first patient dose there in May. And so we're very excited about being able to present some of that data. But realistically, we probably will have our first peak at that at ASCO-GI in 2022. The other thing I want to talk about is leading with research and data. And so we're also really amping up our preclinical studies here at Cardiff. Here, I'm showing you that we are doing an extensive amount of PDX models in collaboration with MD Anderson. And what we're doing here is we're looking at different combinations within the KRAS-mutant tumors as well as looking at KRAS wild-type tumors within them. So in the KRAS-mutant, we're looking at combinations with oxaliplatin with the SHP inhibitors, the G12C inhibitors and also looking at irinotecan-resistant tumors. Also, we're looking at, like I said, in combination with EGFR. So stay tuned. We'll be reporting out some of this work probably toward the end of this year in Q4. But really, the other thing that I want to talk about is that we're seeing a lot of activity with -- in combination with PARP inhibitors. And here, as you know, PARP inhibitors are approved for ovarian, breast, prostate and pancreatic. And although initial responses to PARP inhibitors is high, patients will develop resistance. And the mechanism of resistance are -- one of the major ones is the restoration of the -- what they call the homologous recombination repair. And what -- I won't go into all the science, deep science here, but really, PLK1 facilitates this homologous recombination. And so if you can inhibit this, then you can -- in essence, the theory is that you can resensitize tumors to a PARP inhibitor. And the next slide shows the first data that we've seen on this in ovarian cancer. And we're really seeing -- we're very excited about these data. What you're looking at is a couple of markers there on the bottom. It's showing an almost threefold increase in the overall survival in this preclinical model when you add the combination of onvansertib with a PARP inhibitor, olaparib. And so this is really showing that -- and this is a PARP-resistant PDX model. And you can see then that the combination is really -- in essence, by adding onvansertib, you can resensitize that PARP inhibition. So stay tuned for this as well. This, of course, could open up some other really huge areas, particularly in prostate cancer as well as in ovarian as well as in breast cancer. Next slide. And I think that's it. We really appreciate all of this -- you listening through this. And I think now I will turn it back over to Sara, the operator for the Q&A part of this KOL event. Thank you.

Thanks, Mark. So at this time, we'll be conducting our question-and-answer session. [Operator Instructions] And please hold while we poll for questions, and then we'll turn it over to Vicki to read those questions.

Okay. If everybody is ready. The first question is directed at Dr. Ahn. Dr. Ahn, if you would -- could you speak to your level of comfort taking the 15 mg per meter squared of onvansertib as the move-forward dose both in terms of safety and efficacy?

Yes. So in terms of the first question in terms of safety, which I think is just as important as efficacy, I'm very comfortable using it. In terms of the treatment-associated toxicities, I thought a lot of it was actually attributed to chemotherapy. And so unfortunately, as part of potential registrational study, we did include 5-FU bolus. While in practice, most of us don't give 5-FU bolus or leucovorin given the probably minimal efficacy as well as the short half-life of leucovorin, in practice, most of us don't tend to give it. But it can contribute and it's been associated with a high degree of neutropenia, which we observe in clinical practice on -- off-study as well as in the trial. So I thought a lot of these treatment-associated toxicities were actually from the chemotherapy backbone rather than the investigational agent, which as soon as we decrease or discontinue the 5-FU bolus, the neutropenia did resolve. So in terms of safety, I'm not really concerned. I do think that 15 milligrams per meter squared is the right dose. In terms of efficacy, I would also agree with that. I don't know if there's really much added value from going to the 18 milligrams per meter squared because we did see response even at dose level 0. And so I'm very comfortable in terms of that as the dose for efficacy. And so I think moving forward, I think both the colon cancer study as well as the upcoming pancreas cancer study, I do feel that 15 milligrams per meter squared is the right dose.

Great. Thank you, Dr. Ahn. And thank you -- that question was from Joe Catanzaro from Piper Sandler. And just adding on to that, another question that Joe posed is for you, Dr. Ahn. Can you speak to the patient to whom you discussed as the case report and that patient's ability to tolerate the regimen post the irinotecan and 5-FU dose reductions?

Yes. So the patient continues to tolerate it well, which is kind of what we experienced across kind of all the patients enrolled in the study. So despite her advanced age, I think it's not the age. It's the mileage, right? And so in terms of patients who are -- adequate candidates not only go on chemotherapy as standard practice or clinical trials. She was an appropriate candidate and she continues to tolerate treatment well. So I don't think that [ dominance ] added really any additional toxicities or affected her quality of life, and she is doing -- she continues to do fine. She's a very robust 80-year-old.

All right. Thank you, Dr. Ahn. The next question is for Mark Erlander from Marc Frahm at Cowen. Enrollment in the Phase II seems to be going very well with 9 patients on drug and waiting for their first scan. How big of an update should we expect at ESMO?

Yes. Thank you, Marc, for asking that. Well, right now, what we anticipate is that we have -- as we sit here, we have 16 patients in the Phase II part, and we do anticipate that we will have, total -- including the Ib patients, we'll have a total of greater than 30 patient update at ESMO.

Thanks, Mark. And just also somewhat along the same lines from -- also from Marc Frahm. What are the key issues you hope to gain clarity on at the end of Phase Ib meeting this summer with the FDA?

Great question. Yes. I mean I think the most important thing that we are looking for there is guidance through the regulatory path. As I mentioned, we have a couple -- 2 different scenarios we're looking at. But really, our objective at that meeting will be to get a regulatory guidance and be able to then start to execute on that regulatory path.

Great. Thank you. Next question is to both Dr. Ahn and Dr. Sharma from Joe Catanzaro from Piper. Dr. Ahn and Dr. Sharma, what do you see as the value of the KRAS-mutant allelic frequency data and potential future utility of this assay? Are you using it currently in any way to dictate treatment decisions?

I -- so I can go first. I'm on the study now. I think it's really a proof of the potential targeting of these. I think -- so I think 2 things. One, when you look at ctDNA in general, I think there are various different ways to use it. One specific in this study would be -- is a patient -- is this predictive potentially of the response and decrease in the KRAS -- decrease in KRAS-mutant allelic frequency suggest that it is targeting KRAS-mutant cells, which I think it is. Typically, we do see a predictive value where we do see a nice decrease in the mutant allelic frequency prior to seeing the results on the scan. So there does appear to be an association. I think, two, what will be more interesting as it continues will be -- as the study progresses, one way that we could look at this result is if we identify other mutations of interest that could potentially be mutations of secondary treatment resistance. And so that's something that we typically do with other treatment options. Like when patients receive anti-EGFR monoclonal antibody therapy and we continue to check serial ctDNA samples, we can see emergence of new resistance markers, such as MET amplification or HER2 amplification. And so along those same lines, I think that potentially may be some added value, but it does not necessarily drive my treatment decision at this time because typically, with the -- what we see from the [ CTD ] assays, they typically have a lead time before we see any kind of biomarker-related changes like CEA for at least 4 months. And even CT scans, it could be a lead time of even up to 8 months. And so -- but it is, again, a proof of concept showing that it is targeting the KRAS as a potential as -- targeting KRAS and a nice association with what we tend to see from the clinical outcome as well.

Yes. I think that -- to jump on with that, I think that the assay is really helpful in guiding our path forward. One example, as I showed in our case report, was our participant who had her MAF go down to 0, and that correlated with what we saw in the scans and in the CEA as well. We treated a total of 5 patients on the EAP at our site here. And so we saw different outcomes with respect to the KRAS MAF, and we had some patients who didn't have any decrease. And those patients progressed rather quickly. We had 1 patient whose MAF went down and then went back up. And I -- the way I use that clinically in my -- when I -- because on the EAP, we have a little bit more freedom in how we do things. But on that -- in that patient, when I saw the MAF go back up, I ordered a CT scan a little bit earlier than otherwise was planned, and sure enough, that showed progression. So I think it was helpful maybe as a marker. As Dr. Ahn is saying, we don't know what the timing is, what the lag time might be between changes in ctDNA and what we might see on a scan. But it does seem to be indicative of proof of concept here that we are affecting the KRAS mutational burden and that, that is the mechanism of action by which this drug may be working. So I think it is helpful. It would be interesting to get more data. And certainly, when you have a trial that's going to get up to 100 patients total to look at that correlative data from the ctDNA will be very helpful. We'll have numbers to really make heads and tails out of this.

Great. Thank you, Dr. Ahn and Dr. Sharma. The next question is directed to you, Dr. Ahn. It's from [ Andy Hsieh ] from William Blair & Company. Dr. Ahn, in your experience, following treatment with the onvansertib-containing regimen, are patients more likely to be eligible for subsequent therapy versus existing standard-of-care treatment?

So in terms of the existing standard of care, meaning to go on to potentially receive regorafenib or TAS-102, yes, these patients that have come off study either due to, in most cases, progression or in some cases just due to patient preference, they've been able to receive third and fourth-line therapy. So these associated side effects from the drug hasn't prohibited any treatment for them to receive any further therapy. In terms of enrollment to other potential clinical trials, it hasn't been an issue. So at the Mayo Clinic, we do have a vast array of studies similar to probably what Dr. Sharma has at START. And so we do have some other studies looking at targeting KRAS where patients have been able to get on a study. So it hasn't been prohibitive of that in any way.

Great. Thank you. Mark, this is to you from Joe Catanzaro. For the company, any expectations that the FDA would like to see the initial Phase II data before committing to a potential single-arm accelerated test? What are the KOLs' views also of an appropriate development strategy based on data to date. So Mark, maybe you can start, and then we can also ask Dr. Ahn and Dr. Sharma to chime in.

Sure. I mean I can start. I mean clearly, we're -- when we meet with the FDA, we will not have mature Phase II data from this trial. I expect that they probably will want to see more data. But I think on the other hand, I think we're starting the conversation with them, and I think that's really important so they can see what we've accomplished so far. And I think we can get a good read from them from that already, but I do believe, yes, of course, they will want to see more data as well.

I guess...

Dr. Ahn, Dr. Sharma?

So I can go first. I guess in the ways in terms of drug approval from the FDA at least in oncology, lots kind of have changed historically probably over the past several years where we would typically see a drug going from Phase I to randomized Phase II to eventually a randomized Phase III for confirmation mainly because of the -- highlighting the unmet need. Drugs are now getting approved from Phase Ib, especially for those where there are limited treatment options, and I think KRAS-mutant colorectal cancer would fall under that category where we see drugs; and hepatocellular carcinoma, HER2 amplification, some of these novel-targeted areas, such as like FGFR fusions, where drugs are getting approved just based off Phase Ib or Phase II data based off their high objective response rate to what is historically observed. It really just depends on the balance between the consideration of unmet need and limited treatment options versus what has continued to be seen in studies. So I think with the benchmark of 40% if that continues to flow through in the Phase II, which I think we're all hoping for, for our patients, and I think there's a realistic possibility that it could be looked at favorably.

Yes. I would agree with that. I think that ultimately, a randomized trial is going to be necessary. I think the question would be -- I'm not obviously an FDA representative to be able to speak on that. But I think even if you did an accelerated approval based on Phase II data that was non-randomized, I'm sure the requirement from the FDA would probably be to conduct a subsequent randomized trial. And in this case, probably the natural one would be FOLFIRI and bev versus FOLFIRI/bev plus onvansertib to show that your investigational drug is actually adding something to the chemotherapy backbone. And so I think that's probably where the future of where things are going. But I think the Phase II data will be very interesting to look at. And if it's quite positive as it's been trending, then I think I could -- I wouldn't be surprised to see an initial approval based on that.

Great. Thank you. Dr. Sharma, another question from [ Andy ] at William Blair. For patients with concurrent mutations, HER2, KRAS, EGFR, for example, which one would you address first? And what would you need to see from the KRAS field so that it could be elevated to similar status as the more established EGFR, HER2 mutation?

Sure. Well, we know that the interesting data that have been accumulated regarding HER2 in colorectal cancer are that you can get HER2 mutations in KRAS-nonmutated as well as KRAS-mutated cancers. However, it looks like the utility of targeting HER2 is greater in patients that are KRAS-nonmutated. And that's based on data that's been collected on using agents like trastuzumab and pertuzumab on the taper trial and some of these other trials as well, but we know that these behave differently. So we think the KRAS mutation is sort of an early mutation in these cancers and really a driver of their biology. And therefore, I think we're all pretty interested in targeting KRAS, if possible. We really haven't had good agents to target KRAS in the past, and that's why I think onvansertib is sort of -- could be a potential game changer in that way. So I think that we would all -- if something were available, we'd want to target that KRAS mutation early and earlier the better. And you could still look at some of those other mutations later. But that's how I look at it with respect to other ones. Like HER2 or FGFR, they're all relatively less frequent as well compared to KRAS.

Thank you. Switching gears a little bit, going to take a couple of questions from Bert Hazlett at BTIG. First question, Mark, is could you discuss your expectations of safety and tolerability when you consider combinations with PARP inhibitors?

Well, I mean we do believe that given that onvansertib is really -- when you look at the doses we're using is very well tolerated, we think that there is opportunity there. Obviously, we're -- we'll have to see what happens in the trial. But I mean clearly, from what we see so far, we believe that given the well-tolerability of onvansertib at the doses that we're using, we think that it will probably be no problem but...

And second question, could you -- from Bert also, could you discuss any considerations you're contemplating with onvansertib and IO therapeutics?

I mean that's another great area of exploration. I didn't really have it down on there in the preclinical area, but that's another area that we are exploring as well.

Great. Thank you. And just a couple more questions for everyone. Dr. Sharma, the question was asked just for clarification. Were all EAP patients KRAS-mutated?

Yes. That was a requirement for the study. So some of the other eligibility criteria were a little bit more liberal compared to the Phase Ib/II trial in that they could have multiple lines of prior therapy, et cetera, but they all have to be KRAS-mutated. We don't think the drug is going to be effective, right, in patients that don't have KRAS mutation. So there wouldn't be a reason to use it in that setting.

Okay. Thank you. And Dr. Ahn, although all of the patients obviously in the trial have not been treated by you, but Marc Frahm is asking the question that in the Phase I/II, there were a few new grade 3-plus AEs, including white blood cell decrease. Can you explain the clinical course of these patients? When did the low white blood cell count occur? Did it resolve? And I know, as I said, not all of these are your patients, but I think just from your perspective, when do you generally see a lowering of the white blood cell count? And what is sort of the course for these patients and resolution?

Yes. So typically, the patients that do -- that did experience neutropenia did experience it early on. So usually within cycle 1 day 15 or with cycle 1 day 28. And then I thought a lot of it was actually due to chemotherapy as we kind of briefly touched upon earlier. And so after discontinuing with their 5-FU bolus and leucovorin when they're receiving day 28 -- or day 15 treatment -- or after the delay when they ended receiving their subsequent treatment, they didn't have any further issues.

All right. Thanks.

And so because of those things, yes, I didn't feel that it was really study-drug-related. I thought it was more chemotherapy. In terms of the case presentation that we presented, I think she just tends to be a little bit -- [ her marrow ] tends probably to be a little bit more sensitive. She is 80 years old. So in terms of the chemotherapy and associated side effects, it probably just affected her more. But in terms of most patients that were enrolled, the toxicities we observed early resolved after subsequent chemotherapy modification.

Great. Thank you. And that is the last question that we actually are going to take at this time. I would like to thank everybody for their consideration and attendance today. Hopefully, everyone found this both informative and enlightening, hopefully. Sara, as the operator, I'm going to turn it back over to you to conclude.

Thank you, Vicki. This concludes today's call. You may now disconnect your line.