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Phase I trials: Dr. Sharma

Doc Talks

In this DocTalk, Dr. Manish Sharma from START Midwest talks about phase I colorectal cancer clinical trials with Dr. Manju George, the PALTOWN Scientific Director. Recorded in September, 2023.

Manju George 00:00
Hello, everyone. Welcome to DocTalks I’m Dr. Manju George, the scientific director at Paltown Development Foundation, the nonprofit that supports COLONTOWN and today we have the pleasure of having Dr. MANISH Sharma from START Midwest with us. So before we get started, welcome Dr. Sharma. And please tell us how you got involved with running trials and you know, being part of START Midwest.

Dr. Sharma 00:24
Sure. Thank you. Thanks for the introduction there. Dr. George for the invitation to be here. You know, I have been doing phase one trials basically since I started my oncology career. I did my training at the University of Chicago in hematology oncology, started my fellowship there in 2008. And right away I got involved with drug development. And that was an attractive piece of you know, the reason why I wanted to be an oncologist was to help develop new therapies for cancer patients. So it was a big interest of mine and I was fortunate enough to be at a place where we were doing a lot of phase one trials and a lot of active clinical research, and I got some experience with that and fellowship and then actually I stayed on and joined the faculty at University of Chicago and was there for six years from 2012 to 2018. And at that time, I had an opportunity to come here to Grand Rapids to join this very unique organization here called Start Midwest, which is dedicated to phase one clinical trials for cancer patients. And it’s kind of a unique setup. We’re embedded within a large you know, community oncology practice. So we get a lot of our patients from that practice but also patients get referred in from, you know, the other side of the state or from the whole region, the Midwest region here sometimes patients find us on their own as well. We get a lot of self referrals or referrals from academia when they when they find that we have interesting studies to offer for patients. So it’s been a great you know, career path for me and I’m passionate about about clinical trials and about phase one trials, specifically and I’ve had, you know, amazing experiences interacting with patients, families, and really helping to propel, the next generation of drugs forward to hopefully improve outcomes for our patients.

Manju George 2:14
Okay. Thank you for telling us all about that. I think we can get started now. When people have questions, please type them in chat and then we will get to them at the end of the call.

Dr. Sharma 2:26
Absolutely. Yeah. And I want to make this hopefully somewhat informal. I do have some slides to present but then I’m hoping that my slide presentation will take only 2025 minutes or so. So that we have plenty of time for questions. I like for people to feel like their questions can be addressed and I’m sure if you have a question, it’ll benefit the whole group to hear about it. So, you know, feel free to put those in the chat and then we’ll get to as many as we can. So I titled my talk, phase one clinical trials for metastatic colorectal cancer with a focus on precision oncology. Phase one is a large topic to cover. So I’ll you know, give some, some broad strokes about it, but then also sort of hone in on some precision oncology therapeutics that are coming down the pipeline. I know that Dr. George had pointed out that, that there was some interest in one of our publications recently from a presentation that we did at ASCO and published in Cancer Discovery. So I’ll get into that a little bit toward the end of the talk. So I wanted to dedicate this talk to in loving memory of of my patient, Gretchen Klobuchar, who has has had a long battle with with her cancer and unfortunately, recently passed away this past weekend, after being at this for many, many years and she was a very kind and genuine and humble person, who really was very well loved in in the clinic here by all the staff that she worked with and myself as well. Looked forward to seeing her all the time. And, you know, the other thing about her that I think is very appropriate for this talk is that she was very passionate about clinical trials. She participated in several clinical trials with me as a doctor and and and she also was a very active member in the Colontown community, and I’m sure many of you know her, and she inspired me to continue to do the work that I’m doing and will continue to inspire me going forward. And and so I want to keep her memory in mind as we go through this and I know Don and family are watching as well. So you know, you’re in our thoughts and prayers, you know, everybody at Start Midwest misses Gretchen and we will continue to be inspired to develop better therapies for patients going forward because of patients like her.

So, these are the learning objectives for my talk, to understand the objectives of phase one clinical trials, to understand basic inclusion criteria for phase one clinical trials, who is eligible for these kinds of studies. To understand the concept of precision oncology, and to understand the role of tumor molecular profiling and precision oncology, as well as to discuss examples of precision oncology phase one trials for colorectal cancer patients. So hopefully we’ll be able to get to all those topics and address some of your questions as well.

This is just a quick overview of kind of the phases of clinical research. So you know, when we talk about phase phase one clinical trials, it helps to put that in context. What is phase one and how is it different from phase two and phase three trials So phase one trials typically are smaller studies. And these are what we call first in-human dose escalation studies. Oftentimes the first time that new drugs are being tested in humans after they’ve undergone clinical preclinical testing in the lab, as well as you know, animal testing, they make their way into the into clinic at places like START Midwest and we do these studies with small numbers of patients, typically. They often include patients with what we call advanced solid tumors, which is, you know, to say that this is not a group of patients that all has the same type of cancer. Oftentimes, patients with different types of cancers enroll in these studies. And the objectives are really about safety and tolerability. So, I think one of the things that oftentimes gets asked is, you know, how is phase one different than phase two or three or do you have any of those kinds of studies and I explain that, that the Phase One trials is where all drug development has to start. Because first we have to establish that drugs are safe and tolerable before we can really get into the full examination of whether they work for a particular type of cancer. And so that’s really the objective and phase one, we seek to determine what we call the recommended phase two dose or a range of doses that we will use going forward with a drug. So at the beginning of phase one, we don’t really know what the doses are going to be in future studies, and by the end of that study, you hope to have decided on that. Phase two trials are more what what I would call medium size trials and the objective of those studies is to establish preliminary evidence of efficacy. So phase two is kind of where where you make a go no go decision about a drug. Is this going to be one that we really want to carry forward and pour more research resources into and and study more patients because we think it has a chance of succeeding and making it all the way to FDA approval? Or is this a drug that is, you know, we feel like there’s not enough there to make it worthwhile to carry it forward. So that’s kind of the proving ground, if you will. And then phase three trials are large studies, oftentimes hundreds of patients in size, the objective is to establish efficacy compared to a existing standard of care in a specific patient population. So these are more very carefully designed studies, oftentimes randomized trials and these are what we call registration studies also that lead to possible approval by regulatory agencies, which in the US as the FDA.

So this is an example designed for a phase one clinical trial. I took this from one of the trials that we actually have opened here at START Midwest, the name of the drug is not important here. So I wanted to more get across the concept of how these studies are designed. So you’ll see for this particular study, we started at a dose of 0.3 milligrams per kilogram, so these doses based on body weight, and this is not it’s not an unusual way to design a study. You start with a low dose that’s determined from preclinical testing and animal testing. And then you escalate the dose over time. So the first group of patients in this study would get 0.3 milligrams per kilogram, then if they do well and don’t have any what we call dose limiting toxicity, severe severe adverse effects from the drug, then the next group of patients would get one milligram per kilogram. The next group of patients would get three milligrams per kilogram, then 10 and then 30. So you’re escalating the dose in subsequent groups of patients over time and looking for what we call the maximum tolerated dose the MTD and the recommended phase two dose RP2D. And here it says three to six subjects per cohort. Sometimes you could expand it, this is what we call a typical three plus three escalation where you deal with three patients typically in each cohort, but you could expand to six if need be. And then that’s sort of the part one of the study and then oftentimes, these studies will have what we call a dose expansion cohorts as well. And that’s where you’re looking at larger numbers of patients within certain populations of cancers. So in this particular study, they wanted to look at mesothelioma, gastric cancer and colorectal cancer. So colorectal was one of the dose expansion cohorts on this particular study. And, and that’s oftentimes the case for a lot of phase one trials is that they will select certain tumor types to explore further, once the once the dose has been determined once we know what dose is safe and tolerable. So these are just basic inclusion criteria for phase one trials. You know, these are generally offered to patients with metastatic cancer, which you know, means that their cancer is incurable. So, phase one trials are for that population in particular, and usually to be eligible for a phase one trial, patients need to have had progression of their cancer or have been intolerant to the standard therapies that exist and this typically corresponds with FDA approved therapies, therapies that are considered standard of care. In the case of colorectal cancer, I listed them off here typically this would include include 5FU and or capecitabine oxaliplatin, irinotecan, cetuximab and panitumumab if indicated. There are certain populations who are not indicated to get those those monoclonal antibodies that target EGFR, and then Bevacizumab that there’s a drug called Trifluridine/Tipiracil also known by the by the brand name Lonsurf. And there’s a drug called regorafenib also known by the brand name stivarga. These are all the different FDA approved therapies for a standard colorectal cancer patient. And so, typically they have have seen most or all of these by the time they’re being referred for a phase one trial.

They have to have adequate hematologic function which means talking about blood counts here. So neutrophils, hemoglobin and platelets have to be above certain thresholds, certain parameters and it’ll vary a little bit depending on which study it is but have to be above certain levels in order to qualify. Patients need to have adequate kidney and liver function, again based on chemistry, based on lab testing. And they have to have good performance status. We call it ECOG, zero to one on the ECOG performance status scale. And I’ve included the scale over here just so you can see what it looks like. You know an ECOG zero patient is someone who’s fully active and basically looks like a healthy patient. You wouldn’t be able to tell they have cancer, they are doing everything they would normally do as if they were pre cancer. ECOG one is someone who has some limitations. They’re restricted in some strenuous activities, but still ambulatory and able to carry out work of a light or sedentary nature. So these are patients that can can do household chores. They can do laundry, they can do yard work, those kinds of things. They can do an office job, you know, maybe they work part time from home or they go into the office a little bit. Those types of things. When you get beyond that into ECOG, two, three and four, you know, you’re talking about patients that are more limited by their cancer may be spending most of their time in the bed or chair. You know, these patients are not good candidates for phase one trials because they would not be able to tolerate some of the adverse effects that might happen on one of these studies and so we always want to consider the risks and benefits of these studies, and therefore, thesw studies will exclude typically patients with ECOG performance status beyond one so two, three or four.

The types of phase one trials that are out there for colorectal cancer patients, there’s quite a few of course and I kind of simplified it here by putting together sort of three different categories. But these are in my experience, based on sort of the last, five plus years of doing phase one trials, research in colorectal cancer patients, they almost always fall into one of these three categories Immunotherapy trials, of course, Immunotherapy has been a hot area in oncology for the last, 10 to 15 years. And there are lots of opportunities out there for Immunotherapy studies for patients even with microsatellite stable colorectal cancer. Of course we know that Immunotherapy works for patients with MSI high colorectal cancer but we still are looking for solutions and looking for strategies that will work with Immunotherapy drugs in MSS colorectal cancer. So there are a lot of studies looking at for example, combinations of different Immunotherapy drugs etc. There are also antibody drug conjugate trials. Antibody drug conjugates have kind of had a renaissance recently where there are a lot of studies now with these types of molecules that have an antibody linked to a payload chemotherapy type payload. And the antibody binds to an antigen on the surface of the cancer cell and delivers that chemotherapy payload that toxic payload into the cell. So those are antibody drug conjugates studies. The third category is precision oncology trials. And I’ll I’ll go into detail here and I highlighted in red because that’s going to be the kind of the topic that I’m going to dive deeper into for the rest of the talk. But we’ll talk about what do I mean by precision oncology.

So what is precision medicine and precision oncology? So precision medicine is a form of medicine that uses information about a person’s own genes or proteins to either prevent, diagnose or treat a disease. Right. And when we talk about applying that to oncology, we’re talking about using specific information about a person’s tumor their cancer to help make a diagnosis plan treatment, or find out how well treatment is working or make a prognosis. And of course, when it comes to trials, we’re always talking about treatment. We’re talking about therapeutics. So really what I think of it as is getting the right cancer drug for the right cancer patient at the right time. And some people call this personalized medicine, precision medicine, you know, those are interchangeable, I think in terms of terminology. So this is sort of the old paradigm that what I would call non precision medicine. The one size fits all you know paradigm where if you take three different patients with colon cancer, the red, the blue and the green patient you know, you give them all the same treatment you don’t give anything different based on anything you know about their cancer, you just know that they have colon cancer and so they all get FOLFOX or they all get FOLFIRI, right. And this was the old approach and some patients would respond to that treatment and some patients would not right so you kind of get mixed results in that type of approach. In precision medicine, we’re talking about taking the next step here. So if you take three different colon cancer patients, the red, the blue and the green, you analyze their cancer and you try to find you know how you can treat these three patients differently and you kind of have a red therapy for the red patient and a blue therapy for the blue patient, a green therapy for the green patient and hopefully by by personalizing by doing that the diagnostic biomarker analysis and then tailoring therapy accordingly, hopefully you improve your results get better effects on all those patients. That’s the concept of precision medicine and precision oncology when it’s applied to cancer patients.

Dr. Sharma 29:32
So precision oncology requires what we call tumor molecular profiling to identify targetable alterations and so what I mean by that is you have to actually have either tissue or blood that you’re analyzing, and you’re looking at DNA from the cancer as well as RNA, protein expression. There are a number of different things that we can look at. When we look at the DNA, the genetic material inside the cancer cell. You’re looking for mutations or fusions or deletions, there’s different types of alterations that you can find in that DNA. When you look at RNA, you’re looking for gene amplifications. When you look at protein, you’re looking for expression, you know, and again, this is in either tumor tissue and or blood that you can collect from from patients. There is microsatellite instability testing, I would consider part of this precision oncology approach, where we classify patients as either MSI high or as MSS. Right when in case of colon cancer, we think about in the metastatic setting about 95% of patients that are microsatellite stable with colon cancer. Tumor mutation burden is also something that’s being looked at a lot and reported out. We also know there’s a PD-L1 expression PD-L1 is a protein that we’re looking at expression for that can help with predicting the efficacy of Immunotherapy. So used more so in other diseases, I would say than in colorectal cancer, but that’s one of the things that we’re looking at. Homologous recombination deficiency or HRD testing is something that’s being reported. And there are multiple companies, there are hospitals that provide these kinds of services that you can get a report back from, so depending on what your oncologist sends it off to, you’ll get you’ll get a different test depending on which company they’re using which vendor, but these are some of the ones listed here and this is not meant to be an exhaustive list necessarily but Caris, Foundation Medicine, Strata, Tempus, Guardant health, Neogenomics, Myriad Genetics, and there are a number of cancer centers and hospitals have their own or develop their own tests as well, that they will sometimes use and you can see some of these are used on tissue. Some of them are used on blood, some have both options. So, we can always sort of do this type of testing no matter the situation, whether you have tissue or don’t have tissue, you can always send something off because you can always do it on the blood. Even if you don’t have tissue available for whatever reason or don’t have a location of a lesion that’s easy to biopsy.

So these are examples of reports and I just took this these are some of my patients where I blacked out their names, obviously to protect their privacy. But you know, this is an example of a Caris report on one of my patients. You know, this particular patient had a KRAS G12 V mutation, which is a common one that we see in colon cancer. And you can see they also had something called a PIK3CA mutation that’s identified here. But this is just to give you an example of what are these reports look like? What are we seeing, you know, they break it down into a category of results with therapy association. So ones that we know exactly what to do with the result, we know how the result affects the way we’re going to treat the patient and other ones where they will be called cancer type relevant Biomarkers. We don’t necessarily have therapies, maybe that are that are contingent on these results, but they are relevant, mutations that maybe they’re gonna be relevant for clinical trials, for example, which we’ll talk about in a bit. So that’s an example of a Caris test.

This is a Foundation One liquid test on one of my patients, again, similarly, you see some of the outputs that you get here, the tumor mutation burden, the microsatellite status, the tumor fraction, we call it and then the genomic findings here include a number of different mutations that were found. So in this particular patient, that KRAS G13D mutation was identified, and then a number of other ones here as well. And, again, you can have sort of highlights, they talk about clinical trials later on in the report. And they also talk about the fact that this patient shouldn’t get cetuximab or panitumumab because of that K RAS mutation, that’s well known that we would not use those types of therapies for a tumor that has that mutation.

This is a Guardant 360 test. So again, very similar, this patient had a KRAS G12V mutation as well identified now with the blood instead of on tissue. You know, they also had happened to have a HER2 mutation as well and then a few others as well. So, again, tumor mutation burden, MSI status, MSI was not detected in this patient. So, this is an example of, different types of reports that look slightly different depending on which company is running the test. But the bottom line is you’re getting valuable information about what’s going on in the cancer. And this is all essential information that is needed to do what I call precision oncology and to be able to qualify for clinical trials that are relevant to clinical precision oncology. So there’s a big project called the AACR project Genie that some of you may have heard of, but it’s a publicly available data set and the American Association of Cancer Research has conducted this project and funded it, and they’ve sequenced more than 150,000 samples of patients cancers, and have made that data publicly available. So that includes, you can see how many samples they have for all of these most frequent cancers that are out there. And colorectal is number three on the list here just after lung and breast. So there are almost whatever, this is nine, nine or 10,000, you know, or actually sorry, 14,000 15,000 colorectal cancer samples that have been analyzed to be able to identify and understand what the biology is, what the mutations are, that are present in these kinds of tumors. And from those data, they’ve been able to make this kind of pie chart, that shows you what are the percentages of mutations that we see in colorectal cancer, so, the most frequently mutated genes in colorectal cancer are TP 53 and APC. Unfortunately, we don’t have therapies that specifically target TP53 or APC, but they are frequently mutated in these cancers. You can see that KRAS G12 mutations are frequent 29% or so here, k RAS non G 12 mutations are another 14-15% here, and then you have other ones like PIK3CA et cetera. BRAF mutations, of course, are targetable and 11% of patients have those. So it’s very interesting to see this chart. Of course, there’s going to be overlap because as I showed you on some of those example ones a single patient’s cancer can have multiple different mutations. So that’s why these numbers don’t add up to 100%. Because, of course, many of these, many, many samples will have more than one of these mutations and sometimes four or five or more in one cancer. But this gives us an idea of what we’re looking at and how you might think about it from a drug development angle about what are we going to target with a therapeutic approach? So when you look at colorectal cancer and compare it to other cancers, this is just for K RAS mutations. it’s interesting to me to see that the, the frequency of specific K RAS mutations actually is quite different depending on which cancer you look at. So for example, there was a therapy developed for lung cancer that targets KRAS G 12 C mutations. However, G 12 C mutations are only a very small minority of colorectal cancer KRAS mutations, right. So for colorectal cancer, the more common mutations in K RAS are G12D, G12V and G13 D, and then G 12 C comes 4th. So, these are obviously, hot areas where we would be very interested in developing targeted therapies, precision oncology therapies for these types of mutations and there are a lot of efforts going on to try to do that right now. And you can see how pancreatic cancer likewise, G12D and G12V the more common ones here, among the others. So, we have to think about KRAS sometimes a little bit differently depending on which cancer we’re looking at.

These are examples of precision oncology phase one trials for colorectal cancer patients that are just opened at START Midwest, these are obviously, we’re only one center of many centers around the country and around the world that are doing phase one trials, but I thought it would be interesting to give you a little snapshot of, for example, some of the things that we have open here, we have a study of a polymerase beta inhibitor that’s looking at what we call a DDR pathway alterations. DDR stands for DNA Damage Repair, so BRCA1 BRCA2 and a long list of other ones that are in that group would be the target for that particular therapeutic. We have a study with a Chek1 inhibitor that is, is looking at tumors with oncogene amplification, so those include BRAF, KRAS and again, a long list of many others as well. So that’s relevant to some colorectal cancer patients and patients with other types of tumors as well. We have a study with an immune stimulating antibody conjugate that is looking at any tumors that have HER2 amplification we call ERBB2 is the name of the gene or HER2 being the protein having that amplified and there are colorectal cancer patients who do have HER2 amplification who are candidates for this type of study. In fact, we just considered a patient recently who falls into that category. We have a study with a BRAF inhibitor that’s looking at what we call class II and class III mutations. These are the mutations that are different than V600E, which is the most common BRAF mutation that we see in colorectal cancer. But these other ones, although infrequent, are still present in some patients, and the idea is to try to target those with this particular therapy.

There’s a KRAS G12C inhibitor is obviously for patients who have KRAS G12C mutations and their tumor, and this study is open right now we’ve enrolled a number of patients on it. This is sort of trying to take the successful strategy that was used in lung cancer with KRAS G12C inhibitors and extend that to other tumor types, including colorectal cancer. And then we also have a study ongoing with a KRAS G12D inhibitor, so trying to go after one of those other big pieces of the pie that really haven’t been addressed yet. And of course, that’s for patients with KRAS G12D mutations. So again, kind of precision oncology going after not only K RAS mutations, but specific K RAS mutations among them. And then there’s a study of that I’ll highlight a little bit more here that is with a SHP2 inhibitor and this SHP2 inhibitor is given in combination with encorafenib and cetuximab which are standard FDA approved therapies for patients with BRAF v 600E mutations. So, these are colorectal cancer patients who have BRAF V600E mutations who have already been on encorafenib and cetuximab as a standard therapy, and then their cancer eventually grew on those therapies. And so now what we’re trying to do is really re-sensitize the cancer, to those drugs by adding in a SHP2 inhibitor. So that’s an example of another study that’s open here. This is the paper that we published in Cancer Discovery. This came out actually right after ASCO, our American Society of Clinical Oncology meeting in June, where we presented some of this work, and right after that meeting, this was published online. It’s now published formally in Cancer Discovery as of August, but it’s entitled SHP2 inhibition sensitizes, diverse, oncogene addicted solid tumors to retreatment with targeted therapy. And myself and several others were co authors on this publication. And, it really, the reason I think it was compelling is because it was sort of proof of concept of this idea that you can re-sensitize cancers to targeted therapies by adding in, in this case, a novel therapeutic with the SHP2 inhibitor. So, this was the basic design of the study, in this sort of traditional phase one model up here in the upper left, you can see that typically if we were looking at a combination of drugs in phase one, the old approach or the typical approach was to do monotherapy, give only the one drug and then go through multiple dose levels, do the dose escalation, and then move on to doing dose escalation with a combination of drugs. So this takes a lot longer because that first part of the dose escalation with the monotherapy could take months or even years before you move on to the combination approach. But in this approach that we used in this study, we use this alternative phase one model, where we gave the monotherapy as a what we call lead-in strategy where we only used it for six weeks and then at that point, if the cancer was progressing, we added in the combination partners we added in the other drugs, the targeted therapies, in this case, in the case of colorectal cancer, that was encorafenib and cetuximab and therefore, the patients were able to get on the combination approach much more quickly, and not have to wait for this other part of the study to finish out. And so this is kind of the schematic showing how that works. Two 21 day cycles, meaning two three weeks cycles, six weeks of therapy with the SHP2 inhibitor by itself, and then an imaging evaluation with CT scans, and of course collecting also circulating tumor DNA from the blood. If there was no progression, they could continue on mono therapy but if there was progression of the disease at that point, they moved on to adding the targeted therapy in which for colorectal cancer with BRAF V600E mutation meant encorafenib and cetuximab added to the SHP2 inhibitor together. And that’s the strategy or the approach that we took. My lights shut off.

So okay, we’re going on to this one and this maybe a little bit scientifically complicated to present to this audience. But I thought kind of interesting. This was my patient who was on this study, and you can see that, you know, the prior therapies that included kind of standard things like FOLFOX Bev and FOLFIRI Bev. The patient had received and encorafenib and cetuximab as a standard of care therapy and actually had even been on a clinical trial with an agent called fruquintinib at another site, not our site, and had progressed on all those different therapies over the course of about 15 months. So at that point, the patient enrolled in the study here of the SHP2 inhibitor and for the first six weeks on the study, in this blue line here you can see that the cancer grew, this blue line here represents tumor size. And these other lines here are looking at circulating tumor DNA looking at for example, the BRAF mutation in green here and the circulating tumor DNA. So during those first six weeks, the the tumor DNA was going up and the size of the cancer was also going up. But then once the patient started on combination therapy with cetuximab and encorafenib in combination with the SHP2 inhibitor, we saw the tumor actually shrink on multiple CT scans, it shrunk, kind of stayed there and then shrunk even a little bit more and finally crossed the threshold of what we call a response by our criteria for evaluation what we call the RECIST criteria at 30% reduction. And you can see that initially that ctDNA that BRAF mutation disappeared completely, but then unfortunately at some point started growing again started recurring and eventually the patient unfortunately did have disease progression. Here out here in about 24 months from the time of diagnosis. So had been on the study for over six months and did derive some benefit. In fact, patient had been requiring paracentesis procedures to drain some fluid from the belly, for example, and was able to stop needing those for a period of several months. So no doubt in my mind that the patient clinically benefited, but unfortunately, this strategy didn’t work indefinitely or for years and years. And that’s the challenge that we face, you know, of course, is that even when we succeed, oftentimes our success is short lived and we want to find strategies that will be more enduring in terms of length of duration of response. These are just some CT scan images that show the changes over time. So this is the baseline scan here showing a tumor here in the abdomen that got bigger by week six went on the monotherapy with the with the drug and then shrunk again by week 24. This is week 24 scan. So about 18 weeks later, you can see it’s much smaller than it was here and even the fluid that was surrounding it in the belly here had gone away. So that was sort of symbolic of the time course of improvement here with the patient on the study. So wanted to kind of give you that little flavor of what I can share this information because it’s publicly available. This is published information here. Now obviously on a lot of these trials we have we’re bound by confidentiality and not being able to share interim results or preliminary results until they have been presented in the public domain. But, you know, in this case, this particular one had been published and therefore, it’s instructive and able I’m able to share that with you today. And you can even look up this paper on your own. It’s publicly available. And on the on the PubMed website on the nih.gov. So I think that’s really all I wanted to talk about today. I think these are some take home points I wanted to kind of bring home, and then I’m happy to take some questions. But I think phase one clinical trials are an important part of the drug development process. And I hope I have communicated that with you today. Primary objectives being safety and tolerability. But of course patients can benefit from being on these studies and there’s many examples of that, both in my clinic as well as in clinics across the country across the world.

Precision oncology is the standard of care in 2023 and will impact I think even more patients in the future. We’re rapidly moving away from a one size fits all approach and moving more toward identifying specific mutations in people’s cancer and trying to target those with with therapeutic approaches. I think all patients with metastatic colorectal cancer should have tumor molecular profiling completed and this is not just my opinion, this has been something that’s been published and expressed by expert expert groups and guidelines all across the country and across the world. So that’s something that we should be doing as a matter of routine. And there are many phase one clinical trials available for metastatic colorectal cancer patients with specific molecular alterations in this case, referring to things like gene mutations and or amplifications. I gave you some examples of ones that are open here at START Midwest, but of course these change over time and trials close other trials open. We have other ones that are coming down the pipeline. And of course there are many other centers of course around the country too that are doing this kind of work and I think a big take home point, I’m sure for everybody in COLONTOWN is how important it is to look for clinical trials to be able to, hopefully benefit yourself as well as move the field forward in terms of drug development for future generations. So I’m happy to discuss my Acknowledgments to my colleagues and staff at START Midwest, co investigators and sponsors for our phase one clinical trials that make it possible to do this kind of work and of course, always thinking about our patients and their families. This is why why we do what we do. And it’s very rewarding to work with such such great people and to hopefully make a difference in their lives. So that’s it I’ve got time for questions. And = I think we can we can probably exit sharing my screen and probably look at the chat here to see what you all would like to know about.

Manju George 37:20
Yeah, thank you so much, Dr. Sharma. So I was thinking that maybe we could start with like, going to your second slide about the dose escalation, and maybe explain it a little bit, because I think there is a lot of confusion and the fact that sometimes like to explain a little bit about how do you get to the next dose that you dose escalate, or what you take to the dose expansion phase. Those kinds of things. And then what what people have to keep in mind when they enroll in a phase one trial, like if they’re on the dose escalation part versus dose expansion. What are some of the things to keep in mind?

Dr. Sharma 37:58
Sure, yeah, no problem. I can you let me let me go back I guess to the, to that slide if I can, real quick. You’re thinking about this slide here. Maybe? Yeah. So yeah, this this is just an example designed for a phase one trial that I put out there but you know what? We’re looking at is for example, this one here is what we call it three plus three dose escalation. So what that means is that we’re going to treat three patients at the lowest dose level here, which is 0.3 milligrams per kilogram. And we’re going to watch those patients for a certain length of time that’s pre specified like it might be three weeks or four weeks or six weeks, right, depending on the study. I would say average is about three or four weeks. But during that time, what we’re looking to see is are there any severe adverse effects that are attributed to the study medication, so of course cancer patients have complicated medical histories and sometimes they end up in the hospital for one reason or another, they have a blood clot or they have something else happen, a bowel obstruction, whatever it might be. But what we’re really most focused on during that time is adverse effects that are related to the drug. So if you give somebody a drug and they have severe diarrhea, or they have severe nausea or vomiting, or they get hospitalized for a certain reason, and we think that’s related to the drug, then that would be what we call a dose limiting toxicity (DLT). That would be something that is indicating that the drug is causing some adverse effect, right. And that would be taken into consideration as far as how much further we’re going to escalate the dose, right. And so typically, what will happen is that you get through the first dose level. Let’s say we treat three patients and there are no dose limiting toxicities. There’s nothing severe that happens, no bad adverse effects, then we would move on in the next group of patients, we would move on to the higher dose level. So that’s what’s being indicated here with this step up from 0.3 to one and then likewise, if we treat three patients at one milligram per kilogram, and they all do well, we then move on to three milligrams per kilogram and then 10 and the 30. And we’re looking at a lot of different data along the way. Of course, the most number one thing is the safety and tolerability. Did anybody have severe side effects that were adverse effects that were attributed to the drug? But we’re also looking at something called pharmacokinetic data which are looking at how much of the drug is in the bloodstream at different time points after we give it so we’re collecting a lot of blood samples and examining that to see are we getting enough drug into the blood and is it going to where we want it to go? Oftentimes, there are what we call pharmacodynamic Biomarkers that we’re looking at as well. We’re trying to see is the drug having the expected effect on the body? Right, and there are ways that we can assess that depending on the particular mechanism of action of the drug, and the ways that we can we can look at it but this is what we’re looking at in making this dose escalation, looking at the dose escalation data and then the group of investigators and usually the company or the sponsor of the study, are getting together to discuss this and are making decisions about do we escalate the dose further, do we need to back off on the dose? Have we reached the dose that we would like to be at and once those decisions are made let’s say let’s say in this particular study, that 30 milligrams per kilogram was too high, we were running into toxicity and dose-limiting toxicity is there, but three milligrams per kilogram was fine was safe, then if 10 milligrams per kilogram was also safe, that might be declared as what we call the maximum tolerated dose (MTD) or the recommended phase two dose (RP2D) so we want to pick a dose for further development that we think is safe, and yet high enough that we may be able to have the effective anti-cancer effect that we’re looking for. Right? So that’s where we’re looking for that sweet spot where we can have the effectiveness of the drug but also adequate safety and not any toxicity, so or not too much toxicity I should say, not just any. So that’s really what’s going on and dose escalation and how we pick a dose to then move on to dose expansion and it might be multiple doses. Sometimes dose expansion involves more than one dose that’s being explored. Sometimes even phase two trials involve more than one dose that’s being explored. So I don’t want to make it sound like it’s a definite thing after just that early part of the phase one trial, but that’s part of what we’re trying to decide. Is what are the right doses to carry forward.

Manju George 42:32
Okay, thank you so much. So in this example, then would you move on with the 10 milligram per kilogram in the dose expansion and give it to 20 people?

Dr. Sharma 42:40
We would, yeah, that would be an example of, you know, in this case, this these dose expansion cohorts, all these 20 colorectal cancer patients that went into this dose expansion would all get that dose, and we would be looking to see, okay, how many of them had a response to the treatment, getting more information about safety, in terms of in terms of, any toxicities that they experienced, getting more pharmacokinetic data, pharmacodynamic data. So all those things that we’re collecting as part of a phase one trial, all those pieces of data that are going to help us develop the drug going forward, we would get all that information from those 20 subjects all treated, perhaps at the same dose, or like I said, in some cases, they’ll even pick more than one dose to carry forward into those expansions.

Manju George 43:23
Okay, thank you so much. So from a patient perspective, somebody considering a trial, which has both dose escalation and dose expansion arms, you know, like, what are some of the things that patients need to keep in mind? Are there any any specific things for them to be aware of?

Dr. Sharma 43:39
Yeah, I mean, I think I think what you really want to do is go to a phase one center and have the investigator there, that physician there, provide some input about what they think the best opportunity is for you. Right. So when we when we have patients, for example, referred to START Midwest, we have more than 70 trials that are open right now. And so we have a large menu of options available. What we’ll do is typically try to pick the trial that we think gives the patient the best opportunity for success, right? And so, I think that a lot of that depends on what they’ve received previously. It depends on what we know about their cancer, the precision oncology element, right? I mean, if they have a K RAS G 12 C mutation, and I have a slot open on the K RAS G 12 C inhibitor study, that may be the best match for them, right. And so I think we focus on that more than whether we’re in the escalation, part of the study or the expansion part of the study and things like that. Oftentimes, there are more slots available during dose expansion. So it’s a little bit easier to get on the study because there are more slots available During dose escalation as you can imagine, these slots are sort of intermittently available because if the study is say, open at multiple sites, and you’re only putting three patients on in each cohort, we might get a slot on the first cohort, but not on the second cohort, then we get a slot on the third cohort, not on the fourth cohort, again, so it’s going to be kind of on again off again as far as our site having an available slot open on the study. But I have actually seen patients have responses even on the very first dose level of a dose escalation study. So I would say it’s not an assumed thing or it’s not a truism that if you’re on the dose escalation, part of a study that you’re not going to have any benefit or you’re not going to have a response to the treatment. I think that’s oftentimes what people are concerned about. But we don’t know what the dose is, that’s going to lead to anti-cancer effect ahead of time because these are first in human studies. We’re learning everything from from the beginning. And so we don’t want to make too many assumptions about when we’re going to see an effective result versus not. But of course, if from the patient perspective, if you’re the kind of patient who wants a drug that has a little bit more experience behind it has a little bit more data, then obviously going on a dose expansion part of the study is going to have that advantage. You have a little bit more information. You think we think we know the dose, and we have a little bit more clarity on on what dose we should be giving.

Manju George 46:20
Okay, thank you very much. I think one of the other concern is like when people hear phase one trials, they’re worried about toxicity. So compared to like dose escalation versus the dose expansion, I feel that the in the dose expansion, you might have a little bit more information about the toxicities to expect as well.

Dr. Sharma 46:35
For sure. Yeah. I mean, I think that I’ve seen severe toxicity has happened on any part of a study, right? I mean, you can see it during dose escalation, you can see it during dose expansions. So there’s no part that I would consider completely safe or you’re never going to have a toxicity. You know, because we are giving drugs, these are active drugs, and they can have unintended effects on the body, separate from what we’re trying to do in terms of the anti cancer effect. So, I would say there’s no time that’s completely guaranteed, But of course, yes, you may have a little bit more information about it during dose expansion.

Manju George 47:10
Okay, thank you very much. So then I think we can look at the questions and start from the top and let me see. I will see what is directly relevant to the Phase One trials and then yeah, let’s just look at.

Dr. Sharma 47:27
Yeah, I don’t know if you want to moderate a little bit. There’s quite a few here. So you want to kind of pick out ones that, you know.

Manju George 47:34
I think I saw one question. In the end. It was about phase one trials being opened at more centers, so they’re accessible to more patients, maybe while you answer that I’ll go through the rest and see..

Dr. Sharma 47:44
Yeah. I mean, so one thing is that these trials are open in multiple centers around the country and oftentimes when when sponsors do pick centers, they do keep in mind geographic considerations, you know, try to have a site in the Midwest a site in the in the southern region or the East Coast, the West Coast, etc. So oftentimes, there are multiple sites around you know, you know, START is a global organization, we have a site in San Antonio and a site in in Salt Lake City, Utah. So I know, certainly many of our studies are shared between the multiple centers. And of course, you know, I’m on many studies with Memorial Sloan Kettering and MD Anderson and a lot of these other places that I’m sure people have heard of, where you know, that are there that are geographically in a different part of the country. And so, depending on where people live, they can hopefully find a center that’s relatively close or easy to get to.

Manju George 48:41
Okay, thank you very much. Um, I think a lot of questions in the in the beginning are about Biomarkers like one question was, how often do you have to look for Biomarkers in your cancer? That’s one question and then about the different alterations like mutations versus amplifications versus fusions, things like that. And then another question was like, What is HRD? And how is that important and what trials are the relevant trials looking at HRD in CRC? So maybe you can enter all of that together?

Dr. Sharma 49:08
Sure. No problem. Yeah. So HRD, I would say is an area of current study. It’s still an evolving area, it stands for Homologous Recombination Deficiency. And it’s another way of examining this idea of tumors that may be susceptible to certain types of therapeutics, such as, for example, PARP inhibitors, and other ones that go after the sort of DNA damage repair pathway. So there are definitely some trials that are focused on HRD. I would say not as relevant yet to colorectal cancer as to some other cancers, for example, like ovarian cancer and others, but it is an evolving and growing area. In terms of the question about retesting, so ones Biomarkers I think that’s probably something that’s underutilized in the oncology community. at large. Oftentimes people will get a Caris test or a Foundation test or a Tempus test or whatever company you’re using early on when they are first diagnosed with metastatic disease, and then it doesn’t get rechecked for many years sometimes afterward. And that’s something that can easily be sent off again, and oftentimes, without concerns about cost or insurance not covering etcetera, because it can be justified clinically as this patient has now been on multiple additional therapies. And now I’m wondering if the biology of their cancer has changed in a significant way, where I want to know that I’m targeting the right types of mutations at this point in time, So, so we definitely do send a lot of and oftentimes when we send it the second time, we might do it off the blood and look for circulating tumor DNA because it’s convenient, it’s easy, you don’t have to do a repeat Biopsy, etc. There’s nothing wrong with doing a Biopsy and sending it off on tissue as well. But but the blood based tests are logistically easier to do and you get results back relatively quickly.

Manju George 51:07
Okay, another question is like when you have multiple mutations that show up on reports, how do you decide what mutation to focus on as part of a clinical trial?

Dr. Sharma 51:16
Yeah, that’s a great question. So we do think that some mutations are more actionable than others. So for example, you know, in colorectal cancer, TP53 and APC are the most common mutations, but they’re not necessarily ones that we can target and we don’t necessarily think that they may be driving the cancer per se. So whereas K RAS mutations, for example, are considered driver mutations that are considered very important mutations for the cancer to survive, grow spread. And so we are very interested in targeting K RAS mutations and that’s something that it’s easier said than done. It’s been challenged to develop therapeutics that do target K RAS, but it’s being done now and being looked at and okay, so we have active studies ongoing with G12C and G12D, et cetera. So I think that hopefully we’re getting close to where in the next five to 10 years, we’ll be able to target a lot of these mutations and have a successful strategy, but that’s a great question. Some of it just availability, what trials you have available, but also some of it really is about some mutations we think biologically are more important than others.

Manju George 52:25
Okay, thank you very much. So there’s another question about if you’re interested in going from one phase one trial to another that you want to test many, what are some of the things to keep in mind. Thank you so much for talking about Gretchen. Like, if you could tell us more about I know that she’s been on several different trials, someone like that.

Dr. Sharma 52:42
Yeah. Gretchen was on multiple studies with us. And that’s not uncommon. You know, actually, I’ve had Gretchen as well as many other patients who have been on many trials in a row. And part of that is because when they get referred here, we put them on the initial study, right? And then maybe some time goes by and other studies come open, that weren’t open initially, that now are a good opportunity for them to come on. And of course, we don’t take patients off studies if their cancer isn’t growing or if they can tolerate the treatment. So usually, it depends on how quickly do they progress but if they do have disease progression, say, four months later, or six months later, after going on a study, and they’re still in good shape, they still meet all those nclusion criteria, then we will offer them yet another study, and go on. The idea is at any point in time to offer them the best opportunity that we have available, right? And I don’t know in advance of course, which therapy is going to work. I wish I had a crystal ball like that, but but we the idea is we keep taking our shots, and eventually maybe we’ll find something that does really help and really extend in Gretchen’s case, I do think she was on some studies that did provide clinical benefit where she was able to get some increased life expectancy from being on those studies. And so, I do think, and that’s not uncommon to see that not every study is going to be a success, but but some of them will be and some of them will go on to phase two and three trials and even FDA approval, and so we’re trying to find those winners in the bunch and find what works for that particular patient.

Manju George 54:26
okay, thank you. So when you introduce the trials that you have for colorectal cancer, you had those categories, right, like the Immunotherapy trials, the ADC trials and the targeted therapy. So what would you advise a patient a new patient looking for trials if they’re just generally looking at things, how would they rate all of these groups?

Dr. Sharma 54:45
Yeah, I mean, so again, I guess I would I would advise is that they get they get tumor molecular profiling done. If it hasn’t been done recently even retest for it, talk to their oncologist about it, of course, because patients need to have their oncologist being their advocate and ordering these tests. But I think getting that done and then getting referred to a phase one center with those results available. It’s probably a good starting point, because we have all these kinds of studies open we have Immunotherapy studies, we have ADCs we have these precision oncology studies, for example, all at START Midwest, and so once I see someone’s chart and can see what they’ve had already and what they have in their tumor molecular profile, I can decide what type of therapy would be the best approach initially. And some of its going to depend on practical things like what’s open at that time, right? Some of these studies like we had a large ADC trial that was opened that had a large cohort for colorectal cancer patients of 40 patients, but that is now closed to accrual. So because they reached their target goal. And so some of that is just a matter of timing what’s open now, and it might be different this month versus next month so things are kind of constantly opening and closing. That’s why it’s very hard. I think from a patient perspective, you can look on clinical trials.gov You can do your own research and someone like Gretchen was extremely knowledgeable about her cancer and about her mutations and about what’s available out there and COLONTOWN and everything right. But but ultimately you have to talk to somebody who’s a provider, an investigator at that site, to know what’s truly open and what’s truly available, and what they think would be best as a fit and then there’s the practical limitations of things like do you want to travel Do you want to get on a plane and travel and be on a trial somewhere where that’s far away from your home and takes you away from your family? So I think there’s a lot of considerations that have to be put together to kind of make the best decision. But I think I think getting everything tested and going to a center and getting an opinion is probably a good, very good starting point.

Manju George 56:50
Okay, thank you very much. So this is a specific question about START. So the question is, how does one become a patient at START Midwest for clinical trials? Ιf their health insurance is state specific and not in your state? So that’s one part. The second part is we hear a lot about phase one trials in tertiary cancer centers like MSK or MD Anderson, we don’t hear so much about START Midwest, or other groups that run phase one trials, so what can be done so that patients, and I think I also think that there’s also certain assumptions made about the larger centers versus smaller centers running Phase One trials. So what what kind of advice can you provide to patients looking for trials?

Dr. Sharma 57:34
I mean, I would say, I would say for starters, you know, that that a lot of these data are not published or available, publicly available on who are the big centers and who are the small centers and all those things. I mean, it depends on how you define it. These are great places I have nothing but good things to say about Memorial Sloan Kettering and MD Anderson and all these places that are out there. But we’re a large center for phase one trials where we treated more than 200 patients last year in 2022. And we’re on pace to get to the same, roughly the same number this year so that makes you a large phase one center, right. And so we have a lot of trials to offer, many of the same ones I’m on teleconferences every week with with investigators from those places like Memorial and MD Anderson so we are all working together I mean, this study that we presented the SHP2 inhibitor, that’s with Alex Drilon is from Memorial Sloan Kettering. And Tim Yap is from MD Anderson. We’re all co-authors on that publication together. So this type of work is being done at multiple sites around the country and certainly, pharmaceutical sponsors know about START Midwest and are bringing their trials to us. So I think we just have to get the word out. I mean I think when it comes to Phase One trials, practically speaking, you want to try to go somewhere that you can get to easily so it’s not going to be super practical for someone to come from California or Florida to Grand Rapids, Michigan, right for a trial. So I would encourage them to seek out a center that’s a little bit closer to see if there’s an opportunity there first, but certainly for anybody in the Midwest region or that we do treat patients we’ve treated patients from Indiana and Illinois and Ohio in our surrounding states, all over Michigan, of course. So we do take patients from out of state even and we’ve even had patients come from Ontario from across the border here in Canada. So people are willing to travel sometimes for these types of opportunities, and we’re happy to explore that. But I would say first be aware of what’s around in your area and seek out a center that’s nearby. It doesn’t have to be one of those big-name ones. It could be an academic center, or it could be a Community Oncology Center that does phase one research. And most of us have websites. We have availability, and you can look on clinical trials.gov and find out what’s out there too.

Manju George 59:58
Okay. Thank you very much. I think this will be the last question before you leave. So there has been some, you know, a lot of patient concern about like monotherapy trials where you have one targeted therapy drug, I mean your approach what you did with SHP2 was really, you know, novel and where you’re combining FDA approved combination therapies and then adding on something on top right? So do you have other trials planned or what advice do you have for someone looking for monotherapy trials in colorectal cancer?

Dr. Sharma 1:00:26
And first of all, I would say monotherapy trials don’t necessarily mean that a drug won’t work. Right. So, I presented data at ASCO from our ABBV 400 study, that’s an antibody drug conjugate that was a monotherapy in advanced solid tumors including colorectal cancer, and that’s actually the study that I mentioned that had a large cohort of colorectal cancer patients. So this is all publicly available information. I’m not divulging anything that’s confidential. You can look at the ASCO abstract and all those things but we did see responses in that study and in colorectal cancer patients as we presented at ASCO back in June, and so monotherapy doesn’t mean that it won’t work. I would say that mono therapy, if it’s the right drug could be quite successful of an approach. There are other times where a combination therapy is necessary, like in the SHP2 inhibitor a case where we were using that drug to re-sensitize the cancer to the FDA-approved therapies enco and cetux. So it really depends on the mechanism of action of the drug and how it works. But there are some drugs that are designed to work as monotherapy and others that are going to work much better in combination. So I would say that’s a scientific question that really hopefully you can get an expert opinion about from a Phase One investigator to be able to give you the best advice on which of these is a better option, but if you go to a center with multiple studies open, hopefully that investigator is going to give you offer you something that gives you the best chance of success, regardless of whether it’s monotherapy combination therapy, dose-escalation, dose-expansion, etc.

Manju George 1:02:10
Okay, so the the next question is people when they hear about START Midwest, when compared to like a large center that they have heard of, I mean, it’s just how much they hear about it, they’re worried about getting on a phase one trial. So what can you say to like, you know, tell them that you know, what is going on in a trial center, such as START Midwest,

Dr. Sharma 1:02:33
I think what’s going on is really the same thing that’s going on at any of these other centers. I mean, I’m a I’m a full-time Phase One investigator, you know, I’m a principal investigator on more than 30 Phase One clinical trials, very experienced investigator and we take it very seriously and I mean, we are seeing our patients ourselves or my colleagues obviously work as a group, but myself and my colleagues are seeing all these patients day in and day out. If they get hospitalized, we’re following them in the hospital. We’re coordinating that care across the spectrum. If they get hospitalized at their local area, two hours away, or three hours away, we call and talk to the team there and get on the phone and coordinate all that. So it’s a high level of care that we’re providing I think that’s something where people have to come and see it for themselves and understand it that way. But obviously, Don and others know kind of what we do at START Midwest, people who have come here have been happy with their care. But I think at the end of the day, I wouldn’t get too caught up in what is the name of the place and all that, come visit the place talk to the investigator to the doctor and see what you think about it and develop that relationship. without getting too caught up in names and those types of things because a lot of that depends who’s advertising who’s marketing their name out there who’s buying up spots on NPR and things like that, and that’s not that’s not necessarily the end game. I mean, I think what’s important is for patients to be comfortable with the care that they’re getting. And I think that’s kind of what I would say is just not and I’m not saying everybody should come to START midwest. I really think that what I want to communicate is that although we’re happy to have plenty of referrals, and we need those we would like to have patients, we’d like to treat as many patients as possible. Now here. I want people to find the right clinical trial for them no matter where it is, and whether that be a phase one trial, whether it be a phase two or three trial, whether it be whichever part of the country it might be in but the important thing is, the more clinical trials we do, the more we’re going to succeed in drug development and getting better therapies out there for patients

Manju George 1:04:50
okay, thank you so much. You stayed seven minutes fast and you’re very

Dr. Sharma 1:04:54
well yeah, you’re very welcome. And, you know, I also you know, happy to, you know, be in communication and be an ally for COLONTOWN, going forward and anything I can do to help the community, we’re happy to do that. So. Okay, thank you very much. Thanks to everyone who found time time to join the call. Okay. Bye. Bye, everybody. Thank you. Thanks for having me. Yeah. Thank you. Very much.