A Scientist Explains Why Clinical Trials Are Not a Last Resort - Anne Mette Buhl

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HANNAH LIPPITT: Hello and welcome

to the Totally Clinical podcast brought to you by Teckro. Totally Clinical is a deep dive into the freshest trends, big time challenges and most excellent triumphs of clinical trials. I'm Hannah, your host. Join me as I chat with industry experts, trailblazers, thought leaders and, most importantly, the people benefiting from clinical research. So tune in, settle back and don't touch that dial. It's time to get Totally Clinical.

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HANNAH LIPPITT: This week, Dr. Anne Mette Buhl, senior scientist at the Clearity Foundation, an advocacy group that improves the survival and quality of life of women suffering from ovarian cancer, joins me on the podcast. During this podcast Anne Mette explains why clinical trials should be considered as an alternative to standard of care. Why she's excited about the latest ovarian cancer treatments and what patients need to know about inclusion criteria for oncology clinical trials. Thank you for joining me. Could you start by explaining more about your background and how you came to work at Clearity?

ANNE METTE BUHL: Yes, absolutely. I have a PhD degree in chemistry and my background is really in the field of signal transduction, which you basically can think of... this is how cells communicate. Before Clearity I did clinical research in leukemia. I started in the most common leukemia among adults that's called chronic lymphocytic leukemia, or CLL.

At the time, I worked at the University Hospital of Copenhagen in Denmark, and I identified a novel prognostic gene in CLL that I named Clue One. I was able to secure funding to start a small company in Denmark to continue studying the potential clinical applications of Clue One. And I also actually later continued that work at the Moores Cancer Center at UCSD here in San Diego. Ultimately, I sold the rights to the Clue One gene to a larger company that commercialized the findings.

Around that time, a friend of mine unfortunately had been diagnosed with ovarian cancer. She found support at Clearity and was really thankful, so she got involved with the fundraising at Clearity, and that's kind of actually the first time how I like, that, I heard about Clearity. I also, at that time, I actually talked to another acquaintance who is one of the founding board members of Clearity, and when she heard that I

was looking for a new opportunity, she suggested that I talked to Clearity, and that's six years ago.

HANNAH LIPPITT: So an entrepreneurial background as well as a scientific one. Now, despite the clinical trials process coming under the spotlight during COVID, many people still don't fully understand the process, and there are misconceptions around how trials work. Could you explain more about what the different types of trials are?

ANNE METTE BUHL: Absolutely. The ultimate goal of running clinical trials is to find more effective drugs or drug combinations for patients and the process of taking a drug from pre-clinical research in the lab and all the way to approval is really long and complicated and expensive. A drug has to go through testing in Phase I trials, Phase II trials and Phase III trials and process is highly regulated. Here in the US this process is run by the FDA. The first time a drug is given to humans will be in a Phase I trial, and the Phase I trial really has very distinct purposes. The main purpose of a Phase I trial is to evaluate the safety of the drug. Then it is to find the optimal dosage to give the drug with, and then also to identify any potential side effects of the drug.

So the very early stages of a Phase I trial will is what we call the dose escalation Phase. So you start out giving a very low dose of the drug to a few people – typically three people – they enroll into this cohort people with the lowest dose of the drug. And if no dose limiting toxicities is seen in the and that stage, then you jump to the next lowest level of the drug. In that way you test the drug Kind of in a stepwise fashion to find the best dose that you can give. Basically, you basically try and find the maximum tolerated dose. So that is really the goal of the Phase I trial and when the Phase I trial is finished, the results, of course, have to be submitted to the FDA, and if the FDA feels that there's reason to think that this drug is safe and it makes sense to continue, they will allow the trial sponsor to start a Phase II trial. And Phase II trials are typically a little bit larger than the Phase I trials, typically, about

maybe 50 to 200 patients are treated in a trial, and the Phase II trial is really the first time you are looking for efficacy, so you're really trying to study if a drug is able to stabilize the cancer, or potentially also to shrink tumor, so that’s really the goal.

HANNAH LIPPITT: And the next phase – Phase III – is where patients can benefit from best standard of care treatments, isn't it?

ANNE METTE BUHL: You know, we really ultimately want to find new drugs that are at least as effective – and hopefully even a little bit better – as the best standard therapy that's already available for people. So, a Phase III trial is a much larger study. It typically can enroll maybe a thousand or even two thousand people, and the goal of the Phase III trial is really, you want to confirm that the new drug or drug combination is efficacious and you also want to compare this new treatment to that best standard treatment that the patient would receive if they did not enroll in the clinical trial.

So, to do that, you're really in Phase III trials you, you typically have multiple arms, so patients enroll and then they are randomly assigned to receive either the new treatment, the experimental treatment, or to get in the arm where they are treated by the standard, the current best standard that we know. This this comparison is really necessary because we need to know “Is the new treatment good?” you know, even though in a Phase II trial you may have seen the promising

results, it can be difficult to tell how this new treatment potentially lines up against the best standard that we already know. And so to make sure that this comparison in the Phase III trial is not biased – that the randomization is done – you know, so people are completely randomly assigned to each arm and also that the trial can sometimes also be run blinded, which means that neither the patient or the doctor knows if the patient is getting the standard treatment or is getting the experimental therapy.

HANNAH LIPPITT: Now, a lot of patients see clinical trials as a last resort, but patients can take part at any stage, can’t they?

ANNE METTE BUHL: So that is a common misconception – that clinical trial is something that you consider once you have already basically used up all your other options – and I think that's very wrong. You really can think about clinical trials at any stage of your disease because clinical trials are run for

patients that have just been diagnosed and for patients that have had multiple prior therapies. So you can really think about clinical trials as a way to get access to tomorrow's treatment already today.

And another thing I hear is – when I talk to people – is that the care that you receive on a clinical trial can actually often be better than the care you get when you're treated outside a clinical trial. Because in clinical trials, it will often be more important to monitor, you know, the progression of the disease under the degree of response to a given therapy. So I really think people should basically consider clinical trials for every time they have to make a treatment decision.

HANNAH LIPPITT: Ovarian cancer is a disease where fast access to trials is really important because of the low survival rate, and clinical trials have really helped improve ovarian cancer treatment over the last few years. Could you expand on this?

ANNE METTE BUHL: It's true that we really have seen some really, really big leaps in the ovarian cancer care and those results, those changes, have come by

because of clinical trials. And I think the area that really comes to mind that has affected most women is the area of maintenance therapy, that is really now a standard practice in ovarian cancer treatment. Maintenance treatment is treatment that's given to help keep cancer from coming back after it has disappeared following the initial therapy. So, it used to be that women were in cancer when they are diagnosed would have surgery and then undergo chemotherapy – typically maybe six cycles of chemotherapy – and the vast majority of women, fortunately, would have a good response to that initial therapy. But about five, six years ago, a new type of drug was... went into clinical trials in ovarian cancer. That's a type of drug that's called a PARP inhibitor.

HANNAH LIPPITT: Could you give a bit more detail in layperson's terms? What is a PARP inhibitor?

ANNE METTE BUHL: So cells, when they grow, they have to double all the genetic material that is inside the cell, and that's a very complicated process. And this is a process that's actually also a lot of spontaneous mistakes happen, but our cells are very good at fixing a lot of these mistakes. PARP inhibitors are drugs that actually go in and block some of those repair mechanisms, and cancer cells are particularly prone to these PARP inhibitors because cancer cells

grow faster. So blocking the repair mechanism can really, really hurt cancer cells. The studies that were started in ovarian cancer five, six years back, were that it was determined that we were trying to study whether a PARP inhibitor maintenance therapy could benefit women and whether it could actually help women live for longer without any evidence of disease. And the studies that were like multiple large Phase III studies that looked at this question and all of the studies were really, really, really, really positive.

So basically, we have learned that all women with ovarian cancer

benefit from getting PARP inhibitor maintenance therapy.

So now after these studies were finished, it has now been approved for women that they can get a PARP inhibitor maintenance therapy when they have finished, when they've had a response, when they have had a response to the initial chemotherapy treatment. What we also now understand is that even though all women benefit from PARP inhibitor maintenance therapy, some women benefit more than others.

HANNAH LIPPITT: So, why is genomic testing so important?

So about half of women that have ovarian cancer, they have some underlying genetic changes in their cells that make the cancer cells, particularly sensitive and this underscores the importance of genomic testing and tumor testing for newly diagnosed patients with ovarian cancer. If you get a genomic and tumor testing, it allows you to understand your potential benefit from PARP inhibitor maintenance therapy, so you, in collaboration with your doctor, a woman that has been diagnosed with ovarian cancer can discuss whether a PARP inhibitor maintenance therapy is a good choice for her.

HANNAH LIPPITT: Oncology trials can have quite stringent inclusion and exclusion criteria which can cause some problems for patients, especially if they’re looking to take part in trials at a later stage. What do people need to know about clinical participation in oncology trials?

ANNE METTE BUHL: That's a really important point. You know, inclusion and inclusion criteria really are designed, to kind of specify which patients are being studied in a given trial. And inclusion criteria will typically identify the exact type of the cancer, what stage of the cancer are being studied, and potentially also describe if a specific patient with the same type of genetic alteration can enroll in the trial. Exclusion criteria is more of a way to kind of make sure that people that may confuse the results of the trial or even people that have underlying conditions should not enroll in a trial if a drug is already known to have certain side effects.

But the one thing that I really want to point out is that often an exclusion criteria is how many prior therapies a patient have already had, you know, so a lot of trials, particularly the later stage trials, will require that you have had potentially just two prior therapies and that may be a problem sometimes, you know. This underscores why it's so important to look at clinical trials early because you know, some women that

I talked to have already had four different types of standard chemotherapy treatment, and that makes them ineligible to enroll in certain trials. I just find it very important that people, every time they're making a treatment decision, they should be aware of those two standard options and the clinical trial options and then make the best choice possible based on that.

HANNAH LIPPITT: Yeah, that's something a lot of people wouldn't know. So it's really important to highlight that. I agree. So previously on this podcast, Dr. Deborah Zajchowski – your colleague – discussed Clearity's clinical trial finder so patients can discover trials quickly in that area. Why, in your opinion, is this so important?

ANNE METTE BUHL: Finding a clinical trial is actually a really complicated process, and it can be quite overwhelming. There are fortunately, so, so many different clinical trials out there, and sifting through all that information can be very difficult. Our clinical trial finder really focuses on the trials that are available for women with ovarian cancer, and we also ask a number of questions in the trial finder that helps specify – you know, basically narrow down – the amount of trials available based on a patient's specific situation. It can be

how many prior therapies that patients have had and it can be what type of genetic alterations does this patient have. And it can also be that if a patient is just interested in looking for trials that are enrolling in a certain state.

So instead of potentially looking for... at 200 trials, a patient will maybe now have a list of 20 trials

to consider. So I think that is really... that helps people a lot.

HANNAH LIPPITT: One subject we talk about here at Teckro is access to clinical trials via physicians, but it can be difficult for physicians to know how to easily recommend patients to trials. How do you think this could best be addressed?

ANNE METTE BUHL: Finding a trial can be really difficult, and it's a really time intensive and labor-intensive process. So I unfortunately, I think that the physicians often do not have enough time to also engage in this process. Many physicians are aware of the trials that are available at their institutions, but for some patients, they want to know “What's available in my state?” or “What's available in the whole country?” At Clearity we really have a shared passion to improve outcomes for women with ovarian cancer, so our goal is to help the women that contact us, and we also encourage the women to share all the information that we can give them to take that to their doctor and to discuss the options with their doctor. And we have also physicians that use our tool because it enables them to very quickly get an overview of what are the options, for example, in a particular state. We do also have another program that's called Steps Through Ovarian Cancer, where we offer women psychosocial support, and the goal is really to help every woman live with ovarian cancer on her own terms.

HANNAH LIPPITT: Is there anything else you’d like to add about the importance of clinical trials?

ANNE METTE BUHL: I just hope that these explanations about how clinical trials are designed and what’s the purpose of different clinical trials has helped remove fear about enrolling in a clinical trial and has helped people understand that clinical trials are important to consider at any stage of their disease.

HANNAH LIPPITT: And that's your dose of Totally Clinical. You can download our podcast on Apple, Spotify and Google. Please subscribe and leave a rating and review so more people can find the show. See you on your next visit and remember to bring your friends. Thanks for listening! Goodbye!