Dose Escalation, Combination Strategy Keep Aprea Ahead In Its Oncology Trials

A conversation between Aprea Therapeutics CMA Eugene (Gene) Kennedy, MD, and Clinical Leader Executive Editor Abby Proch

Those who have run a clinical trial for a small organization know the imperative to make every choice count. Usually, that’s because money, and therefore time, is in short supply.

Eugene Kennedy, MD, chief medical advisor at Aprea Therapeutics, understands it well and so helped the company meet the moment with clinical design choices that capitalized on its therapy’s mechanism of action, advances in standard of care, and concurrent trial planning.

In this interview, Kennedy discusses the very intentional choices it made when designing its 3+3 dose escalation study for its WEE1 inhibitor, APR-1051, while keeping an eye on future trials that would likely use study combination strategies.

What are the nuances of this 3+3 dose escalation Phase 1 trial?

Eugene Kennedy, MD: One of the catches, and it's become more common in the last 10-plus years, is that if your drug is tolerated relatively well, you only treat, say, three patients before you move to the next higher dose. And  this dose was safe enough to give to people, but it's hard to know from three patients whether you are really helping anybody. It used to be that people would go through the Phase 1 safety study and then go into an expensive medium-size Phase 2 study where you'd try to answer those “Is this really working?” questions.

But what a lot of investigators and companies have done more recently is expand the Phase 1 to treat more patients at doses that look safe. So, you can find out whether there are specific populations of patients that you're helping, because those would be good populations to investigate in a larger study. This way, when you start enrolling more patients in your later-phase study, you're not going in blind.

You’re targeting different types of multiple advanced-stage solid tumors. What was the rationale for including such a heterogeneous population?

That gets back to the mechanism of this drug and how we believe it works. Our drug is designed to take advantage of mutations that occur in the DNA damage repair pathways. When cells divide, things go wrong, and mutations can occur. Some mutations could be beneficial, such as with evolution, while some mutations can be negative, as with cancer, and they can accumulate to a point where the cells can't divide properly. But to keep that replication as correct as possible, cells have repair mechanisms, and our drug is designed to interrupt some of those repair mechanisms.

Individual types of cancers don't have a monopoly on having one of these mutations, so we aren't wedded to any one type of cancer. That's why we can work across multiple different cancer types, provided that they have these mutations.

When a patient is diagnosed with cancer, is it profiled in such a way that this mutation would be known before trial recruitment?

There has been a big change in the way these trials have been conducted and cancer has been treated in the last 10 years. Next gen-sequencing (NGS) is becoming more common, and it's essentially the standard of care. Oncologists take either the biopsy or a part of the tumor that was removed and send it to a cancer center for testing. It gives a list of all the mutations found in these tumors that are actionable. The patients come with this information already, because at the time of early clinical studies, you are not enrolling newly diagnosed patients. We partner with doctors at cancer centers, and then the doctor and the patient have a discussion and decide whether they want to sign up for the trial.

Has NGS evolved alongside the concept of treating according to a patient’s mutation?

It's sort of a stair-step evolution, because the idea of targeting mutations isn't new. But before the testing was widely available and commonly done, it was quite expensive. And the sponsor of the trial would have to pay to complete this. And it could be thousands of dollars per patient.

Let's say you're looking for a mutation that occurs in 5% of colon cancer. If one scientist was working on this 5% and another scientist is working on another 5%, you add it all up eventually and you should make some progress. But to find that 5% mutation, before NGS screening was commonly available, it was thousands of dollars per patient screened.

The barrier to entry, especially for smaller companies, was originally affordability. But now that this sequencing is more commonly available, it does help the trial initiate and run more efficiently. You don't have to wait weeks.

Having this widely available is starting to accelerate the ability to move forward with these cancer treatments. It's an exciting time to be working in this field because you can already see it happening with Revolution’s targeted therapy for KRAS, a mutation common in pancreatic cancer. It's not a cure, but doubling survival is more than all of us had done up to that point, quite frankly. It's progress, and it's great.

Once a patient is enrolled, do you then stratify them by their cancer types? Or how do you approach your analysis?

We are looking at five groups of patients based on their mutations: a specific form of endometrial cancer, HPV-related cancers, head and neck cancers, gynecological cancers, and even some subsets of colorectal cancer. We think they all have a chance to benefit, more so than patients without these mutations.

Once we have enough data, we will stratify by mutation, by tumor type, and more to determine whether one mutation in one type of cancer gives you the same chance to respond as the same mutation in a different type of cancer. And that's one of the reasons we have this backfill expansion – if you have three patients and one out of three responded, well, that's a 30%+ response rate. If two out of three responded, you think this is the best thing ever. But the next nine could either respond or not. You don't know. When you get 10 patients, then maybe you start to get a better idea. But you have to pick a number to say these are the folks we think are most likely to be helped, at least in round one.

A company our size can't do everything at once. So, when we go into Phase 2, we're going to have to identify groups who we think are most likely to benefit based on our Phase 1 data. Does that mean we're never going to go back and offer it to some of the other groups? Of course not. But you have to build this thing one brick at a time. We'll try to find the folks who are most likely to benefit first. If they do, then we can build the pyramid higher and wider as we go toward approval.

Would you also consider the option of a monotherapy, combination strategy, or both as you head into Phase 2?

That's a question a lot of companies have to address. If you look at the way cancer care is delivered currently, there's not a lot of diseases that are treated with just a single drug. If you look at the NCCN [National Comprehensive Cancer Network] guidelines, very few of them, at least in the first or second line, say, "Use this one drug." It's usually two or even three drug combinations.

When you're developing a drug, you have two missions: determine if your drug works as a monotherapy and to what degree. The FDA is not going to let you proceed to approval unless you have evidence that your drug is helping.

But you also have to start looking at how you are going to integrate it into the care that patients are already receiving. . You want to have a plan.

What you need to do is a slightly staggered approach. Right now, we're doing a Phase 1 dose escalation. The ultimate goal is to determine which dose is safe to move forward with. And it's also really nice if you can start to tease out whether this is helping patients.

But you do not have to wait until that's all over with and then go to Phase 2, Phase 3, approval, and then back to combinations. Once you start to show that some doses are safe, you can start to think about combinations from an efficacy and toxicity point of view.

Also, is it practical to put these drugs together? If one drug has to be put in through an IV over 6 hours and the other one has to be put in an IV by itself over 6 hours, then that's 12 hours — and what patient wants to spend 12 hours on an IV?

We haven't announced any combination studies yet, but they're on our mind because small companies don't have the luxury of going through a Phase 1 study and then waiting to make the next decision. You don't have successful drugs bringing income in, so you need to keep moving forward. You need to keep being responsible for the stakeholders and keep your eyes focused on helping patients that need it the most.

Some companies investigational drugs have not been approved by the FDA yet, but they're already announcing trials with combinations. While they're moving their one asset or their one experimental drug forward toward, hopefully, being an approved drug, they're starting to build on top of that.. All companies should do that from an early stage.

Editor’s note: This transcript has been edited for clarity.

About The Expert:

Eugene (Gene) Kennedy, MD, joined Aprea in early 2026 as chief medical advisor. He brings over 15 years of clinical and industry experience to the team, including cross-functional leadership driving clinical development and regulatory strategies for oncology and immuno-oncology-focused organizations. Prior to Aprea, Gene was chief medical officer at several pharmaceutical and biotech organizations, including Carisma Therapeutics, Galera Therapeutics, Innovative Cellular Therapeutics, Lumos Pharma, and NewLink Genetics. Before joining NewLink Genetics, Gene served as an associate professor of surgery at Thomas Jefferson University and held leadership roles at Johns Hopkins Hospital and Louisiana State University. He received his MD from the Medical College of Virginia and a bachelor’s degree from the University of Virginia.