Dr Agresta Talks Venetoclax, CPX-351 for Young Patients With R/R AML

Laura Agresta, MD, Assistant Professor of Pediatric Hematology/Oncology, Michigan State University, East Lansing, Michigan, discusses a phase 1 study of venetoclax and CPX-351 in young patients with relapsed/refractory (R/R) acute myeloid leukemia (AML); these data were presented at the virtual 2021 American Society of Clinical Oncology (ASCO) Annual Meeting.

Transcript

My name is Dr. Laura Agresta. I'm an Assistant Professor of Pediatric Hematology/Oncology at Michigan State University.

The V2 study is a combination CPX-351, which is a liposomal cytarabine/daunorubicin nanoparticle. We're combining that with an oral BCL-2 inhibitor called venetoclax with the goal of being able to induce a minimal residual disease negative state that allows them to go to a curative pathway through stem cell transplant in the setting of relapsed/refractory AML and certain other leukemias.

We're very motivated to find these kinds of more effective combinations because despite significant advances in therapy for AML, about 30% to 40% of young patients will still relapse. It's very challenging after relapse to find a curative pathway.

In young patients, curative intense salvage therapy involves intensive reinduction followed by hematopoietic stem cell transplant. The challenge lies in reinducing a minimal residual disease negative state so that the transplant has the best chance of being successful. That's our goal in studying this combination.

We had both clinical and laboratory data that led to the development of this trial. Clinically, this trial I started when I was at Cincinnati Children's with Mike Absalon and John Perentesis. Cincinnati had run the first in pediatrics safety trial of CPX-351.

The excitement about CPX-351 is that it takes the 2 most potent anti-AML chemotherapies, which are cytarabine and daunorubicin, at an exactly synergistic ratio within this nanoparticle. Then, the nanoparticle actually directs the drugs to the bone marrow, the origin of the leukemia. That ratio persists for over 24 hours.

This formulation, we know from our preclinical data, is potentially more potent than just giving those 2 conventional chemotherapies in the traditional way.

The Cincinnati trial demonstrated that CPX-351 was safe in children. The Children's Oncology Group, COG, then did a phase II trial that demonstrated an 81% complete response rate in pediatric patients with AML and first relapse, which is twice the historical rate and really, really promising.

Around this time, there's this completely new anti-cancer agent entering clinical trials in adults. It's a small molecule inhibitor taken by mouth called venetoclax. Venetoclax targets an inhibitor of the apoptosis cascade called VCL-2 that some leukemias overexpress. That helps them resist conventional chemotherapies.

For our integrated pilot study with single-cell RNA sequencing in that first CPX-351 trial, we sequenced before, during, and after the CPX-351 and demonstrated an enrichment for genes regulating apoptosis, suggesting the blasts may be primed for apoptosis following CPX-351.

That was our rationale for adding venetoclax to CPX-351, with this goal of overcoming chemotherapy resistance.

This study is very straightforward. It's 1 course of study therapy with the goal of that MRD negative state to get to a transplant. Patients on study received CPX-351 on days 1, 3, and 5 at the FDA approved dose. To that, we add venetoclax, which is taken daily.

We still have a few more patients to accrue on study before we meet our statistical endpoints for analysis. At that point, I'll be able to share our data.

I can say at this point that we have been extremely pleased with both the safety profile and the clinical outcomes of the study therapy. We believe that continuing to study this combination is very worthwhile.

If this combination is successful, as we expect, we hope it will offer a more effective form of reinduction therapy for young people with R/R AML and certain other types of acute leukemias.

In addition, we are doing correlative studies to try to help determine which patients with R/R leukemia will benefit the most from this combination compared to some other novel combinations that are still in development.

After any pilot study like this one, the next step is to investigate the combination as part of a larger multi-institutional trial and include those correlative studies that help us identify who the best responders are and who needs a different combination.

My hope is that in the future this combination may be part of something called an umbrella trial, which is newer to pediatric oncology, but there is already an example of an umbrella trial called the PedAL trial up and running through LLS and COG for AML.

The idea of any umbrella trial is to enroll patients who all have a disease, but then look at the molecular signature of their particular, for example, leukemia blasts, and then assign a therapy combination based on their specific molecular signature.

My hope is that this combination will fit into a trial like that in the near future.

This is a very hard thing for a family to hear, that after going through the rigorous up-front therapy of AML that the cancer has come back.

Most families also know at that time that the prognosis, in the setting of relapse, is not as good as it was at the beginning when the assumption was that they would respond to the initial therapies.

I am impressed every day with the fortitude of people who, in the midst of getting this news, want to help move the field forward, make outcomes better for the next child or young person that comes along, by participating in clinical research like this.

I see it every day and it gives me hope.

At the moment, this pilot study is only open at Cincinnati Children's. The hope is that if we can complete accrual and get the data out that it will be a therapy that is more accessible to people across the country.

We always talk to our patients about any potential trials that they might be eligible for, explaining the risks and benefits of enrolling in a trial, as well as comparing it to the therapy they would get if they didn't want to participate in the research.

As I said, I am so impressed every day by people who, in the setting of hearing the news that nobody ever wants to hear, volunteers to help us move the field forward.