Beat AML trial designed to match ‘right patient with the right drug’

Issue: January 25, 2017

SAN DIEGO — A newly launched precision medicine trial has the potential to dramatically change the treatment paradigm for acute myeloid leukemia, according to participants in a panel discussion held at the ASH Annual Meeting and Exposition.

“There have been no significant advances in the standard of care for AML patients for more than 40 years,” Louis J. DeGennaro, PhD, president and CEO of the Leukemia & Lymphoma Society (LLS), said during the session. “[The society] has convened what I believe is an unprecedented collaboration of research experts, clinicians [and] medical centers ... to take on this challenge.”

The society launched the Beat AML Master Trial in October at five institutions: Dana-Farber Cancer Institute, Massachusetts General Hospital Cancer Center, Memorial Sloan Kettering Cancer Center, Oregon Health & Science University’s Knight Cancer Institute and The Ohio State University Comprehensive Cancer Center. An additional six sites are expected to join by mid-2017.

The trial is open to patients aged 60 years or older with newly diagnosed AML.

Byrd, Levine and Druker during Press Breifing: Beat AML.

Photo courtesy of the American Society of Hematology

All patients will undergo tumor sequencing. The results — which will be available within 7 days — will help researchers match patients to the most appropriate study arm. Treatment in each arm will target patients’ specific tumor genotype.

“For 40-plus years, AML has been treated as a single disease,” said John C. Byrd, MD, chair of leukemia research and director of the division of hematology at The Ohio State University Comprehensive Cancer Center, as well as a HemOnc Today Editorial Board member. “The fine work by many biologists has shown it likely is 10 or 15 diseases, maybe more. This trial, rather than treating everybody the same, will allow us to direct therapy for each person’s leukemia and give a chance for these medicines to work.”

The approach is a transformative shift from standard therapy for AML, one of the deadliest and most difficult-to-treat blood cancers.

“Aggressive chemotherapy puts patients in the hospital for 28 days, it makes them very sick, and most patients themselves would call it barbaric,” Byrd said. “We are going to move away from that if the therapy is not potentially curative and instead give a more targeted epigenetic therapy.”

The trial — expected to last 3 to 4 years — will test at least seven and as many as 10 investigational agents simultaneously.

The trial’s “nimble” design, which allows for treatment arms to be opened and closed based upon the efficacy and safety each regimen demonstrates, differs considerably from conventional cancer clinical translation, according to Ross L. Levine, MD, physician–scientist at Memorial Sloan Kettering Cancer Center.

“We often do experiments in the lab, and we have a hypothesis about how it may or may not work,” Levine said. “Then we go into the clinic and try the approach in a series of patients, and none of those patients have the same makeup or disease as the model we used to test and validate the drug. This happens every day in academia and industry. Here, we have a unique opportunity to make sure the ideas that we’re bringing out of the best labs around the world are tried in the right patient, and that for every patient, we’re asking the right question.”

The ability to complete tumor sequencing so quickly distinguishes the Beat AML trial from other studies, Levine said.

“This design allows us, in a very reasonable time that matches the urgency of the situation, to have very advanced knowledge of the molecular makeup of every patient’s leukemia and to make the right treatment decision,” Levine said. “It’s hard to overestimate how important that is and how different it is from many other precision cancer trials, where a test can take as long as 2 to 4 weeks.”

When cytogenetic and genomic sequencing data are returned, patients will be matched to trial arms based on prognostic features and specific markers, such as IDH1, IDH2 or FLT3 mutations. Patients with no markers will be included in a marker-negative arm.

“The idea is that everybody enrolled on the screening part of the program gets a prespecified treatment that they’d be eligible to receive,” said Brian J. Druker, MD, director of Knight Cancer Institute at Oregon Health & Science University.

Researchers hope to accrue 20 to 25 patients in each treatment arm.

“It really is about matching the right patient with the right drugs,” Druker said. “Even with very small patient numbers, if we do this correctly, we can see large effects.”

Those effects may be enough to support regulatory approvals of agents for certain subsets of patients with AML.

“The FDA is hugely enthusiastic about this trial as a precedent-setting, paradigm-changing clinical trial,” said Kenneth C. Anderson, MD, president-elect of ASH and director of the Lebow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center at Dana-Farber Cancer Center. “We’ll start with AML, but hopefully this will be a model for other blood cancers, as well.” – by Mark Leiser