Study Seeks New AML Therapies

For more than 40 years, treatment for acute myeloid leukemia (AML) hasn't changed, with patients generally receiving a chemotherapeutic combination of cytarabine and daunorubicin, followed by a stem cell transplant for those who can tolerate it. Yet, the prognosis has remained poor, particularly for patients over age 60, whose 5-year survival rate is less than 20%.

In an effort to change that picture, a group of physician-scientists, drug manufacturers, government regulators, and patients, led by the Leukemia and Lymphoma Society (LLS), has launched the Beat AML Master Trial. This large umbrella study will simultaneously test multiple investigational agents—both targeted drugs and immunotherapies—advancing ones that show promise and dropping those that prove ineffective. New drugs can be added to the protocol over time.

The umbrella trial design, in which multiple drugs are tested on different genetic aberrations in a single cancer type, isn't new. Lung MAP (for lung cancers) and I-SPY (for breast cancers) employ a similar strategy. However, the Beat AML Master Trial is one of the first to be led by an independent nonprofit organization, which will also pursue FDA approval for any drugs deemed successful in the trial, said Louis DeGennaro, PhD, president and CEO of the LLS, at a press conference announcing the trial. With LLS acting as a neutral party, more pharmaceutical companies may join the effort to bring drugs to market more quickly.

“The secret sauce of this trial is the idea that we're going to work faster by collaborating in open and transparent ways,” said Ross Levine, MD, of Memorial Sloan Kettering Cancer Center (MSKCC) in New York, NY. In addition to MSKCC, the Ohio State University Comprehensive Cancer Center (OSUCCC) in Columbus, Oregon Health & Science University Knight Cancer Institute in Portland, and Dana-Farber Cancer Institute and Massachusetts General Hospital, both in Boston, will serve as the initial trial sites.

Researchers plan to enroll 500 patients over age 60 newly diagnosed with AML in the trial. Participants will have their cancer's genome sequenced and be put into a trial arm based on nine different genomic signatures, said John Byrd, MD, of OSUCCC.

Unlike other trials, none of the participants will receive standard chemotherapy alone. If there is not a suitable drug match for a patient's genetic markers, they will be offered chemotherapy in combination with an existing targeted therapy, Byrd explained. Patients who do not respond to their investigational drug can also receive conventional therapy with the targeted therapy, he added.

Most of the patients who will be eligible for the trial are unable to tolerate intensive chemotherapy, so their outcomes are even worse than average, said Brian Druker, MD, director of the Knight Cancer Institute. The targeted therapies are expected to be better tolerated than toxic chemotherapy, and will be given after diagnosis, when they will likely be more effective, instead of waiting for disease relapse, he added.

DeGennaro said that the trial will begin by testing these four drugs:

• Alexion's samalizumab (ALXN6000), a humanized monoclonal antibody that targets CD200

• Boehringer Ingelheim's BI 836858, which induces antibody-dependent cellular cytotoxicity against CD33-expressing tumor cells

• Celgene and Agios's enasidenib (AG-221/CC-90007), a selective IDH2 inhibitor

• Gilead Sciences' entospletinib, an inhibitor of the tyrosine kinase Syk, which blocks B-cell receptor signaling

Three to six more drugs may be added over the course of the trial, which will run for 3 to 5 years.

“This is about working toward a common goal,” said Levine. “We really want to make a difference for our patients.” –Karen Weintraub

For more news on cancer research, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.