publication date: Oct. 21, 2016
LLS Starts Beat AML Master Trial
By Tessa Vellek
After four decades of few improvements in the treatment for acute myeloid leukemia, the Leukemia and Lymphoma Society has launched a precision medicine trial to identify targeted treatments for patients with AML.
The society’s trial—called Beat AML Master Trial—was announced by Vice President Joe Biden Oct. 17 at a White House event rolling out Moonshot-related initiatives.
Like other “master protocol” trials, Beat AML will test multiple experimental treatments at once. The trial will enroll newly-diagnosed patients who are older than 60. Though AML often strikes at this age, older patients are often not candidates for highly toxic chemotherapy regimens and are least likely to benefit from them.
The trial will launch initially at five cancer centers—The Ohio State University Comprehensive Cancer Center, Memorial Sloan Kettering Cancer Center, the Oregon Health and Science University Knight Cancer Institute, Dana-Farber Cancer Institute, and Massachusetts General Hospital Cancer Center.
In the beginning, there will be four treatment arms.
Four biopharmaceutical companies—Alexion, Boehringer Ingelheim, Celgene, and Gilead Sciences—are providing the following investigational drugs for the trial, respectively: samalizumab (ALXN6000), BI 836858, enasidenib (AG-221/CC-90007), entospletinib. None of these drugs is approved.
The first patients are expected to be enrolled by December 2016. Six additional clinical sites are expected to start enrolling patients in April, and the trial will eventually grow to between 15 to 20 sites, and the number of treatment arms will expand to 10, LLS said.
LLS anticipates that 500 patients will be treated in the Master Trial. Once enrolled, trial duration for patients will range from one to three years.
LLS didn’t provide a cost estimate for the trial. However, Biden announced that LLS has committed $50 million to go on the offensive against acute myeloid leukemia.
In conjunction with the LLS research team led by Amy Burd, lead investigators for Beat AML are: John Byrd, director of the Division of Hematology, Department of Internal Medicine at The Ohio State University; Brian Druker, director of the Knight Cancer Institute at Oregon Health & Science University; and Ross Levine, physician-scientist and Laurence Joseph Dineen Chair in Leukemia Research at Memorial Sloan Kettering Cancer Center. All of the lead investigators have worked closely with LLS to plan and design the master protocol for the trial.
“Beat AML exemplifies perfectly the tenets of the Moonshot—fostering collaboration and sharing of vital data, advancing precision medicine, and most importantly the urgency of getting new and better treatments to patients faster,” Louis DeGennaro, president and CEO of LLS, said at a press conference Oct. 18. “Patients diagnosed with AML today are receiving the same therapy they would have been administered in 1973, a combination of toxic chemotherapy.
“It’s not surprising that the overall prognosis for these patients remains poor, with a five-year survival rate of less than 20 percent for patients over the age of 60. Clearly, a one-size-fits-all treatment regimen doesn’t work. What’s needed to improve outcomes for patients are precisely targeted treatments. That’s what the Beat AML initiative is all about.”
Beat AML will employ comprehensive genomic profiling to find and match specific AML genetic mutations in newly-diagnosed patients over the age of 60, with an investigational drug or drug combination to attack the specific molecular mutations causing the cancer.
“We do anticipate that this trial will stand as a model for other cancer trials,” said Burd, vice president of research strategy at LLS. “For cancers where there are multiple subtypes, using genomic technology to identify the genetic differences so that the patients can be directed to a study arm with the most appropriate targeted therapy makes sense. Having one master protocol which enables us to be nimble about quickly moving drugs out of the trial that are not working, and other drugs into study arms, is also something we believe can be replicated.”
Upon diagnosis, patients in the study will have a bone marrow sample sent to Foundation Medicine, which will utilize its proprietary comprehensive genomic profiling assay for hematologic malignancies to determine the patient’s subtype of leukemia. This process will take up to seven days, during which the patient will be stabilized. Once the genetic marker comes back, patients will be assigned to a targeted treatment based on nine different markers.
“This treatment is based upon a precision medicine determination, but it also incorporates whether [patients] are in the subset of AML patients that are curable, potentially with our current therapy, then they have something added onto that,” Byrd said. “If they are not curable, then they move onto a targeted therapy, a non-aggressive-chemotherapy approach.”
Byrd said that the seven-day wait for targeted treatment will not pose a risk for patient outcomes.
“We have been taught for many years that you need to treat AML before the sun sets, within a day or two,” Byrd said. “And studies have shown that outcome is the same whether someone is treated immediately or after a period of stabilization. The most common thing that almost all AML patients that survived the disease relayed to us that was striking, is that they had post-traumatic stress disorder because of having to proceed with therapy so soon.”
The trial is utilizes a “window” design: if patients are not responding they will go onto a combination with a hypomethylating drug.
The Beat AML trial will enroll newly-diagnosed patients, rather than relapsed or refractory patients, which is common in most AML trials. AML patients who relapse from their treatment tend to have far more genetic mutations, so identifying the genetic mutations early may offer a better chance for successful treatment, according to LLS.
Patient-reported outcomes will serve as a measure of success in the trial, a feature that is consistent with the recommendations of the Cancer Moonshot NCI Blue Ribbon Panel Report.
“From our standpoint, the long-term goal is two-fold,” Levine said. “First and foremost, this is about bringing new drugs to our patients. Our AML patients have been waiting for trials. They need our efforts, they need us to work together, and they need us to work faster. And it’s also about showing the way for other blood cancers and other cancers and even other diseases.”
AML is the most lethal of the blood cancers, which together are the third leading cause of cancer deaths in the United States, according to LLS. AML is responsible for more than 10,000 deaths each year.
“Why has the fight against AML not kept the pace of that of other cancers, you may be wondering,” DeGennaro said. “It’s not that AML has been ignored. Rather, it’s actually because AML is a complex group of more than 10 types of blood cancers.”
DeGennaro said that the new trial may help identify new successful treatments for AML.
“Our vision for this is to identify molecular drivers, identify functional targets, combine these drugs into a master treatment, and bring those forward as quickly as we can, and that requires collaboration,” Druker said. “Collaboration between different academic medical centers, collaboration between different drug companies. LLS has been a neutral convening partner as well as a funding agency to accelerate this process.”
LLS is the first philanthropic organization that has sponsored a master protocol trial.
“The Leukemia & Lymphoma Society is uniquely qualified to lead this unprecedented clinical trial collaboration, rare for a non-profit and a first for LLS,” DeGennaro said. “Beat AML, as we have named this Master Trial, showcases LLS’s stature in the cancer ecosystem. It demonstrates our ability to convene the medical and research communities to think and act boldly in the quest for new and better treatments for blood cancer patients, and our aim to accelerate the rate at which precisely targeted breakthrough therapies reach the patients who urgently need them.”
FDA has offered support and guidance to LLS throughout the designing of the trial. In other trials, observers said that master protocol studies could prove to offer an inside track to approval.
LLS has brought multiple pharmaceutical companies together to test a combination of drugs. “The secret sauce of this trial is that we will work faster by collaborating in an open and transparent way,” Levine said. “We have all heard, most importantly from our vice president, of the need for rapid open transparency and the ability to share ideas and efforts. This brings it in a crystalized way back to our patients.”
Along with LLS, the participating pharmaceutical companies will cover some of the cost of the trial.
Beat AML Master Trial collaborators include: Foundation Medicine, a leading molecular information company, which will utilize its proprietary comprehensive genomic profiling assay for hematologic malignancies, for all of the patients; INC Research, a clinical research organization, which is helping LLS manage the logistics of the trial; Protocol First, providing a web-based digital application to guide the clinicians; and myClin, providing a clinical trial knowledge platform to streamline communications between the clinical trial sites and maintain engagement and regulatory compliance.
“This is a unique opportunity to put the interests of a particularly underserved patient population front and center by bringing multiple biopharmaceutical companies with investigational medicines targeting AML together,” said Martina Flammer, vice president of clinical development and medical affairs, Specialty Care, at Boehringer Ingelheim.
Other pharmaceutical companies have expressed interest in joining the study, and additional treatment arms may be added over time, LLS said.
“The goal of any company is to get their drugs to market as quickly as possible,” Druker said at the press conference. “So if we show a path forward that we can test drugs in the newly-diagnosed untreated setting, take the winners forward for FDA approval, and companies see this is a faster way of getting approvals, then this paradigm can be extensible to many other disease types.”
DeGennaro said Beat AML’s collaboration design is likely replicable to other settings.
“FDA is supportive of our master trial, because its design has the potential to stand as a model for cancer clinical trials in the future,” DeGennaro said. “We have every desire to take this protocol forward in other blood cancers and with what we will believe will be significant success, it’s very likely that the design for this trial will be copied in other cancers as well.”
Other precision medicine trials include: NCI-MATCH (Molecular Analysis for Therapy Choice), ALCHEMIST (Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial), Lung-MAP (Lung Cancer Master Protocol), NCI MPACT (Molecular Profiling-Based Assignment of Cancer Therapy), NCI-Pediatric MATCH (Molecular Analysis for Therapy Choice), Exceptional Responders study, and ASCO’s TAPUR study (Targeted Agent and Profiling Utilization Registry).