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Precision Medicine Master Trial Aims to Tailor Therapy for Acute Myeloid Leukemia Patients

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NEW YORK (GenomeWeb) – A clinical trial for acute myeloid leukemia that employs next-generation sequencing and precision medicine treatment may be groundbreaking because of the level of collaboration among partners, according to the Leukemia & Lymphoma Society, the trial sponsor.

The Beat AML Master Trial may also provide a framework for how future clinical trials seeking precision medicine outcomes are conducted, according to its lead investigators.

"It really is a remarkable example of collaboration between academic medical centers, a sequencing company, and pharmaceutical partners to try to advance therapies for patients," Brian Druker, a lead investigator in the master trial and director of the Knight Cancer Institute at Oregon Health & Science University, told GenomeWeb.

"And despite the fact that we got started long before Vice President Biden announced the Moonshot initiative," he said, "this is exactly in line with what [the vice president] is talking about. It's about collaboration and trying to get ten years of progress in five years."

The trial will launch at five leading cancer centers — the Ohio State University Comprehensive Cancer Center, Memorial Sloan Kettering Cancer Center, OHSU Knight Cancer Institute, Dana-Farber Cancer Institute, and Massachusetts General Hospital Cancer Center. Four biopharmaceutical companies are participants — Alexion, Boehringer Ingelheim, Celgene, and Gilead Sciences — and will provide the investigational drugs samalizumab, BI 836858, enasidenib, and entospletinib, respectively.

As a result of a competitive bid process, LLS selected Foundation Medicine as its NGS diagnostic test partner. The trial will employ FoundationOne Heme, the company's genomic profile test for sarcomas, pediatric cancers, and hematologic cancers, including leukemia, lymphoma, and myeloma.

Foundation Medicine launched the test in 2013 after developing it in collaboration with MSKCC. The assay is designed to provide physicians with information that guides patient treatment options based on the genomic profile of the disease.

"The important point about this test is that it will turn the panel around in seven days," Druker said. "With proper medical supervision, patients can wait for one week."

Many physicians will implement treatment within 48 hours of diagnosis with acute meyloid leukemia, according to the trial's lead investigators.

"When patients are currently diagnosed with AML, they often get a call to go immediately to the emergency room," said one of the trial's lead investigators, John Byrd, of the Ohio State University Comprehensive Cancer Center. "The diagnosis is rushed and the same therapy is given to virtually all AML patients — an intensive chemotherapy course that will cure the disease only for a very small subset. The great majority of patients are not cured and are left with little hope for long-term survival and a lot of side effects from chemotherapy."

Druker said that the capability to turn around test results in around a week was an important factor for the trial, because it quickly enables the treating physicians to make decisions based on the genetic results.

"Data supports our belief that you can probably wait at least a week before you start treatment, but you don't want to wait much longer," Druker said. "There are certainly situations where you need to do something right away. Patients may need antibiotics or leukapheresis where you lower the white cell blood count to stabilize them."

AML patients who relapse from treatment tend to have far more genetic mutations, so identifying the genetic mutations early may offer a better chance for successful treatment. The investigators are trying to get treatment to patients early, when the disease is less heterogeneous, Druker said.

AML is among the best-characterized cancers, he added, and the healthcare community has known about AML's genetic markers for 20 years, or more. "There are a host of mutations that have been well described for this disease," he said. "Some of the treatments that we are looking at are also targeted at surface blockers that are expressed on AML cells. We're trying to use all types of genotypic and phenotypic information to approach this disease more effectively."

One of the BAML trial's lead investigators, Ross Levine of MSKCC, was part of a team that performed a mutational analysis of 18 genes in 398 patients younger than 60 years of age. The group found that "DNMT3A and NPM1 mutations and MLL translocations predicted an improved outcome with high-dose induction chemotherapy in patients with AML," and the researchers opined that their findings suggested that mutational profiling could potentially be "used for risk stratification and to inform prognostic and therapeutic decisions."

"There are some great success stories where classical chemotherapy has been a cure, and there are also a lot of challenges with managing the long-term complications of therapy," Levine said. "For AML, it is a more daunting challenge because although you get a very high rate of response, most patients relapse, and one of the inspirations for this trial is that although chemotherapy is effective for the disease, it is not curative for most patients. What we'd like to do is test how newer molecularly targeted drugs and immune modulatory drugs work in patients with AML and see if they are more effective and less toxic. In some cases, where we know that chemotherapy works, we'll add the new drugs to chemotherapy to enhance the response."

AML has seen few improvements in treatments in more than 40 years, and it is among the most lethal of blood cancers, being responsible for more than 10,000 deaths per year and being the third-leading cause of cancer deaths in the US, according to LLS.

For the BAML trial, FDA has granted a safe-to-proceed status to LLS, based on its investigational new drug application. The pharmaceutical companies and LLS are covering the cost of the trial. The lead investigators expect that the trial will proceed for between 3 and 4 years and could enroll up to 500 patients. Once enrolled, trial duration for patients will range from 1 to 3 years.

The Beat AML Master Trial seeks to change the paradigm for how the cancer is treated using an innovative precision medicine protocol, Louis DeGennaro, president and CEO of LLS, said in a conference call to announce the trial.

"Patients diagnosed with AML today are receiving the same therapy that would have been administered in 1973 — a combination of toxic chemotherapies," he said. "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."

The fight against AML has not kept pace with other blood cancers, but this is not because AML has been ignored, he said. "AML is a complex group of more than 10 different types of blood cancers. Clearly a one-size-fits-all treatment regime doesn't work, and what's needed to improve outcomes for patients are more precisely targeted treatments."

Although Foundation Medicine has been selected as the exclusive genetic test partner for this particular trial, other companies were not far behind in terms of capabilities, expertise, and the ability to turn test results around within a week, Druker said. If the collaborative framework for this master trial can be reproduced in other trials, other genomic test companies could certainly become involved, he said.

One of the unique features of the trial, he said, was that almost every enrolled patient will receive treatment.

Approximately 26 percent of LLS's current research budget is invested in AML research. LLS has invested nearly $100 million over the past five years to better understand and treat the disease.

In 2009, LLS partnered with Celator Pharmaceuticals, which was acquired by Jazz Pharmaceuticals in 2016, to advance an investigational drug, CPX-351. According to LLS, the drug recently outperformed standard therapy in a Phase 3 trial of patients with secondary AML, a high-risk subset of the disease. It has the potential to become the first new treatment approved in the US for AML patients in 40 years, LLS said.

"We hope that this trial is going to be paradigm shifting not only for AML, but also for other disease areas," Byrd said. "A lot these mutations and genetic markers are in other diseases, so the drugs can move forward and be approved and then get applied in other diseases. …What's learned from this trial can be applied to other types of cancers where an umbrella-based approach would be warranted."

The first patients for the BAML trial are expected to be enrolled by December this year, and the trial may eventually be expanded to include between 15 and 20 clinical trial sites.

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