Acute myeloid leukemia (AML) is a cancer that develops in bone marrow where new blood cells are created. It quickly moves into the blood, where it can be fatal in a matter of months. It can also spread to other parts of the body, including the lymph nodes, liver, spleen, brain, spinal cord, and testicles.
“AML is one of the most deadly blood cancers,” says Andrea Greif, senior director of communications for The Leukemia & Lymphoma Society (LLS). “Unfortunately, it is also one where we have seen very little progress. The standard of care is currently the combination of two types of chemotherapy, which, for older patients in particular, can be very toxic. Many patients simply cannot tolerate the treatment. Despite progress in treating other forms of blood cancer, AML had suffered through a 40-year drought in new treatments until earlier this year, when four therapies finally broke through to achieve FDA approval. LLS's investment assisted each of these somewhere along their development pathway. However, there continues to be a critical need for new treatment options for those patients.”
LLS realized it was funding a lot of research in the AML space through its research grants and felt it was time to take a closer look at this unmet need. LLS has also learned that AML should not be treated as a one-size-fits-all disease. AML is really multiple subtypes of blood cancers with different genetic mutations. It can actually be looked at as a conglomeration of rare diseases.
“Technology has been improving and that has enabled us to take a closer look at the underlying causes of blood diseases,” states Greif. “At the same time, we are now seeing more agents emerging from pharma. Technology is helping us to better understand the disease and new drugs are finally showing signs of addressing some of the genetic mutations. These factors are finally coming together at the right time and giving us some hope in the battle against AML. We believe it will lead to new and more targeted therapies for patients.”
A New Trial Brings New Hope
One problem for patients has been getting access to the best treatment option. Dr. Len Rosenberg, head of clinical operations at Beat AML, a division of The LLS, notes a patient coming into a medical institution for an AML treatment may likely not get the precision matched, most promising treatment currently in development by pharma.
“The traditional method of doing drug development was simply not working for these patients” states Rosenberg. “Chemotherapy was not meeting the needs of patients, and there were not enough patients with specific targeted mutations to convene a timely and efficient clinical trial. With that as the backdrop, LLS felt it had to get more deeply involved in this process for the benefit of the patients and to increase the speed and efficiency of AML trials.”
The solution was the Beat AML trial using a Master Trial configuration. LLS reached out to pharma companies and requested it be allowed to hold the IND (Investigational New Drug) for their most promising drugs and perform the genomic testing of AML patients. Institutions with patients could then enter the trial and have access to a number of promising treatments, each with a particular potential mutation target.
“We are taking elderly patients suspected of having AML and, within seven days, receiving a report from a centralized genomics facility on their predominant mutation, determined via testing on their bone marrow,” says Rosenberg. “That report allows our medical advisors to match the patient to the best-in-class available therapeutic in the Master Trial. In many rare disease trials, there may not be a treatment available to every patient diagnosed. I want to stress that all patients diagnosed with AML in our trial will have the option to receive a treatment recommended by one of the top leukemia researchers in the U.S.”
The trial also takes away any potential influence from sponsors, sites, and investigators, making the needs of the patient the primary deciding factor in the treatment decision. Rosenberg notes this process makes the Beat AML trial timely and cost effective, while also removing any bias and making use of the best decision-makers available to recommend the most promising treatments to patients. “This is a trial model that has not been done before with this magnitude and complexity,” he says. “It is being conducted through a nonprofit that is determined to put the patient first,” he says. “That puts this type of trial front-and-center with the FDA and other stakeholders involved.”
Technology Plays A Huge Role
LLS also partnered with the FDA for advice on convening the clinical trial, to enable timely input and reviews. Vendors (e.g. CROs, IRBs, central labs, and eclinical technology companies) were also invited to participate.
“The technology aspect was an important one,” says Rosenberg. “With all of the stakeholders involved in this project, we had to make sure we could centrally communicate, distribute information, and analyze and report results to everyone involved using flexible systems. At any point in time, an institution could be running 5 or 10 sub-protocols to our Master Protocol. They would need to have all of this information readily available at their fingertips.”
The end result of the Master Protocol and sub-protocols was a very complex trial environment. Execution required the combination of the traditional methods of performing trials with novel technologies, all pulled together under the LLS umbrella.
An example of one of the technology partners involved is myClin. Rosenberg refers to them as the Facebook of clinical trials, and notes the company’s software tool contains all the key information surrounding a trial’s execution, as well as a communication hub for all the vendors involved. More importantly, the tool allowed LLS to start the trial with built-in components of a quality management system that permitted the generation of audit trails for things such as training.
“Key participants in the trial needed to be trained,” says Rosenberg. “They were able to go to myClin, get trained, and document the training. When there are multiple protocols being conducted simultaneously, coupled with changes in protocols and changes in personnel, the system proved to be a critical component of the trial.”
Other partners involved in the trial include Medidata, WCG, and Protocol First. INC Research/inVentiv Health is the CRO partner working with LLS.
Get The Right Drugs To The Right Patients
To participate in the trial, patients had to be newly diagnosed with AML and be 60 years of age or older. According to Rosenberg, research shows newly diagnosed patients who are over the age of 60 had the worst prognosis of AML patients, generally not surviving 5 years past the original diagnosis. This made these patients a good fit for the precision therapeutics available through the Beat AML trial as newly diagnosed patients have a higher probability of responding to treatments than previously treated patients.
“We are not giving patients conventional treatments,” stresses Rosenberg. “We are signing up pharma companies very early in the discovery process. Our advisors look at the landscape of available therapeutics that could be targeted for these AML patients. LLS negotiates with the pharma companies upfront to ensure their best-in-class investigational treatments are part of the Beat AML trial from the outset. Our goal is to match patients with the best available treatment.”
As with any other trial, LLS had to file an IND application with the FDA before beginning the trial. Since participating pharma companies already had open INDs in place, LLS had to cross-reference all of those applications in its IND to enable the FDA to evaluate those data packages already on file. Two supply depots are used to ensure each trial location has access to any Master Trial treatment a patient might require once their need is determined.
Patient consent also becomes a bit trickier. Patients must first consent to the master screening protocol, which is a process that takes seven days and examines the patient’s bone marrow for the predominant mutation. When the results are received, each patient is assigned to a treatment arm (sub-protocol). Each arm is for a recommended therapeutic that has been sub-contracted from a pharma company. At that point, the patient must re-consent to that treatment arm and be made aware of any risks specific to the therapy. Once patients re-consent, they receive their designated therapeutic, which could be administered orally or intravenously. The treatment course is different for each patient.
Patients are being enrolled at seven major cancer centers throughout the U.S. The trial kicked off in the fall of 2016 and now has over 160 patients enrolled. Results are expected to be presented by the end of 2018.