By Allison Proffitt 

October 5, 2020 | Last month, the Leukemia & Lymphoma Society (LLS) and PRA Health Sciences announced their partnership in LLS’s first-of-its-kind global master clinical trial to develop new treatments for children with relapsed acute leukemia. The LLS PedAL (Pediatric Acute Leukemia) master clinical trial will simultaneously test multiple targeted therapies for children who experience a relapse of their acute leukemia. Now PRA has signed on as the contract research organization for the trial. 

“From the point of view of LLS, a master clinical trial is a trial where the patient's biology and the patient's disease is at the center of the trial and that determines what types of therapy can be offered to the patient,” Gwen Nichols, Chief Medical Officer at the Leukemia and Lymphoma Society, explained to Clinical Research News. It’s a flipping of the standard clinical trial, she said. Instead of starting with a drug and seeking patients, the trial will start with patients and seek the right therapies.

Approximately 40% of children with acute myeloid leukemia (AML) and 20% of children with high-risk acute lymphoblastic leukemia (ALL) will relapse, according to LLS data. While those percentages are dishearteningly high, childhood leukemia remains a rare disease with all the clinical trial challenges that entails.

The PedAL trial will include one master protocol with hopefully many study arms, or sub-studies, focused on different targets. There will likely be some standard-of-care control arms, and some virtual controls arms. LLS will serve as the single sponsor, gathering collaborators across pharma, liaising with regulatory groups in the US and Europe, and insulating pharma from the some of the risks of recruiting and running small, rare disease pediatric trials. LLS has a distinct advantage over traditional pharma study sponsors, Nichols argues, because the Society does not have a financial interest in the molecules being tested. “Our only interest is that we get the right trial and do it properly,” Nichols said.

The master trial is a great model for relapsed pediatric leukemia because it will connect the most kids to the most drug developers, explained Brandon Early, VP of Project Delivery at PRA. “All of those kids come into one master protocol and then based on their subsequent biology, assign them to any sub-studies.” 

PedAL is also a timely model. In the US, pharma companies now need to adhere to the RACE Act. The Research to Accelerate Cures and Equity (RACE) for Children Act was enacted in August 2017, and, beginning in August 2020, any original new drug application or biologics license application submitted for a new active ingredient must, in general, contain reports of molecularly targeted pediatric cancer investigations if the drug is intended to treat an adult cancer or directed at a molecular target that the FDA determines to be substantially relevant to the growth or progression of a pediatric cancer. 

But pediatric cancer trials are still challenging to recruit and run. As a pharma company, Nichols explained, “You have a molecule you think might hit one of the targets of pediatric leukemia. Let's say you're an incredibly generous company and you're ready to start pediatric development. You would need—if it's a targeted agent—you'd need to screen hundreds of kids to find the couple dozen that would fit on your trial. That doesn't work for pharma because that's a huge expense and a time commitment, and it doesn't work for the kids because they don't get offered a therapy except for 10% of them or 12% of them or whatever the number is, depending on how common the target is.”

With the PedAL trial, LLS and PRA hope to facilitate the screening of many pediatric patients and allocate them to several appropriate trial arms. Pharma companies, then, will pay for their patients and their arms, but not for all of the screening and infrastructure that goes into the initial testing and division of patients. The IP for the compound and testing arm belongs to the pharma company. “We're doing this because we want them to move it forward in development and get it approved if it's efficacious,” Nichols said.

For Trials and Data

But the goal of LLS and PRA is not only a master clinical trial through which patients can be placed on several treatment arms. “Screening itself will yield more information about the underlying biology for these children, generate more subsequent research on just the basic biological science, and then create that feedback loop… to give pharma companies more targets to go after,” Early said. “Hopefully we'll just create a big old snowball here!”

And what to do with this blizzard of data? 

LLS is, “keeping this, all the data about the biology of the leukemias,” Nichols explained. “We're consolidating it, we're sharing it with researchers. And right now, we're in the process of consolidating data that already exists so that we can start building a historical control that's a work tool.” 

The historical control, Nichols hopes, will help keep a lot of sick kids off study control arms. “The reason we have to do [control arms] now is because we don't have good quality historical data. And that's part of what we're building with this master trial: the ability both retrospectively and prospectively to collect the data.”

Such a databank will help answer future questions when pharma inevitably comes with targets, Nichols hopes. Questions like: How many kids every year have that targeted AML? How many respond to standard of care? How long will a trial take? What will a trial look like? What's the appropriate place to intervene?

She expects that data to inform future trials as well, letting pharma companies really tease apart the promise of potential therapies: Is this a therapy that gets you to bone marrow transplant? Is this a therapy that is a bridge to that transplant? Or is this a potential therapy that could be curative and avoid a transplant?

CRO Challenge

The PedAL trial is meant to introduce a lot of structure and efficiency into the process of asking and answering these types of questions, but don’t let “efficiency” suggest “simple”. 

“It's a way to get operational efficiency for the patient population,” Early said, but Nichols jumped in to clarify: “It is operationally efficient for the companies and for the patients, but it is operationally challenging from an organizational point of view!” she interjected.

“It requires a lot of finesse to get all the operational details right,” Early conceded, acknowledging the challenges before PRA.

Trials will happen at more than 200 sites worldwide that are part of the NCI-supported Children's Oncology Group (COG) network of children's hospitals, including those in the U.S., Australia, New Zealand, and Canada. Many of these sites are familiar to PRA, but some will be new. 

“In something of this magnitude, there is a lot of operational considerations,” said Early. “There's a lot of operational planning that needs to happen there; there's a lot of regulatory engagement.”

PRA plans to build the master trial with multiple tiers of activation, using just-in-time activation as children are identified at some institutions. “The idea would be to limit the burden on the sites so that they don't have to do all of the maintenance and care and feeding of it on the open trial,” he said. In the meantime, PRA is focused on getting the little details correct, meeting all of the regulatory requirements, and ensuring ease of communication and ease of understanding, Early said. “We're looking to leverage technology to help us here in working with the sites and making their lives easier and centralizing as much as we can.”

Among those technologies, PRA is finalizing considerations around eConsent, data collection instruments for patient reported outcomes, and what digital enhancements would make trials easier on patients and parents, Early said. “We're taking a long, hard look at how patients move through the healthcare system, move through their treatments, and leaning on the investigators to really make sure that we've fit that together as much as we can. For a lot of these kids, they are probably attached to their phone all the time, so anything we can do to keep it digital when they come into clinical research and not moving into an analog phase would be good,” he explained.

Countdown to Enrollment

LLS began laying groundwork for the LLS PedAL master clinical trial in November 2019, with Nichols leading a team of experts in pediatric acute leukemia to conceive, develop, and implement LLS PedAL. In early February 2020, representatives spoke at the annual ACCELERATE conference in Brussels, Belgium on the initiative. In June, LLS and the National Cancer Institute (NCI) and the Children’s Oncology Group (COG) announced their collaboration.

Early in the process, LLS anticipated treating the first patient in the spring or summer of 2020. Now LLS PedAL is on track to begin treating patients by summer 2021. 

“We decided not to try and rush this through, but rather make sure that Europe and the United States are aligned so we can do one trial for each compound, not two completely different trials because the European health authorities see it differently than the FDA does,” Nichols explained. 

Right now that means LLS is focused on teasing out consensus on endpoints, how to define response, and more. “We have to be sure our European colleagues feel the same way, that it's going to be accepted throughout the world so that we don't have tiny trials in many different places and never answer a question,” she said.

Nichols couldn’t name any pharma collaborators yet, but she said that LLS does have memorandums of understanding with partners. “We do not have formal contracts until all of the study designs are finalized,” she said. “We're pretty darn close. Since we're bringing their compounds to the regulators, they're on board.”

She expects the earliest trials to happen with adult compounds that are poised for pediatric development, she said. “But we do have several compounds that have very little pediatric data but that the pediatricians are incredibly interested in because they are targets for poor prognosis leukemias. I think while they may not be the first we put through, they will be close followers,” she added.

LLS’s goal is to launch the PedAL trial with sufficient organizational, regulatory, and scientific agreement between collaborators so that new cancer drugs reach the children that need them. “So many trials that start, never finish,” Nichols lamented. “Well, that doesn't help children at all.”