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Leukemia and Lymphoma Society PedAL Trial Aims to Advance Pediatric Precision Oncology


NEW YORK – The Leukemia and Lymphoma Society's new Pediatric Leukemia Master Clinical Trial (PedAL) aims to bring precision therapies to childhood leukemia, a disease area neglected by pharmaceutical trials due to the small market size and high cost of development.

PedAL, launched last month, is a global master protocol clinical trial that will screen blood and bone marrow patients under 22 with relapsed or refractory acute leukemias for genomic alterations, then match them to available pediatric leukemia Phase I/II sub-trials. Those will be opened on an ongoing basis as new information arises linking targeted therapies to relevant biomarkers.

LLS is conducting PedAL in partnership with the National Cancer Institute, Children's Oncology Group, and the European Pediatric Acute Leukemia Foundation. The blood cancer research advocacy group is also supporting the development of a search tool, called GEARBOx (Genomic Eligibility Algorithm at Relapse for Better Outcomes), with the University of Chicago's Pediatric Cancer Data Commons, which will allow doctors to match patients to treatments and clinical trials.

Gwen Nichols, chief medical officer at LLS, said the idea for a trial like PedAL originated from her work as a pharmaceutical researcher bringing new compounds from the laboratory into the clinic. "I had several compounds that I was helping develop that had a good rationale to go into pediatric cancer early, and I could not get the powers that be to take the risk of doing pediatrics early," said Nichols.

The rarity of pediatric cancers compared to adult cancers adds expense to the development process, particularly when it comes to precision therapeutics. "The market size is so small that the cost of development in pediatrics was greater than any hoped-for return," said Nichols, recalling that a pediatric indication always seemed to be an afterthought for drugmakers, following some success in the adult setting.

"That just seemed incredibly backwards to me as a parent and as a human being," she said. "I understood it from a business point of view, but I said, 'If I ever get the opportunity to change this, I will.' And LLS supported that opportunity."

LLS's previous umbrella trial, Beat AML, matched older, previously untreated patients with acute myeloid leukemia to first-line treatments based on their cancers' molecular profiles. It showed that patients who received precision therapies lived significantly longer than patients on standard treatments.

Nichols proposed that LLS sponsor a trial like Beat AML in pediatric cancer and see if it could overcome the scale and cost challenges that discourage pharmaceutical companies from attempting them on their own. "In developing therapies for rarer subgroups, for precision oncology, we spend a lot of time trying to find the patients that fit the drug instead of finding the patient's abnormality and then saying, 'Where's the drug that fits this patient?'" Nichols said. "With a master trial, you can turn that paradigm on its head."

A master protocol trial starts by determining the patient's biomarkers and identifies treatment or trial options based on that, instead of searching for the right patients to match a predetermined biomarker and protocol.

Nichols views master protocol trials as an important path forward in precision oncology. "We've got to think of new ways to develop drugs that don't do it one drug at a time," said Nichols. "The smaller the market is, the more difficult it's going to be to do it effectively, because you have to screen hundreds of patients or have hundreds of sites open at the same time to find those patients, and that's a waste of patient resources as well as financial resources. We need to be thinking of novel models."

That challenge is compounded in pediatric cancers, where there are few targeted therapies to start with, and molecular profiling often doesn't reveal targetable mutations in patients. However, Nichols said, there is fairly good knowledge of cytogenetic markers in childhood cancers, such as chromosomal abnormalities, and it has become standard practice to test for those to stratify children into prognostic risk categories, which in turn, can inform whether they should have aggressive chemotherapy or a transplant.

What's new with PedAL is that patients will be guided to sub-trials based on results from the FoundationOne Heme panel, a pediatric leukemia-specific panel, from Foundation Medicine. Samples will also be held for whole-genome sequencing as a part of a future research effort, if the quantity is sufficient. "Interestingly, adding NGS has already changed the risk category for over 20 percent of the kids," said Nichols. "It's not that we're discovering new abnormalities. If there isn't a FISH probe for the specific abnormality, it can be missed." And sequencing known translocation break points can also provide data which then informs the cytogenetics.

Then, drawing on data from previous children's oncology trials and from European databases, such as those maintained by the International Berlin-Frankfurt-Münster Study Group, researchers can estimate what percentage of children have those abnormalities and potentially match them either to a drug approved for adult leukemias or treatments for completely different indications, allowing a new sub-trial to be opened.

To aid in matching participants to trials, LLS is collaborating with the University of Chicago's Pediatric Cancer Data Commons group to develop the GEARBOx platform. Its purpose is to facilitate easy access to information about clinical trials for pediatric cancer patients with relapsed or refractory disease. Once fully developed, the tool will be used within PedAL but will also become a much-needed resource for the pediatric cancer community.

"Currently, the process of identifying potential trials for children is cumbersome and error-prone," said Samuel Volchenboum, associate chief research informatics officer at the University of Chicago's Biological Sciences Division. "Clinical trials criteria are difficult to parse, and many clinicians have a difficult time determining for which trials their patients may be eligible."

GEARBox gathers data from and presents them to the clinician through a user interface organized by match status. The platform currently includes information on seven trials for children with relapsed or refractory AML. Volchenboum said additional trials will be added in the coming months, and the platform will be expanded to included trials for acute lymphoblastic leukemia and other pediatric malignancies.

Pediatric cancers differ from adult cancers in that Phase I trials are often done on patients that have exhausted approved therapies and are in a clinical trial as a last resort. However, for pediatric patients, even if they've relapsed a second time, the goal is still to cure them.

That means appropriate dosing and safety are even more important because that pediatric patient may still have the option of a transplant or another therapy later. "We move therapies in when they're ready to be given to kids in a way that we know has a chance of benefitting them," Nichols said.

In practical terms, that may mean pediatric patients will have a long wait for an appropriate sub-trial to open after they are screened. However, LLS has engaged clinical trial nurse navigators who can help patients and their families find clinical trials anywhere in the US if there is no sub-trial open yet within PedAL that the patients match to. "We understand that progress will be slow to get our trial up and fully populated with targeted therapeutics," said Nichols. "Unlike a pharmaceutical company, we don't have to come back and say we accrued this many patients in this period of time."

There is also financial support and other resources available through LLS to help the children and families access those remote trials.

Meanwhile, the first sub-trial open in PedAL is exploring Abbvie/Genentech's Venclexta (venetoclax) with chemotherapy in people up to age 21 with relapsed acute myeloid leukemia without FLT3/internal tandem duplication. The trial, which is being conducted by LLS in partnership with Abbvie, will enroll 98 participants who are unable to receive additional anthracyclines, or are relapsing for the second time. They will be assigned to an experimental arm and receive venetoclax with chemotherapy or they'll be in the control arm and receive chemotherapy only. Outcome measures include overall survival, event-free survival, duration of response, and other measures of efficacy and safety.

According to an Abbvie spokesperson, by partaking in PedAL, the drugmaker is focusing on the scientific aspects of the study in order to gather additional data about Venclexta in the pediatric setting, rather than aiming for a specific marketing or commercial goal.