HemOnc Today's PharmAnalysis

HemOnc Today's PharmAnalysis


Press Release

Disclosures: Nichols reports previous employment with and stock ownership in Roche/Genentech. Kolb reports no relevant financial disclosures.
August 24, 2020
7 min read

Global trial ‘aligned around a single mission’ of advancing pediatric leukemia treatments


Press Release

Disclosures: Nichols reports previous employment with and stock ownership in Roche/Genentech. Kolb reports no relevant financial disclosures.
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A collaborative global master clinical trial by The Leukemia & Lymphoma Society, Children’s Oncology Group and NCI aims to meaningfully advance the development of targeted treatments for children with acute leukemia.

The trial, LLS PedAL, will concurrently evaluate multiple targeted therapies for children whose acute leukemia has relapsed.

Gwen L. Nichols, MD, chief medical officer of The Leukemia & Lymphoma Society

The effort reflects the organizations’ commitment to making real progress in this historically dormant area of oncologic drug development, according to Gwen L. Nichols, MD, chief medical officer of The Leukemia & Lymphoma Society (LLS).

“I’m an adult hematologist/oncologist and I did laboratory research for a number of years, as well as a 10-year stint in pharmaceutical early development,” Nichols said in an interview with Healio. “So, even though I am not a pediatrician, my background has led me to understand just how broken the system is.”

Nichols said pharmaceutical companies cannot be blamed for the issues inherent to pediatric oncology drug development.

“It’s very easy to say that pharma is bad, but the truth is, it’s a business, and the business model wasn’t working,” Nichols told Healio. “The FDA and the European Medicines Agency put a lot of important regulations in place to encourage pediatric drug development, but the ‘one-drug-at-a-time’ model doesn’t really work for pediatrics or for many rare diseases.”

The ‘will to collaborate’

Nichols discussed the limitations of evaluating a single drug at a time, noting that the cost of conducting clinical trials for these drugs is based on the number of trial centers that are necessary and the time it takes to accrue patients.

“Time is money,” Nichols told Healio. “If you are trying to find an agent for a pediatric disease like pediatric acute leukemia, where the number of patients is in the hundreds or maybe thousands worldwide, but not 10,000 or 20,000, you will need to open up hundreds and hundreds of clinical trial sites to find those patients.”

Nichols added that each site might only see two or three patients per year, and the time needed for patient accrual generally becomes costly. Often, these trials end without answering a question.

“It’s even worse if you’re looking at a targeted agent that might only work for a subset of patients,” she said. “And targeted agents are the goal. We don’t want to keep using a one-size-fits-all therapy. We want to be more specific, but from an operational point of view, it doesn’t work.”

E. Anders Kolb, MD, chair of the Children’s Oncology Group (COG) Myeloid Disease Committee and co-chair of LLS PedAL, said the PedAL initiative is intended to shift the paradigm of new-drug evaluation.

E. Anders Kolb, MD
E. Anders Kolb

“It’s probably necessary now more than ever because of the shift in the regulatory landscape and the alignment of our regulators in Europe and the U.S. around the requirements for pediatric drug testing,” Kolb said in an interview with Healio. “One of the weaknesses in our paradigms for the last 40 years is that we operated independently. North America operated independently from Europe, and European regions operated independently from each other.”

Kolb said at that time, only four drugs were used consistently in the treatment paradigms for pediatric leukemia, and although the organizations had the “will to collaborate,” they lacked the resources needed to overcome barriers to collaboration.

“We’ve since recognized that with regulatory alignment, an exciting pipeline of novel therapies and our understanding of the genomic changes that drive pediatric leukemias, now is the time to get our act together in the academic community,” Kolb told Healio. “Now is the time to create a system that meets all of the requirements and pushes forward the most exciting new drugs. And that’s when LLS came to the table and said, ‘We want to help.’”

Customized treatment

Approximately 40% of children with acute myeloid leukemia and 20% of children with high-risk acute lymphoblastic leukemia experience disease relapse. The LLS PedAL trial will being by evaluating three novel therapies for children with relapsed acute leukemia and will add treatments as they become available. Every child with relapsed AML and many with ALL will undergo screening to determine their disease subtype and will then receive the most suitable treatment for that subtype.

“Our intention isn’t just to test drugs in kids. Our intention is to identify drugs that are most effective,” Kolb said. “For that, we need to fully characterize every patient’s leukemia cells and get a full understanding of the child’s clinical history and any comorbidities or toxicities that they have so that we can help the enrolling physicians, patients and families make informed choices on what trials are most likely to provide benefit for that specific patient.”

The study will be conducted at more than 200 locations worldwide that belong to the NCI-supported COG network of children’s hospitals. These include hospitals in the U.S., Australia, New Zealand and Canada. The LLS PedAL team also will work with collaborators in the U.K. and EU to bring the trial to those areas.

“Our partnership with ongoing collaborations allows a lot of speed in opening up multiple sites with a single contract,” Nichols told Healio. “That makes a huge difference, because if you have to do a separate contract with 200 different sites, that’s 200 different lawyers and it costs a huge amount. It’s what leads to some of the costs that pharma incurs and is what dissuades them from doing pediatric development until they absolutely have to.”

Kolb said the trial will assess new delivery options for conventional therapies, as well as immunotherapies that are broadly targeted, including bispecific, T-cell engaging and cellular antibodies.

“We’re also looking at small molecule inhibitors of cellular events that are critical for the growth of pediatric leukemia cells,” he said. “So, we are looking at the range of potential therapies. At the moment, our pipeline is quite robust and we have a lot of trials in development.”

Kolb said pharmaceutical companies typically wait to develop drugs for children until there is a clear signal and development plan for adults.

Conversely, “we want to test drugs early; we want access to drugs early,” he said.

Nichols added that it is important to recognize that children are not “little adults” and have their own distinct biology and disease mechanisms.

“What drives the tumor, even if it looks the same under the microscope in a 60-year-old and a 6-year old, is often very, very different,” she told Healio. “Although we call it the same thing and it may have some of the same markers, the underlying biology and what can stop it is different. So, we can’t just cut down the dose of something that we found works in adults and hope that it will work for kids.”

Eliminating ‘data silos’

The LLS PedAL trial also plans to use standardized technology that will enable trial sites to consolidate, share and analyze data about children with blood cancer. These data will improve clinicians’ understanding of how children respond to new therapies and will document the underlying causes of resistance or relapse.

“One of the barriers to having multiple different cooperative groups around the globe treating children with AML independently is that the data ends up moving in data silos that can’t be easily shared,” Kolb said. “It becomes hard for us to learn about a rare disease if we don’t have access to all the patients. Some molecular subsets that we’re looking at may only occur in a few dozen to a few hundred patients a year globally. If we don’t identify all these patients, we’re not going to know what that subset means.”

The researchers identified these data silos as a significant limitation to the way the academic community has conducted studies. To facilitate global data sharing, Kolb and colleagues have been developing a data dictionary.

“This will include an agreed-upon set of terms that are used to describe every child’s leukemia and every child’s response to treatment,” Kolb said. “The terms will describe everything from age to the molecular characterization of the leukemia and the response to drugs.”

The comprehensive dictionary, based on work conducted at The University of Chicago and University of Duisburg-Essen in Germany, will allow for uniformity of language among researchers.

“It’s kind of a Rosetta Stone for our data,” Kolb said. “It will improve the power of our historical data set immensely, and it will allow us, looking forward, to make sure we are all speaking the same language and using the same terms.”

A model for other groups

Nichols said she is hopeful that LLS PedAL will not only move things forward in terms of pediatric leukemia treatment, but also serve as an example for other oncology groups.

“The global nature of this is very important,” Nichols told Healio. “It’s important for pharmaceutical companies because they have to meet European, Australian, Japanese, Canadian and U.S. regulatory requirements. Also, this is a model we hope other organizations will use. There will be improvements on this, and I’m hoping other pediatric organizations especially and other groups will be able to take what we’ve learned and improve on it specific to their disease.”

Kolb said he also hopes other organizations can benefit from the trial and utilize some of its systems for other pediatric cancers.

“The whole thing in itself is an experiment,” Kolb told Healio. “We recognize that there are challenges to drug development, and our hypothesis is that this philanthropy partnership will address some of those challenges. But at the end of the day, we are testing a system where we have members of the academic community aligned around a single mission: the care of children with a specific, rare disease.”

For more information:

Gwen L. Nichols, MD, can be reached at 3 International Drive, Rye Brook, NY 10583.

E. Anders Kolb, MD, can be reached at 1600 Rockland Road, Wilmington, DE 19803.