Speeding Up Success with Precision Medicine Cancer Trial


An innovative new clinical trial launching this year at The Children’s Hospital of Philadelphia may not only help patients who have no further proven treatment options for neuroblastoma, a high-risk cancer, but may also be a model for how precision medicine clinical trials can spur better and faster cancer therapy discoveries in the future.

The trial uses a dynamic design, which allows researchers to quickly translate findings from the lab based on the evolving individual characteristics of each patient’s tumor. It is the first time such a strategy is being applied to a prospective clinical trial in children with cancer. Known as the NExt-generation Personalized NEuroblastoma THErapy (NEPENTHE) trial, it is moving forward with a new $1.5 million grant from Alex’s Lemonade Stand Foundation (ALSF), announced in December.

“The novelty of this trial could be viewed on numerous levels,” said principal investigator Yael Mossé, MD, a CHOP pediatric oncologist and assistant professor at the Perelman School of Medicine at the University of Pennsylvania. “It’s based on rigorous preclinical data, understanding the molecular drivers that are important in this disease. It’s combining multiple novel drugs, not just one at a time. And it’s bringing that to the clinic and assigning patients to therapy based on what their tumor genetics are teaching us at the time that they meet us with relapsed or refractory cancer.”

Going Beyond Traditional Clinical Trial Designs

The three-year Bio-Therapeutics Impact Award from ALSF seeks to strategically advance research-based treatment of neuroblastoma, an often lethal childhood cancer that remains difficult to cure. Usually appearing as a solid tumor in the chest or abdomen, neuroblastoma accounts for a disproportionate share of cancer deaths in children, despite many recent improvements in therapy. The NEPENTHE trial will enroll children who have suffered a relapse of neuroblastoma or whose neuroblastoma did not respond to the initial treatment.

Neuroblastoma is “a microcosm of the childhood cancer problem,” Dr. Mossé said. It is a group of tumors that has one name and generally looks similar under the microscope. Yet, by working with patients, researchers have learned time and again that the disease is extremely heterogeneous, due in large part to the many different underlying genetic and molecular causes of disease, which can both interact to affect treatment responsiveness and change over time in cases where the cancer relapses after treatment. That pattern — one disease by name, many diseases at the molecular level — has not routinely been addressed in the design of traditional clinical trials for childhood cancers.

“We’re setting ourselves up for failure,” Dr. Mossé said, of those traditional clinical trial designs. Most trials of new drugs enroll patients with relapsed or refractory disease for whom no curative options remain — regardless of whether there is any reason to think that the investigational drug will act on the molecular cause of the patient’s cancer. And they test just one drug at a time.

“Our improved understanding of neuroblastoma biology and treatment will guide this trial and help us to continually design combination therapies that are potentially more effective and less toxic for our young patients,” said NEPENTHE Co-investigator John Maris, MD, who leads CHOP’s internationally prominent research laboratory focused on neuroblastoma.

Looking Ahead to Future Precision Medicine Clinical Trials

The NEPENTHE trial will be a collaborative effort, enlisting the expertise of numerous other specialists throughout CHOP and other institutions. Dr. Mossé hopes that ultimately investigators can use NEPENTHE as a model for future precision medicine clinical trials — dynamically linking clinical needs to preclinical insights — that could apply more broadly to other childhood cancers.

The founding grant for this trial was provided in 2014 by the Band of Parents and Arms Wide Open, dedicated to supporting new treatments for neuroblastoma. Additional charitable support came from Solving Kids’ Cancer Foundation and the Open Hands Overflowing Hearts Foundation.

NEPENTHE is not the only clinical trial for neuroblastoma that Dr. Mossé hopes to get up and running early in 2016. Read more about her team's recent published findings of a drug compound with promising preclinical results against a treatment-resistant neuroblastoma mutation on our blog, Cornerstone.

For more information, see the CHOP press releases about the NEPENTHE trial and next-generation ALK inhibitor.

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