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Next-Generation Personalized Neuroblastoma Therapy (Nepenthe)

Children’s Hospital of Philadelphia
Yael Mosse, MD & John Maris, MD
Grant Type: 
Bio-Therapeutic Impact Award
Year Awarded: 
Type of Childhood Cancer: 
Project Description: 


Neuroblastoma remains a devastating clinical problem and continues to be a leading cause of childhood cancer morbidity and mortality despite dramatic increases in therapy. Recent developments in cancer research are changing our understanding of neuroblastoma biology and treatment on the basis of the molecular underpinnings of individual tumors, and are challenging us to design more rational and less toxic therapies.

Project Goal

We propose a paradigm-shifting collaborative clinical trial for children with relapsed or refractory neuroblastoma to identify the genetic features of the cancer at time of relapse that predict drug efficacy, and to provide combination therapies to target these vulnerabilities. We have designed a program to allow for the addition of new therapies based on ongoing laboratory studies, with the overarching goal of substantially changing how we think about neuroblastoma at relapse and how these insights may inform the design of upfront clinical trials for newly diagnosed patients with high-risk neuroblastoma.

Project Update (April 2023)

Dr. Yael Mossé is the lead author on a new paper published in April 2023 in Nature Medicine. The paper shares the results of Dr. Mossé’s clinical trial for lorlatinib, a targeted therapy that showed success treating children with neuroblastoma tumors harboring the ALK mutation.

The results have led to incorporating lorlatinib into a Phase 3 trial that makes the treatment protocol available as an upfront treatment to children newly diagnosed with ALK-driven neuroblastoma.

The paper, “Lorlatinib with or without chemotherapy in ALK-driven refractory/relapsed neuroblastoma: phase I trial results,” was published in Nature Medicine on April 3, 2023. 

Project Update (December 2022)

With Alex’s Lemonade Stand Foundation support, Dr. Mossé led a research team that discovered that a drug called lorlatinib was the only ALK-inhibitor effective against neuroblastoma that expresses the ALK mutation. That research resulted in a Phase 1 trial of the drug in the New Approaches to Neuroblastoma Therapy (NANT) Consortium.  Patients in the Phase 1 trial showed positive responses to lorlatinib and minimal side effects, allowing kids in treatment to live more normal lives despite having cancer.

Lorlatinib is now being tested in a Children’s Oncology Group (COG) Phase 3 trial as an up-front treatment for children. Used in conjunction with chemotherapy, this treatment could substantially improve chances of a cure for children with high-risk neuroblastoma whose tumors harbor an ALK alteration and do so with reduced short- and long-term side effects. This trial is open at the more than 240 COG sites across the United States.

Project Update (July 2019)

The clinical trial for Next Generation Personalized Neuroblastoma Therapy (NEPENTHE) is now enrolling patients. The purpose of this study is to match genomic aberrations in tumor cells at time of relapse to rationally designed combinations of molecularly targeted agents. This study will be done in two parts:

  • Part I: Tumor will be accessed at study entry via a biopsy and subjected to deep sequencing to identify protocol-specified biomarkers for therapy assignment. 
  • Part II: If the tumor contains a genetic change defined by the study as being actionable, and other criteria are met, participants will be assigned to therapy based upon the genetic changes identified in the tumor biopsy.

ContactAlana Fitzsimmons

Full details of the trial.

Co-funded by: 
Northwestern Mutual Foundation