R01FD008167

Phase II, multi-arm, molecularly-guided umbrella trial for children and young adults with high-grade glioma - Project summary

High-grade gliomas (HGGS), including diffuse intrinsic pontine glioma (DIPG), are a leading cause of cancer-related death in children, adolescents, and young adults.

Despite intensive multimodal therapy, prognosis for pediatric, adolescent, and young adult patients with these aggressive brain and/or spine tumors remains dismal, with 5-year overall survival (OS) <10%.

Genome-wide sequencing analyses have identified recurrent somatic alterations of receptor tyrosine kinases, cell cycle regulation, DNA repair, and/or PI3K/AKT/MTOR signaling pathways within molecularly distinct subgroups of pediatric HGG/DIPG, with therapeutic and prognostic implications.

However, lack of consistent, prospective and comprehensive tumor molecular profiling in pediatric early phase trials of targeted agents and insufficient assessment of correlative biomarkers of response and resistance have hampered the interpretation of trials’ results and impeded the rational development of successive studies.

Motivated by this critical need to develop novel, effective, and well-tolerated therapies for pediatric HGG/DIPG and guided by recent discoveries which have improved understanding of their genomic landscape, we have developed and recently opened TARGET, an innovative molecularly-guided, multi-arm, multi-institutional Phase II umbrella trial, with central, comprehensive molecular characterization using a multi-omic approach (whole exome sequencing, RNA-based fusion panel, DNA methylation array) with rapid return of results (within 3 weeks) to guide assignment to one of eight biologically-targeted treatment arms, all with upfront radiotherapy (RT).

Efficacy of these targeted therapy arms will be assessed through evaluation of survival outcomes, compared to molecularly-stratified, historical controls.

Furthermore, we will collect serial, well-annotated biospecimens (peripheral blood, cerebrospinal fluid, tumor tissue), as well as neuro-imaging to determine multimodal biomarkers predictive of response and resistance.

Longitudinal genomic and immunologic profiling will be performed, and integrated with imaging data for correlative analyses, focused on (A) validating “liquid biopsy” molecular assays, (B) identifying genetic alterations which confer the greatest sensitivity to investigated targeted therapies within each arm, and (C) determining genomic and immunologic signatures that predict radiographic response to RT, including distinguishing between inflammatory pseudoprogression and true tumor growth.

These samples provide an unprecedented opportunity to systematically characterize and evaluate biological determinants of therapy response.

Finally, submission of serial MRIs at standardized disease evaluation timepoints will allow prospective validation of volumetric radiographic response assessments using artificial intelligence methodology, comparison to conventional bidimensional measures, and correlation with outcomes.

If feasible and effective, this precision medicine approach, utilizing genomic, immunologic, and imaging biomarkers validated here may be incorporated into the treatment of pediatric HGG/DIPG to expand molecularly-guided therapy options and improve outcomes.

Research Institute At Nationwide Children's Hospital

TO ASSIST INSTITUTIONS AND ORGANIZATIONS, TO ESTABLISH, EXPAND, AND IMPROVE RESEARCH, DEMONSTRATION, EDUCATION AND INFORMATION DISSEMINATION ACTIVITIES, ACQUIRED IMMUNODEFICIENCY SYNDROME (AIDS), BIOLOGICS, BLOOD AND BLOOD PRODUCTS, THERAPEUTICS, VACCINES AND ALLERGENIC PROJECTS, DRUG HAZARDS, HUMAN AND VETERINARY DRUGS, CLINICAL TRIALS ON DRUGS AND DEVICES FOR ORPHAN PRODUCTS DEVELOPMENT, NUTRITION, SANITATION AND MICROBIOLOGICAL HAZARDS, MEDICAL DEVICES AND DIAGNOSTIC PRODUCTS, RADIATION EMITTING DEVICES AND MATERIALS, FOOD SAFETY AND FOOD ADDITIVES. THESE PROGRAMS ARE SUPPORTED DIRECTLY OR INDIRECTLY BY THE FOLLOWING CENTERS AND OFFICES: CENTER FOR BIOLOGICS EVALUATION AND RESEARCH (CBER), CENTER FOR DRUG EVALUATION AND RESEARCH (CDER), CENTER FOR DEVICES AND RADIOLOGICAL HEALTH (CDRH), CENTER FOR VETERINARY MEDICINE (CVM), CENTER FOR FOOD SAFETY AND APPLIED NUTRITION (CFSAN), NATIONAL CENTER FOR TOXICOLOGICAL RESEARCH (NCTR), THE OFFICE OF ORPHAN PRODUCTS DEVELOPMENT (OPD), THE CENTER FOR TOBACCO PRODUCTS (CTP), AND OFFICE OF REGULATORY AFFAIRS (ORA), AND THE OFFICE OF THE COMMISSIONER (OC). SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAMS: TO STIMULATE TECHNOLOGICAL INNOVATION, TO ENCOURAGE THE ROLE OF SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION BY MINORITY AND DISADVANTAGED PERSONS IN TECHNOLOGICAL INNOVATION. FUNDING SUPPORT FOR SCIENTIFIC CONFERENCES THAT ARE RELEVANT TO THE FDA SCIENTIFIC MISSION AND PUBLIC HEALTH ARE ALSO AVAILABLE.

93.103 - Food and Drug Administration Research

FDA Office of Acquisition and Grant Services (OAGS) [HHS - FDA]

FDA Office of the Commissioner [HHS - FDA]

Ohio United States

State-Wide

Clinical Studies of Orphan Products Addressing Unmet Needs of Rare Diseases (R01) Clinical Trials Required (RFA-FD-23-001)