For the purposes of this NOFO, the FDA OCE refers to cancers with an approximate annual incidence in the U.S. of 300 to 400 people or less as ultra-rare (a more stringent criterion compared to the threshold for a rare disease specified in the Orphan Drug Act based on a U.S. prevalence of <200,000 people). 

Many of the challenges involved in drug development for ultra-rare cancers are similar to those for rare diseases and can include:

• Difficulty enrolling sufficient numbers of patients to clinical trials
• Limited financial incentives for drug development
• Insufficient understanding of the cancer pathophysiology, molecular characteristics, and natural history
• Limited or lack of timely access to molecular testing to determine eligibility for treatment with targeted therapies
• Complexities associated with designing clinical trials that are adequate to establish safety and effectiveness 

Advancing technologies such as single cell multi-omic analyses have helped define some ultra-rare cancers at the molecular level, providing new opportunities for targeted drug development. Pediatric oncology has several examples of tumor types with known translocation-induced, oncogenic driver fusion proteins. Other examples of ultra-rare cancers defined today by molecular pathology include: neuroectodermal tumors, pulmonary blastoma, desmoplastic small round cell tumor (DSRCT), epithelioid sarcoma, diffuse intrinsic pontine glioma, fibrolamellar carcinoma, and malignant rhabdoid tumors.

Purpose and Research Objectives 

The purpose of this NOFO is to support new approaches that can be applied to facilitate therapeutic development in ultra-rare pediatric and adult cancers, including molecularly-defined subsets of more common cancers. 

Specific areas of interest include, but are not limited to, the following examples:

• Development of infrastructure for a coordination network and data repository for patient-level data across institutions and internationally to support drug development and regulatory decision-making for one or more ultra-rare cancers.
• Investigations to explore opportunities to develop and validate early clinical endpoints and other novel efficacy endpoints for evaluation of treatments for ultra-rare cancers.
• Development and implementation of a collaborative multi-stakeholder effort to support generation and use of real-world data leveraging a registry framework for use in development of new therapies for pediatric patients with diffuse midline glioma (DMG) (including diffuse intrinsic pontine glioma, DIPG).
• Innovative approaches to identify new biologically-driven opportunities for clinical development of previously approved drugs or biologics (hereafter referred to as drugs), including drugs for which development has been discontinued, in ultra-rare cancers.
• Research to develop novel approaches to preserve the availability of drugs for which commercial developers have discontinued adult development that have strong potential in ultra-rare cancers but lack financial incentives for commercial development
• Development of methods to incorporate use of telemedicine and/or pragmatic trial design elements (e.g., collecting laboratory and/or imaging data from local facilities) for patient assessments to facilitate enrollment of patients with ultra-rare cancers
• Development of nanoparticle-based delivery approaches for therapeutic nucleic acids targeting onco-fusion transcription factors in metastatic tumor animal models using targeted bioPROTAC degradation or genomic editing strategies. Successful efforts should demonstrate effective delivery and expression in-vivo to tumor cells, and downregulation of the target transcription factor protein while minimizing off-target effects and limiting sequestration of the nanoparticle by the liver, spleen, and lungs.
• Research to exhaustively characterize the plasma-membrane protein expression (surfaceome) of an ultra-rare cancer and the presumed healthy tissue of origin, as well as the resident-tissue stem cells, by single-cell transcriptomics and proteomics. These studies, and available correlative database analyses, should be designed to identify possible combinatorial signatures of plasma membrane proteins unique to the ultra-rare tumor. Tumors of interest include Sclerosing epithelioid fibrosarcoma and atypical teratoid rhabdoid tumors (ATRT).