Without an explanation for severe and sometimes life-threatening symptoms, patients and their families are left in a state of unknown. Many individuals find themselves being passed from physician to physician, undergoing countless and often repetitive tests in the hopes of finding answers and insight about what the future may hold. This long and arduous journey to find a diagnosis does not end for many patients- the Office of Rare Diseases Research (ORDR) notes that 6% of individuals seeking their assistance have an undiagnosed disorder. In 2008, the National Institutes of Health (NIH) Undiagnosed Diseases Program (UDP) was established with the goal of providing care and answers for these individuals with mysterious conditions who have long eluded diagnosis. The NIH UDP is a joint venture of the NIH ORDR, the National Human Genome Research Institute Intramural Research Program (NHGRI-IRP), and the NIH Clinical Research Center (CRC) (1-3). The goals of the NIH UDP are to: (1) provide answers for patients with undiagnosed diseases; (2) generate new knowledge about disease mechanisms; (3) assess the application of new approaches to phenotyping and the use of genomic technologies; and (4) identify potential therapeutic targets, if possible. To date, the UDP has evaluated 3300 medical records and admitted 750 individuals with rare and undiagnosed conditions to the NIH Clinical Center. The NIH UDP has identified more than 70 rare disease diagnoses and several new conditions. The success of the NIH UDP prompted the NIH Common Fund to support the establishment of a network of medical research centers, the Undiagnosed Diseases Network (UDN), for fiscal years 2013-2020. The clinical sites will perform extensive phenotyping, genetic analyses, and functional studies of potential disease-causing variants. The testing performed on patients involves medically indicated studies intended to help reach a diagnosis, as well as research investigations that include a skin biopsy, blood draws, and DNA analysis. In addition, the UDN will further the goals of the UDP by permitting the sharing of personally identifiable phenotypic and genotypic information within the network. By sharing participant information and encouraging collaboration, the UDN hopes to improve the understanding of rare conditions and advance the diagnostic process and care for individuals with undiagnosed diseases.

Type: Observational

Start Date: Sep 2015

open study

This study is testing and implementing an equity-focused, community-based intervention that improves women's access to cervical cancer screening and adherence to follow up after an abnormal result. The study's objective is to assess and compare the feasibility of different methods of distributing at-home HPV testing kits for cervical cancer screening among individuals who are under-screened.

Type: Interventional

Start Date: Apr 2026

open study

This randomized phase II trial will characterize the efficacy, adverse event (AE) profile, and safety of two regimens of 5-FU given as 2L+ treatment to patients with RM-HNSCC. Eligible patients for this trial will have previously received platinum and PD-1 inhibitor therapy. The experimental regimen (Arm 1) will comprise the two days every two weeks (2D-Q2W) regimen of 5-FU. The standard regimen (Arm 2) will consist of the four days every three weeks (4D-Q3W) regimen of 5-FU. The primary hypotheses is that each regimen of 5-FU will result in an ORR of 10% of greater assessed by RECIST v1.1 criteria. The study will also describe treatment-related AEs assessed by CTCAE v5.0, dose interruptions, discontinuations, and modifications in each regimen.

Type: Interventional

Start Date: Apr 2026

open study

Researchers are looking for new ways to treat extensive-stage small cell lung cancer (ES-SCLC). ES-SCLC is a type of lung cancer that has spread throughout the lung, to the other lung, or to other parts of the body. A standard (usual) treatment for ES-SCLC uses both chemotherapy and immunotherapy. - Chemotherapy is a treatment that works to destroy cancer cells or stop them from growing. - Immunotherapy is a treatment that helps the immune system fight cancer. Gocatamig and I-DXd (short for ifinatamab deruxtecan) are study medicines. Researchers want to know if giving gocatamig and I-DXd together can treat ES-SCLC. Researchers will also look at giving the study medicines with standard treatment. Gocatamig is a T-cell engager therapy. I-DXd is an antibody drug conjugate. - T-cell engager therapy is a certain type of immunotherapy that uses T-cells to find and destroy cancer cells. - A T-cell is a type of white blood cell, which are cells that help the body fight infection. - An antibody drug conjugate (ADC) is a treatment that attaches to a protein on cancer cells and delivers treatment to destroy those cells. The goals of this study are to learn: - About the safety of combining gocatamig and I-DXd and if people tolerate them together - If people who receive gocatamig and I-DXd have ES-SCLC respond, which means the cancer gets smaller or goes away

Type: Interventional

Start Date: Jan 2026

open study

The goal of this clinical trial is to learn how tests undertaken by people at high risk of developing psychosis (aged 17 to 30 years old) change when those people are given the study drug MT1988 daily for 8 weeks. This will help identify tests that could be used in later trials developing treatments for symptoms in people at high risk of developing psychosis, to measure whether those new treatments are effective. The main question this trial aims to answer is: Can any of the tests (biomarkers) used in this study detect changes in participants dosed with one of two different dose levels of MT1988? Researchers will compare the results from two dose levels of MT1988 to a placebo group. Researchers do not expect to see the test results change in participants taking placebo and this will be compared to changes expected in test results in participants taking MT1988. Participants will: - take a dose of MT1988 or placebo twice per day for 8 weeks - attend clinic appointments every two weeks to undertake assessments - report any side effects they experience to the researchers

Type: Interventional

Start Date: Mar 2026

open study

This phase III trial compares the effect of immunotherapy (IO) with stereotactic body radiation therapy (SBRT) to IO alone in treating patients with liver cancer (hepatocellular cancer) that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced). The usual approach is treatment with IO-based drug combinations, such as atezolizumab and bevacizumab, durvalumab and tremelimumab, or ipilimumab and nivolumab. IO with monoclonal antibodies, such as durvalumab, tremelimumab, atezolizumab, nivolumab and ipilimumab, may help the body's immune system attack the tumor, and may interfere with the ability of tumor cells to grow and spread. Bevacizumab is in a class of medications called antiangiogenic agents. It works by stopping the formation of blood vessels that bring oxygen and nutrients to tumor. This may slow the growth and spread of tumor cells. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill cancer cells and shrink tumors. SBRT is a type of external radiation therapy that uses special equipment to position a patient and precisely deliver radiation to tumors in the body (except the brain). The total dose of radiation is divided into smaller doses given over several days. This type of radiation therapy helps spare normal tissue. Giving IO with SBRT may be more effective than IO alone in helping patients with advanced hepatocellular cancer live longer.

Type: Interventional

Start Date: Feb 2026

open study

Safety, tolerability and efficacy of Descarte-08 in children, adolescents and young adults with childhood-onset systemic lupus erythematosus, ANCA-associated vasculitis, juvenile myasthenia gravis, and juvenile dermatomyositis

Type: Interventional

Start Date: Jan 2026

open study

FORTITUDE-HCM is a global, multicenter, double-blind, parallel-group, placebo-controlled Phase 2b study that will assess the efficacy and safety of ninerafaxstat compared to placebo on top of Standard of Care in patients with symptomatic nHCM

Type: Interventional

Start Date: Oct 2025

open study

This study is designed to demonstrate the efficacy and assess safety and tolerability of oral daily alpelisib in participants with PIK3CA-related overgrowth spectrum (PROS).

Type: Interventional

Start Date: Oct 2025

open study

Researchers are looking for new ways to treat types of breast cancer that are both: - High-risk, which means the cancer may have a higher chance of getting worse or coming back after treatment - Early-stage, which means the cancer is in the breast or the lymph nodes around the breast The 2 types of breast cancer in this study are triple-negative breast cancer (TNBC) and hormone receptor (HR)-low positive/human epidermal growth factor receptor-2 (HER2) negative breast cancer. These cancers have zero or a low amount of a protein called HER2 and other proteins that attach to the hormones estrogen or progesterone. Sacituzumab tirumotecan (also known as sac-TMT or MK-2870), the study medicine, is a type of targeted therapy. A targeted therapy is a treatment that works to control how specific types of cancer cells grow and spread. The main goals of this study are to learn if people who receive sac-TMT, pembrolizumab, and chemotherapy: - Have fewer cancer cells found in the tumors and lymph nodes removed during surgery compared to those who receive only pembrolizumab and chemotherapy - Live longer without the cancer growing, spreading, or coming back compared to people who receive only pembrolizumab with chemotherapy

Type: Interventional

Start Date: Jun 2025

open study

Characteristics and clinical course of disease In participants with cardiomyopathy associated with Friedreich Ataxia (CLARITY-FA)

Type: Observational

Start Date: Sep 2025

open study

This is an open-label, comprehensive, iterative investigation of evaluating the use of induction chemotherapy, high-dose chemotherapy, and focal radiation therapy in children with newly diagnosed Embryonal Tumor With Multilayered Rosettes (ETMR).

Type: Interventional

Start Date: Mar 2025

open study

CIDP is an autoimmune disease. This means that the body's germ fighting (immune) system attacks itself. In CIDP, the immune system attacks the protective covering around the nerves called myelin. Over time, these nerves lose their ability to send signals to the muscles in the body. This leads to muscle weakness and loss of sensation in arms and legs among other symptoms. Participants with CIDP can be treated with a protein called immunoglobulin (or IG). TAK-411 is a special type of immune globulin G (hsIgG) that has been chemically changed. It is made from IG that comes from human plasma. This study will test if TAK-411 can decrease inflammation and improve symptoms of CIDP. The main aim of this study is to check how TAK-411 affects the physical functioning of adults with CIDP when compared with results of the placebo group of a historical trial. Participants may be treated with TAK-411 for up to 1 year (51 weeks) and will be followed up for 3 weeks after last dose. During the study, participants may visit their study clinic up to approximately 21 times.

Type: Interventional

Start Date: May 2025

open study

This is a Phase II/III study. Patient population is adult participants with PSMA-positive mCRPC who had treatments with androgen receptor pathway inhibitor (ARPI) and taxane-based chemotherapy and progressed on or after [177Lu]Lu-PSMA targeted therapy. Treatment of interest: the investigational treatment is AAA817 regardless of subsequent anti-neoplastic treatment. The control treatment is investigator's choice of Standard of Care, regardless of subsequent anti-neoplastic treatment

Type: Interventional

Start Date: Feb 2025

open study

This study focuses on determining the pharmacokinetic and pharmacodynamic effect of DSP-0390 in brain and blood from patients with IDH-mutant glioma undergoing tumor resection. Tissue will be collected during surgical resection. Blood will be drawn at various time points throughout the 2 weeks of treatment. The hypothesis is that DSP-0390 will accumulate in brain tumor tissue at pharmacologically relevant concentrations, and that alterations in cholesterol metabolism driven by mutant IDH will increase susceptibility to DSP-0390 and lead to tumor cell death.

Type: Interventional

Start Date: Apr 2025

open study

The goal of this observational study is to understand how young children with LAMA2-related dystrophy move and change over time. We will also learn about how this condition impacts other body systems. Participants will undergo: - Neuromuscular assessments - Blood collections - Swallowing and breathing assessments - Questionnaires

Type: Observational

Start Date: May 2025

open study

This study evaluates an individualized approach combining highly active maintenance treatment with elranatamab with peripheral blood-based clonotypic measurable residual disease (MRD) testing in patients with newly diagnosed multiple myeloma. The overall goal is to generate efficacy data for a personalized maintenance approach using bone marrow-based MRD testing (clonoSEQ) to guide post-autologous hematopoietic cell transplant (AHCT) maintenance with elranatamab for this patient population.

Type: Interventional

Start Date: Dec 2024

open study

This is a phase Ib/II study evaluating the safety and efficacy of zunsemetinib (ATI-450) with capecitabine in patients with hormone receptor-positive and HER2-negative (HR+/HER2-) metastatic breast cancer (MBC).

Type: Interventional

Start Date: Jan 2025

open study

The current protocol is to determine the biodistribution, metabolism, excretion and brain uptake of 11C-M503. The goal of this radiotracer is to quantify alpha-synuclein that is abnormally deposited in the brain of people with Parkinson's disease (PD). Investigators will compare uptake in participants with PD versus participants with multiple system atrophy (MSA) and progressive supranuclear palsy (PSP), as well as non-Parkinsonism volunteers. This multicenter project funded by an NIH U19 grant, is centered at U Pennsylvania (Penn, Grant PI: Robert Mach) in collaboration with U Pittsburgh (Pitt) (non-clinical site) Yale U, U of California at San Francisco (UCSF) and Washington University in St. Louis (WU). The University of Pennsylvania will act as the sIRB for this multi-center human subjects project and participants will be recruited from all sites.

Type: Interventional

Start Date: Feb 2024

open study

The purpose of this study is to evaluate the efficacy and safety of lutetium (177Lu) vipivotide tetraxetan (AAA617) in participants with oligometastatic prostate cancer (OMPC) progressing after definitive therapy to their primary tumor. The data generated from this study will provide evidence for the treatment of AAA617 in early-stage prostate cancer patients to control recurrent tumor from progressing to fatal metastatic disease while preserving quality of life by delaying treatment with androgen deprivation therapy (ADT).

Type: Interventional

Start Date: Mar 2024

open study

This is a multicenter, two-part trial in participants with FAP.

Type: Interventional

Start Date: Jul 2023

open study

This phase II trial compares the effect of usual treatment of docetaxel chemotherapy plus trastuzumab, to ado-emtansine (T-DM1) in patients with HER2-postive salivary gland cancer that has come back (recurrent), that has spread from where it first started (primary site) to other places in the body, or cannot be removed by surgery (unresectable). This trial is also testing how well trastuzumab deruxtecan works in treating patients with HER2-low recurrent or metastatic salivary gland cancer. Trastuzumab is a form of targeted therapy because it works by attaching itself to specific molecules (receptors) on the surface of cancer cells, known as HER2 receptors. When trastuzumab attaches to HER2 receptors, the signals that tell the cells to grow are blocked and the cancer cell may be marked for destruction by body's immune system. Trastuzumab emtansine contains trastuzumab, linked to a chemotherapy drug called emtansine. Trastuzumab attaches to HER2 positive cancer cells in a targeted way and delivers emtansine to kill them. Trastuzumab deruxtecan is a monoclonal antibody called traztuzumab, linked to a chemotherapy drug called deruxtecan. Trastuzumab is a form of targeted therapy because it attaches to specific molecules (receptors) on the surface of cancer cells, known as HER2 receptors and delivers deruxtecan to kill them. Docetaxel is in a class of medications called taxanes. It stops cancer cells from growing and dividing and may kill them. Trastuzumab emtansine may work better compared to usual treatment of chemotherapy with docetaxel and trastuzumab or trastuzumab deruxtecan in treating patients with recurrent, metastatic or unresectable salivary gland cancer.

Type: Interventional

Start Date: Mar 2023

open study

This is a multicenter trial to establish the efficacy of cooling and the optimal duration of induced hypothermia for neuroprotection in pediatric comatose survivors of cardiac arrest. The study team hypothesizes that longer durations of cooling may improve either the proportion of children that attain a good neurobehavioral recovery or may result in better recovery among the proportion already categorized as having a good outcome.

Type: Interventional

Start Date: Aug 2022

open study

This is a phase I trial of CA-4948 in combination with FOLFOX/PD-1 inhibitor with or without trastuzumab for unresectable gastric, GEJ, and esophageal cancer. During the Dose Escalation portion of the study, different dose levels of CA-4948 in combination with FOLFOX/nivolumab will be evaluated by BOIN algorithm. Dose Expansion will include Cohorts A and B. Expansion Cohort A will enroll up to 12 patients with HER2 negative gastric, GEJ, and esophageal cancer at the expansion dose of CA-4948 determined during Dose Escalation and will use the same treatment regimen of FOLFOX/nivolumab. Expansion Cohort B will investigate CA-4948 at the dose determined during Dose Escalation in combination with FOLFOX/pembrolizumab and trastuzumab in up to 12 patients with HER2 positive disease; however, the initial 6 patients will be considered safety lead-in to confirm the safety and tolerability of this combination; if determined to be safe, an additional 6 patients will be enrolled for a total of 12 in Cohort B.

Type: Interventional

Start Date: Jun 2023

open study

The current study will use a new treatment approach based on the molecular characteristics of each participant's tumor. The study will test the feasibility in the pilot phase of performing real-time drug screening on tissue taken during surgery in patients with relapsed medulloblastoma or ependymoma and of having a specialized tumor board assign a treatment plan based on the results of this screening and genomic sequencing. The aim of this trial is to allow every child and young adult with relapsed medulloblastoma and ependymoma to receive the most effective and least toxic therapies currently available and will pave the way for improved understanding and treatment of these tumors in the future. Moreover, if successful, it could serve as a paradigm for personalized medicine programs for other types of cancer.

Type: Interventional

Start Date: Feb 2022

open study