Upacitinib in Treatment of JAK/STAT Pathway Disorders With Activating Mutations

This study focuses on a genetic condition that affects the Janus Kinase-Signal Transducer and Activator of Transcription (JAK-STAT) immune signaling pathway. A specific change in the DNA leads to overactivation of this pathway, which can result in immune dysregulation and related clinical symptoms. Currently, five genetic mutations are known to cause these JAK-STAT pathway driven immune disorders: STAT1, STAT3, STAT5B, STAT6, and JAK1 (collectively referred to as JAK-STAT disorders). This study is a basket clinical trial, meaning patients with these different but related genetic conditions are enrolled in the same study and treated with the same investigational therapy. The purpose of this study is to evaluate the safety and tolerability (ability to tolerate) of a drug called Upadacitinib in patients with JAK-STAT disorders with activating mutations. This drug belongs to a class of drug called Janus kinase (JAK) inhibitors, also known as JAKinibs. It is a type of immune system modulating medication that regulates (fixes) the JAK- STAT signaling pathway. Upadacitinib has been approved by the FDA for multiple immunological diseases and disorders. Presently, there is no FDA approved treatment for this group of JAK-STAT disorders. The study will also investigate immune factors in the blood to develop diagnosis methods that can be used in the future for better medical management of these disorders. The study consists of four phases: screening phase, open label phase, randomized withdrawal phase and maintenance phase. The study will last approximately 12 months. While in the study, participants will receive a once daily dose of Upadacitinib that best helps control their disease. During the study participants will be asked to answer questions about their health and medical history. They will also complete physical exams, blood tests, and other questionnaires.

Inclusion Criteria: * At least 30kg * Patients with a confirmed JAK/STATGOF mutation with evidence of immune dysregulation * Current disease status meeting criteria as defined in the disease scoring module * Expected survival of more than 12 months * Willingness to allow storage of biological samples for future research * Agreement to use highly effective contraception (for female participants) Exclusion Criteria: * Hypersensitivity to the study drug or any medication in the same class * Active infections * Central nervous system (CNS) manifestations * Pregnancy * Medical conditions or use of concomitant medications that may interfere with the effect or evaluation of the study drug * Laboratory abnormalities as specified in the protocol * Receipt of a live vaccine within 30 days prior to study treatment * High risk or history of osteoporosis, thrombosis, gastrointestinal (GI) perforation, or malignancy