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

NCT07670156 | Not Yet Recruiting Phase 1 DMC FDA Drug

• 2 other identifiers: H-523664UH3TR003908
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 3

Brief Summary

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.

Conditions

JAK1 GOF; STAT1 GOF; STAT3 GOF; STAT5B GOF; STAT6 GOF

Keywords

Upadacitinib; JAK-STAT Pathway Disorders; Immunodeficiency; Primary Immune Regulatory Disorder (PIRD); Inborn Error of Immunity (IEI); early onset autoimmunity; autoimmune cytopenia; immune dysregulation; STAT1; STAT3; lymphoproliferation; STAT5b; STAT6; JAK1

Outcome Measures

Primary Outcomes (3)

• Treatment Efficacy - TIme to first occurrence of disease reactivation

  All patients that complete the open label dose-escalation phase and are randomized will be included in the efficacy analysis population. Efficacy of the Optimal Tolerated Dose (OTD) will be assessed by comparing the time to first occurrence of disease reactivation using Primary Immune Regulatory Deficiency (PIRD) score during the 8-week Randomized Withdrawal (RW) phase between the Upadacitinib and placebo groups. The PIRD score is a disease scoring method that capture the clinical manifestations of all PIRDs including JAK/STAT GOF disorders. The presence of a disease state and its severity is graded on a scale of 1-5. 1 indicates the absence of the disease. Disease flare is defined as an increase in PIRD score by ≥1 in disease manifestations.

  During the 8 weeks of the randomized withdrawal phase

• Safety and Tolerability - Percentage of Patients with Adverse Events of Special Interest

  All patients that receive at least one dose of study drug will be included in the analyses to evaluate safety and tolerability of the study drug. Safety and tolerability will be summarized for each phase of the study and will be assessed primarily based on adverse events of special interest. Assessment of safety and tolerability will primarily be done by calculating the percentage of patients with adverse events of special interest.

  Throughout the whole treatment period (1 year)

• Safety and Tolerability - Percentage of Patients with Organ Toxicity

  All patients that receive at least one dose of study drug will be included in the analyses to evaluate safety and tolerability of the study drug. Safety and tolerability will be summarized for each phase of the study and will be assessed based on organ toxicity. Organ toxicity will be assessed by clinical labs. Assessment of safety and tolerability will primarily be done by calculating the percentage of patients with organ specific toxicities.

  Throughout the whole treatment period (1 year)

Secondary Outcomes (2)

• Change in Quality of life during treatment- adults

  During the 16 weeks of OL Phase and 28 weeks of MP

• Change in Quality of life during treatment- children

  During the 16 weeks of OL Phase and 28 weeks of MP

Study Arms (2)

Upadacitinib (Drug)

ACTIVE COMPARATOR

During the 8-week randomized withdrawal (RW) phase, participants in this arm will receive upadacitinib at the dose that was determined to work best for them (optimal treatment dose, OTD) during the earlier open-label phase of the study (15 mg, 30 mg, or 45 mg OTD). This study is not designed to compare the different dose levels. Therefore, participants receiving any of the three dose levels will be considered as one arm because each participant is receiving their own OTD.

Drug: Upadacitinib

Matching Placebo

PLACEBO COMPARATOR

During the 8-week RW phase, participants assigned to receive placebo will receive placebo tablets that match their OTD selected during the earlier phase of the study.

Drug: Placebo

Interventions

Upadacitinib DRUG

Participants will receive the dose that worked best for them (optimal treatment dose, OTD) during the earlier open-label phase of the study, which may be 15 mg, 30 mg, or 45 mg taken once daily. The study drug will be taken by mouth as tablets.

Also known as: Rinvoq

Upadacitinib (Drug)

Placebo DRUG

Participants assigned to the placebo group will receive placebo tablets taken once daily. The placebo will be matched to the participant's optimal treatment dose (OTD) determined during the earlier open-label phase of the study.

Matching Placebo

Eligibility Criteria

• Age: 12 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• Lisa Satter: lead
• National Center for Advancing Translational Sciences (NCATS): collaborator
• AbbVie: collaborator

Study Sites (3)

Washington University in St.Louis

St Louis, Missouri, 63110, United States

Location

Columbia University

New York, New York, 10032, United States

Location

Baylor College of Medicine

Houston, Texas, 77030, United States

Location

MeSH Terms

Conditions

Immunologic Deficiency Syndromes

Interventions

upadacitinib

Condition Hierarchy (Ancestors)

Immune System Diseases

Study Officials

• Lisa F Satter, MD

  Baylor College of Medicine

  STUDY CHAIR

Central Study Contacts

Supriya Parikh

CONTACT

8328242589; supriya.parikh@bcm.edu

Sik Yu So

CONTACT

8328241318; sikyu.so@bcm.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Double Blinded
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Associate Professor of Pediatrics

Model Details: The study will follow a basket clinical trial design for JAK-STAT pathway disorders. The study consists of: (1) Open Label (OL) Dose Escalation Phase (3 dose escalations or continuation; each lasting 28 days); (2) Double Blind Placebo Controlled Randomized Withdrawal (RW) Phase; (3) Maintenance Phase (MP). For the double-blind randomized withdrawal phase, patients will be randomized to receive either the optimal treatment dose from the OL phase or Placebo using a 1:1 randomization ratio using variable block sizes.

Study Record Dates

• First Submitted: June 19, 2026
• First Posted: June 26, 2026
• Study Start: August 1, 2026
• Primary Completion (Estimated): August 1, 2028
• Study Completion (Estimated): August 1, 2028
• Last Updated: July 2, 2026

Record last verified: 2026-07

Locations

US (3)