Upacitinib in Treatment of JAK/STAT Pathway Disorders With Activating Mutations (SAFE-JAKi)

Safety and Efficacy of Upadacitinib 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.

Study Overview

• Status: Not yet recruiting
• Conditions: JAK1 GOF; STAT1 GOF; STAT3 GOF; STAT5B GOF; STAT6 GOF
• Intervention / Treatment: Drug: Upadacitinib; Drug: Placebo

Detailed Description

This is a phase 1/2, multi-center trial with an open label dose-escalation phase (OL) followed by a double-blind placebo-controlled randomized withdrawal phase (RW) to study the safety, tolerability, and preliminary efficacy of Upadacitinib in patients with confirmed and symptomatic gain of function mutations in the JAK-STAT pathway. Upon completion of the randomized withdrawal phase, each patient will enter the maintenance phase (MP) where all patients will receive Upadacitinib.

OL Phase (16 weeks): The subject will be escalated two times if tolerated and clinically indicated based upon disease response. The starting dose will be 15 mg per day for patients greater than or equal to 12 years of age (and at least 30 kg in weight). The subject will remain at this dose level for 28 days. The subject will visit the clinical site on day 1 of each dose escalation visit and then will be remotely monitored (phone call and laboratory monitoring to check complete blood counts) on Day 3 and Day 10.

Patients must have a disease status score of 2 or higher utilizing the Primary Immune Regulatory Deficiency (PIRD) Disease Modules prior to initiation of dose-escalation of the drug. The PIRD score is a disease scoring method that capture the clinical manifestations of all PIRDs including JAK/STAT GOF disorders. The PIRD scores for clinical improvement across organ systems for each patient will standardize the ability to quantify improvement across divergent disease phenotypes and assess outcomes based on clinical improvement within each disorder. Patients who demonstrate a response to study treatment, as determined by improvement in PIRD score, may proceed to the RW Phase. Patients who do not meet eligibility criteria for the RW Phase will enter MP.

During the OL Phase, the optimal treatment dose (OTD) for each patient will be determined. OTD will be defined as the dose that achieved complete response or partial response based on the PIRD scores.

RW Phase (8 weeks): For the double-blind randomized withdrawal phase, patients will be randomized to receive either the Optimum tolerated dose (OTD) dose from the OL phase or Placebo using a 1:1 randomization ratio. Subject will come to the study site every 4 weeks. The subject can discontinue the RW phase if he/she experiences a flare (worsening of disease symptoms) and will enter the Maintenance Phase outlined below. For measuring disease flare Primary Immune Regulatory Disorders (PIRD) score will be used. It will be deemed a flare if the score increases by ≥1 in disease manifestation. During the RW-phase, the reference for a disease flare (for the primary endpoint assessment) will be the end of the OL phase PIRD score.

MP Phase (28 weeks): Subject will be monitored closely for any drug related toxicities (blood counts, lipid and metabolic panels) and continue to take the highest tolerated dose level attained during the escalation phase. The subject will return to the clinical site on day 168, day 217, day 266, day 315 and day 364. Upon conclusion of the maintenance phase at day 364 the study team will safely transition the subject to clinically viable treatment alternatives that are commercially available (after a 3 days washout period for Upadacitinib).

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Supriya Parikh; Phone Number: 8328242589; Email: Supriya.Parikh@bcm.edu
• Study Contact Backup: Name: Sik Yu So; Phone Number: 8328241318; Email: sikyu.so@bcm.edu

Study Locations

• United States
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Washington University in St.Louis
      • Contact: Megan Cooper, MD, PhD; Phone Number: 314-286-0262; Email: cooper_m@wustl.edu
      • Principal Investigator: Megan Cooper, MD, PhD
  • New York
    • New York, New York, United States, 10032
      • Columbia University
      • Principal Investigator: Joseph Oved, MD
      • Contact: Joseph Oved, MD; Phone Number: 332-292-7978; Email: jho2001@cumc.columbia.edu
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
      • Contact: Supriya Parikh; Phone Number: 8328242589; Email: Supriya.Parikh@bcm.edu
      • Contact: Daisy Vita; Phone Number: 8328241319; Email: dxtran1@texaschildrens.org
      • Principal Investigator: Lisa Satter, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Upadacitinib (Drug); 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; 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.; Other Names: Rinvoq
Placebo Comparator: Matching Placebo; 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; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Quality of life during treatment- adults	Quality of life (QOL) will be assessed using validated age-adjusted tools (SF-36 for adults) at screening, beginning of the Randomized Withdrawal (RW) phase, beginning of the Maintenance Phase (MP), end of the MP. The SF-36 (36-Item Short Form Health Survey) is an open-source patient-reported questionnaire to measure quality of life (QoL) across multiple health domains. It contains 36 items grouped into eight scales, each assessing a different aspect of health. To assess the change in quality of life during the Open-Label (OL) phase, change from screening values will be calculated using assessments at the beginning of the RW phase. To assess the change in quality of life during the MP, the change in the QOL scores from beginning of the MP to the end of the MP will be calculated.	During the 16 weeks of OL Phase and 28 weeks of MP
Change in Quality of life during treatment- children	Quality of life (QOL) in children will be assessed using validated age-adjusted tools (Peds-QL for children) at screening, beginning of the Randomized Withdrawal (RW) phase, beginning of the Maintenance Phase (MP), end of the MP. The PedsQL Measurement Model is a modular approach to measuring health-related quality of life (HRQOL) in healthy children and adolescents. It uses age-appropriate questionnaires to assess physical, emotional, social, and school functioning from the child's and/or parent's perspective. Its modular design allows it to be adapted for various conditions, making it widely used in clinical research and healthcare settings. To assess the change in quality of life during the Open-Label (OL) phase, change from screening values will be calculated using assessments at the beginning of the RW phase. To assess the change in quality of life during the MP, the change in the QOL scores from beginning of the MP to the end of the MP will be calculated.	During the 16 weeks of OL Phase and 28 weeks of MP

Collaborators and Investigators

• Sponsor: Lisa Satter
• Collaborators: AbbVie; National Center for Advancing Translational Sciences (NCATS)
• Investigators: Study Chair: Lisa F Satter, MD, Baylor College of Medicine

Study record dates

Study Major Dates

• Study Start (Estimated): August 1, 2026
• Primary Completion (Estimated): August 1, 2028
• Study Completion (Estimated): August 1, 2028

Study Registration Dates

• First Submitted: June 19, 2026
• First Submitted That Met QC Criteria: June 19, 2026
• First Posted (Actual): June 26, 2026

Study Record Updates

• Last Update Posted (Actual): June 26, 2026
• Last Update Submitted That Met QC Criteria: June 19, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Immunodeficiency; Upadacitinib; JAK1; lymphoproliferation; immune dysregulation; autoimmune cytopenia; STAT1; STAT3; STAT6; JAK-STAT Pathway Disorders; Primary Immune Regulatory Disorder (PIRD); Inborn Error of Immunity (IEI); early onset autoimmunity; STAT5b
• Additional Relevant MeSH Terms: Immune System Diseases; Immunologic Deficiency Syndromes; upadacitinib
• Other Study ID Numbers: H-52366; 4UH3TR003908 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No