A Phase 1/2 Open-label Study to Evaluate the Safety and Efficacy of Tofacitinib for Chronic Granulomatous Disease With Inflammatory Complications

• Status: Enrolling by invitation
• Trial end date: 2025-01-31

Summary

This is a phase 1/2 open-label trial to study the safety and to explore the biological efficacy of tofacitinib in patients with confirmed and symptomatic inflammatory complications (gastrointestinal [GI], skin, lung) related to chronic granulomatous disease (CGD). After a 3-month regimen of tofacitinib, participants inflammatory complications will be objectively assessed. Samples collected before, during, and after therapy will be evaluated for pathologic, molecular, and cellular changes in response to therapy, thereby refining our knowledge of the mechanisms driving inflammatory complications in CGD patients while evaluating the safety of this novel therapy. Inhibition of Janus kinase (JAK) pathways is a novel therapeutic intervention for CGD patients with inflammatory complications that are not responsive to standard therapies. Preliminary data highlight the potential role of increased activation of the JAK/signal transducer and activator of transcription (STAT) pathway in the pathogenesis of CGD. These data, paired with the success in treating other monogenic immune disorders characterized by JAK/STAT pathway activation (ie, STAT1 gain-of-function, STING-associated vasculopathy of infancy) with JAK inhibitors (JAKIs), suggest that JAKIs are a reasonable candidate therapy for the difficult-to-treat inflammatory manifestations of CGD. Tofacitinib, a first generation JAKI, is an attractive candidate for this purpose given the following: 1) it is FDA-approved for treatment of moderate to severe ulcerative colitis, 2) CGD colitis shares many clinical and pathologic features of inflammatory bowel disease, and 3) the GI, pulmonary, and skin inflammatory complications of CGD respond poorly to standard therapies and cause significant morbidity. Patients taking tofacitinib are at increased risk for developing serious infections, so participants will maintain their current antifungal and antibacterial medications, and will start a shingles prophylaxis regimen. Major adverse cardiovascular (CV) events, such as heart attack, stroke, blot clots, cancer, and death have also been reported in patients with preexisting CV risk factors. Patients with CV risk factors or a history of major adverse CV events will be excluded from the study, and participants will be closely monitored for signs and symptoms. The hypothesis of this study is that CGD patients with poorly controlled GI, skin, and pulmonary inflammatory manifestations can be safely treated with tofacitinib and will experience improvement in clinical symptoms, pathological findings, and molecular and cellular biomarkers.

• Phase: Phase 1/Phase 2

Details

• Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Treatments: Tofacitinib