Zanubrutinib in Patients With IgG4-Related Disease

A Phase II, Single-Site, Open-Label Study of Zanubrutinib in Patients With IgG4-Related Disease

The aim of this clinical trial is to evaluate the safety and efficacy of zanubrutinib in treating patients with IgG4-related disease

Study Overview

• Status: Completed
• Conditions: IgG4 Related Disease
• Intervention / Treatment: Drug: Zanubrutinib 80 MG

Detailed Description

This will be a single-site, open-label study in symptomatic patients with IgG4-related disease affecting the submandibular and/or lacrimal glands. All patients will receive zanubrutinib orally at a dose of 80mg BID for 24 weeks.

The primary objective of this study is to demonstrate that zanubrutinib treatment reduces reduces the volume of the submandibular and/or lacrimal glands on PET/MRI at week 24 compared to baseline.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Palo Alto, California, United States, 94304
      • Stanford University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Men or women aged 18 to 85, inclusive, at the time of initial screening

• Have histopathologically confirmed IgG4-RD in the submandibular gland and/or the lacrimal gland confirmed by international consensus pathology criteria

  • Presence of a lymphoplasmacytic infiltrate with 10 IgG4+ plasma cells per high-power field and/or an IgG4+/IgG+ plasma cell ratio of 40%
• All women must test negative for pregnancy and agree to use a reliable method of birth control
• No current treatment with immunosuppressive medications other than prednisone 40mg daily (or other glucocorticoid equivalent) with stable dosing for 28 days

Exclusion Criteria:

• Unstable prescribed dose of glucocorticoids within 28 days prior to baseline
• Any treatment with a synthetic DMARD including but not limited to hydroxychloroquine, methotrexate, leflunomide, or sulfasalazine within 28 days prior to baseline
• Any treatment with a cytotoxic or immunosuppressive drug including but not limited to cyclophosphamide, mycophenolic acid, azathioprine, cyclosporine, sirolimus, or tacrolimus within 28 days prior to baseline
• Any treatment with a BTK inhibitor within 6 months before baseline
• Any treatment with a JAK inhibitor within 28 days prior to baseline
• Use of biologic agents including infliximab, abatacept, or tocilizumab within 56 days prior to baseline
• Use of a B cell depleting therapy (such as rituximab) within 12 months prior to baseline
• A history of, or current, inflammatory or autoimmune disease (that could affect the interpretation of safety or efficacy outcomes) other than IgG4-related disease
• Evidence of active tuberculosis, HIV, or hepatitis B or C infection
• History of cancer other than non-melanoma skin cancer, cervical dysplasia or carcinoma in situ (cured >1 year), prostate cancer (cured >5 years), or colon cancer (cured >5 years)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Zanubrutinib; Zanubrutinib orally at a dose of 80mg BID for 24 weeks	Drug: Zanubrutinib 80 MG; Zanubrutinib 80 MG for 24 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Volume of the Submandibular Glands on PET-MRI	To demonstrate that zanubrutinib treatment reduces the volume of the submandibular glands on PET-MRI at week 24 compared to Baseline.	Baseline and Week 24
Volume of the Lacrimal Glands on PET-MRI	To demonstrate that zanubrutinib treatment reduces the volume of the lacrimal glands on PET-MRI at Week 24 compared to Baseline.	Baseline and Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
FDG Avidity (SUVmax) of the Submandibular Glands on PET	Effect of zanubrutinib on change in FDG avidity (SUVmax) of the submandibular glands on PET at Weeks 12 and 24 compared to Baseline.	Baseline, Week 12, and Week 24
FDG Avidity (SUVmax) of the Lacrimal Glands on PET	Effect of zanubrutinib on change in FDG avidity (SUVmax) of the lacrimal glands on PET at Week 24 compared to Baseline.	Baseline, Week 12, and Week 24
Change in Total Metabolic Lesion Volume (tMLV) of Lacrimal Glands, Submandibular Glands, Parotid Glands, and Lymph Notes on PET		Baseline, Week 12, and Week 24
Change in Total Lesion Glycolysis (TLG) of Submandibular and/or Lacrimal Glands on PET		Baseline, Week 12, and Week 24
Change in Submandibular Glands on MRI	Change in parenchymal architecture scored 0 to 4 and sialography scored 0 to 4 where 0 is normal, healthy gland and 4 is worse outcome.	Baseline, Week 12, and Week 24
Change in Parotid Glands on MRI	Change in parenchymal architecture scored 0 to 4 and sialography scored 0 to 4, where 0 is normal, healthy gland and 4 is worse outcome.	Baseline, Week 12, and Week 24
Change in Lacrimal Glands on MRI	Change in parenchymal architecture scored 0 to 4, where 0 is normal, healthy gland and 4 is worse outcome.	Baseline, Week 12, and Week 24
Change in the Volume of the Parotid Glands on PET/MRI		Baseline, Week 12, and Week 24
Change in the Volume of the Submandibular Glands on PET/MRI		Baseline and Week 12
Change in the Volume of the Lacrimal Glands on PET/MRI		Baseline, and Week 12
Change in Serum IgG4 Level		Baseline, Week 12, and Week 24
Change in Plasmablast Count	Change in percentage of CD19+ B cells in blood	Baseline, Week 12, and Week 24
Change in Absolute Regulatory B Cell Count	Percentage of regulatory B cells in the blood, assessed using flow cytometry.	Baseline, Week 12, and Week 24
Change in the IgG4-RD Responder Index	The IgG4-RD Responder Index detects change in disease activity and identifies improvements/worsening in the same or different organ systems. It encompasses more than 25 organs/sites and records the following for each organ/site: (i) activity trend (through a 0-3 [normal/resolved - worsening] organ/site score); (ii) presence of symptoms due to active disease; (iii) need for urgent care; (iv) presence of damage; and (v) presence of symptoms due to damage. The final activity score at each visit is obtained by summing all organ/site scores (i) and by doubling items needing urgent care (iii). The IgG4-RD Responder Index Total Activity Score ranges from 0 to a maximum of 162. Higher scores represent greater (i.e. worse) disease activity. A score of 0 represents no disease activity other than residual fibrosis.	Baseline, Week 12, and Week 24
Proportion of Patients With no Disease Flares	Number and percentage of patients who did not have an IgG4-RD flare	Week 12 to Week 24
Change in Total Salivary Grey Scale Ultrasound Score (TUS)	Each parotid and submandibular gland scored from 0 to 3 with a higher score indicating worse disease, total summed scores across all four glands will be assessed for change (overall score range: 0 to 12, with a higher score indicating worse disease)	Baseline, Week 12, and Week 24
Change in Highest Score Among the Salivary Glands for the Grey Scale Ultrasound Score (HSUS)	Each parotid and submandibular gland (n=4) scored from 0 to 3 with a higher score indicating worse disease, highest score will be assessed for change (overall score range: 0 to 12, with a higher score indicating worse disease)	Baseline, Week 12, and Week 24
Change in Glandular Inflammation Total Ultrasound Score (iTUS)	Each parotid and submandibular gland (n=4) scored from 0 to 3 with a higher score indicating worse disease, total summed scores across all four glands will be assessed for change (overall score range: 0 to 12, with a higher score indicating worse disease)	Baseline, Week 12, and Week 24
Change in Highest Score Among the Salivary Glands for the Glandular Inflammation Ultrasound Score (iHSUS)	Each parotid and submandibular gland (n=4) scored from 0 to 3 with a higher score indicating worse disease, highest score will be assessed for change (overall score range: 0 to 12, with a higher score indicating worse disease)	Baseline, Week 12, and Week 24
Change in Physician Global Assessment of Disease	Symptoms rated on a 100 mm visual analog scale (VAS). Score range: 0 to 100, higher scores correspond to worse disease state.	Baseline, Week 12, and Week 24
Change in Patient Global Assessment of Disease	Symptoms rated on a 100 mm VAS. Score range: 0 to 100, higher scores correspond to worse disease state.	Baseline, Week 12, and Week 24
Change in VAS for Ocular Symptoms - Dryness	Symptoms rated on a 100 mm VAS. Score range: 0 to 100, higher scores correspond to worse disease state.	Baseline to Week 24
Change in VAS for Dryness Symptoms	Symptoms rated on a 100 mm VAS. Score range: 0 to 100, higher scores correspond to more dryness. Participants were asked to assess their dryness, taking into account all areas, including ocular and salivary symptoms.	Baseline, Week 12, Week 24
Change in FACIT-F Fatigue Score	Total score range: 0-52, lower scores correspond with more fatigue. FACIT = Functional Assessment of Chronic Illness Therapy.	Baseline, Week 12, and Week 24
Change in RAND Short Form-36	The summary scores range from 0 to 100, with higher scores indicating better levels of function and/or better health.	Baseline, Week 12, and Week 24
Change in C3 Lab	Complement component 3 (C3) level in blood	Baseline, Week 12, and Week 24
Change in C4 Lab	Complement component 4 (C4) level in blood	Baseline, Week 12, and Week 24
Change in Total IgG Lab		Baseline, Week 12, and Week 24
Change in IgE Lab		Baseline, Week 12, and Week 24
Change in IgG1 Lab		Baseline, Week 12, and Week 24
Change in ESR Lab	Change in erythrocyte sedimentation rate (ESR)	Baseline, Week 12, and Week 24
Change in CRP Lab	Change in serum C-reactive protein (CRP) level	Baseline, Week 12, and Week 24
Incidence of Safety Parameters Including Adverse Events	Number of participants with treatment-emergent adverse events (TEAEs).	Baseline to Week 32
Incidence of Safety Parameters Including Abnormal Laboratory Results	Number of participants with any grade 3 or 4 treatment-emergent laboratory abnormality	Baseline to Week 32

Collaborators and Investigators

• Sponsor: Matthew C. Baker
• Collaborators: Stanford University

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2022
• Primary Completion (Actual): February 11, 2025
• Study Completion (Actual): April 3, 2025

Study Registration Dates

• First Submitted: October 20, 2020
• First Submitted That Met QC Criteria: October 20, 2020
• First Posted (Actual): October 26, 2020

Study Record Updates

• Last Update Posted (Actual): April 1, 2026
• Last Update Submitted That Met QC Criteria: March 11, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Autoimmune Diseases; Immune System Diseases; Immunoglobulin G4-Related Disease; Tyrosine Kinase Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; zanubrutinib
• Other Study ID Numbers: 58497

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No