Zanubrutinib in Patients With IgG4-Related Disease

Matthew C. Baker10 enrolled

Overview

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

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

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

IgG4 Related Disease

Interventions

Zanubrutinib 80 MGDRUG

Zanubrutinib 80 MG for 24 weeks

Eligibility

Sex: ALLMin age: 18 YearsMax age: 85 Years

Medical Language ↔ Plain English

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)

Locations (1)

Stanford University

Palo Alto, California, United States

Outcomes

Primary Outcomes

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.

Time frame: 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.

Time frame: Baseline and Week 24

Secondary Outcomes

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.

Time frame: 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.

Time frame: 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

Time frame: Baseline, Week 12, and Week 24

Change in Total Lesion Glycolysis (TLG) of Submandibular and/or Lacrimal Glands on PET

Time frame: 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.

Time frame: Baseline, Week 12, and Week 24

Data from ClinicalTrials.gov

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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.

Time frame: 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.

Time frame: Baseline, Week 12, and Week 24

Change in the Volume of the Parotid Glands on PET/MRI

Time frame: Baseline, Week 12, and Week 24

Change in the Volume of the Submandibular Glands on PET/MRI

Time frame: Baseline and Week 12

Change in the Volume of the Lacrimal Glands on PET/MRI

Time frame: Baseline, and Week 12

Change in Serum IgG4 Level

Time frame: Baseline, Week 12, and Week 24

Change in Plasmablast Count

Change in percentage of CD19+ B cells in blood

Time frame: 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.

Time frame: 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.

Time frame: 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

Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: Baseline, Week 12, and Week 24

Change in Highest Score Among the Salivary Glands for the Glandular Inflammation Ultrasound Score (iHSUS)

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: Baseline, Week 12, and Week 24

Change in C3 Lab

Complement component 3 (C3) level in blood

Time frame: Baseline, Week 12, and Week 24

Change in C4 Lab

Complement component 4 (C4) level in blood

Time frame: Baseline, Week 12, and Week 24

Change in Total IgG Lab

Time frame: Baseline, Week 12, and Week 24

Change in IgE Lab

Time frame: Baseline, Week 12, and Week 24

Change in IgG1 Lab

Time frame: Baseline, Week 12, and Week 24

Change in ESR Lab

Change in erythrocyte sedimentation rate (ESR)

Time frame: Baseline, Week 12, and Week 24

Change in CRP Lab

Change in serum C-reactive protein (CRP) level

Time frame: Baseline, Week 12, and Week 24

Incidence of Safety Parameters Including Adverse Events

Number of participants with treatment-emergent adverse events (TEAEs).

Time frame: 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

Time frame: Baseline to Week 32