Elotuzumab in Immunoglobulin G4-Related Disease (IgG4-RD)

Phase 2TerminatedNCT04918147

National Institute of Allergy and Infectious Diseases (NIAID)8 enrolled

Overview

This is a two-part multi-center clinical trial in participants with active IgG4-RD. Part 1 (Cohort 1a and Cohort 1B) is an open-label, dose escalation phase to determine the safety of elotuzumab for investigation in IgG4-RD. Part 2 (Cohort 2) is a randomized, placebo-controlled, double-blinded (masked) trial phase to compare the effects of elotuzumab and prednisone to elotuzumab placebo and prednisone in participants with IgG4 RD. Approximately 75 participants with active IgG4-RD will be enrolled in the overall program, 12 in Part 1 and 63 in Part 2. Randomization in Part 2: 2 to 1, with approximately forty-two participants randomized to elotuzumab plus prednisone taper, and twenty-one participants randomized to placebo for elotuzumab plus prednisone taper. The total duration of participation for each participant in this trial will be 48 weeks (11 months).

Immunoglobulin G4-Related Disease (IgG4-RD) is a chronic fibro-inflammatory condition that can affect virtually every organ system, including the pancreas, biliary tract, salivary and lacrimal glands, orbits, lungs, kidneys, meninges, pituitary gland, prostate and thyroid. It may also involve the retroperitoneum. This multi-organ immune-mediated condition, once regarded as a group of isolated, single-organ diseases, is now recognized to be an overarching, single-disease entity linked by common histopathological and immunohistochemical features. IgG4-RD tends to afflict middle-aged to elderly individuals. Although IgG4-RD can affect a single organ at presentation, it is not uncommon for participants to present with or develop multi-organ disease. As the disease progresses, additional organs develop lesions and the cellular inflammation characterizing early disease moves toward a more fibrotic stage, causing major tissue damage, dysfunction and ultimately organ failure. It is unclear whether IgG4 itself is involved in the pathogenesis of the disease. The goals of IgG4-RD treatment are to reduce inflammation and organ swelling and to prevent or reverse tissue fibrosis. No approved therapy exists for IgG4-RD. This study will enroll adult participants who meet the 2019 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Classification Criteria for IgG4-RD, and who have active IgG4-RD with disease manifestations in at least two organ systems. Primary study objectives: * To determine the safety and tolerability of the addition of elotuzumab to prednisone in participants with IgG4-RD, and * To compare the effect of the addition of elotuzumab versus placebo to prednisone on the IgG4-RD Responder Index (IgG4-RD RI), a measure of IgG4-RD disease activity.

Study Type

Interventions

elotuzumabDRUG

Elotuzumab is a humanized recombinant monoclonal antibody (mAb) targeted against SLAMF7, a cell surface glycoprotein.

placebo for elotuzumabDRUG

The placebo for elotuzumab is 0.9% sterile normal saline for injection.

methylprednisoloneDRUG

Premedication administered intravenously, 45 to 90 minutes prior to each elotuzumab/placebo infusion, per protocol. Dosage in milligrams (mg).

diphenhydramineDRUG

Premedication administered orally or intravenously, 45 to 90 minutes prior to each elotuzumab/placebo infusion, per protocol. Dosage in milligrams (mg).

acetaminophenDRUG

Premedication administered orally, 45 to 90 minutes prior to each elotuzumab/placebo infusion, per protocol. Dosage in milligrams (mg).

famotidineDRUG

Premedication administered orally or intravenously, 45 to 90 minutes prior to each elotuzumab/placebo infusion, per protocol. Dosage in milligrams (mg).

prednisoneDRUG

Prescribed dosing with prednisone begins on the day of the first elotuzumab/placebo infusion, administered orally. The ten-week dosing taper proceeds, per protocol. Dosage in milligrams (mg).

Eligibility

Sex: ALLMin age: 18 YearsMax age: 70 Years

Medical Language ↔ Plain English

Inclusion Criteria: Individuals who meet all of the following criteria are eligible for enrollment as study participants: 1. Participant must be able to understand and provide informed consent and be willing to comply with study procedures and follow up. 2. Are at least 18 years of age and not older than 70 years of age at screening. 3. Meet the ACR/EULAR Classification Criteria for IgG4-RD \[30, 31\]. 4. Have active disease based at screening on an IgG4-RD RI ≥4, with disease manifestations in at least two organ systems. 5. May have newly-diagnosed or relapsing disease at screening. Relapsing disease is defined as IgG4-RD that has previously been in remission but is now active again. 6. May be on treatment or off treatment for IgG4-RD at the time of screening. If on treatment, must be willing to discontinue those other treatments before the baseline visit. 7. No history of severe allergic reactions to monoclonal antibodies. 8. Female participants of childbearing potential must have a negative pregnancy test upon study entry. 9. Female participants of childbearing potential and male participants with a partner of childbearing potential must agree to consistently and correctly use FDA approved highly effective methods of birth control for the entire duration of the study and 6 months after last elotuzumab infusion. 10. Immunization with one of the FDA authorized or licensed SARS-CoV-2 vaccines as per CDC recommendations at the time of informed consent is required for study entry. Vaccinations must have been completed at least 2 weeks prior to start of study therapy. Exclusion Criteria: Individuals who meet any of these criteria are not eligible for enrollment as study participants: 1. Presence of a condition other than IgG4-RD that (e.g., asthma) is likely to require systemic Glucocorticoids (GC) for disease control during the period of the trial. 2. Malignancy within 5 years (except successfully treated in situ cervical cancer, resected squamous cell or basal cell carcinoma of the skin.) 3. The following lab values as indicators of hepatic dysfunction: 1. Serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than three times the upper limit of normal (ULN) 2. Total bilirubin \> two times the ULN unless caused by Gilbert's disease. Gilbert's disease with total bilirubin \> three times ULN. 3. Serum albumin \< 2.5 gm/dL. 4. Evidence of another uncontrolled condition which, in the judgment of the investigator, could interfere with participation in the trial according to the protocol. 5. Active infection requiring hospitalization or treatment with systemic antimicrobial agents within the 30 days prior to treatment allocation/randomization. 6. Prior use of rituximab or other B cell depleting agents within 9 months of enrollment unless B cells have been demonstrated to have repopulated. 7. Use of any investigational agent or biologic and non-biologic DMARDs within 5 half-lives of the agent (or 6 months if the half-life is unknown) prior to enrollment. 8. Any of the following laboratory tests at the Screening Visit: 1. White blood cell count (WBC) \< 3.0 x 103/µL. 2. Absolute neutrophil count (ANC) \< 1.5 x 103/µL. 3. Hemoglobin \< 10 g/dL. 4. Platelet count \< 75 x 109/L. 5. Estimated glomerular filtration rate (eGFR) ≤ 45 ml/minute/1.73 m2. 9. The use of supplemental oxygen at baseline. 10. At or within 90 days of screening: Positive Interferon-Gamma Release Assay (IGRA). Indeterminate IGRAs must be repeated (with same or other IGRA per local policy) and shown to be negative. Alternatively, if the assay remains indeterminant, a participant must have a negative PPD. Finally, if the participant has had the Bacille Calmette-Guerin (BCG) vaccine or has some other condition complicating the interpretation of TB testing, consultation with infectious disease specialist must be obtained before receipt of the first investigational infusion. a. Participants diagnosed with latent TB are eligible but must have received appropriate prophylaxis for 30 days before their first investigational infusion. 11. Medical history or serologic evidence at Screening of chronic infections including: 1. Human immunodeficiency virus infection. 2. Hepatitis B as indicated by surface antigen or hepatitis B core antibody positivity 3. Hepatitis C as indicated by anti-hepatitis C antibody positivity; if a participant is Hepatitis C antibody positive, they will be eligible to participate in the study if he/she is negative for viral load at Screening. 12. Live vaccines within 8 weeks of initiating study therapy. 13. Participant is pregnant or breastfeeding, or planning a pregnancy while enrolled in the study. 14. Substance use disorder, including the recurrent use of alcohol and/or drugs within the past year associated with clinically significant impairment associated with failure to meet major responsibilities at work, school, or home. 15. IgG4-RD that is dominated primarily by advanced fibrotic lesions. Specifically, participants whose disease manifestations consist only of 1. retroperitoneal fibrosis, 2. fibrosing mediatinitis, 3. sclerosing mesenteritis, or 4. Riedel's thyroiditis. Participants with these disease manifestations can be included, however, only if they have disease in 2 organ systems that is not of an advanced fibrotic nature and otherwise meet the Inclusion and Exclusion Criteria. 16. Evidence a SARS-CoV-2 (COVID-19) infection started within the 30 days prior to treatment allocation/randomization. Participants diagnosed with SARS-CoV-2 (COVID-19) infection more than 30 days prior to treatment allocation/randomization must have symptoms resolved and be deemed fit to participate in the trial.

Outcomes

Primary Outcomes

The Percent of Participants in Each Cohort Who Experience at Least One Grade 3 or Higher Adverse Event (AE).

The severity of AEs were classified using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 5.0

Time frame: Up to Week 48 post treatment initiation

Secondary Outcomes

The Percent of Participants Who Experience at Least One Grade 2 or Higher Adverse Event (AE).

The severity of AEs was classified using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 5.0.

Time frame: Up to Week 48 post treatment initiation

The Percent of Participants With a Grade 3 or Higher Infection

The number of AEs classified as infections that were Grade 3 or higher. The severity of AEs was classified using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 5.0.

Time frame: Up to Week 48 post treatment initiation

The Percent of Participants Who Experience a Malignancy.

The number of participants with malignancies reported as AEs. The severity of AEs was classified using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 5.0.

Time frame: Up to Week 48 post treatment initiation

The Percent of Participants Who Experience a Hepatotoxicity

Hepatotoxicity is defined as an increase in the aspartate aminotransferase (AST) or alanine aminotransferase (ALT) to elevations three times the upper limit of normal.

Time frame: Up to Week 48 post treatment initiation

The Percent of Participants Who Experience a Serious Adverse Event

An adverse event (AE) is considered "serious" if, in the view of either the investigator or sponsor, it results in any of the following outcomes (21 CFR 312.32(a)): 1\. Death. 2. Life-threatening event: An AE is considered "life-threatening" if, in the view of either the investigator or Sponsor, its occurrence places the participant at immediate risk of death. It does not include an AE that, had it occurred in a more severe form, might have caused death. 3. Inpatient hospitalization or prolongation of existing hospitalization. 4. Persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions. 5. Congenital anomaly or birth defect. 6. Important medical events that may not result in death, be life threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the participant and may require medical or surgical intervention to prevent one of the outcomes listed above.

Time frame: Up to Week 48 post treatment initiation

The Percent of Participants Who Experience Infusion Reactions

The number of participants with infusion reactions reported as AEs. Infusion reactions are defined as any adverse reaction within 24 hours of infusion which are Grade 2 or higher events and at least possibly related to study drug. The severity of AEs was classified using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 5.0.

Time frame: Up to 24 hours post treatment infusion

The Percent of Participants That Reach the Following Threshold Levels of IgG4-Related Disease Responder Index (IgG4-RD RI) Improvement at 24 Weeks: 50% and 75%.

The IgG4-RD RI 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). Higher scores represent greater (i.e. worse) disease activity. % improvement in the IgG4-RD RI = 100 x ( (Baseline IgG4-RD RI Activity Score - Week 24 IgG4-RD RI Activity Score) / Baseline IgG4-RD RI Activity Score). Participants who use glucocorticoids/immunosuppressants beyond that permitted by protocol, or who experience a disease flare before 24 weeks will be defined as achieving no disease response (0%).

Time frame: Baseline and Week 24

Number of Participants With Disease Flares

IgG4-Related Disease flare was defined as recurrence of disease activity such that additional immunosuppressive therapy beyond the trial protocol is indicated. Such additional therapy may include glucocorticoids or alternative immunosuppressive agents. At the time of a potential disease flare, investigators documented the features of the disease flare in each involved organ, including laboratory evaluations, radiology studies, and other procedures (e.g., biopsy). Disease flares were reported as adverse events.

Time frame: Up to Week 48 post treatment initiation

Change From Baseline in Physician Global Assessment

The Physician Global Assessment of the participant's current disease activity was recorded on a 100 mm linear horizontal visual analog scale, where the left hand extreme of the line is considered "Very Good" (0 mm, symptom free and no IgG4-RD symptoms) and the right hand extreme is considered "Very Bad" (100 mm, maximum IgG4-RD activity). Only active disease (as opposed to damage) is considered in the scoring. Change was calculated as the value at Week 12, 24 or 48 minus the value at Baseline.

Time frame: Baseline, Weeks 12, 24 and 48

Change From Baseline in Patient Global Assessment

The Patient Global Assessment of the participant's current disease activity was recorded on a 100 mm linear horizontal visual analog scale, where the left hand extreme of the line is considered "Very Good" (0 mm, symptom free and no IgG4-RD symptoms) and the right hand extreme is considered "Very Bad" (100 mm, maximum IgG4-RD activity). Change was calculated as the value at Week 12, 24 or 48 minus the value at Baseline.

Time frame: Baseline, Weeks 12, 24 and 48

Disease-Related Damage, as Measured by the Damage Section of the IgG4-Related Disease (IgG4-RD) Responder Index.

An assessment of damage caused by IgG4-RD in each affected organ is part of the Responder Index. The IgG4-RD RI encompasses more than 25 organs/sites and records the following set of information 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. Activity and damage are considered separately from the standpoint of scoring, because only disease activity can be expected to respond to treatment. Damage is defined as organ dysfunction that has occurred as a result of IgG4-RD and is considered permanent. The total damage score at each visit is defined as the total number of damaged organs and can range from 0 (no damage) to more than 26 (severe damage).

Time frame: Screening and Week 24

Elotuzumab in Immunoglobulin G4-Related Disease (IgG4-RD)

Overview

Conditions

Interventions

Eligibility

Locations (3)

Outcomes

Primary Outcomes

Secondary Outcomes