• Proportion of Participants in Cohort 1a Who Experience at Least One Grade 3 or Higher Adverse Event [ Time Frame: Up to Week 24 post treatment initiation ]
  Safety measure. Evaluation of the severity of adverse events. Reference: National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 5.0.
• Proportion of Participants in Cohort 1b Who Experience at Least One Grade 3 or Higher Adverse Event [ Time Frame: Up to Week 24 post treatment initiation ]
  Safety measure. Evaluation of the severity of adverse events. Reference: National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 5.0.
• Participants in Cohort 2: Percent Change in Immunoglobulin G4-Related Disease Responder Index (IgG4-RD RI) Score [ Time Frame: Baseline (Day 0, prior to treatment initiation), Week 24 ]
  Efficacy measure. The IgG4-RD RI is used to assess disease response to treatments in IgG4-RD clinical trials.

• Proportion of Participants by Cohort Group who Experience at Least One Grade 2 or Higher Adverse Event [ Time Frame: Up to Week 48 post treatment initiation ]
  Safety measure. Evaluation of the severity of adverse events. Reference: National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 5.0.
• Proportion of Participants by Cohort Group with a Grade 3 or Higher Infection [ Time Frame: Up to Week 48 post treatment initiation ]
  Safety measure. Evaluation of the severity of infectious disease(s) adverse events. Reference: National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 5.0.
• Proportion of Participants by Cohort Group who Experience a Malignancy [ Time Frame: Up to Week 48 post treatment initiation ]
  Safety measure. Evaluation of the severity of infectious disease(s) adverse events. Reference: National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 5.0.
• Proportion of Participants by Cohort Group who Experience a Hepatotoxicity [ Time Frame: Up to Week 48 post treatment initiation ]
  Safety measure. Defined as an increase in the serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) to elevations three times the upper limit of normal (ULN).
• Proportion of Participants by Cohort Group who Experience a Serious Adverse Event [ Time Frame: Up to Week 48 post treatment initiation ]
  Safety measure defined as an adverse event or suspected adverse reaction that, in the view of either the investigator or sponsor results in any of the following outcomes (21 CFR 312.32(a)):

  • Death
  • A life-threatening event
  • Inpatient hospitalization or prolongation of existing hospitalization
  • Persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions
  • Congenital anomaly or birth defect
  • 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
• Proportion of Participants by Cohort Group who Experience Infusion Reactions [ Time Frame: Up to 24 hours post treatment infusion ]
  Safety measure 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.
• Proportion of Participants in Cohort 2 who Experience at Least One Grade 3 or Higher Adverse Event [ Time Frame: Up to Week 48 post treatment initiation ]
  Safety measure. Evaluation of the severity of adverse events. Reference: National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 5.0.
• Proportion of Participants in Cohort 2 in Complete Remission at Week 24 [ Time Frame: Week 24 post treatment initiation ]
  Efficacy measure, defined as:

  • An IgG4-RD Responder Index (IgG4-RD RI) score of 0,
  • A glucocorticoid dose of 0 mg/day, and
  • No disease flare since beginning treatment.
• Proportion of Participants by Cohort Group who Achieve ≥50 Percent (%) Improvement in IgG4-RD Responder Index (IgG4-RD RI) Score at Week 24 [ Time Frame: Week 24 post treatment initiation ]
  Efficacy measure. The IgG4-RD RI is used to assess disease response to treatments in IgG4-RD clinical trials. 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.
• Proportion of Participants by Cohort Group who Achieve ≥75 Percent (%) Improvement in IgG4-RD Responder Index (IgG4-RD RI) Score at Week 24 [ Time Frame: Week 24 post treatment initiation ]
  Efficacy measure. The IgG4-RD RI is used to assess disease response to treatments in IgG4-RD clinical trials. 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.
• Number of Immunoglobulin G4-Related Disease (IgG4-RD) Flares by Cohort Group by Week 24 [ Time Frame: Up to Week 24 post treatment initiation ]
  Efficacy measure, defined as a recurrence of disease activity such that additional immunosuppressive therapy beyond the trial protocol is indicated.
• Number of Immunoglobulin G4-Related Disease (IgG4-RD) Flares by Cohort Group by Week 48 [ Time Frame: Up to Week 48 post treatment initiation ]
  Efficacy measure, defined as a recurrence of disease activity such that additional immunosuppressive therapy beyond the trial protocol is indicated.
• Change from Baseline in Physician Global Assessment (PhGA)-By Cohort Group [ Time Frame: Baseline, Weeks 1, 5, 9, 16, 24, and 48 ]
  Efficacy measure.
• Change from Baseline in Patient Global Assessment (PGA)-By Cohort Group [ Time Frame: Baseline, Weeks 1, 5, 9, 16, 24, and 48 ]
  Efficacy measure.
• Proportion of Participants by Cohort Group with Disease-Related Damage at Week 24 [ Time Frame: Week 24 post treatment initiation ]
  Efficacy measure. Disease-related damage, as measured by the damage section of the IgG4-RD Responder Index (IgG4-RD RI). The IgG4-RD RI is used to assess disease response to treatments in IgG4-RD clinical trials.

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 participant follow-up 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.

• IgG4 Related Disease
• IgG4-RD

• Drug: elotuzumab
  Elotuzumab is a humanized recombinant monoclonal antibody (mAb) targeted against SLAMF7, a cell surface glycoprotein.
  Other Names:

  • BMS-901608
  • Empliciti®
• Drug: placebo for elotuzumab
  The placebo for elotuzumab is 0.9% sterile normal saline for injection.
  Other Name: normal saline
• Drug: methylprednisolone
  Premedication administered intravenously, 45 to 90 minutes prior to each elotuzumab/placebo infusion, per protocol. Dosage in milligrams (mg).
  Other Name: Solu-Medrol®
• Drug: diphenhydramine
  Premedication administered orally or intravenously, 45 to 90 minutes prior to each elotuzumab/placebo infusion, per protocol. Dosage in milligrams (mg).
  Other Name: Benadryl®
• Drug: acetaminophen
  Premedication administered orally, 45 to 90 minutes prior to each elotuzumab/placebo infusion, per protocol. Dosage in milligrams (mg).
  Other Name: Tylenol®
• Drug: famotidine
  Premedication administered orally or intravenously, 45 to 90 minutes prior to each elotuzumab/placebo infusion, per protocol. Dosage in milligrams (mg).
  Other Name: H2 blocker
• Drug: prednisone
  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).
  Other Name: corticosteroid

• Experimental: Cohort 1a: Elotuzumab-One-Month Regimen (Open-Label) + Pred Taper

  Per protocol: Six participants will receive elotuzumab on days 0,7, 14, 21, and the prescribed 10-week prednisone taper.

  • Elotuzumab: 10 mg/kg administered once weekly, intravenously (IV push or bolus), per protocol.
  • Prednisone taper (Pred Taper): Prescribed 10-week dosing taper beginning on Day 0 that involves daily doses by mouth, per protocol. Dosage in milligrams (mgs).
  Interventions:

  • Drug: elotuzumab
  • Drug: methylprednisolone
  • Drug: diphenhydramine
  • Drug: acetaminophen
  • Drug: famotidine
  • Drug: prednisone
• Experimental: Cohort 1b: Elotuzumab-Three-Month Regimen (Open-Label) + Pred Taper

  Per protocol: Six participants will receive elotuzumab on days 0,7, 14, 21, then weeks 5,7,9 and 11 (three-month regimen), and the prescribed 10-week prednisone taper.

  • Elotuzumab: 10 mg/kg administered as referenced above, intravenously (IV push or bolus), per protocol.
  • Prednisone taper (Pred Taper): Prescribed 10-week dosing taper beginning on Day 0 that involves daily doses by mouth, per protocol. Dosage in milligrams (mgs).
  Interventions:

  • Drug: elotuzumab
  • Drug: methylprednisolone
  • Drug: diphenhydramine
  • Drug: acetaminophen
  • Drug: famotidine
  • Drug: prednisone
• Experimental: Cohort 2: Arm A- Elotuzumab (Randomized) + Pred Taper

  Safety and efficacy analyses from Cohort 1a and Cohort 1b will occur prior to initiating Cohort 2 (Randomized).

  Forty-two participants will receive elotuzumab on days 0,7, 14, 21, then weeks 5,7,9 and 11 (three-month regimen), and the prescribed 10-week prednisone taper.

  • Elotuzumab: 10 mg/kg administered as referenced above, intravenously (IV push or bolus), per protocol.
  • Prednisone taper (Pred Taper): Prescribed 10-week dosing taper beginning on Day 0 that involves daily doses by mouth, per protocol. Dosage in milligrams (mgs).
  Interventions:

  • Drug: elotuzumab
  • Drug: methylprednisolone
  • Drug: diphenhydramine
  • Drug: acetaminophen
  • Drug: famotidine
  • Drug: prednisone
• Placebo Comparator: Cohort 2: Arm B-Placebo (Randomized) + Pred Taper

  Safety and efficacy analyses from Cohort 1a and Cohort 1b will occur prior to initiating Cohort 2 (Randomized).

  Twenty-one participants will receive placebo for elotuzumab on days 0,7, 14, 21, then weeks 5,7,9 and 11 (three-month regimen), and the prescribed 10-week prednisone taper.

  • Placebo for elotuzumab: Administered on same schedule as elotuzumab described in Cohort 2 Arm A: intravenously (IV push or bolus), per protocol.
  • Prednisone taper (Pred Taper): Prescribed 10-week dosing taper beginning on Day 0 that involves daily doses by mouth, per protocol. Dosage in milligrams (mgs).
  Interventions:

  • Drug: placebo for elotuzumab
  • Drug: methylprednisolone
  • Drug: diphenhydramine
  • Drug: acetaminophen
  • Drug: famotidine
  • Drug: prednisone

• Wallace ZS, Naden RP, Chari S, Choi HK, Della-Torre E, Dicaire JF, Hart PA, Inoue D, Kawano M, Khosroshahi A, Lanzillotta M, Okazaki K, Perugino CA, Sharma A, Saeki T, Schleinitz N, Takahashi N, Umehara H, Zen Y, Stone JH; Members of the ACR/EULAR IgG4-RD Classification Criteria Working Group. The 2019 American College of Rheumatology/European League Against Rheumatism classification criteria for IgG4-related disease. Ann Rheum Dis. 2020 Jan;79(1):77-87. doi: 10.1136/annrheumdis-2019-216561. Epub 2019 Dec 3. Review.
• Khosroshahi A, Wallace ZS, Crowe JL, Akamizu T, Azumi A, Carruthers MN, Chari ST, Della-Torre E, Frulloni L, Goto H, Hart PA, Kamisawa T, Kawa S, Kawano M, Kim MH, Kodama Y, Kubota K, Lerch MM, Löhr M, Masaki Y, Matsui S, Mimori T, Nakamura S, Nakazawa T, Ohara H, Okazaki K, Ryu JH, Saeki T, Schleinitz N, Shimatsu A, Shimosegawa T, Takahashi H, Takahira M, Tanaka A, Topazian M, Umehara H, Webster GJ, Witzig TE, Yamamoto M, Zhang W, Chiba T, Stone JH; Second International Symposium on IgG4-Related Disease. International Consensus Guidance Statement on the Management and Treatment of IgG4-Related Disease. Arthritis Rheumatol. 2015 Jul;67(7):1688-99. doi: 10.1002/art.39132. Review.

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. Meet the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Classification Criteria for IgG4-Related Disease (IgG4-RD);
3. Have active disease based at screening on an IgG4-RD Responder Index (RI) ≥4, with disease manifestations in at least two organ systems;

4. 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;

5. 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 (Day 0) visit;

6. No history of severe allergic reactions to monoclonal antibodies;
7. Female participants of childbearing potential must have a negative pregnancy test upon study entry;
8. Female participants of childbearing potential and male participants with a partner of childbearing potential must agree to use Food and Drug Administration (FDA) approved methods of birth control for the entire duration of the study; and,

9. Immunization with one of the FDA authorized or licensed Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) vaccines is required for study entry

   • Vaccination series must have been completed at least 2 weeks prior to start of study therapy
   • Participants with Coronavirus Disease 2019 (COVID-19) infections within the preceding three months must have 2 consecutive negative nasal swab Polymerase Chain Reaction (PCR) tests performed at least 24 hours apart.

Exclusion Criteria:

Individuals who meet any of these criteria are not eligible for enrollment as study participants:

1. Treatment with more than 40 mg/day of prednisone within 28 days of the Baseline (Day 0) visit;
2. 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;
3. Malignancy within 5 years (except successfully treated in situ cervical cancer, resected squamous cell or basal cell carcinoma of the skin);

4. The following lab values as indicators of hepatic dysfunction:

   • Serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater (>) than three times the upper limit of normal (ULN)

   • Total bilirubin >two times the ULN unless caused by Gilbert's disease

     ---Gilbert's disease with total bilirubin > three times ULN

   • Serum albumin <2.5 mg/dL;
5. Evidence of another uncontrolled condition which, in the judgment of the investigator, could interfere with participation in the trial according to the protocol;
6. Active infection requiring hospitalization or treatment with systemic antimicrobial agents within the 30 days prior to randomization;
7. Prior use of rituximab or other B cell depleting agents within 9 months of enrollment, unless B cells have been demonstrated to have repopulated;
8. Use of any investigational agent or biologic and non-biologic disease-modifying antirheumatic drugs (DMARDs) within 5 half-lives of the agent (or 6 months if the half- life is unknown) prior to enrollment;

9. Any of the following laboratory tests at the Screening Visit:

   • White blood cell count (WBC) <3.0 x 10^3/microliter (µL)
   • Absolute neutrophil count (ANC) <1.5 x 10^3/µL
   • Hemoglobin <10 g/dL
   • Platelet count <75 x 10^9/L
   • Estimated glomerular filtration rate (eGFR) ≤45 ml/minute/1.73m^2;
10. The use of supplemental oxygen at baseline (Day 0);

11. Positive Quantiferon gold assay

    • Indeterminate Quantiferon gold assays must be repeated (with same or other interferon gamma release assay (IGRA) per local policy) and shown to be negative

      ---Alternatively, if the Quantiferon gold assay remains indeterminant, a participant must have a negative purified protein derivative (PPD)

    • If the participant has had the Bacillus Calmette-Guérin (BCG) vaccine or has some other condition complicating the interpretation of tuberculosis (TB) testing, consultation with infectious disease specialist must be obtained before receipt of the first investigational infusion ----Note: Participants diagnosed with latent TB are eligible but must have received appropriate prophylaxis for 30 days before their first investigational infusion;

12. Medical history or serologic evidence at Screening of chronic infections including:

    • Human immunodeficiency virus (HIV) infection
    • Hepatitis B as indicated by surface antigen or hepatitis B core antibody positivity
    • 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;
13. Live vaccines within 8 weeks of initiating study therapy;
14. Participant is pregnant or breastfeeding, or planning a pregnancy while enrolled in the study;
15. 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;

16. IgG4-RD that is dominated primarily by advanced fibrotic lesions (°)

    --Specifically, participants whose disease manifestations consist only of:

    • retroperitoneal fibrosis,
    • fibrosing mediastinitis,
    • sclerosing mesenteritis, or
    • Riedel's thyroiditis

    (°) Participants with these (Exclusion item 16) 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; or,

17. Co-enrollment: While participating in AIG01, participants may not be in another interventional trial, but may be in observational registries or cohorts as long as the total combined volume of blood to be drawn does not exceed the National Institutes of Health (NIH) limit of and objectives do not confound the current study.

• Autoimmunity Centers of Excellence
• Bristol-Myers Squibb
• Rho Federal Systems Division, Inc.