Isatuximab in Patients With Monoclonal Gammopathy of Renal Significance

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to see whether Isatuximab can help improve kidney function of participants with MGRS. Isatuximab is approved by the Food and Drug Administration (FDA) for the treatment of adult patients with multiple myeloma, but it is not approved by the FDA to treat MGRS. This means that the use of isatuximab in this study is considered 'investigational'.

Detailed Description
-----------------
Monoclonal gammopathy is a common disorder but only a small fraction of patients with monoclonal gammopathy of undetermined significance (MGUS) develop renal disease and the reason for abnormal deposition of immunoglobulin in renal parenchyma remains unclear in these disorders. The proposed research will be conducted as a part of clinical trial which intends to prospectively evaluate the effect of anti-plasma cell therapy on renal outcomes in patients with monoclonal gammopathy of renal significance (MGRS). The study specifically intends to sequence the immunoglobulin heavy and light chain genes to determine any abnormalities that could lead to production of a misfolded immunoglobulin thus leading to deposition in renal parenchyma.

Official Title
-----------------
A Single Arm, Multicenter, Phase II, Open-Label Trial to Evaluate Efficacy of Isatuximab in Patients With Monoclonal Gammopathy of Renal Significance

Conditions
-----------------
Monoclonal Gammopathy

Intervention / Treatment
-----------------
* Drug: Isatuximab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Renal biopsy proven diagnosis of an MGRS disorder including the following: Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) C3 glomerulopathy associated with monoclonal gammopathy Non-Amyloid Fibrillary Glomerulonephritis Light chain Proximal Tubulopathy Immunotactoid Glomerulopathy A concurrent diagnosis of Monoclonal gammopathy (with +ve Serum and/or Urine protein electrophoresis or Bone marrow biopsy) is required in patients with C3 glomerulopathy but not for other disorders. Patients with concurrent MGUS, non-high risk smoldering myeloma are eligible for enrollment. Measurable Proteinuria ≥1gram over 24 hours. Prior Therapy: Newly diagnosed as well as patients with previous therapy but persistent renal dysfunction and persistent proteinuria ≥1gram over 24 hours are eligible for enrollment. Patients who received a prior cluster of differentiation 38 (CD38) antibody therapy are not eligible for study. In patients who have received prior therapy a wash out period of 12 weeks for chemotherapy based therapies and 24 weeks for Rituximab based therapies is required between completion of prior therapy and cycle 1 Day1 of study therapy. Age ≥18 years. Eastern Cooperative Oncology Group (ECOG) performance status ≤2. Life expectancy of greater than 6 months Participants must have normal organ and marrow function as defined below: Leukocytes ≥3,000/microliters (mcL) absolute neutrophil count ≥1,500/mcL platelets ≥100,000/mcL total bilirubin within normal institutional limits Aspartate aminotransferase (AST) (SGOT)/alanine transaminase (ALT)(SGPT) ≤2.5 × institutional upper limit of normal Estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2. Exclusion Criteria: Participants who have had chemotherapy based therapy within 12 weeks or Rituximab based therapy within prior 24 weeks prior to starting the cycle 1 Day 1 of trial therapy Participants who are receiving any other investigational agents concurrently. History of severe allergic reactions or anaphylaxis attributed to compounds of similar chemical or biologic composition to Isatuximab. Diagnosis of Multiple Myeloma or High risk smoldering Multiple Myeloma or a B cell lymphoma meeting criteria for therapy. Renal Biopsy showing the coexistence of other significant diagnosis e.g. diabetic nephropathy. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Pregnant and Lactating women are excluded from this study because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with Isatuximab. HIV-positive Participants are ineligible because of increased risk of lethal infections when treated with immunosuppressive therapy.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: The study will be a single arm, prospective, multi-center, phase II, open- label study including 27 subjects in total. The study will consist of a screening phase, treatment phase, post-treatment observation phase and follow-up phase
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Isatuximab for MGRS<br>Subjects will receive Isatuximab for 6 months and will be followed for an additional one year post therapy for outcome follow-up. | Drug: Isatuximab<br>* Isatuximab in IV form (10mg/kg q weekly x 4 doses followed by 10mg/kg q 2 weeks) for a total of 6 month duration. Doses should be initiated at 175 mg/hour up to a maximum of 400 mg/hour. Isatuximab (SAR) is monoclonal antibody (mAb).<br>* Other names: Sarclisa;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Renal Response Rate | Renal response defined as a decrease in 24-hour proteinuria by >50% at any point post therapy. | Up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Adverse Events | The number of adverse events recorded for participants using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. | Up to 12 months | 
| Percentage of Participants with Immunoglobulin Gene Mutations | The percentage of participants with immunoglobulin gene mutations as determined by next generation sequencing. | Baseline, up to 4 weeks prior to treatment |