Isatuximab in Lung Transplant Recipients

Study Overview
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Brief Summary
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The purpose of this study is to determine the safety and feasibility of adding isatuximab to standard of care therapies in patients who will receive a lung transplant, but have significant antibodies against the donor (desensitization), or patients who have previously received a lung transplant and develop antibodies against the donor (antibody-mediated rejection, AMR). The study will compare the impact of isatuximab on the recurrence of antibodies after they have been removed from the blood by a process known as plasmapheresis that is standard of care for this condition. The use of isatuximab in lung transplant recipients is investigational, meaning it is not Food and Drug Administration (FDA) approved for use in lung transplant recipients. This study is a pilot study investigating the feasibility and safety of isatuximab in lung transplant patients. Isatuximab is an FDA approved drug indicated for the treatment of multiple myeloma. It may also be useful for transplant recipients with antibodies against the donor because it eliminates the cells that make antibodies.

Detailed Description
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This dual-arm pilot study will enroll approximately 6 patients undergoing lung transplantation at NYU Langone Health who are either receiving peri-transplant desensitization, or who are admitted for treatment of AMR. All patients will be treated with standard-of-care consisting of plasmaspheresis, IVIG, and rituximab. Additionally, the experimental agent, isatuximab, will be added to this treatment protocol. The patients will first receive 4 weekly doses of isatuximab, followed by 4 bi¬-weekly doses (total 8 doses given over 12 weeks). Patients will be followed with standard-of-care immunologic assessment consisting of weekly DSA assessment and flow cytometry crossmatch (only in the desensitization arm). Additionally, patients undergoing peri-transplant desensitization will have a bone marrow biopsy with pathologic examination and cell counts performed at the time of transplant and repeated at the 30-day bronchoscopy to assess for plasma cell elimination.

Official Title
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A Pilot Study of Isatuximab in Addition to Standard Therapy for Desensitization or Antibody-mediated Rejection in Lung Transplant Recipients

Conditions
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Antibody-mediated Rejection, Allosensitization

Intervention / Treatment
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* Drug: Isatuximab
* Procedure: bone marrow biopsy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Cohort A (Desensitization) Inclusion Criteria: Age ≥ 18 years Listed and will receive a lung transplant or multi-organ transplant involving a lung at NYU Langone Health that is deemed to require peri-transplant desensitization Able and willing to provide informed consent Pre-transplant DSA > 5,000 MFI in undiluted serum (measured as individual DSA MFI or as sum of multiple DSAs >1000 MFI in the undiluted serum) Cohort B (AMR) Inclusion Criteria: Age ≥ 18 years Received a lung transplant or multi-organ transplant involving a lung at NYU Langone Health Able and willing to provide informed consent Allograft dysfunction in the setting of at least one of the following criteria: Histopathology suggestive of AMR Lung biopsy demonstrating C4d deposition Positive DSA > 2,000 MFI (as individual DSA MFI) Exclusion Criteria: Prior or current treatment with rituximab within 6 months of isatuximab administration Prior or current treatment with tocilizumab within 6 months of isatuximab administration Contraindication to isatuximab due to intolerance or hypersensitivity Pregnant or breastfeeding women Known malignancy Active infection without adequate treatment or source control Known hepatitis B viral infection Known HIV infection

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Peri-transplant desensitization group<br>Listed and will receive a lung transplant or multi-organ transplant involving a lung at NYU Langone Health that is deemed to require peri-transplant desensitization. Participants will be treated with standard-of-care consisting of plasmaspheresis, IVIG, rituximab and the experimental agent, isatuximab. Patients will be followed with standard-of-care immunologic assessment consisting of weekly DSA assessment and flow cytometry crossmatch (only in the desensitization arm). Additionally, participants will have a bone marrow biopsy with pathologic examination and cell counts performed at the time of transplant and repeated at the 30-day bronchoscopy to assess for plasma cell elimination | Drug: Isatuximab<br>* The dose will consist of isatuximab 10 mg/kg actual body weight given weekly for the first 4 weeks, followed by 10 mg/kg biweekly for an additional 4 doses. Isatuximab is a clear, colorless to slightly yellow solution. It is supplied as 100 mg/5 mL or 500 mg/25 mL single-dose vials.<br>* Other names: SARCLISA®;Procedure: bone marrow biopsy<br>* Bone marrow biopsy at the time of lung transplantation and at approximately 1 month following completion of therapy. Initial bone marrow biopsy to be performed during the lung transplant operation and to be collected from the sternum by the operating surgeon. Follow-up bone marrow biopsy to be completed by credentialed hematologist during a regularly scheduled follow-up bronchoscopy with standard procedural anesthesia sedation.<br>|
| Experimental: Treatment of antibody-mediated rejection<br>Received a lung transplant or multi-organ transplant involving a lung at NYU Langone Health. Participants will be treated with standard-of-care consisting of plasmaspheresis, IVIG, rituximab and the experimental agent, isatuximab. | Drug: Isatuximab<br>* The dose will consist of isatuximab 10 mg/kg actual body weight given weekly for the first 4 weeks, followed by 10 mg/kg biweekly for an additional 4 doses. Isatuximab is a clear, colorless to slightly yellow solution. It is supplied as 100 mg/5 mL or 500 mg/25 mL single-dose vials.<br>* Other names: SARCLISA®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Resolution, as measured by the number of participants with less than 1 episode of Antibody-mediated rejection (AMR) | Participants undergoing desensitization will have stable supplemental oxygen requirement or no supplemental oxygen requirement | Day 0 (Visit 1) | 
| Clinical Resolution, as measured by the number of participants with less than 1 episode of Antibody-mediated rejection (AMR) | Participants undergoing desensitization will have stable supplemental oxygen requirement or no supplemental oxygen requirement | Day 28 (Visit 5) | 
| Clinical Resolution, as measured by the number of participants with no presence of Donor-specific antibody (DSA) | Participants undergoing desensitization will have no presence of Donor-specific-antibody | Day 0 (Visit 1) | 
| Clinical Resolution, as measured by the number of participants with no presence of Donor-specific antibody (DSA) | Participants undergoing desensitization will have no presence of Donor-specific-antibody | Day 28 (Visit 5) | 
| Clinical Resolution, as measured by the number of participants with reduction of DSA titer | Participants undergoing desensitization will have no presence of Donor-specific-antibody measured by DSA titer or by C1q assay. | Day 0 (Visit 1) | 
| Clinical Resolution, as measured by the number of participants with reduction of DSA titer | Participants undergoing desensitization will have no presence of Donor-specific-antibody measured by DSA titer or by C1q assay. | Day 28 (Visit 5) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in effects of pre-treatment Donor-Specific-Antibodies (DSAs ) with <2000 Mean fluorescent intensity (MFI) at 1:16 dilution | Percent Mean fluorescent intensity (MFI) change in undiluted serum | Day 0 (Visit 1), Day 14 (Visit 3), Day 28 (Visit 5), Day 56 (Visit 7), Day 84 (Visit 9) | 
| Change in effects of pre-treatment Donor-Specific-Antibodies (DSAs ) with 2001-7999 Mean fluorescent intensity (MFI) at 1:16 dilution | Percent moderate titer DSA with <1000 Mean fluorescent intensity (MFI) at 1:16 dilution | Day 0 (Visit 1), Day 14 (Visit 3), Day 28 (Visit 5), Day 56 (Visit 7), Day 84 (Visit 9) | 
| Change in effects of pre-treatment Donor-Specific-Antibodies (DSAs ) ≥ 8000 Mean fluorescent intensity (MFI) at 1:16 dilution | Percent Mean fluorescent intensity (MFI) reduction of high titer DSAs at 1:16 dilution | Day 0 (Visit 1), Day 14 (Visit 3), Day 28 (Visit 5), Day 56 (Visit 7), Day 84 (Visit 9) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Desensitization, antibody-mediated rejection, isatuximab