Isatuximab in Lung Transplant Recipients

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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Antibody-mediated Rejection; Allosensitization
• Intervention / Treatment: Drug: Isatuximab; Procedure: bone marrow biopsy

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 6
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Tyler Lewis, PharmD; Phone Number: 866-838-5864; Email: Tyler.lewis@nyulangone.org

Study Locations

• United States
  • New York
    • New York, New York, United States, 10016
      • NYU Langone Health
      • Contact: Tyler Lewis, PharmD
      • Principal Investigator: Luis Angel, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Peri-transplant desensitization group; 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; 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.; Other Names: SARCLISA®; Procedure: bone marrow biopsy; 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.
Experimental: Treatment of antibody-mediated rejection; 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; 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.; Other Names: SARCLISA®

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: NYU Langone Health
• Investigators: Principal Investigator: Luis Angel, MD, NYU Langone Health

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2024
• Primary Completion (Estimated): January 1, 2026
• Study Completion (Estimated): January 1, 2027

Study Registration Dates

• First Submitted: May 8, 2023
• First Submitted That Met QC Criteria: May 8, 2023
• First Posted (Actual): May 17, 2023

Study Record Updates

• Last Update Posted (Estimated): February 26, 2024
• Last Update Submitted That Met QC Criteria: February 22, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Desensitization; antibody-mediated rejection; isatuximab
• Other Study ID Numbers: 22-00992

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices) will be shared upon reasonable request and as agreed upon by the study team members.
• IPD Sharing Time Frame: Beginning 9 months and ending 36 months following article publication or as required by a condition of awards and agreements supporting the research.
• IPD Sharing Access Criteria: The investigator who proposed to use the data will have access to the data upon reasonable request. Requests should be directed to tyler.lewis@nyulangone.org. To gain access, data requestors will need to sign a data access agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes