Open-label Study to Determine the Maximum Tolerated Dose of DSG3-CAART in Mucosal-dominant PV Patients (mPV)

Study Overview
=================
Brief Summary
-----------------
Mucosal-dominant pemphigus vulgaris (mPV) is a B-cell mediated autoimmune disorder in which painful blisters are formed on the mucosal membrane, including the mouth, nose, throat, eyelids, anus, and genitals. This phase 1 study is being conducted to find the maximum tolerated dose and optimal fractionated infusion schedule of an investigational cell therapy, DSG3-CAART, that can be given to patients with mPV who are inadequately managed by standard therapies. DSG3-CAART may potentially lead to complete and durable remission of disease.

Official Title
-----------------
A Phase 1, Open-label, Safety and Dosing Study of Autologous Desmoglein 3 Chimeric Autoantibody Receptor T Cells (DSG3-CAART) in Subjects With Active, Anti-DSG3, Mucosal-dominant Pemphigus Vulgaris

Conditions
-----------------
Mucosal -Dominant Pemphigus Vulgaris

Intervention / Treatment
-----------------
* Biological: DSG3-CAART


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Confirmed diagnosis of mPV by prior or screening biopsy and prior positive anti- DSG3 antibody ELISA mPV inadequately managed by at least one standard immunosuppressive therapies Active mPV at screening Anti-DSG3 antibody ELISA positive at screening Exclusion Criteria: Active cutaneous lesions associated with PV that indicates mucocutaneous rather than mucosal-dominant disease Rituximab in last 12 months unless PV symptoms have recently worsened or anti-DSG3 antibody titers have recently increased Prednisone > 0.25mg/kg/day Other autoimmune disorder requiring immunosuppressive therapies Investigational treatment in last 6 months Absolute lymphocyte count < 1,000/µL at screening

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DSG3-CAART<br>Cohort A: Fractionated infusions of DSG3-CAART at increasing dose levels (6-9 groups) administered as a single cycle. Cohort B: Consolidation of infusion of DSG3-CAART to fewer fractionations than in Cohort A using the selected dose from Cohort A (1 group) administered as a single cycle. Cohort C: Infusion of final selected dose and fractionation of DSG3-CAART from Cohorts A and B (1 group) administered as a single cycle | Biological: DSG3-CAART<br>* Intravenous infusions of DSG3-CAART alone at different doses and different fractionations. Subjects may also receive varying doses of DSG3-CAART as part of a sub-study, which will employ pre-treatment with intravenous immunoglobulin, cyclophosphamide, and with or without fludarabine to potentially increase the in vivo expansion, persistence and activity of DSG3-CAART.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events, including Dose Limit Toxicity | The primary endpoint of the study is the incidence of adverse events that are related to DSG3-CAART therapy within 3 months of DSG3-CAART cell infusion. | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of CAAR-transduced cells | Percent of total cells for infusion that are CAAR-transduced cells by flow cytometry | Baseline | 
| Total DSG3-CAART positive cells | Total DSG3-CAART positive cells for each manufacturing run by flow cytometry | Baseline | 
| Cellular kinetics profile of DSG3-CAART | Cellular kinetics profile of DSG3-CAART assessed by quantitative polymerase chain reaction | Up to 36 months | 
| Change in DSG3 autoantibody titer | Change in DSG3 autoantibody titer by ELISA compared to pre-infusion visit | Up to 36 months | 
| Serologic remission | Proportion of subjects achieving serologic remission, determined by negative DSG3 ELISA titer | Up to 36 months | 
| Pemphigus Disease Area Index (PDAI) | Change in PDAI compared to pre-infusion visit, scored on a 0-250 scale where a greater number represents more disease activity | Up to 36 months | 
| Clinical remission: complete remission off therapy and complete remission on minimal therapy | Proportion of subjects achieving complete remission, determined by a PDAI activity score of 0 for at least 2 months, either off therapy or on minimal therapy | Up to 36 months | 
| Time to clinical remission and time to serologic remission | Time to clinical remission and time to serologic remission from the last infusion | up to 36 months | 
| Duration of clinical remission and duration of serologic remission | Duration of clinical remission and duration of serologic remission sustained after achieving the initial remission | up to 36 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Pemphigus, Pemphigus Vulgaris, CAAR-T Therapy, CAR-T Therapy, Desmoglein 3, Cell Therapy, Autoimmune Disease, Autoimmunity, Skin Diseases, Vesiculobullous, Immunotherapy, Adoptive, Immune System Diseases