Polyclonal Regulatory T Cells (PolyTregs) for Pemphigus

Study Overview
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Brief Summary
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T cells, a type of white blood cell called a lymphocyte, play an important role in the immune system. One subtype, the regulatory T cell (Treg) helps to regulate the immune system and may provide protection against the development of autoimmune disease. The hope is that these naturally occurring Treg cells can be utilized for the treatment of autoimmune disease and potentially replace the use of chronic immunosuppressive therapies that are associated with multiple side effects. There has been a small study showing safe administration of Tregs with decreased disease activity in patients with insulin-dependent diabetes. Tregs are being studied in lupus, cancer and organ transplantation. This phase I trial will be conducted as an open-label, dose-escalation, multicenter trial in adult participants with active pemphigus.The purpose of this study is to test the safety and effect of Treg therapy in participants who have skin (cutaneous) involvement due to pemphigus.

Detailed Description
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Up to 12 adults between the ages of 18 and 75 years of age who have been diagnosed with pemphigus and meet all other entry criteria will be enrolled to receive one infusion of their own expanded Tregs at one of the following doses: 1.0 x 10^8 PolyTregs or 2.5 x 10^8 PolyTregs. Safety, disease activity, and mechanism of action will be assessed over a three year period, using biospecimens from blood and skin. Study therapy administration will occur during an overnight stay, followed by 2 weekly visits, then monthly visits from Week 8 to Week 12, then quarterly visits from Week 26 to Week 52, then twice a year visits until Week 156.

Official Title
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A Phase I, Open-Label, Multicenter Trial Exploring the Safety and Tolerability of Autologous Polyclonal Regulatory T Cell Therapy in Adults With Active Pemphigus (APG01)

Conditions
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Pemphigus Foliaceus, Pemphigus Vulgaris

Intervention / Treatment
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* Biological: Cohort 1: 1.0 x 10^8 PolyTregs
* Biological: Cohort 2: 2.5x10^8 PolyTregs


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ability to provide informed consent; Diagnosis of Pemphigus Vulgaris (PV) or Pemphigus Foliaceus (PF), defined by H&E staining (e.g., Haemotoxylin and Eosin) and direct immunofluorescence staining of skin biopsy at any time prior to enrollment; Pemphigus treated with systemic corticosteroids within the 2 years prior to screening (historic or current), or treated with rituximab ≥ 12 months prior to screening; Presence of: anti-Dsg3 antibodies (>20.0 U/ml) at screening visit consistent with diagnosis of pemphigus vulgaris or, anti-Dsg1 antibodies (>20.0 U/ml) at screening visit consistent with diagnosis of pemphigus foliaceus. Active of PV or PF as defined by Pemphigus Disease Area Index (PDAI) overall activity score 3-10 at screening visit, and PDAI overall activity score 1-12 at baseline visit; Positive test for Epstein-Barr Virus (EBV) antibody; Adequate venous access to support draw of 400 ml whole blood and infusion of investigational therapy; and An absolute Treg count of ≥ 42 cells/μL within 6 weeks prior to whole blood collection at Week -2 (i.e., 2 weeks prior to planned PolyTreg Infusion). Exclusion Criteria: Initiation of systemic corticosteroid therapy, prednisone dose > 25 mg/d (or equivalent) or change in prednisone dose within 4 weeks prior to screening; Addition of a new medication, or change in the dose of any background medication used to treat any aspect of pemphigus within the timeframes listed below. Specifically: methotrexate, mycophenolate mofetil, mycophenolic acid, azathioprine, cyclosporine or dapsone within the 6 weeks prior to screening or in the time between screening and study drug infusion, intravenous Immunoglobulin (IVIG) within 12 weeks prior to screening or in the time between screening and study drug infusion (subjects on IVIG must be on stable dose for at least 12 weeks prior to screening), treatment with cyclophosphamide within 12 weeks prior to screening or in the time between screening and study drug infusion. Doses of background medications at screening: methotrexate > 25 mg/week, mycophenolate mofetil > 3000 mg/d, mycophenolic acid > 1080 mg/bid, azathioprine > 200 mg/d, cyclosporine > 2 mg/kg/d, dapsone >250 mg/d,or intravenous immunoglobulin (IVIG) > 4mg/kg monthly. Use of rituximab within the 12 months prior to screening; Change in dosing frequency, concentration, or applied surface area of topical steroids and/or topical calcineurin inhibitors within 2 weeks prior to screening; Paraneoplastic pemphigus; Pemphigus erythematosus; Pemphigus vegetans; Immunoglobulin A (IgA) pemphigus; Drug-induced pemphigus; Blood donation within 10 weeks prior to baseline visit (Day 0); Hemoglobin < 10 g/dL; White blood cell (WBC) count < 3,000/ mm^3 (equivalent to < 3 x10^9/L); Lymphocyte count < 800/mm^3 (equivalent to < 0.8 x10^9/L); Absolute neutrophil count < 1,500/mm^3 (equivalent to < 1.5 x10^9/L); Platelets < 100,000/mm^3 (equivalent to < 100 x 10^9/L); Liver function test [aspartate aminotransferase (AST)], alanine aminotransferase (ALT), or alkaline phosphatase (ALK)] results that are ≥ 2 times the upper limit of normal (ULN); Direct bilirubin > ULN; End stage renal disease [estimated glomerular filtration rate (eGFR) < 20 ml/min/1.73m^2 using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation]; At or within three months of screening: a positive QuantiFERON(R)-TB Gold test or positive purified protein derivative tuberculin skin test (PPD) [>5mm induration, regardless of Bacille Calmette Guerin (BCG) vaccine administration] unless completion of treatment has been documented for active Tuberculosis (TB), an indeterminate QuantiFERON (R)-TB Gold test unless followed by a subsequent negative PPD or negative QuantiFERON(R)-TB Gold test as well as a consultation with and clearance by local infectious disease (ID) department. Recent or ongoing active bacterial, viral, fungal, or opportunistic infections requiring systemic anti-infective therapy; Evidence of current or prior infection with human immunodeficiency virus (HIV), hepatitis B [as assessed by HBsAg and anti-hepatitis B core antigen (HBc) Ab] or hepatitis C [as assessed by anti-Hepatitis C Virus (anti-HCV) Ab]; Detectable circulating EBV or Cytomegalovirus (CMV) genomes or active infection; Chronic infection that is currently being treated with suppressive anti-infective therapy, including but not limited to tuberculosis, pneumocystis, CMV, herpes zoster, and atypical mycobacteria, with the exception of historical orolabial or localized cutaneous herpes simplex infections treated with suppressive anti- viral therapy; Receipt of a live-attenuated vaccine within 12 months prior to screening; Concomitant malignancies or a history of malignancy, with the exception of completely treated basal cell carcinoma of the skin; Pregnancy; Lactating or breastfeeding; Unwilling or unable to use reliable method(s) of contraception: For females of child-bearing potential, from four weeks prior to Day 0 through 1 year after Treg dosing; For males, from the day of Treg infusion (baseline visit) to three months after Treg infusion. Use of an investigational therapeutic medication, or other biologic medications except rituximab, within the past 90 days, or 5 half-lives prior to screening, whichever is greater; Concomitant medical condition that places the subject at risk by participating in this study, including but not limited to: another severe, systemic autoimmune disease or condition (besides pemphigus) requiring systemic immunosuppressive therapy (e.g., rheumatoid arthritis, Systemic Lupus Erythematosus (SLE), systemic sclerosis, primary Sjogren's syndrome, primary vasculitis, psoriasis, multiple sclerosis, ankylosing spondylitis, and inflammatory bowel disease), or severe, progressive, or poorly controlled renal, hepatic, hematological, gastrointestinal, pulmonary, cardiac, or neurological disease, or history of significant infection or recurrent infection that, in the investigator's opinion, places the subject at risk by participating in this study, or any other concomitant medical condition that, in the investigator's opinion, places the subject at risk by participating in this study. Comorbidities requiring glucocorticoid therapy, including those which have required three or more courses of systemic glucocorticoids within the previous 12 months; Current or history within the past year of substance abuse; or Inability to comply with study and follow-up procedures.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: 1.0 x 10^8 PolyTregs<br>A single intravenous infusion of 1.0 x 10^8 PolyTregs will be administered. | Biological: Cohort 1: 1.0 x 10^8 PolyTregs<br>* Each participant will receive a target cell dose of 1.0 x 10^8 polyclonal Tregs.<br>* Other names: CD4+CD127lo/negCD25+ PolyTregs;|
| Experimental: Cohort 2: 2.5x10^8 PolyTregs<br>A single intravenous infusion of 2.5x10^8 PolyTregs will be administered. | Biological: Cohort 2: 2.5x10^8 PolyTregs<br>* Each participant will receive a target cell dose of 2.5x10^8 polyclonal Tregs.<br>* Other names: CD4+CD127lo/negCD25+ PolyTregs;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Significant Adverse Events Through Week 52 | Number of significant adverse events, defined as any related National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) version 4.03 Grade 3 or higher adverse event or any related serious adverse event (SAE). Related is defined as being possibly related or related to the ex vivo expanded autologous PolyTregs, as determined by the safety review committee. An SAE is any untoward medical occurrence that, at any dose* results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect or is medically significant. *Polyclonal Tregs: Ex Vivo Expanded Autologous CD4+CD127lo/-CD25+ Polyclonal Regulatory T Cells. | Up to Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Significant Events Through Week 156 | Number of significant adverse events, defined as any related National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) version 4.03 Grade 3 or higher adverse event or any related serious adverse event. Related is defined as being possibly related or related to the ex vivo expanded autologous PolyTregs*, as determined by the safety review committee. An SAE is any untoward medical occurrence that, at any dose* results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect or is medically significant. *Polyclonal Tregs: Ex Vivo Expanded Autologous CD4+CD127lo/-CD25+ Polyclonal Regulatory T Cells. | Up to Week 156 | 
| Number of Participants With Adverse Events (AEs) Related to Treatment, Polyclonal Tregs Infusion Through Week 52 | All adverse events (AEs) of specified grades, 3 to 5, according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03 (NCI CTCAE v4.03) as a measure of safety and toxicity of the PolyTregs infusion*. *Polyclonal Tregs: Ex Vivo Expanded Autologous CD4+CD127lo/-CD25+ Polyclonal Regulatory T Cells. | Up to Week 52 | 
| Number of Grade 3 to 5 Adverse Events (AEs) Through Week 52 | All adverse events (AEs) within specified grades, 3 to 5, according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03 (NCI CTCAE v4.03), as a measure of safety and toxicity of the PolyTregs infusion*. *Polyclonal Tregs: Ex Vivo Expanded Autologous CD4+CD127lo/-CD25+ Polyclonal Regulatory T Cells. | Up to Week 52 | 
| Number of Grade 3 to 5 Adverse Events (AEs) Through Week 156 | All adverse events (AEs) within specified grades, 3 to 5, according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03 (NCI CTCAE v4.03), as a measure of safety and toxicity of the PolyTregs infusion*. *Polyclonal Tregs: Ex Vivo Expanded Autologous CD4+CD127lo/-CD25+ Polyclonal Regulatory T Cells. | Up to Week 156 | 
| Number of Serious Adverse Events (SAEs) Through Week 156 | An SAE is any untoward medical occurrence that, at any dose* results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect or is medically significant. **Polyclonal Tregs: Ex Vivo Expanded Autologous CD4+CD127lo/-CD25+ Polyclonal Regulatory T Cells. | Up to Week 156 | 
| Number of Infection-Related Adverse Events (AEs) Through Week 156 | Safety measure. Monitoring for signs and symptoms of infection-related AEs (e.g., viral, bacterial, or fungal organism, particularly opportunistic infections). | Up to Week 156 | 
| Number of Infusion-Related Reactions Within 24 Hours of PolyTregs Infusion | Any infusion-related adverse events (AEs) Grade 1 or higher that occur within 24 hours of polyclonal Tregs* infusion. This study will grade the severity of AEs according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.03. *Polyclonal Tregs: Ex Vivo Expanded Autologous CD4+CD127lo/-CD25+ Polyclonal Regulatory T Cells. | Up to 24 hours post infusion | 
| Change From Baseline in Pemphigus Disease Area Index (PDAI) | Pemphigus Disease Area Index (PDAI) is a cutaneous and mucosal disease activity assessment performed by the investigator, based on evaluation of lesions in well-defined anatomical locations. The score is weighted for the number and size of lesions, with a score of 0 (absent) to 10 given for skin (12 body locations), scalp and mucous membrane showing disease activity (erosions/blisters or new erythema). Damage, such as post inflammatory hyperpigmentation or erythema from resolving lesion(s), are scored separately from the main score as absent (0) or present (1) for each body area or scalp resulting in a score of 0 to 12 or 0 to 1, respectively. Thus, PDAI ranges from 0 to 263, with 250 points representing disease activity (120 points for skin activity; 10 points for scalp activity; 120 points for mucosal activity) and 13 points representing disease damage. | From Baseline (Week 0) to Weeks 1, 2, 8, 12, 26, 39, 52, 78, 104, 130, and 156 | 
| Change From Baseline in Desmoglein (DSG) Autoantibody Titers | Desmoglein (DSG) autoantibodies serum levels, measured by ELISA (enzyme-linked immunosorbent assay, compared to pre PolyTregs infusion DSG autoantibody levels*. *Polyclonal Tregs: Ex Vivo Expanded Autologous CD4+CD127lo/-CD25+ Polyclonal Regulatory T Cells. | Up to Week 156 | 
| Time to Initial Flare/Relapse by Week 156 | Time from initiation of polyTregs infusion* to the the time of the appearance of ≥3 new lesions within 1 month that did not heal spontaneously within 1 week, or to the time when there was an extension of lesions that were present at the polyTregs infusion initiation. *Polyclonal Tregs: Ex Vivo Expanded Autologous CD4+CD127lo/-CD25+ Polyclonal Regulatory T Cells. | Up to Week 156 | 
| Number of Participants on a Prednisone Dose ≤10 Milligrams Per Day (mg/Day) | A measure of efficacy. This will be assessed at Weeks 12, 26, 39, 52, 78, 104, 130, and 156. | Up to Week 156 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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autologous polyclonal regulatory T cell therapy, PolyTregs, open-label, Phase 1 (safety)