Autologous Polyclonal Tregs for Lupus

Phase 1

Terminated

Conditions: Lupus Erythematosus, Cutaneous
Lupus Erythematosus, Discoid
Lupus Erythematosus, Systemic

Interventions: Biological: Ex vivo Expanded Human Autologous Polyclonal Regulatory T Cells

Registration Number: NCT02428309

Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Brief Summary: The primary purpose of this Phase 1 study is to evaluate the safety, tolerability, and effect of 3 different doses of Treg therapy in adults with skin (cutaneous) involvement of their lupus. Targeting cutaneous disease offers the ability to control background therapy, readily detect clinical effects, and perform research analyses not only in blood but also skin. Safety, disease activity, and mechanism of Tregs will be evaluated. The intent is to support dose selection for a future larger efficacy trial in lupus.

Detailed Description: The investigational therapy in this trial, regulatory T cells (Tregs), is evaluating an alternative to traditional immunosuppressive therapies for the treatment of systemic lupus erythematosus (SLE, lupus). Too frequently, aggressive therapies are inadequate in the control of the disease and have potent side effects and complications. The collection and expansion of one's own T cells harnesses a naturally occurring regulatory mechanism to restore self-tolerance in people with lupus. Tregs are a specialized subset of T cells that function to control the immune response. Studies have shown that in active lupus, the numbers and function of Treg cells are significantly decreased, which contributes to an overactive immune system and an increase in disease activity. The hope is that these naturally occurring Treg cells can be used for the treatment of autoimmune diseases, including lupus.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 1

Inclusion Criteria

Ability to provide informed consent.
Diagnosis of SLE by American College of Rheumatology (ACR) criteria or biopsy proven primary cutaneous lupus.
Presence of ≥ 2 active cutaneous lupus lesions based on (1) visual morphology and (2) at least a grade 2 erythema on CLASI activity score. Histopathologic confirmation is required unless the active lesions are of the same morphology to previously histologically proven cutaneous lupus lesions.
The cutaneous lupus lesions must include any of the following subtypes:
- Acute cutaneous lupus including maculopapular lupus rash and photosensitive lupus rash,
- Subacute cutaneous lupus,
- Chronic cutaneous lupus including discoid lupus and hypertrophic (verrucous) lupus,
- Lupus timidus
Positive test for Epstein-Barr virus (EBV) antibody.
Adequate venous access to support draw of 400 mL whole blood and infusion of investigational therapy.

Exclusion Criteria

New onset of cutaneous lupus which has not been treated with broad spectrum sunscreen (UVA and UVB) in combination with either antimalarials or another systemic medication for at least 3 months.
Prednisone dose > 15mg/day within the 30 days prior to screening.
Addition of a new medication, or change in the dose of any background medication, used to treat any aspect of SLE. Specifically:
- addition or change in systemic glucocorticoids, antimalarials, methotrexate, mycophenolate mofetil, mycophenolic acid, azathioprine, cyclosporine, tacrolimus, thalidomide, lenalidomide, dapsone, acitretin, or isotretinoin within 90 days prior to screening
- treatment with cyclophosphamide within 90 days prior to screening.
Doses of background medications at Screening visit:
- hydroxychloroquine > 400 mg/day,
- chloroquine > 250 mg/day,
- quinacrine >100 mg/day,
- methotrexate > 25 mg/week,
- mycophenolate mofetil (MMF)> 3000 mg/day,
- mycophenolic acid > 720 mg/day BID,
- azathioprine > 200 mg/day,
- cyclosporine > 5 mg/day divided BID,
- tacrolimus > 6 mg/day
- thalidomide > 300 mg/day,
- lenalidomide > 10 mg/day,
- dapsone > 250 mg/day,
- acitretin > 50 mg/d (or > 1 mg/kg/day),
- isotretinoin > 120 mg/d (or > 2 mg/kg/day).
Intravenous immunoglobulin (IVIG), plasmapheresis, or leukopheresis within the 90 days prior to screening.
Use of rituximab within the 12 months prior to screening.
Change in dosing frequency, concentration, or applied surface area of topical steroids, tacrolimus, and/or pimecrolimus within 4 weeks prior to screening.
Active severe central nervous system lupus.
SELENA-SLEDAI's seizure, psychosis, organic brain syndrome, visual disturbance,cranial nerve disorder, lupus headache, cerebrovascular accident (CVA), vasculitis,arthritis, myositis, mucosal ulcers, pleurisy, pericarditis, and fever scores > 8 total.
Active lupus nephritis (spot protein / creatinine ratio > 1.0 mg/mg).
End stage renal disease (estimated glomerular filtration rate [eGFR] < 20 ml/min/1.73m^2 using the CKD-EPI equation [53]).
Drug induced lupus.
Hemoglobin < 10 g/dL.
White blood cell (WBC) count < 2,500/ mm^3 (equivalent to < 2.5 x10^9/L).
Lymphocyte count < 625/mm^3 (equivalent to < 0.625 x10^9/L).
Absolute neutrophil count < 1,500/mm3 (equivalent to < 1.5 x10^9/L).
Platelets < 75,000/mm^3 (equivalent to < 75 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.
Active bacterial, viral, fungal, or opportunistic infections requiring systemic antiinfective therapy.
Presence of positive purified protein derivative tuberculin skin test (PPD, > 5mm induration [regardless of Bacille Calmette Guerin (BCG) vaccine administration]) or positive or indeterminate QuantiFERON(R)-TB Gold In-Tube Test (QFT-G_IT) at screening.
Evidence of infection with human immunodeficiency virus (HIV), hepatitis B (as assessed by HBsAg and anti-HBc) or hepatitis C.
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.
Herpes simplex virus infection requiring chronic, suppressive therapy with an anti-viral medication.
Receipt of a live-attenuated vaccine within 12 months prior to screening.
Concomitant malignancies or a history of malignancy, with the exception of adequately treated basal and squamous cell carcinoma of the skin, or carcinoma in situ of the cervix.
Pregnancy.
Breastfeeding.
Unwilling or unable to use reliable method(s) of contraception from four weeks prior to Day 0 throughout three months after Treg dosing (males) or for two years after Treg dosing (females). Note: investigators of female participants of childbearing potential on concurrent MMF, and those participants themselves, whether or not they plan to become pregnant, are strongly encouraged to participate in Mycophenolate Risk Evaluation and Mitigation Strategy (REMS).
Use of an experimental therapeutic agent within the calendar year prior to screening.
Use of biologic medications other than rituximab within the 90 days or 5 half-lives,whichever is greater, prior to screening.
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 lupus) requiring systemic immunosuppressive therapy (e.g., rheumatoid arthritis, 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, either related or unrelated to SLE, or
- history of significant infection or recurrent infection that, in the investigator's opinion, places the subject at risk by participating in this study
- 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.
Inability to comply with study and follow-up procedures.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Low Dose Treg Cohort	Ex vivo Expanded Human Autologous Polyclonal Regulatory T Cells	3-6 participants will receive a single infusion of 1 x 10\^ 8 autologous polyclonal Tregs (ex vivo selected and expanded)
Medium Dose Treg Cohort	Ex vivo Expanded Human Autologous Polyclonal Regulatory T Cells	Sequential dose escalation, 3-6 subjects will receive a single infusion of 4 x 10\^ 8 autologous polyclonal Tregs (ex vivo selected and expanded)
High Dose Treg Cohort	Ex vivo Expanded Human Autologous Polyclonal Regulatory T Cells	Sequential dose escalation, 3-6 participants will receive a single infusion of 16 x 10\^ 8 autologous polyclonal Tregs (ex vivo selected and expanded)

Primary Outcome Measures

Name	Time	Method
Number of Significant Adverse Events (AEs) Through Week 48	From time of signed informed consent to Week 48	A significant adverse event is any related National Cancer Institute's Common Terminology Criteria for Adverse Events, Version 4.0 Grade 3 or higher AE or any related serious adverse event. Related is defined as being possibly, probably, or definitely related to the ex vivo expanded autologous PolyTregs, as determined by the safety review committee.

Secondary Outcome Measures

Name	Time	Method
Number of Lupus Flares Through Week 152 by Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) and Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) Criteria	From time of signed informed consent to Week 152	An activity score increase of ≥4 CLASI points defines a flare. A mild/moderate flare includes at least one of the following SELENA-SLEDAI criteria: Increase in the SLEDAI Score of ≥3 points, new or worse discoid, photosensitive, profundus, cutaneous vasculitis, bullous lupus, nasopharyngeal ulcers, pleuritic, pericarditis, arthritis, fever attributable to SLE; increase in prednisone (\<0.5 mg/kg/day); added NSAID or Plaquenil; increase in PhGA (\<2.5 \[on a 3.0 indexed VAS scale\]). A severe flare includes at least one of the following SELENA-SLEDAI criteria: Increase of \>12 in the SLEDAI Score; new or worse CNS-SLE, vasculitis, nephritis, myositis, platelet count \<60,000/mm\^3, hemolytic anemia with hemoglobin \<7% or decrease in hemoglobin \>3%; prednisone \>0.5 mg/kg/day; new Cyclophosphamide, Azathioprine, Methotrexate, Mycophenolate Mofetil, or hospitalization attributable to SLE; increase in PhGA to \>2.5.
Number of Significant Adverse Events (AEs) Through Week 152	From time of signed informed consent to Week 152	A significant adverse event is any related National Cancer Institute's Common Terminology Criteria for Adverse Events, Version 4.0 Grade 3 or higher AE or any related serious adverse event. Related is defined as being possibly, probably, or definitely related to the ex vivo expanded autologous PolyTregs, as determined by the safety review committee.
Change From Baseline: Alkaline Phosphatase (ALK), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST)	Baseline (Visit 0) and Weeks 4, 12, 48, and 152	Change=Post Baseline value minus Baseline value. A positive difference reflects an increased laboratory parameter value over time; a negative difference reflects a decreased laboratory parameter value over time. Normal laboratory values are based on subject age, gender, and the specific laboratory methods that were used to determine the lab values.
Change From Baseline in mg/dL: Total Bilirubin, Creatinine	Baseline (Visit 0) and Weeks 4, 12, 48, and 152	Change=Post Baseline value minus Baseline value. A positive difference reflects an increased laboratory parameter value over time; a negative difference reflects a decreased laboratory parameter value over time. Normal laboratory values depend on a subject age, gender, and the specific laboratory methods that were used to determine the lab values.
Change From Baseline in Physician's Global Assessment (PhGA)	Baseline (Visit 0) and Weeks 12, 24, 36, 48, 100, 126, and 152	The physician's global assessment (PhGA) is a visual analog 3-inch scale in the SELENA-SLEDAI that is scored from 0 to 3 by the physician. A score of 0 corresponds to no lupus disease activity and a score of 3 corresponds to severe disease activity. A positive change from baseline indicates more disease activity.
Number of Grade 3 or Higher Adverse Events (AEs) Through Week 152	From time of signed informed consent to Week 152	Adverse events (AEs) Grade 3 or higher were graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events, Version 4.0.
Number of Infection-Related Adverse Events (AEs) Through Week 152	From time of signed informed consent to Week 152	If the adverse event was believed to be caused by a viral, bacterial, or fungal organism, regardless of whether it was treated with antibiotics or not, then it was classified as infection-related.
Number Infusion-Related Adverse Events (AEs) Within 24 Hours of Infusion	From time of infusion to 24 hours post infusion	Any infusion-related adverse events Grade 1 or higher within 24 hours of polyclonal Treg infusion. This study graded the severity of adverse events according to the National Cancer Institute's Common Terminology Criteria for Adverse Events, Version 4.0.
Change From Baseline in Cell Counts: White Blood Cells (WBC), Total Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils, Platelets	Baseline (Visit 0) and Weeks 4, 12, 48, and 152	Change=Post Baseline value minus Baseline value. A positive difference reflects an increased laboratory parameter value over time; a negative difference reflects a decreased laboratory parameter value over time. Normal laboratory values depend on a subject age, gender, and the specific laboratory methods that were used to determine the lab values.
Change From Baseline Red Blood Cell Count	Baseline (Visit 0) and Weeks 4, 12, 48, and 152	Change=Post Baseline value minus Baseline value. A positive difference reflects an increased laboratory parameter value over time; a negative difference reflects a decreased laboratory parameter value over time. Normal laboratory values depend on a subject age, gender, and the specific laboratory methods that were used to determine the lab values.
Change From Baseline in SELENA-SLEDAI Total Score	Baseline (Visit 0) and Weeks 12, 24, 36, 48, 100, 126, and 152	The Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus (SLE) Disease Activity Index (SELENA-SLEDAI) score is a weighted scale score ranging from 0 to 105 based on the presence or absence of 24 manifestations of SLE. The SELENA-SLEDAI assesses disease activity for 10 days prior to and including the day of assessment. Positive change in the SELENA-SLEDAI score indicates increased disease activity.
Change From Baseline in Patient's Global Assessment (PGA)	Baseline (Visit 0) and Weeks 12, 24, 36, 48, 100, 126, and 152	The global assessment (PGA) is a visual 3-inch analog scale from 0 to 3 in which the participant marks the scale according to perceived disease activity. A score of 0 corresponds to no lupus disease activity and a score of 3 corresponds to severe disease activity. A positive change from baseline indicates more disease activity.
Change From Baseline in g/dL: Albumin, Hemoglobin	Baseline (Visit 0) and Weeks 4, 12, 48, and 152	Change=Post Baseline value minus Baseline value. A positive difference reflects an increased laboratory parameter value over time; a negative difference reflects a decreased laboratory parameter value over time. Normal laboratory values depend on a subject age, gender, and the specific laboratory methods that were used to determine the lab values.
Change From Baseline in Serum C3 Complement Levels	Baseline (Visit 0) and Weeks 12, 24, 36, 48, 100, 126, and 152	C3 is a blood test that measures the activity of the complement component 3 (C3) protein. The normal C3 range is 71 to 159 mg/dL. Those with active systemic lupus erythematosus (SLE) may have a lower-than-normal level of C3. A decrease in C3 level over time may indicate SLE disease activity.
Change From Baseline in Serum C4 Complement Levels	Baseline (Visit 0) and Weeks 12, 24, 36, 48, 100, 126, and 152	C4 is a blood test that measures the activity of the complement component 4 (C4) protein. The normal range is 13 to 30 mg/dL. Individuals with active systemic lupus erythematosus (SLE) may have a lower-than-normal level of C4. A decrease in C4 level over time may indicate disease activity.
Change From Baseline in mmol/L: Potassium, Sodium, Chloride	Baseline (Visit 0) and Weeks 4, 12, 48, and 152	Change=Post Baseline value minus Baseline value. A positive difference reflects an increased laboratory parameter value over time; a negative difference reflects a decreased laboratory parameter value over time. Normal laboratory values depend on a subject age, gender, and the specific laboratory methods that were used to determine the lab values.
Change From Baseline in mm/hr: Sedimentation Rate (ESR)	Baseline (Visit 0) and Weeks 4, 12, 48, and 152	Change=Post Baseline value minus Baseline value. A positive difference reflects an increased laboratory parameter value over time; a negative difference reflects a decreased laboratory parameter value over time. Normal laboratory values depend on a subject age, gender, and the specific laboratory methods that were used to determine the lab values.
Change From Baseline in Anti-dsDNA Antibody Titers	Baseline ( Visit 0) and Weeks 12, 24, 36, 48, 100, 126, and 152	Double-stranded DNA is one of multiple diagnostic tests for SLE and high levels may be associated with disease activity. The positive range is based on the normal range from the local laboratory. A positive change from baseline value indicates the detection of autoantibodies to double-stranded DNA.
Change From Baseline in Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) Activity Score	Baseline (Visit 0) and Weeks 12, 24, 36, 48, 100, 126, and 152	The Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) is a validated, physician-based assessment tool used to measure cutaneous lupus severity. Severity is calculated based on disease activity (erythema and scale) and damage (dyspigmentation and scarring) for the cumulative areas of involved skin. Severity categories based on the CLASI activity score are as follows: mild (0-9), moderate (10-20), and severe (21-70). A 4-point or 20% change in the CLASI activity score identifies a clinically meaningful change. A 4-point increase in the CLASI activity score indicates a flare.