Autologous Polyclonal Tregs for Lupus

A Phase I, Open-Label, Dose Escalation Trial Exploring the Safety and Tolerability of Autologous Polyclonal Regulatory T Cell Therapy in Adults With Active Cutaneous Lupus (ALE08)

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.

Study Overview

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.

Study Type

Interventional

Enrollment (Actual)

1

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

    • California
      • San Francisco, California, United States, 94143
        • University of California, San Francisco

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 60 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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 Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Low Dose Treg Cohort
3-6 participants will receive a single infusion of 1 x 10^ 8 autologous polyclonal Tregs (ex vivo selected and expanded)
Other Names:
  • Ex vivo Expanded Autologous CD4+CD127lo/-CD25+ Polyclonal Regulatory T Cells
Experimental: Medium Dose Treg Cohort
Sequential dose escalation, 3-6 subjects will receive a single infusion of 4 x 10^ 8 autologous polyclonal Tregs (ex vivo selected and expanded)
Other Names:
  • Ex vivo Expanded Autologous CD4+CD127lo/-CD25+ Polyclonal Regulatory T Cells
Experimental: High Dose Treg Cohort
Sequential dose escalation, 3-6 participants will receive a single infusion of 16 x 10^ 8 autologous polyclonal Tregs (ex vivo selected and expanded)
Other Names:
  • Ex vivo Expanded Autologous CD4+CD127lo/-CD25+ Polyclonal Regulatory T Cells

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Significant Adverse Events (AEs) Through Week 48
Time Frame: 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.
From time of signed informed consent to Week 48

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Significant Adverse Events (AEs) Through Week 152
Time Frame: 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.
From time of signed informed consent to Week 152
Number of Grade 3 or Higher Adverse Events (AEs) Through Week 152
Time Frame: 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.
From time of signed informed consent to Week 152
Number of Infection-Related Adverse Events (AEs) Through Week 152
Time Frame: 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.
From time of signed informed consent to Week 152
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
Time Frame: 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.
From time of signed informed consent to Week 152
Number Infusion-Related Adverse Events (AEs) Within 24 Hours of Infusion
Time Frame: 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.
From time of infusion to 24 hours post infusion
Change From Baseline: Alkaline Phosphatase (ALK), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST)
Time Frame: 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.
Baseline (Visit 0) and Weeks 4, 12, 48, and 152
Change From Baseline in g/dL: Albumin, Hemoglobin
Time Frame: 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.
Baseline (Visit 0) and Weeks 4, 12, 48, and 152
Change From Baseline in mg/dL: Total Bilirubin, Creatinine
Time Frame: 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.
Baseline (Visit 0) and Weeks 4, 12, 48, and 152
Change From Baseline in mmol/L: Potassium, Sodium, Chloride
Time Frame: 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.
Baseline (Visit 0) and Weeks 4, 12, 48, and 152
Change From Baseline in Cell Counts: White Blood Cells (WBC), Total Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils, Platelets
Time Frame: 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.
Baseline (Visit 0) and Weeks 4, 12, 48, and 152
Change From Baseline Red Blood Cell Count
Time Frame: 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.
Baseline (Visit 0) and Weeks 4, 12, 48, and 152
Change From Baseline in mm/hr: Sedimentation Rate (ESR)
Time Frame: 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.
Baseline (Visit 0) and Weeks 4, 12, 48, and 152
Change From Baseline in Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) Activity Score
Time Frame: 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.
Baseline (Visit 0) and Weeks 12, 24, 36, 48, 100, 126, and 152
Change From Baseline in SELENA-SLEDAI Total Score
Time Frame: 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.
Baseline (Visit 0) and Weeks 12, 24, 36, 48, 100, 126, and 152
Change From Baseline in Patient's Global Assessment (PGA)
Time Frame: 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.
Baseline (Visit 0) and Weeks 12, 24, 36, 48, 100, 126, and 152
Change From Baseline in Physician's Global Assessment (PhGA)
Time Frame: 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.
Baseline (Visit 0) and Weeks 12, 24, 36, 48, 100, 126, and 152
Change From Baseline in Anti-dsDNA Antibody Titers
Time Frame: 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.
Baseline ( Visit 0) and Weeks 12, 24, 36, 48, 100, 126, and 152
Change From Baseline in Serum C3 Complement Levels
Time Frame: 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.
Baseline (Visit 0) and Weeks 12, 24, 36, 48, 100, 126, and 152
Change From Baseline in Serum C4 Complement Levels
Time Frame: 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.
Baseline (Visit 0) and Weeks 12, 24, 36, 48, 100, 126, and 152

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Study Chair: Maria Dall'Era, MD, University of California, San Francisco
  • Study Chair: Anna Haemel, MD, University of California, San Francisco
  • Study Chair: Jeffrey Bluestone, PhD, University of California, San Francisco
  • Study Chair: Michael Rosenblum, MD, PhD, University of California, San Francisco

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

August 27, 2015

Primary Completion (Actual)

September 2, 2016

Study Completion (Actual)

October 3, 2018

Study Registration Dates

First Submitted

April 23, 2015

First Submitted That Met QC Criteria

April 23, 2015

First Posted (Estimate)

April 28, 2015

Study Record Updates

Last Update Posted (Actual)

November 12, 2019

Last Update Submitted That Met QC Criteria

October 22, 2019

Last Verified

October 1, 2019

More Information

Terms related to this study

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Yes

IPD Plan Description

The plan is to share participant level data and additional relevant materials in the Immunology Database and Analysis Portal (ImmPort), a long-term archive of clinical and mechanistic data from DAIT-funded grants and contracts. Currently: study in progress-no data sharing.

IPD Sharing Time Frame

The aim is to share data available to the public within 24 months upon completion of the study.

IPD Sharing Access Criteria

Will be available to the public.

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Lupus Erythematosus, Systemic

Clinical Trials on Ex vivo Expanded Human Autologous Polyclonal Regulatory T Cells

3
Subscribe