Clinical trial NCT02428309: Autologous Polyclonal Tregs for Lupus
Official title: 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)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Lupus Erythematosus, Cutaneous
Lupus Erythematosus, Discoid
Lupus Erythematosus, Systemic
Keywords: active cutaneous lupus
systemic lupus erythematosus (SLE)
autologous polyclonal regulatory T cell Therapy
polyclonal Tregs for treatment of lupus
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Autoimmunity Centers of Excellence
First posted: 2015-04-28
Enrollment: 1
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Number of Significant Adverse Events (AEs) Through Week 48
timeFrame: From time of signed informed consent to Week 48
Secondary outcomes:
measure: Number of Significant Adverse Events (AEs) Through Week 152
timeFrame: From time of signed informed consent to Week 152
measure: Number of Grade 3 or Higher Adverse Events (AEs) Through Week 152
timeFrame: From time of signed informed consent to Week 152
measure: Number of Infection-Related Adverse Events (AEs) Through Week 152
timeFrame: From time of signed informed consent to Week 152
measure: 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
timeFrame: From time of signed informed consent to Week 152
measure: Number Infusion-Related Adverse Events (AEs) Within 24 Hours of Infusion
timeFrame: From time of infusion to 24 hours post infusion
measure: Change From Baseline: Alkaline Phosphatase (ALK), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST)
timeFrame: Baseline (Visit 0) and Weeks 4, 12, 48, and 152
measure: Change From Baseline in g/dL: Albumin, Hemoglobin
timeFrame: Baseline (Visit 0) and Weeks 4, 12, 48, and 152
measure: Change From Baseline in mg/dL: Total Bilirubin, Creatinine
timeFrame: Baseline (Visit 0) and Weeks 4, 12, 48, and 152
measure: Change From Baseline in mmol/L: Potassium, Sodium, Chloride
timeFrame: Baseline (Visit 0) and Weeks 4, 12, 48, and 152
measure: Change From Baseline in Cell Counts: White Blood Cells (WBC), Total Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils, Platelets
timeFrame: Baseline (Visit 0) and Weeks 4, 12, 48, and 152
measure: Change From Baseline Red Blood Cell Count
timeFrame: Baseline (Visit 0) and Weeks 4, 12, 48, and 152
measure: Change From Baseline in mm/hr: Sedimentation Rate (ESR)
timeFrame: Baseline (Visit 0) and Weeks 4, 12, 48, and 152
measure: Change From Baseline in Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) Activity Score
timeFrame: Baseline (Visit 0) and Weeks 12, 24, 36, 48, 100, 126, and 152
measure: Change From Baseline in SELENA-SLEDAI Total Score
timeFrame: Baseline (Visit 0) and Weeks 12, 24, 36, 48, 100, 126, and 152
measure: Change From Baseline in Patient's Global Assessment (PGA)
timeFrame: Baseline (Visit 0) and Weeks 12, 24, 36, 48, 100, 126, and 152
measure: Change From Baseline in Physician's Global Assessment (PhGA)
timeFrame: Baseline (Visit 0) and Weeks 12, 24, 36, 48, 100, 126, and 152
measure: Change From Baseline in Anti-dsDNA Antibody Titers
timeFrame: Baseline ( Visit 0) and Weeks 12, 24, 36, 48, 100, 126, and 152
measure: Change From Baseline in Serum C3 Complement Levels
timeFrame: Baseline (Visit 0) and Weeks 12, 24, 36, 48, 100, 126, and 152
measure: Change From Baseline in Serum C4 Complement Levels
timeFrame: Baseline (Visit 0) and Weeks 12, 24, 36, 48, 100, 126, and 152
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
Study officials:
affiliation: University of California, San Francisco
name: Maria Dall'Era, MD
role: STUDY_CHAIR
affiliation: University of California, San Francisco
name: Anna Haemel, MD
role: STUDY_CHAIR
affiliation: University of California, San Francisco
name: Jeffrey Bluestone, PhD
role: STUDY_CHAIR
affiliation: University of California, San Francisco
name: Michael Rosenblum, MD, PhD
role: STUDY_CHAIR
affiliation: University of California, San Francisco
name: David Wofsy, MD
role: STUDY_CHAIR
References: