Phase 2 N=9 Treatment

Lymphocyte Depletion and Stem Cell Transplantation to Treat Severe Systemic Lupus Erythematosus

Lupus Erythematosus, Systemic

Bottom Line

View on ClinicalTrials.gov: NCT00076752 ↗

Enrolled (actual)

Serious AEs

88.9%

Results posted

Jun 2014

Primary outcome: Primary: Relapse-free Complete Clinical Response — 54 Months

Study Design & Population

Study type: Interventional
Phase: Phase 2
Interventions: fludarabine phosphate (Drug); cyclophosphamide (Drug); Rituxan (rituximab) (Biological); filgrastim (Biological); methylprednisolone (Drug); immunologic technique (Other); laboratory biomarker analysis (Other); autologous hematopoietic stem cell transplantation (Procedure); Diphenhydramine (Drug); Mesna (Drug)
Age: Pediatric, Adult · 15+ yrs
Sex: All
Sponsor: National Cancer Institute (NCI)
Primary completion: Oct 2013

Outcome Measures

Outcome	Result	p-value
PRIMARY Relapse-free Complete Clinical Response	54	—
SECONDARY Number of Participants With Adverse Events	8	—
SECONDARY Anti-Nuclear Antibody	5.4; 4.7; 3.7; 3.2; 2.7; 2.6	—
SECONDARY Extractable Nuclear Antigen (ENA)	66.9; 64.8; 61.5; 58.5; 51.3; 57.2	—
SECONDARY Anti-Double Stranded Deoxyribonucleic Acid (DNA) Antibody	17.3; 8.8; 0; 0; 0; 0	—
SECONDARY Anti-Smith-Ribonuclear Protein Antibody	49; 51.6; 31.5; 29.8; 28.5; 20	—
SECONDARY White Blood Cells	6.89; 0.47; 10.32; 3.84; 4.21; 5.81	—
SECONDARY Absolute Neutrophil Count	5.66; 0.45; 9.11; 2.72; 2.78; 3.44	—
SECONDARY Absolute Lymphocyte Count	0.54; 0.0065; 0.42; 0.53; 0.82; 1.75	—
SECONDARY Platelet Count	251; 113; 166; 187; 170; 226	—
SECONDARY Cluster of Differentiation 3 (CD3) + Cells	2.99; 239.47; 435.97; 699.47; 1493.29; 1678.76	—
SECONDARY Cluster of Differentiation 4 (CD4) + Cells	2.58; 103.37; 112.8; 316.25; 702.87; 958.03	—
SECONDARY Cluster of Differentiation 8 (CD8) + Cells	0.34; 138.68; 318.47; 334.91; 736.67; 674.69	—
SECONDARY Cluster of Differentiation 19 (CD19) + Cells	0.01; 0.23; 6.7; 45.32; 142.69; 246.83	—
SECONDARY Natural Killer Cells	0.03; 117.06; 116.57; 123.18; 158.9; 115.18	—
SECONDARY Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)	4.25; 4.13; 3.63; 1.6; 0; 0	—

Summary

This study will examine a new approach to treating patients with severe systemic lupus erythematosus (SLE) that involves collecting stem cells (cells produced by the bone marrow that develop into blood cells) from the patient, completely shutting down the patient's immune system, and then giving back the patient's stem cells. SLE is a chronic, inflammatory disorder of the immune system that can affect many organs. It is called an autoimmune disease because the patient's lymphocytes (white blood cells that normally protect against invading organisms), go out of control and attack the body's own tissues. Patients between 15 and 40 years of age with severe SLE affecting a major organ that is resistant to standard treatment may be eligible for this study. Candidates are screened with a medical history and physical examination, blood and urine tests, skin tuberculin test, and radiology studies to evaluate the extent of disease. They have endocrinology, nutrition, dental, and social work consultations, ultrasound or MUGA (multi-gated acquisition scan) scan heart imaging, electrocardiogram and lung function tests, bone marrow biopsy, and lymph node aspirate. Depending on which organs are affected, patients may have additional tests, such as lumbar puncture (spinal tap), kidney or lung biopsy, MRI (magnetic resonance imaging) of the brain and spinal cord, and PET (positron emission tomography) scan. They also complete quality of life questionnaires and have disability functional testing and neurocognitive (thinking) assessments. Participants have a central venous line (plastic tube) inserted into a neck or chest vein for administering stem cells and medicines and for drawing blood. They undergo seven apheresis procedures during the course of the study to collect stem cells for transplant and for research. For apheresis, whole blood is collected through a needle in an arm vein and directed to a cell-separating machine where the white cells are extracted and the rest of the blood is returned to the patient through the same needle. Patients are primed with three medications (methylprednisolone, rituximab, and cyclophosphamide) through the central line to help control the disease. In addition, a medication called G-CSF (growth colony stimulating factor) is injected under the skin for several days to boost production of stem cells. After enough stem cells have been collected for transplantation (infusion through the central line), patients are admitted to the hospital for an 8-day conditioning regimen followed by transplantation. The conditioning treatment consists of rituximab, fludarabine, and cyclophosphamide to eliminate all the white blood cells from the blood and bone marrow. The stem cells are then infused and the patient is closely monitored by a team of physicians and nurses. When the stem cells have engrafted, the bone marrow has recovered, and the patient feels well enough - usually 2 to 3 weeks after transplant - the patient is discharged from the hospital. Prednisone tapering begins as soon as feasibly possible, but no later then 28 days after transplant. Patients return to the National Institutes of Health (NIH) Clinical Center for frequent follow-up visits during the first 2 to 3 months following transplant. The time between visits is then extended to once every 3 months the first year, then every 6 months the second year, and then at least yearly for 5 years after the transplant. These visits include a physical examination, blood and urine tests, lumbar puncture (if there is central nervous system involvement), other appropriate biopsies and tests as needed to monitor the patient's health, short apheresis procedures to collect blood for research purposes, and quality of life questionnaires. Some select procedures will be optional. Bone marrow biopsies and lymph node aspirates are done at beginning and at 6, 12, and 24 months after transplant. PET scans are done at 1, 6, 12, and 24 months. ...

Eligibility Criteria

-INCLUSION CRITERIA

Age 15-40 years
Must fulfill at least 4 of the following 11 criteria for systemic lupus erythematous (SLE) as defined by the American College of Rheumatology:

-Malar rash. Fixed erythema, flat or raised, over the malar eminences, tending to spare the nasolabial folds.

Discoid rash. Erythematous raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring may occur in older lesions.
Photosensitivity. Skin rash as a result of unusual reaction to sunlight, by patient history or physician observation.
Oral ulcers. Oral or nasopharyngeal ulcerations, usually painless, observed by a physician.
Arthritis. Nonerosive arthritis involving two or more peripheral joints, characterized by tenderness, swelling, or effusion.
Serositis. a.) Pleuritis - convincing history of pleuritic pain or rub heard by a physician or evidence of pleural effusion

b.) Pericarditis - documented by electrocardiogram (ECG) or rub or evidence of pericardial effusion

-Renal disorder. a.) Persistent proteinuria greater than 0.5 grams per day or greater than 3+ if quantitation not performed

b.) Cellular casts - may be red cell, hemoglobin, granular, tubular, or mixed.

Neurologic disorder. a.) Seizures - in the absence of offending drugs or known metabolic derangements; eg, uremia, ketoacidosis, or electrolyte imbalance

b.) Psychosis - in the absence of offending drugs or known metabolic derangements; eg, uremia, ketoacidosis, or electrolyte imbalance

-Hematologic disorder. a.) Hemolytic anemia - with reticulocytosis

b.) Leukopenia - less than 4000/ L total on two or more occasions

c.) Lymphopenia - less than 1500/ L on two or more occasions

d.) Thrombocytopenia - less than 100,000/ L in the absence of offending drugs

Immunologic disorder. a.) Anti-deoxyribonucleic acid (DNA): antibody to native DNA in abnormal titer

b.) Anti-SM: presence of antibody to SM nuclear antigen

c.) Positive finding of antiphospholipid antibodies based on (1) an abnormal serum level of immunoglobulin G (IgG) or immunoglobulin M (IgM) anti-cardiolipin antibodies, (2) a positive test result for lupus anticoagulant using a standard method, or (3) false positive serologic test for syphilis known to be positive for at least 6 months and confirmed by Treponema Pallidum immobilization or fluorescent treponemal antibody absorption test

-Antinuclear antibodies. An abnormal titer of ANAs by immunofluorescence or an equivalent assay at any point in time in the absence of drugs known to be associated with drug-induced lupus syndrome.

Have severe and active lupus, refractory to immunosuppressive therapy, defined as one of the following (a-d):

a.Nephritis: Biopsy proven Diffuse Proliferative Glomerulonephritis (World Health Organization (WHO) Class IV) with or without superimposed membranous changes

i.Active disease:

A kidney biopsy within three months of enrollment showing active WHO Class IV disease. Activity will be determined based on the presence of endocapillary cellular proliferation compromising the capillary loops or cellular crescents or necrosis on light microscopy or subendothelial deposits on electron microscopy.
If a biopsy is contraindicated patients can be enrolled if they had a previous biopsy showing Diffuse Proliferative Glomerulonephritis (WHO Class IV) and at the time of enrollment have all of the following:
Proteinuria greater than 1gm/day
Active urine sediment defined as hematuria (greater than 10 red blood cell (RBC)/hpf (high power field) on a nephrology urinalysis of a 50 mL urine sample) with dysmorphic RBC and/or cellular casts on a nephrology urinalysis of a 50 mL urine sample
Low C3 (less than 69 mg/dL) and/or elevated dsDNA antibodies (greater than 25EU)
Need for prednisone greater than 20 mg/day due to increased renal activity after at least 6 months of cyclophosphamide.

ii. Treatment resistant:

Patients with active disease after

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Data sourced from ClinicalTrials.gov (NCT00076752). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.