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A Phase I Dose Escalation Study of B-Lymphocyte Stimulator (BLyS) Administered Subcutaneously in Patients With Selective IgA Deficiency

Phase 1
Not Enrolling
IgA Deficiency

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Trial Information

A Phase I Dose Escalation Study of B-Lymphocyte Stimulator (BLyS) Administered Subcutaneously in Patients With Selective IgA Deficiency

B Lymphocyte Stimulator (BLyS (Trademark)) is a member of the tumor necrosis factor (TNF)
superfamily of cytokines that is expressed on peripheral blood monocytes and dendritic
cells. Cellular receptors for BLyS are detected on mature immunoglobulin (Ig) expressing
B-lymphocytes. In vitro studies show that BLyS increases B cell number, Ig production,
antigen-specific immunoglobulin response, and induces production of secretory IgA.

B-cells collected from patients with Common Variable Immune Deficiency show evidence for
BLyS binding to B cells and enhanced immunoglobulin secretion.

In 28-day toxicology studies in mice, pharmacological effects were restricted to B lymphoid
tissues including B lymphocyte hyperplasia, increased splenic weight without significant
increase in spleen size, and increased immunoglobulin production. Murine models suggest
that all of the pharmacological effects are fully and rapidly reversible.

The biological profile of BLyS suggests that it may have therapeutic utility in the
treatment of immunodeficiency disorders characterized by low or absent immunoglobulin such
as selective IgA deficiency (IGA-D).

Risk that BLyS might contribute to IGA-D complications has been assessed. A series of
special in vitro and short-term in vivo studies have shown BLyS does not enhance
tumorigenicity or allergy/hypersensitivity. Enhanced autoimmunity with immune complex
formation could not be ruled out in two mouse studies in which BLyS was administered at
higher doses on multiple dosing schedules. Renal changes with glomerular protein deposits
were noted in a subset of mice treated at 0.1 and 1.0 mg/kg in the first study and 0.3 and
3.0 mg/kg in the second study. Renal changes have not been reproducible in either of 2
repeat mouse studies designed to replicate conditions on the first study. Renal changes
were not observed in the GLP toxicity study in which mice were treated for 4 weeks with BLyS
followed by a 2-week recovery period, or in an exploratory monkey study.

This study is a phase I; single-dose, open-label, non-randomized, dose escalation study of
BLyS administered subcutaneously to a total of 20 evaluable subjects with IgA-D. Each
subject will receive a single dose of BLyS.

The proposed study consists of a screening phase, a 1-day treatment phase with
pharmacokinetic sampling, day 2 and day 3 follow-up, and 1, 2, 4, 8, and 12-week acute
safety evaluations. Dose escalation to the next cohort is dependent on results of the
2-week acute safety evaluation. Autoimmunity and interim infection history will be
evaluated 4-6 weeks and 6 and 12 months. Long-term data will be collected on incidence of
malignancy for a minimum of one year.

Inclusion Criteria


Eligible subjects must meet the diagnostic criteria for IgA deficiency as defined by WHO
or PAGID/ESID (Conley, 1999).

Diagnosis of IgA-D with recurrent or chronic sinopulmonary infection or chronic

Serum IgA at least 2 standard deviations below the mean at screening.

Eligible patients will be at least 18 years of age.

Liver function tests (SGOT, SGPT, alkaline phosphatase, total bilirubin) within 1.25 x
upper limit of normal.

Serum creatinine within normal limits.

Patients must be able to understand and sign an informed consent form.


A history of malignancy (other than adequately treated in situ carcinoma or non-melanotic
skin cancer).

Active clinically-significant autoimmune manifestations within 2 years of study entry; any
history of IgA nephropathy or Henoch-Schonlein purpura.

Pre-existing renal disease; proteinuria greater than trace at screening.

Symptomatic cardiac disease (greater than grade 1 NCI CTC) at screening. Patients with
adequately treated well-controlled hypertension or minor arrythmias are eligible.

Pulmonary disease requiring treatment, bronchiectasis on baseline chest x-ray or FEV1 less
than 75% normal limits at baseline evaluation. Patients with adequately treated
well-controlled asthma are eligible.

Splenomegaly associated with cytopenias.

Significant cytopenias: Anemia (Hct less than 30%); Neutropenia (ANC less than
1500/microL); Thrombocytopenia (Platelets less than 75,000/mm(3)).

Biopsy-proven granulomatous disease.

B-lymphocyte count at screening less than 50/microL.

Use immune-based therapies (other than IVIG) such as chronic corticosteroid use, growth
factors or other immune-modulating drugs within 4 weeks of screening (inhaled
corticosteroids are permitted).

Pregnant female or nursing mother. (All females of childbearing potential must have had a
negative blood or urine pregnancy test at screening. Over the course of the study, all
female subjects must have practiced a method of contraception with greater than 90%
reliability, or be sterile or postmenopausal.)

Participation in any clinical trial involving investigational or conventional drugs within
30 days of screening.

Known active hepatitis (testing not required for study entry).

Type of Study:


Study Design:

Endpoint Classification: Safety Study, Primary Purpose: Treatment


United States: Federal Government

Study ID:




Start Date:

October 2001

Completion Date:

August 2004

Related Keywords:

  • IgA Deficiency
  • Immunodeficiency
  • Primary
  • Cancer
  • Genetics
  • IGA Deficiency
  • Immune Deficiency
  • IgA Deficiency



National Cancer Institute (NCI) Bethesda, Maryland  20892