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Combination of Cyclophosphamide and Fludarabine for Lupus Nephritis: Tolerance, Toxicity, Efficacy and Effects on B and T Lymphocyte Regeneration

Phase 1
Not Enrolling
Glomerulonephritis, Lupus Nephritis, Systemic Lupus Erythematosus

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Trial Information

Combination of Cyclophosphamide and Fludarabine for Lupus Nephritis: Tolerance, Toxicity, Efficacy and Effects on B and T Lymphocyte Regeneration

Studies at the NIH Clinical Center have shown that intermittent pulse cyclophosphamide
therapy is effective for treating patients with severe lupus nephritis, but may result in
substantial rates of sustained amenorrhea. Initial studies in patients with autoimmune
rheumatic diseases have also suggested a beneficial effect from the lymphocyte-specific
nucleoside analogs chlorodeoxyadenosine and fludarabine. Cyclophosphamide induces DNA
cross-links whereas, nucleoside analogs inhibits DNA repair indicating complementary and
partially synergistic modes of action. Whether combination of lower doses of
cyclophosphamide with nucleoside analogs will increase efficacy while at the same time
minimize toxicity from higher-cumulative doses of cyclophosphamide has not been determined.
In this phase I/II study, 15 patients with proliferative lupus nephritis will be treated as
outpatients with a combination of oral cyclophosphamide (500 mg/m(2)) on day 1 followed by
fludarabine (30 mg/m(2)) subcutaneously on days 1, 2 and 3 every month for 3 cycles. The
cumulative dose of cyclophosphamide in this regimen is approximately 2.5g as compared to
greater than or equal to 30g in the standard NIH cyclophosphamide regimen. In this study
the tolerance and toxicity of this combination will be studied. Regeneration of T and B
cells following depletion including analysis of antigen-repertoire and function will also be
examined. Preliminary efficacy information, including rates and time to renal remission and
rates of preservation of renal function, will be analyzed to be used for future controlled
studies. Pharmacokinetic analysis will be performed on a subset of patients to determine
the bioavailability and pharmacokinetic parameters of subcutaneous fludarabine.

Inclusion Criteria

Patients must be 18 years of age or older and able to provide informed consent.

Patients must have at least 4 criteria for SLE as defined by the American Rheumatism
Association (ARA).

Active glomerulonephritis with:

Renal biopsy within 1 year with class III or class IV active lupus nephritis, AND;

Abnormal urine analysis:

Greater than 10 RBC/hpf and cellular (RBC, WBC or mixed) casts, OR;

Greater than 10 RBC/hpf and proteinuria greater than 2 g/day, OR;

Proteinuria greater than 3.5 g/day.

No patients with severe proliferative lupus nephritis: a. very active renal histology
with crescents or necrosis in more than 25% of glomeruli; or b. rapidly progressive
glomerulonephritis (doubling of serum creatinine in less than or equal to 3 months); or c.
severe impairment of renal function Cr greater than 2.5 mg/dL or GFR less than 50 mL/min
measured by inulin clearance.

Patient has not had previous immunosuppressive therapy:

Patients must not be receiving azathioprine, cyclosporine, methotrexate. Patients
receiving these drugs will be eligible only if these drugs are discontinued and after a
waiting period of greater than or equal to 4 weeks;

Patients must not be receiving cyclophosphamide:

Greater than 3 pulses (maximum 1 g/m(2)/pulse) within the last 12 months or since last
renal biopsy showing active disease; OR

greater than 6 pulses ever.

Patients must not have had pulse therapy with glucocorticoids or any experimental therapy
during the 4 weeks before study entry.

Patients who need at study entry oral corticosteroids in dosages greater than 0.5
mg/kg/day of predisone to control extrarenal disease are not eligible.

Patients with active or chronic infection are not eligible.

Patients who are pregnant, breast-feeding or using inadequate birth control are not

Patients who have poorly controlled diabetes mellitus or with evidence of end-organ damage
are not eligible.

No history of cerebrovascular accident, seizures within the last 5 years or chronic
neurologic disease.

No history of malignancy other than squamous cell and/or basal carcinoma of the skin.

No confounding medical illness that in the judgment of investigators would pose added risk
for study participants such as:

Unstable coronary artery disease, cardiomyopathy or dysrhythmia requiring therapy;

Pulmonary disease (PFTs less 70% of predicted value or DLCO less than 60%), or;

Hematologic disease (Hb less than 8 mg/dL, platelets less than 100,000 micro liters or WBC
less than 2,500/micro liters.

Type of Study:


Study Design:

Endpoint Classification: Safety Study, Primary Purpose: Treatment


United States: Federal Government

Study ID:




Start Date:

January 1998

Completion Date:

November 2002

Related Keywords:

  • Glomerulonephritis
  • Lupus Nephritis
  • Systemic Lupus Erythematosus
  • Remission
  • Renal Function
  • Infection
  • Germinal Center
  • Immunoglobulin
  • Glomerulonephritis
  • Systemic Lupus Erythematosus
  • Lupus Nephritis
  • Glomerulonephritis
  • Lupus Erythematosus, Systemic
  • Lupus Nephritis
  • Nephritis



National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) Bethesda, Maryland  20892