A Phase I, Open-Labeled, Dose-Ascending Clinical Trial of Immunotherapy of MRA, A Humanized Anti-IL 6 Receptor Monoclonal Antibody, In Patients With Systemic Lupus Erythematosus
- IINCLUSION CRITERIA:
Age at entry at least 18 years
Must give written informed consent prior to entry in the protocol
Must fulfill at least 4 of the following criteria for SLE as defined by the American
College of Rheumatology:
- Malar rash. Fixed Erythema, flat or raised, over the malar eminences.
- Discoid rash. Erythematous raised patches with adherent keratotic scaling and
follicular plugging; atrophic scarring may occur.
- Photosensitivity. Exposure to UV light causes rash.
- Oral Ulcers. Includes oral and nasopharyngeal, observed by physician.
- Arthritis. Nonerosive arthritis involving two or more peripheral joints,
characterized by tenderness, swelling or effusion.
- Serositis. Pleuritis or pericarditis documented by ECG or rub or evidence of
- Renal disorder. Proteinuria greater than 0.5 g/d or greater than 3+, or cellular
- Neurologic disorder. Seizures without other cause or psychosis without other cause.
- Hematologic disorder. Hemolytic anemia or leukopenia (less than 4000/microL) or
lymphopenia (less than 1500/microL) or thrombocytopenia (less than 100,000/microL) in
the absence of offending drugs.
- Immunologic disorder. Anti-dsDNA, anti-Sm, and/or anti-phospholipid.
- 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 induce ANAs.
Moderately active lupus not requiring immediate immunosuppressive therapy other than oral
prednisone less than or equal to 0.3 mg/kg/day (or its equivalent). Moderately active
lupus is defined by either of these two (a and b) sets of criteria:
a. Chronic glomerulonephritis with inadequate response to at least 6 months of adequate
immunosuppressive therapy (with pulse methylprednisolone, cyclophosphamide, azathioprine,
cyclosporine, mycophenolate mofetil or high dose daily corticosteroids, MTX or IV Ig), and
i. less than 30% increase in creatinine compared to lowest level during treatment,
ii. proteinuria less than or equal to 1.5 times the baseline before treatment,
iii. less than or equal to 2+ cellular casts in the urinary sediment (on a scale of 0-4),
iv. Extra-renal disease activity does not exceed 10 on the non-renal components of the
b. Patients with moderately active extra-renal lupus defined as an extra-renal
SELENA-SLEDAI score in the range of 3 to 10, inclusive. The SELENA-SLEDAI score should
have been stable for at least two weeks prior to screening.
One or more of the following:
i) Serum dsDNA level greater than or equal to 30 IU
ii) IgG anticardiolipin antibody levels greater than or equal to 20 GPL
iii) CRP greater than 0.8 mg/dL
iv) ESR greater than 25 mm/hr for men; ESR greater than 42 mm/hr for women.
Stable doses of prednisone less than or equal to 0.3 mg/kg/day (or its equivalent) for at
least 2 weeks before the first treatment.
Pregnant or lactating women. Women of childbearing potential are required to have a
negative pregnancy test at screening.
Women of childbearing potential and fertile men who are not practicing or who are
unwilling to practice birth control during and for a period of three months after the
completion of the study
Any therapy with human or murine antibodies or any experimental therapy within 3 months
Therapy with cyclophosphamide; pulse methylprednisolone or IV Ig within 4 weeks; or
azathioprine, mycophenolate mofetil, cyclosporine or methotrexate within 2 weeks of first
Initiation or a change in the dose of an ACE-inhibitor within 2 weeks of first study
Allergy to murine or human antibodies
History of anaphylaxis
Serum creatinine greater than 3.0 mg/dL
Active severe CNS lupus (encephalopathy, cerebrovascular accident, transverse myelitis,
severe depression, psychosis)
Previous history of ischemic heart disease or evidence of ischemic heart disease on ECG
Congestive heart failure or cardiomyopathy
History of thrombosis or recurrent 2nd trimester abortions (3 or more) and elevated levels
of anti-cardiolipin antibodies or lupus anticoagulant unless the patient is on
History of malignancy with the exception of basal cell or squamous cell carcinoma of the
skin or in situ carcinoma of the cervix within the last 3 years
Active infection that requires the use of intravenous antibiotics and does not resolve
within 1 week of Day 1
Any active viral infection that does not resolve within 10 days prior to Day 1
History of reactivation on EB viral infection or greater than 1,000 EBV genome
equivalent/10(6) cells in PBMC preparations
Active hepatitis B, hepatitis C or HIV infection
WBC less than 3500/microL or ANC less than 3000/microL or Hgb less than 8.0 g/dL or
platelets less than 50,000/microL or absolute lymphocyte count less than or equal to
ALT and/or AST greater than 2 times the upper limit of normal (ULN) or alkaline
phosphatase greater than 1.5 times the ULN
Significant concurrent medical condition that, in the opinion of the principal
investigator, could affect the patient's ability to tolerate or complete the study
Live vaccines within 4 weeks of first infusion