Belimumab and Rituximab Combination Therapy for the Treatment of Diffuse Cutaneous Systemic Sclerosis

The specific objectives of this study are to:

1. Determine whether rituximab/belimumab/mmf is safe and tolerable in the treatment of
patients with early diffuse cutaneous (dc)SSc when compared to patients treated with
placebo/placebo/mmf, as assessed by comparison of adverse and serious adverse effects.
In this study stand of care will be protocolized as mycophenolate mofetil.

2. Determine whether rituximab/belimumab/mmf is more effective than placebo/placebo/mmf, as
measured by change in CRISS, which is a composite outcome measure provisionally endorsed
by the ACR for scleroderma clinical trials. It incorporates change in the mRSS, FVC
percent predicted, physician and patient global assessments, and HAQ-DI. Additionally,
hemoglobin corrected diffusion capacity (DLCO), Medsger Severity Scale (MSS), and by
other physician and patient derived outcome measures will be used.

3. Determine the biological activity of rituximab/belimumab/mmf vs placebo/placebo/mmf as
assessed by effect on histology of skin, gene expression of skin and blood, change in
B-Cell profiles including assessment of B regulatory cells, and effect on serological
and cutaneous biomarkers of disease activity.

Inclusion Criteria:

1. Age greater than or equal to eighteen years and less than or equal to 80.

2. Classification of systemic sclerosis (SSc), as defined using the 2013 American College
of Rheumatology/European Union League Against Rheumatism classification of SSc.

3. Diagnosis of dcSSc, as defined by LeRoy and Medsger.

4. Disease duration of less than or equal to 3 years as defined by the date of onset of
the first non-Raynaud's symptom.

5. A modified Rodnan Skin Score (mRSS) of > 14

Exclusion Criteria:

1. Inability to render informed consent in accordance with institutional guidelines.

2. Disease duration of greater than 3 years.

3. Patients with mixed connective tissue disease or "overlap" unless the dominant
features of the illness are diffuse systemic sclerosis.

4. Limited scleroderma.

5. Systemic sclerosis-like illness associated with environmental or ingested agents such
as toxic rapeseed oil, vinyl chloride, or bleomycin.

6. The use of other anti-fibrotic agents including colchicine, D-penicillamine, or
tyrosine kinase inhibitors (nilotinib, imatinib, dasatinib) in the month prior to
enrollment.

7. Use in the prior month of corticosteroids at doses exceeding the equivalent of
prednisone 10 mg daily. Use of corticosteroid at < 10 mg of prednisone can continue
during the course of the study.

8. Concurrent serious medical condition which in the opinion of the investigator makes
the patient inappropriate for this study such as uncontrollable CHF, arrhythmia,
severe pulmonary or systemic hypertension, severe GI involvement, hepatic impairment,
serum creatinine of greater than 2.0, active infection, severe diabetes, unstable
atherosclerotic cardiovascular disease, malignancy, HIV, or severe peripheral vascular
disease.

9. A positive pregnancy test at entry into this study. Men and women with reproductive
potential will be required to use effective means of contraception through the course
of the study, such as (1) surgical sterilization (such as a tubal ligation or
hysterectomy), (2) double-barrier methods (such as a condom and occlusive cap
(diaphragm or cervical/vault caps) plus spermicidal agent
(foam/gel/film/cream/suppository)(3) an intrauterine device (IUD) or intrauterine
system (IUS) (4) estrogenic vaginal ring (5) percutaneous contraceptive patches, or
(6) implants of levonorgestrel or etonogestrel. Approved hormonal contraceptives (such
as birth control pills, patches, implants or injections) may interact with and reduce
the effectiveness of MMF so women receiving MMF who are using oral contraceptives for
birth control should employ an additional method (e.g. barrier method). Contraceptive
measures such as Plan B (TM), sold for emergency use after unprotected sex, are not
acceptable methods for routine use.

10. Women not willing to use effective birth control for the duration of the study

11. Breastfeeding.

12. Participation in another clinical research study involving the evaluation of another
investigational drug within ninety days of entry into this study.

13. The presence of severe lung disease as defined by a diffusion capacity of less than
30% of predicted or requiring supplemental oxygen and forced vital capacity (FVC) of
less than 45% of predicted.

14. Grade 3 hypogammaglobulinemia

15. Have a significant IgG deficiency (IgG level < 400 mg/dL)

16. Have an IgA deficiency (IgA level < 10 mg/dL)

17. Have a historically positive HIV test or test positive at screening for HIV

18. Neutrophils <1.5X10E9/L

19. Hepatitis status:

1. Serologic evidence of current or past Hepatitis B (HB) infection based on the
results of testing for HBsAg and HBcAb as follows:

1. Patients positive for HBsAg or HBcAb are excluded b) Positive test for Hepatitis C
antibody 20. Known active bacterial, viral, fungal, mycobacterial, or other infection or
any major episode of infection requiring hospitalization or treatment with IV antibiotics
within 4 weeks of screening, or oral antibiotics within 2 weeks prior to screening 21.
Infection history:

1. Currently on any suppressive therapy for a chronic infection (such as tuberculosis,
pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster and atypical
mycobacteria)

2. Hospitalization for treatment of infection within 60 days of Day 0.

3. Use of parenteral (IV or IM) antibiotics (antibacterials, antivirals, anti-fungals, or
anti-parasitic agents) within 60 days of Day 0 22. Suppressive therapy for a chronic
infection (such as tuberculosis, pneumocystis, cytomegalovirus, herpes zoster and
atypical mycobacteria) 23. Any other disease, metabolic dysfunction, physical
examination finding, or clinical laboratory finding giving reasonable suspicion of a
disease or condition that contraindicates the use of an investigational drug or that
may affect the interpretation of the results or render the patient at high risk from
treatment complications 24. Prior use of Belimumab, Rituximab, or other B-Cell
depleting therapies ever 25. The use of other biologics including TNF inhibitors,
abatacept, or tocilizumab within the washout period below for each particular drug:

Tocilizumab - 1 month for patients on 2mg/kg or 4 mg/kg. 2 months for patients on
8mg/kg.

Cyclophosphamide (oral or IV) - 3 months. Abatacept - 2.5 months. TNF Inhibitors :
Etanercept - 1 mo, Infliximab - 2 mo, Adalimumab - 2.5 mo. Any biologic
investigational agent (e.g., abetimus sodium, anti CD40L antibody, BG9588/ IDEC 131) -
365 days prior to belimumab.

Any non-biologic investigational agent - 30 days prior to belimumab.

26. Have evidence of serious suicide risk including any history of suicidal behavior
in the last 6 months and/or any suicidal ideation in the last 2 months or who in the
investigator's judgment, pose a significant suicide risk.

27. Current drug or alcohol abuse or dependence, or a history of drug or alcohol abuse
or dependence within 364 days prior to Day 0.

28. History of an anaphylactic reaction to parenteral administration of contrast
agents, human or murine proteins or monoclonal antibodies 29. Live vaccines within 30
days prior to baseline 30. Have a history of malignant neoplasm within the last 5
years with the exception of basal cell or squamous cell carcinoma of the skin treated
with local resection only or carcinoma in situ of the uterine cervix treated locally
and with no evidence of metastatic disease for 3 years 31. Have a history of a primary
immunodeficiency 32. Have any other clinically significant abnormal laboratory value
in the opinion of the investigator 33. Have any intercurrent significant medical or
psychiatric illness that the investigator considers would make the candidate
unsuitable for the study 34. Non English speakers