Evaluation of Belimumab Impact on a BLyS Activity Signature Test in the Absence of Confounding Polypharmacy

This will be an open label, non-randomized trial of belimumab in at least 20 subjects to test the feasibility of belimumab as a single agent and to capitalize on simplified background treatment regimens to determine immunologic differences between patients who do versus do not meet clinical response criteria.

Primary Objective: This study will determine clinical response to belimumab using the SRI 4 (SLE Responder Index) which was used in the Phase III belimumab trials which led to its approval by the FDA. The population entered will be similar to the Phase III study population However, in this case background medications will be withdrawn at entry and brief steroid rescue with intramuscular depomedrol will provide immediate relief to cover the delay in belimumab effects. The co-primary objectives will be to determine time to disease flare compared to a historical control study (Biomarkers of Lupus Disease) and to determine whether more belimumab responders (defined by the SLE Responder Index) have a 50% decrease in the predefined BLAST signal (BlyS Activity Signal Test) than non-responders. This pilot study is not powered to draw firm conclusions about response rates in the absence of ongoing standard of care medications, but should 7-12 patients (of 20 completing the 6 month endpoint) meet the SRI response criteria, the feasibility of a larger, placebo controlled trial would be justified. The following instruments will be used to measure clinical lupus activity during the study: BICLA, SRI 5, changes in joint counts, global SLEDAI, BILAG, CLASI, PGA, and SF-36 and LFA-REAL measures.

The following are the definitions of these clinical outcome measures: SRI stands for SLE Responder Index which is a composite score comprised of a 4 (or alternatively 5) point decrease in the SLEDAI (SLE Disease Activity Index) coupled to no increase in the BILAG (British Isles Lupus Assessment Group) Index and no more than 10% increase in the Physician's Global Assessment. The global SLEDAI or BILAG is simply a comparison of the total SLEDAI or numerical composite BILAG score at baseline and after receiving belimumab. The CLASI refers to the Cutaneous Lupus Erythematosus Disease Area and Severity Index. the LFA REAL stands for the Lupus Foundation of America Rapid Evaluation of Activity in Lupus. The latter is a pilot instrument which will be tested in this study.

We will also integrate exploratory biologic discovery into the clinical trial to support both pre-specified and exploratory biomarker discovery. Data will be generated that might be used to help select more appropriate patient subsets for future trials and to guide optimal dosing strategies. Optimizing patient selection and dosing are important goals for further increasing demonstrable effect size in trials by increasing the response rates in the treatment groups. Thus, despite being a small pilot study, an ambitious goal is included to provide potential preliminary data conducive to optimize the use of belimumab. In general these analyses will also be descriptive, however our experience in the BOLD study suggests that comparing a group of 6-12 patients (presumed clinical response rate) who are enriched in expression of a particular biomarker vs a different group of 14-8 patients (defined in this case on basis of non-response to belimumab, or in the BOLD study by assignment to IFN high vs low subgroups) may, by virtue of representing different immunologic subsets of disease, produce statistically significant results in mean/median values of a number of biomarkers. More importantly, comparing "before and after" levels of BLyS and other cytokines may be quite sensitive to belimumab when it has clinical impact as well.

Obtaining this kind of preliminary data to better understand optimal patient selection could be a valuable approach to further increasing effect size in a future clinical trial. In fact, the two Parts of this project (single agent assessment and biomarker assessment) are co-dependent, since each increases the likelihood of interpretable data in patients with moderate severity. Indeed Part 2 would be less feasible without the strategy of Part 1 to decrease the conflicting immune signals of background medications, which have clouded interpretation of many treatments for SLE in the past.

Again, this will be an open label, six month study of belimumab treatment given to patients who qualify to receive this treatment under the United States labeling. Additionally, at entry to this study, patients must have a SLEDAI score of at least 6 which is identical to the disease activity minimum required for belimumab Phase III studies. Entry criteria will require results of a full clinical evaluation, CBC with differential, comprehensive metabolic profile (including liver function tests) and urinalysis (with reflex protein/creatinine ratio) prior to dosing.

The first dose will be given within 4 weeks of the screening visit and may take place as soon as the entry laboratories are returned. However, those patients who are stopping a major immune suppressant and/or those who require a steroid injection at entry will be encouraged to wait a minimum of 3 weeks before the initial belimumab dose. Blood samples for biomarkers (see below) will be drawn at the screening visit and just prior to the first dose to maximize disease assessment prior to steroid rescue as well as after withdrawal of background treatments. These will provide baseline data on the BLAST expression profile for each patient, which will be derived and standardized through the study of active SLE B Cells and in vitro B Cell gene expression responses to BLyS signaling. The highest BLAST signal recorded at either screening (prior to steroids) or baseline (after immune suppression withdrawal) will be employed as the baseline BLAST signal.

Subjects will be evaluated monthly by an investigator/subinvestigator who are trained for SLEDAI, BILAG 2004, and CLASI. Additional assays will be patient reported outcomes including the Short Form 36 (SF36) and the LFA REAL physician and patient endpoints. The co-primary clinical endpoint will be time to flare after the last steroid injection compared to the results of the BOLD study. The co-primary mechanistic endpoint will be measured at 3 months. This will be a comparison of rates of BLAST 50 response (50% decrease in fold change expression of BLAST panel genes as compared to healthy controls) in those who do or do not meet the clinical endpoint of SRI 4 without use of off-protocol medications. The SRI 4 endpoint will be met by meeting both the SRI criteria and no initiation of off- protocol immune suppressants or steroids. Although the stipulation of no off-protocol medications was not integrated into the initial definition of SRI it was required to meet the endpoint of the Phase III belimumab trials, since those who received off protocol treatments were removed from those studies and counted as non-responders. This brings our primary clinical endpoint in line with the intent of the primary endpoint in the Phase III belimumab studies. However our patients will not necessarily be removed from study for use of off protocol medications. After being designated a permanent non-responder in the primary endpoint such a patient might be further followed for exploratory analysis of improvement on additive medications.

This study will enroll patients until 20 have completed the protocol through the six month point. All patients will receive belimumab 10 mg/kg at baseline, 2 weeks later, 2 weeks after that and then q month. At each monthly visit history, physical, and blood tests (appropriate and as scheduled) to complete the outcome measures will be performed, and adverse event reporting and medication updates will be performed. Subjects may continue to take nonsteroidal anti-inflammatory medications (including prn NSAIDS) and up to 20 mg prednisone (or oral steroid equivalent) daily at screening and during the study although steroids will be tapered as tolerated. If the patient is taking hydroxychloroquine or an immune suppressant (e.g. mycophenolate mofetil, azathioprine, leflunomide, methotrexate, or a calcineurin inhibitor) at screening, these standard of care treatments must be stopped prior to the baseline visit, preferably a minimum of two weeks before baseline. Patients can elect to receive one or more depomedrol injection(s) up to a total of 320 mg total in individualized increments beginning at the time of the screening visit (if necessary) and/or up to and including the Month 2 visit. Daily oral steroids will be tapered as tolerated if and when the patient begins to improve.

Eligibility Criteria:
Inclusion Criteria:

1. Patients who meet 1987 ACR criteria for SLE with 1996 modifications
2. SLEDAI \>/= 6 at screening visit
3. Positive ANA OR anti-dsDNA within one year of screening
4. In the opinion of the investigator there is intent to treat with a biologic (e.g. patient failed standard of care treatment) however there is no organ threatening disease

Exclusion Criteria:

1. Hg less than 8.0 or hemolytic anemia
2. Lymphocyte count less than 0.4
3. AST/ALT greater than 2.5 times ULN
4. Infection requiring IV antibiotics within a month of screening or oral antibiotics within two weeks of first dose
5. Active chronic infections (such as tuberculosis) which have not been treated or tb exposure in a person under 40 who has not received suppressive therapy for at least 3 months. Herpes zoster outbreak within three months of dosing. (Suppressive therapy for herpes simplex is not an exclusion criterion).
6. Cancer within 5 years (except for completely excised cervical carcinoma in situ or excised non-melanoma skin cancer)
7. Inability or unwillingness to follow the protocol
8. If WOCBP, inability or unwillingness to practice an acceptable method of contraception (including abstinence, barrier method with spermicide, or hormonal treatment
9. Inability or unwillingness to withdraw from hydroxychloroquine and/or any immune suppressive therapy being taken despite option for immediate steroid treatment and later treatment rescues as needed.
10. Any illness or condition that, in the opinion of the investigator, would cause undue hardship or risk to the subject by participating in the protocol

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