Open-label Study of Tofacitinib for Moderate to Severe Skin Involvement in Young Adults With Lupus

A 3-part Open-label Study Assessing Safety, Tolerability, Pharmacokinetic and -Dynamic Profiles, and Efficacy of Tofacitinib in Young Adults From Age 18 to 45 With Moderate to Severe Skin Involvement Due to Lupus

This 76-week, 3-part Phase 1b/2 study is intended to evaluate the pharmacological properties (pharmacokinetics and pharmacodynamics), safety, tolerability and preliminary effectiveness of TOFA administrated to young adults (18-45 years) with moderately to severely active SLE-CL. Subjects will be studied at the Cincinnati Children's Hospital Medical Center (CCHMC) and in Cleveland at MetroHealth Medical Center.

Cohort 1 (n=10, weight > 40kg and age > 18 years and ≤ 45 years ) will undergo intense PK-sampling to determine exposures following TOFA dosed at 5 mg BID. TOFA dose escalation will not be considered for inadequate response of SLE-CL.

Cohort 2 (n=10, weight > 40kg and age > 18 years and ≤ 45 years) will be treated with the same dose as Cohort 1. No PK sampling will occur for Cohort 2. Enrollment of Cohort 2 will only start once Cohort 1 has completed 8 weeks of TOFA and results of PK analyses from Cohort 1 are available.

• Part A (up to week 8) requires stable background medications;
• Part B (up to week 24) allows for tapering of corticosteroids (CS) in the setting of significant clinical improvement of SLE-CL as defined by a decrease in Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) activity score by >50% from baseline , and
• Part C (until week 76) permits tapering of other background medications in subjects with clinical remission of SLE-CL (CLASI activity score=0). TOFA dosing is kept stable during Part C.

Inclusion Criteria:

1. Male or female > 18 years of age and < 45 years of age and > 40 kg body weight.
2. Fulfilled at least 4 out of the 11 Classification Criteria for SLE by the time of screening.
3. Willing to give written informed consent, must fully understand the requirements of the trial, and must be willing to comply with all trial visits and assessments.
4. CLASI activity score of 8 or higher at screening and baseline despite standard of care therapy.
5. Stable dose of prednisone of ≤ 20 mg/day within 2 weeks of enrollment.
6. Female subjects of childbearing potential must use a highly effective method of contraception to prevent pregnancy (abstinence is considered highly effective) and must agree to continue to practice adequate contraception for the duration of their participation in the trial and for 28 days after their last dose of TOFA.
7. Female subjects of childbearing potential must have a negative serum pregnancy test at screening and a negative urine pregnancy test at Trial Day 1 before dosing.
8. For subjects receiving leflunomide treatment, total daily dose does not exceed 20 mg.
9. A negative QuantiFERON-TB Gold In-Tube test performed within the 3 months prior to screening, or within the screening period prior to baseline. A negative PPD test can be substituted for the QuantiFERON-TB.
10. Subjects either have protective varicella titers or evidence of having been vaccinated against varicella.

Exclusion Criteria:

1. Mild SLE-CL defined as a CLASI activity score of 7 or lower at screening and baseline.

2. Increase in CS dosing within 2 weeks prior to Trial Day 1, or expected to require an increase in CS dosing during the first 4 weeks of the study.

3. Use of i.v. corticosteroids within 4 weeks prior to Trial Day 1.

4. Increase in dosing of methotrexate, leflunomide, within 4 weeks before Trial Day 1 or expected to require an increase during the first 8-weeks of the study.

5. Increase in dosing of hydroxychloroquine, or chloroquine within 4 weeks before Trial Day 1 or expected to require an increase during the first 8-weeks of the study.

6. Rituximab within 1 year of Trial Day 1.

7. Increase in dosing of any medication or herbal treatment considered to have immunosuppressive properties with 4 weeks before Trial Day 1.

8. Prior treatment with or known intolerability of TOFA.

9. Use of cyclophosphamide (i.v. or oral), cyclosporine, or tacrolimus within 12 weeks prior to Trial Day 1.

10. Treatment with other investigational agents within the last 6 months or 5 half-lives, or as per washout requirement from the previous protocol, whichever is longer.

11. Estimated glomerular filtration rate less than or equal to 60 mL/min /1.73 m2.

12. Known positive Human Immunodeficiency Virus (HIV), Hepatitis C Virus (HCV), or Hepatitis B surface antigen (HBsAg) serology.

13. Any condition, including findings in the laboratory tests, medical history, or other screening assessments, that, in the opinion of the Investigator, constitutes an inappropriate risk or a contraindication for participation in the trial or that could interfere with the trial's objectives, conduct, or evaluation.

14. Active central nervous system SLE deemed to be severe or progressive and/or associated with significant cognitive impairment leading to inability to provide informed consent and/or comply with the protocol.

15. Significant renal disease due to a reason(s) other than Lupus Nephritis (e.g. diabetes mellitus, renovascular disease, or antiphospholipid syndrome).

16. Severely active Lupus Nephritis defined as a renal BILAG A score.

17. History of dialysis within 3 months prior to Trial Day 1 or expected to need during the trial.

18. History of or planned renal or other organ transplantation.

19. Known active clinically significant viral, bacterial or fungal infection, or any major episode of infection requiring hospitalization or treatment with parenteral anti-infectives within 8 weeks of screening, or completion of oral anti-infectives within 2 weeks of Trial Day 1.

20. Breastfeeding or currently pregnant.

21. Legal incapacity or limited legal capacity to provide informed consent or assent.

22. Blood dyscrasias, including:

    • Hgb <10 g/dL or Hct <33%.
    • WBC <3.0 x 109/L.
    • Neutrophil count <1.2 x 109/L.
    • Platelet count <100 x 109/L.
    • Lymphocyte count of <0.5 x 109/L.

23. AST or ALT > 1.5 times the upper limit of normal or any other clinically significant laboratory abnormality.

24. History of any other rheumatic autoimmune disease.

25. Infections:

    • Latent or active TB or any history of previous TB.
    • Chronic infections.
    • Any infection requiring hospitalization, parenteral antimicrobial therapy or judged to be opportunistic by the investigator within the 6 months prior to the first dose of study drug.
    • Any treated infections within 2 weeks.
    • History of recurrent (more than one episode) herpes zoster or disseminated (a single episode) herpes zoster or disseminated (a single episode) herpes simplex.
    • History or current symptoms suggestive of any lymphoproliferative disorder, including Cytomegaly Virus (CMV) or Epstein Barr Virus (EBV) related lymphoproliferative disorder, history of lymphoma, leukemia, or signs and symptoms suggestive of current lymphatic disease.

26. Subjects taking potent and moderate cytochrome P450 3A4 (CYP3A4) inhibitors (see Appendix 2).

27. Subjects taking potent and moderate CYP3A4 inducers (see Appendix 2).

28. Subjects who have been vaccinated with live or attenuated vaccines within the 6 weeks prior to the first dose of study medication. All subjects should be up-to-date with respect to standard of care vaccinations (as defined by their country health ministry) as permitted by past immunosuppressive therapy for SLE.

29. Subjects with a malignancy or with a history of malignancy with the exception of adequately treated or excised non-metastatic basal cell or squamous cell cancer of the skin or cervical carcinoma in situ.

30. Subjects with a history or current diagnosis of diverticulitis.