Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Clinical Effect of GSK2646264 in Cutaneous Lupus Erythematosus Subjects
Condition: Lupus Erythematosus, Cutaneous
MeSH terms: Lupus Erythematosus, Systemic; Lupus Erythematosus, Cutaneous
Intervention: GSK2646264 1%; Placebo
Intervention description: A cream for topical application with a concentration of 1% GSK2646264.; Subjects will receive matching Placebo topically.
Intervention MeSH terms: GSK2646264
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 11.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: No
Keywords: Cutaneous Lupus Erythematosus-CLE; Spleen Tyrosine Kinase-SYK; Photoprovocation-PV; GSK2646264

Summary:

      This study is designed to examine safety, tolerability, pharmacokinetics, pharmacodynamics
      and clinical effect of repeat dosing of GSK2646264 in patients with subacute and chronic
      cutaneous lupus erythematosus (CLE) lesions and in acute CLE like lesions induced by
      photoprovocation (PV).

      Current study is two group study. In Group A, Patients with fewer than two active lesions
      will be enrolled and exposed to photoprovocation (PV) for 3 consecutive days. Patients that
      develop PV lesions at any time during this period, as determined by the local investigative
      team, will receive 1% strength GSK2646264 on 1 lesion and placebo on 1 lesion daily and
      either 1% strength GSK2646264 or placebo on an area of uninvolved skin, for skin
      pharmacokinetic (PK) of study drug, for 28 days.

      In Group B, Patients that have a minimum of 2 active existing CLE lesions as determined by
      the investigators will be enrolled into group B and have one lesion treated with 1%
      GSK2646264 and 1 lesion with placebo.

      A completed patient will be defined as a subject who receives at least 25 days of study drug
      and completes the end of treatment biopsy (at day 28) and assessment. Thereafter patients
      will be followed for 28 days in Group A only or until complete resolution of induced PV
      lesions, as determined by the investigator.
    

Eligibility criteria:

        Inclusion Criteria

          -  Between 18 and 70 years of age inclusive, at the time of signing the informed consent.

          -  Subject values for the following parameters thyroid-stimulating hormone (TSH), free
             thyroxine (T4), and free triiodothyronine (T3) within the normal range.

          -  Subject has confirmed diagnosis of Lupus Erythematosus Tumidus (LET) (group A only),
             subacute or chronic CLE as determined by the investigators.

          -  Body weight >= 50 kg and body mass index (BMI) within the range 19.9 - 35 kilogram
             (kg)/meter square (m^2) (inclusive)

          -  Male OR Female.

        Females: Non-reproductive potential defined as:

          -  Pre-menopausal females with one of the following: Documented tubal ligation,
             Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of
             bilateral tubal occlusion , Hysterectomy, Documented Bilateral Oophorectomy

          -  Postmenopausal defined as 12 months of spontaneous amenorrhea. In questionable cases a
             blood sample with simultaneous follicle stimulating hormone (FSH) and estradiol levels
             consistent with menopause (refer to laboratory reference ranges for confirmatory
             levels). Females on hormone replacement therapy (HRT) and whose menopausal status is
             in doubt will be required to use one of the highly effective contraception methods if
             they wish to continue their HRT during the study. Otherwise, they must discontinue HRT
             to allow confirmation of post-menopausal status prior to study enrolment.

        Reproductive potential and agrees to follow one of the options listed in the Modified List
        of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential
        (FRP) from 28 days prior to the first dose of study medication and until 12 days after the
        last dose of study medication and completion of the follow-up visit.

          -  Capable of giving signed informed consent which includes compliance with the
             requirements and restrictions listed in the consent form and in this protocol.

          -  All subjects must be free from scarring or skin markings (e.g. tattoos or piercings)
             and open wounds on the defined areas of the body that cream will be applied onto or
             that will be exposed to PV, unless in the opinion of the investigator it will not
             compromise the subjects' safety and quality of data.

          -  Able to refrain from exposure to extended and direct sunlight during the study period,
             from screening until follow up, especially the area that is under treatment during the
             study.

          -  Able to refrain from using self-tanning products on the areas on which the study cream
             will be applied for the duration of the study from screening to follow-up.

          -  Able to refrain from shaving and waxing the areas on which the study cream will be
             applied during the duration of the study from screening to follow up.

          -  Patient stable on either no treatment or on :

               -  Corticosteroids (=<7.5milligram [mg]/day prednisone or prednisone equivalent or
                  less) for a minimum of 30 days prior to screening and through to Day 28.

               -  and /or hydroxychloroquine (=<400mg daily dose) for a minimum of 60 days prior to
                  the initial photoprovocation for group A or Randomisation Visit for group B
                  through to day 28.

               -  Topical steroids applied to the defined areas of the body that are not exposed to
                  photoprovocation or study cream from screening to Day 28.

               -  Topical calcineurin inhibitors and retinoids applied to the defined areas of the
                  body that are not exposed to photoprovocation or study cream from screening to
                  Day 28.

        Exclusion Criteria

          -  ALT >2xupper limit of normal (ULN);

          -  Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is
             fractionated and direct bilirubin <35%)

          -  Current or chronic history of liver disease, or known hepatic or biliary abnormalities
             (with the exception of Gilbert's syndrome or asymptomatic gallstones)

          -  QTcF > 450 millisecond (msec), or QTcF > 480 msec in subjects with Bundle Branch Block

          -  History of any past or present benign or malignant skin conditions and disease, unless
             in the opinion of the investigator it will not compromise the subjects safety and
             quality of data.

          -  Subjects with a history of Graves disease

          -  Subjects with a history of thyroid cancer.

          -  Unable to refrain from vitamins, herbal and dietary supplements (including St John's
             Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half
             lives (whichever is longer) prior to the screening visit until the completion of the
             follow-up assessments, unless in the opinion of the Investigator, in consultation with
             the GlaxoSmithKline (GSK) Medical Monitor if required, the medication will not
             interfere with the study procedures or compromise subject safety.

          -  Clinically significant abnormality in the hematological, clinical chemistry, or
             urinalysis screen, as judged by the investigator after discussion with the medical
             monitor.

          -  Subjects who start prohibited medications or therapies at any time during the study
             may be withdrawn from the study. Subjects who start prohibited medications or
             therapies may remain in the study only with the approval of the Medical Monitor and at
             the discretion of the Sponsor.

          -  The following medications and therapies are prohibited at any time during the study:

               -  Use of other investigational agents (biologic or non-biologic; investigational
                  applies to any drug not approved for sale in the country in which it is used).

               -  Co-enrolment into another study of an investigational agent or non-drug therapy.

               -  Use of biological agents (e.g., alemtuzumab [ATG], rituximab,) during the
                  clinical study or within 12 months to first dose of study treatment.

               -  Use of other immunosuppressive drugs commonly used in Systemic lupus
                  erythematosus (SLE) including Azathioprine, Methotrexate, Mycophenolate,
                  Cyclophosphamide within 3 months to first dose of study treatment.

          -  History of regular alcohol consumption within 3 months of the study defined as:

        Alcohol will be allowed but limited to an average weekly intake of <21 units for males or
        <14 units for females).

          -  Direct exposure to ultraviolet (UV) light (e.g. sunbathing) to the testing areas
             within 2 weeks of study entry.

          -  History of sensitivity to any of the study medications, or components thereof or a
             history of drug or other allergy that, in the opinion of the investigator or Medical
             Monitor, contraindicates their participation (refer to the Investigator Brochure for a
             list of excipients).

          -  Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test
             result at screening or within 3 months prior to first dose of study treatment.

          -  A positive pre-study drug screen.

          -  Where participation in the study would result in donation of blood or blood products
             in excess of 450 milliliter (ml) within 3 months.

          -  The subject has participated in a clinical trial and has received an investigational
             product within the following time period prior to the first dosing day in the current
             study: 30 days, 5 half-lives or twice the duration of the biological effect of the
             investigational product (whichever is longer).

          -  Exposure to more than 4 investigational medicinal products within 12 months prior to
             the first dosing day.

        Country Specific Exclusion criteria wording for Germany:

          -  Subjects that are employees of either GlaxoSmithKline (sponsor) or one of the study
             centres (investigators).

          -  Subjects who live in detention on court order or on regulatory action.

          -  Oral Prednisolone

               -  Greater than 7.5 mg by mouth daily.

               -  Any increase in dose from screening to Day 28

          -  Hydroxychloroquine

               -  Greater than 400 mg oral daily.

               -  Any increase in dose from screening to Day 28.

          -  Photosensitizing drugs within 5 half-lives prior to the photoprovocation visit.