A Study of Safety, Tolerability and Pharmacokinetics of Apremilast (CC-10004) in Pediatric Subjects With Moderate to Severe Plaque Psoriasis

A Phase 2, Multicenter, Open-Label Study to Assess the Safety, Tolerability and Pharmacokinetics of Apremilast (CC-10004) in Pediatric Subjects With Moderate to Severe Plaque Psoriasis

This is a Phase 2, multicenter, open-label study in subjects with moderate to severe plaque psoriasis aged 6 to 17 years, inclusive, intended to assess the safety, tolerability, and PK of apremilast with 2 weeks of oral apremilast treatment followed by a 48-week extension of apremilast treatment. Moderate to severe plaque psoriasis is defined as Psoriasis Area Severity Index (PASI) ≥ 12, Body Surface Area (BSA) ≥ 10%, and static Physician Global Assessment (sPGA) of ≥ 3. The total study duration for each subject will last for up to a total of 107 weeks which includes screening, treatment (including the PK portion of the study and the extension treatment period), two short-term follow-up periods and a long-term follow-up period.

Each subject will undergo a screening period of up to 5 weeks, a treatment period of 2 weeks with PK sample collection, and an extension treatment period of 48 weeks, to allow subjects access to apremilast treatment if medically appropriate (following the completion of the 2 week PK portion). Regardless of when they stop treatment, subjects should complete two post treatment follow-up visits at approximately 4 and 8 weeks after the last dose. All subjects should complete the final follow-up visit at Week 102 or at a timepoint 52 weeks after the last dose of apremilast was taken in subjects who have withdrawn at any time prior to Week 50. At least 32 subjects will be enrolled into this study to provide an adequate PK profile and safety assessment in subjects of different ages and body weight ranges. Subjects will be divided into 2 age groups (adolescents [ages 12 to 17 years, inclusive] and children [ages 6 to 11 years, inclusive]), with at least 16 subjects in each group. Apremilast treatment will start in older and heavier subjects.

Group 1 (ages 12 to 17 years, inclusive; weight ≥ 35 kg)

• The data collected from the first 8 subjects will be reviewed by an independent data monitoring committee (DMC) to determine if it is appropriate to proceed with dosing the balance of Group 1 subjects and to proceed with dosing in the Group 2 subjects.

and an evaluation of these data by the DMC has been completed.

Group 2 (ages 6 to 11 years, inclusive; weight ≥ 15 kg)

• The dose regimens (dose strength and/or dose frequency) for these first 8 subjects will be based upon the PK and safety assessments from the first 8 subjects in Group 1.
• For the remaining subjects in Group 2, the dose (dose strength and/or dose frequency) will be based upon the subject weight as determined by the PK and safety assessments. The dose strength and/or dose frequency will be adjusted for any safety concerns or for unexpected changes in exposure. In the event of a dose regimen adjustment after the second PK and safety assessment, the first 8 subjects in Group 2 will return to the site for the appropriate dosing adjustment.

Inclusion Criteria:

- Subjects must satisfy all of the following criteria to be enrolled in the study:

1. Male or female subjects 6 to 17 years of age, inclusive, at the time the informed consent document is signed by the legal guardian

2. Group 1 Only: ages 12 to 17 years, inclusive, and weighs ≥ 35 kg

3. Group 2 Only: ages 6 to 11 years, inclusive, and weighs ≥ 15 kg

4. Subject is able to swallow the apremilast tablet

5. Able to sign an assent with a legal guardian who can understand and voluntarily sign an informed consent

6. Able to adhere to the study visit schedule and other protocol requirements

7. Must agree to withhold vaccinations during the first 2 weeks of dosing. Inactivated vaccines will be allowed during the extension treatment period

8. Diagnosis of chronic plaque psoriasis for at least 6 months prior to Screening

9. Have moderate to severe plaque psoriasis at Screening and Baseline as defined by:

   • Psoriasis Area and Severity Index (PASI) score ≥ 12; and
   • Body surface area (BSA) ≥ 10%; and
   • Static Physician Global Assessment (sPGA) ≥ 3 (moderate to severe)

10. Disease inadequately controlled by or inappropriate for topical therapy for psoriasis

11. Candidate for systemic or phototherapy

12. Have not been exposed to any or have been exposed to no more than one systemic agent for psoriasis

13. At Screening, laboratory values must be within the following ranges:

    • White blood cell (WBC) count Age (yrs) Males (x 103 /µL) Females (x 103 /µL) 6-11 3.5 - 13.65 3.5 - 13.65 12-18 3.5 - 13.15 3.5 - 13.15
    • Platelet count Age (yrs) Males (x 103 /µL) Females (x 103 /µL) 6-11 117 - 394 117 - 394 12-18 126 - 400 126 - 400
    • Hemoglobin (Hb) Age (yrs) Males (g/dL) Females (g/dL) 6-11 10.0 - 15.5 10.0 - 15.5 12-18 11.0 - 18.1 10.0 - 16.4

14. Male subjects who engage in activity in which conception is possible must use barrier contraception (male latex condom or nonlatex condom NOT made out of natural [animal] membrane [for example, polyurethane]) while on apremilast and for at least 28 days after the last dose of apremilast

15. All females of childbearing potential (FCBP) must either practice abstinence* from heterosexual contact or use one of the approved contraceptive options as described below while on apremilast and for at least 28 days after dministration of the last dose of apremilast. For the purposes of this study, a female subject is considered of childbearing potential if she is ≥ 12 years old or has reached menarche, whichever occurred first At the time of study entry, and at any time during the study when a female subject of childbearing potential's contraceptive measures or ability to become pregnant changes, the Investigator will educate the subject regarding abstinence or contraception options and the correct and consistent use of effective contraceptive methods in order to successfully prevent pregnancy Females of childbearing potential must have a negative pregnancy test at Screening and Baseline. All FCBP who engage in activity in which conception is possible must use one of the approved contraceptive options described below: Option 1: Any one of the following effective methods: hormonal contraception (oral, injection, implant, transdermal patch, vaginal ring); intrauterine device (IUD); tubal ligation; or partner's vasectomy; OR Option 2: Male or female condom (latex condom or nonlatex condom NOT made out of natural [animal] membrane [for example, polyurethane]; PLUS one additional barrier method: (a) diaphragm with spermicide; (b) cervical cap with spermicide; or (c) contraceptive sponge with spermicide * Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.

Exclusion Criteria:

• The presence of any of the following will exclude a subject from enrollment:

  1. History of or currently active inflammatory bowel disease

  2. Major concurrent medical conditions, pregnancy or lactation

  3. Any condition that confounds the ability to interpret data from the study

  4. Guttate, erythrodermic, or pustular psoriasis

  5. Psoriasis flare or rebound within 4 weeks prior to Screening

  6. Evidence of skin conditions that would interfere with clinical assessments

  7. History of human immunodeficiency virus infection, or positive result to hepatitis B surface antigen or hepatitis C antibodies at Screening

  8. Clinically significant abnormality on 12-Lead ECG at Screening

  9. History of active mycobacterial infection with any species (including Mycobacterium tuberculosis) within 3 years of the Screening Visit and without documentation of successful treatment

  10. Congenital and acquired immunodeficiencies (eg, Common Variable Immunodeficiency),immunoglobulin A deficiency

  11. History of recurrent significant infections

  12. Active infection or infection treated with antibiotic treatment within 2 weeks of first dose

  13. Any history of or active malignancy

  14. History of allergy/intolerance to any component of the investigational product, ie, apremilast, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, hypromellose 15 cP, titanium dioxide, polydextrose FCC, talc, maltodextrin, medium chain triglycerides, iron oxide red, iron oxide yellow, and iron oxide black.

  15. Deficiencies in lactose metabolism, ie, galactose-1-phosphate uridylyltransferase, UDPglactose 4-epimerase, galactokinase or Fanconi Bickel syndrome, including congenital lactase deficiencies, and glucose-galactose malabsorption.

  16. Any other significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study or which places the subject at unacceptable risk if he/she were to participate in the study

  17. Prior history of suicide attempt at any time in the subject's lifetime prior to screening or enrollment in the study or major psychiatric illness requiring hospitalization within 3 years

  18. Answering '"Yes'" to any question on the Columbia-Suicide Severity Rating Scale during screening or at baseline

  19. Having received biologic therapy within 5 terminal half-lives, including but not limited to the following time periods:

      • Four weeks prior to baseline for etanercept
      • Ten weeks prior to baseline for adalimumab
      • Twenty-four weeks prior to baseline for ustekinumab

  20. Topical therapy within 2 weeks of baseline (including but not limited to topical corticosteroids, topical retinoid or vitamin D analog preparations, tacrolimus, pimecrolimus, or anthralin/dithranol)

      • Exceptions: low-potency corticosteroids (please refer to the Investigators' Manual) will be allowed as background therapy for treatment of the face, axillae, and groin in accordance with the manufacturers' suggested usage during the course of the study
      • Subjects with scalp psoriasis will be permitted to use coal tar shampoo and/or salicylic acid scalp preparations on scalp lesions
      • An unmedicated skin moisturizer (eg, Eucerin®) will be also permitted for body lesions only. Subjects should not use these topical treatments within 24 hours prior to the clinic visit

  21. Systemic therapy for psoriasis within 4 weeks prior to baseline (including but not limited to cyclosporine, corticosteroids, methotrexate, oral retinoids, mycophenolate, thioguanine, hydroxyurea, sirolimus, sulfasalazine, azathioprine, and fumaric acid esters)

  22. Use of phototherapy (ie, UVB, PUVA)within 4 weeks prior to baseline

  23. Use of any investigational drug within 4 weeks prior to baseline, or 5 pharmacokinetic/pharmacodynamic half-lives, if known (whichever is longer)

  24. Children in Care: a child who has been placed under the control or protection of an agency, organization, institution or entity by the courts, the government or a government body, acting in accordance with powers conferred on them by law or regulation

  25. Prior treatment with apremilast