Patient case: 14-year-old female with Li-Fraumeni syndrome; genetic feature: TP53

Clinical trial: A Safety, Efficacy and Systemic Exposure Study of CD5789 Cream in Adults and Adolescents With Lamellar Ichthyosis

Summary: This is a phase 2 randomized, multi-center, double-blind, vehicle controlled, 12-week, safety, efficacy, and systemic exposure study followed by a 12-week open-label extension of trifarotene cream in adults and adolescents with autosomal recessive ichthyosis with lamellar scale

Detailed description: This is a 2-cohort, multicenter study in subjects with moderate to severe LI. Adults (Cohort A) and adults and adolescents (Cohort B) will be randomized in a double-blind fashion to 1 of 2 doses of active or vehicle and treated twice weekly for 12 weeks. Subjects who complete the randomized, double-blind portion of the study will be eligible to enter a 12 week, open-label extension study.
  Approximately 15 adults (≥18 years old) will be randomized into the first cohort of subjects (Cohort A) in a 1:1:1 ratio and treated twice weekly for up to 12 weeks. If no safety issues are identified, both adults and adolescents (ages 12-17 years, inclusive) will be allowed to enroll in Cohort B. Subjects in Cohort B will be randomized 1:1:1 and treated twice weekly for up to 12 weeks in the same manner as subjects in Cohort A.
  All subjects who complete 12 weeks of double-blind study treatment will be eligible to enroll in a 12-week open-label extension. Subjects in the open-label extension will receive active twice weekly for up to 12 weeks.

Eligibility: Inclusion Criteria:
  1. For Cohort A: subject is ≥18 years old; for Cohort B: subject is ≥12 years old.
  2. Subject has known diagnosis of LI.
  3. Subject has moderate to severe (VIIS 3-4) LI on at least 2 of the body areas assess (chest/abdomen, back, arms and legs).
  4. Subject has signed an ICF at Screening before any investigational procedures. Subjects <18 years of age (or Age of Majority) must sign an assent form in conjunction with an ICF signed by the parent/legal representative.
  5. Subject who is participating in photography has signed a photography ICF.
  6. Subject who is participating in the optional PK substudy has signed a PK ICF.
  7. Subject is not of childbearing potential, i.e., a female who has not yet begun menstruating or who is postmenopausal (absence of menstrual bleeding for 1 year before Baseline, without any other medical reason, hysterectomy or bilateral oophorectomy), OR
  -  Subject is a woman of childbearing potential (WOCBP) or a male subject with sexual partners capable of reproduction who agrees to use 2 effective forms of contraception during the study and for at least 1 month after the last study drug application. The 2 authorized forms of contraception are condom used with 1 of the following methods of contraception:
  -  bilateral tubal ligation
  -  combined oral contraceptives (estrogens and progesterone) or implanted or injectable contraceptives with a stable dose for at least 1 month before Baseline
  -  hormonal intrauterine device (IUD) inserted at least 1 month before Baseline OR Agrees to abstain from sex during study participation and for 1 month after the last application of study drug and to use a highly effective contraceptive as backup if he or she becomes sexually active during the study.
  AND Male subjects may not donate sperm during the study and for at least 1 month after the last study drug application.
  Note: Subjects who are premenstrual at Screening but begin menses during the study should follow the pregnancy testing schedule for WOCBP and must abstain from sexual intercourse while in the study and for at least 1 month after the last study drug application.
  8. Women of child-bearing potential must be nonlactating and have negative pregnancy test results at Screening (serum) and on Day 1 before study drug administration (urine).
  9. Subject is reliable and capable of adhering to the protocol and visit schedule, in the investigator's judgment, and has signed informed consent/assent, as applicable.
  10. Subject is taking no more than 3500 IU/day Vitamin A (e.g., as in a multivitamin).
  Exclusion Criteria:
  -  Inclusion criteria:
  1. For Cohort A: subject is ≥18 years old; for Cohort B: subject is ≥12 years old.
  2. Subject has known diagnosis of LI.
  3. Subject has moderate to severe (VIIS 3-4) LI on at least 2 of the 4 body areas assessed (chest/abdomen, back, arms and legs).
  4. Subject has signed an ICF at Screening before any investigational procedures. Subjects <18 years of age (or Age of Majority) must sign an assent form in conjunction with an ICF signed by the parent/legal representative.
  5. Subject who is participating in photography has signed a photography ICF.
  6. Subject who is participating in the optional PK substudy has signed a PK ICF.
  7. Subject is not of childbearing potential, i.e., a female who has not yet begun menstruating or who is postmenopausal (absence of menstrual bleeding for 1 year before Baseline, without any other medical reason, hysterectomy or bilateral oophorectomy), OR
  -  Subject is a woman of childbearing potential (WOCBP) or a male subject with sexual partners capable of reproduction who agrees to use 2 effective forms of contraception during the study and for at least 1 month after the last study drug application. The 2 authorized forms of contraception are condom used with 1 of the following methods of contraception:
  -  bilateral tubal ligation
  -  combined oral contraceptives (estrogens and progesterone) or implanted or injectable contraceptives with a stable dose for at least 1 month before Baseline
  -  hormonal intrauterine device (IUD) inserted at least 1 month before Baseline OR Agrees to abstain from sex during study participation and for 1 month after the last application of study drug and to use a highly effective contraceptive as backup if he or she becomes sexually active during the study.
  AND Male subjects may not donate sperm during the study and for at least 1 month after the last study drug application.
  Note: Subjects who are premenstrual at Screening but begin menses during the study should follow the pregnancy testing schedule for WOCBP and must abstain from sexual intercourse while in the study and for at least 1 month after the last study drug application.
  8. Women of child-bearing potential must be nonlactating and have negative pregnancy test results at Screening (serum) and on Day 1 before study drug administration (urine).
  9. Subject is reliable and capable of adhering to the protocol and visit schedule, in the investigator's judgment, and has signed informed consent/assent, as applicable.
  10. Subject is taking no more than 3500 IU/day Vitamin A (e.g., as in a multivitamin).
  Exclusion criteria:
  1. Subject has any variant of ichthyosis other than LI or another disorder of keratinization including syndromic ichthyoses.
  2. Subject has a history of or current moderate or severe stinging/burning or pruritus at Screening.
  3. Subject has an ongoing cutaneous infection or any other significant concomitant skin disease (other than the LI) which, in the investigator's opinion, may interfere with the study assessments.
  4. Subject with a known lipid disorder unless well controlled by stable doses of lipid lowering agents for at least 6 months.
  5. Subject was previously treated with trifarotene/CD5789, including the acne formulation, or participated in previous studies for ichthyosis.
  6. Subject has known skeletal disease, hypertriglyceridemia, hypercholesterolemia, liver disease, or other poorly controlled medical conditions.
  7. Subject has a medical condition that potentially alters bone metabolism (e.g., osteoporosis, thyroid dysfunction, Cushing syndrome), Crohn's disease, or any other significant concomitant disease other than LI that, in the investigator's opinion, may put him or her at risk if he or she takes part in the study, and/or that may interfere with the study assessments.
  8. Subject is being treated for major depression disorder.
  9. Subject with positive serology for hepatitis B surface antigen, hepatitis C, or human immunodeficiency virus antibody at Screening.
  10. Subject with any of the following laboratory values at Screening:
  1. Aspartate aminotransferase or alanine aminotransferase >1.5 × upper limit of normal defined by the laboratory
  2. Triglycerides >200 mg/dL
  3. Total cholesterol >250 mg/dL
  4. Hemoglobin <12.5 g/dL for men and <11.5 g/dL for women
  5. Platelets <150 × 109/L or >400 × 109/L.
  11. Subject has any clinically other significant abnormal laboratory value (hematology, chemistry, or urinalysis) at Screening that, in the investigator's opinion, may put the subject at risk if he or she takes part in the study, and/or that may interfere with the study assessments.
  12. Subject has a history of long QT syndrome or clinically significant electrocardiogram (ECG) abnormalities, including clinically significant conduction disorders or significant arrhythmias, QTcF interval >450 ms, PR interval is not between 120 and 220 ms (inclusive), HR >100 bpm or <50 bpm, QRS interval >110 ms, or QT intervals that cannot be consistently analyzed.
  13. Subject has a known allergy or sensitivity to any of the components of the investigational products.
  14. Subject has been exposed to excessive ultraviolet (UV) radiations on the treated zones within 1 month before Baseline visit or who is planning intensive UV exposure during the study (e.g., occupational exposure to the sun, sunbathing, phototherapy, etc.).
  15. Subject is inherently sensitive to sunlight.
  16. Subject is presumed to be abusing drug or alcohol at Screening or Baseline Visits based on medical history or current clinical symptoms.
  17. Subject is participating in another interventional clinical trial.

Relevance to patient case: not relevant