(Z)-Endoxifen in Girls With MAS-Associated Peripheral Precocious Puberty

1. Female child aged ≥ 4 to \< 10 years at the time of informed consent.
2. Body weight ≥ 16 kg.
3. Clinical or molecular diagnosis of McCune-Albright syndrome (MAS), with peripheral precocious puberty and at least one additional characteristic manifestation of MAS other than café-au-lait skin macules, such as polyostotic fibrous dysplasia or another autonomous endocrine manifestation distinct from the participants PPP.
4. Clinical evidence of gonadotropin-independent (peripheral) precocious puberty, including onset of vaginal bleeding before 8 years of age and recurrent vaginal bleeding documented as at least 2 episodes during the prior 6 months.
5. Prepubertal or low-normal basal luteinizing hormone (LH) and follicle-stimulating hormone (FSH), consistent with predominantly gonadotropin-independent disease activity.
6. Advanced bone age, defined as bone age exceeding chronological age by ≥1 year at screening, determined using the protocol-specified standardized radiographic method and central or qualified local reading procedures.
7. Active peripheral estrogen activity at study entry that, in the Investigator's judgment, is the primary driver of current clinical manifestations.
8. Ability to swallow small capsules with water. Capsule-swallow training may be provided during screening using non-drug training capsules, or other age-appropriate standard site procedures.
9. Adequate hepatic, renal, hematologic, and coagulation function based on protocol-defined laboratory criteria.
10. Parent or legal guardian able and willing to provide written informed consent, with age-appropriate participant assent when applicable.
11. Participant and parent/caregiver are willing and able to comply with study visits, daily diary completion, study treatment administration, and required procedures.

Exclusion Criteria

1. Prior bilateral oophorectomy or hysterectomy.
2. Central precocious puberty (CPP).
3. The need for the use of GnRH agonists during the trial.
4. Use of a selective estrogen receptor modulator, aromatase inhibitor, other estrogen-modifying agent, or high-dose progestin within 1 month or 5-half-lives, whichever is longer.
5. Use of any bone-directed therapies.
6. Dominant central precocious puberty requiring initiation or intensification of gonadotropin-releasing hormone analog therapy at screening.
7. Clinically significant uncontrolled endocrinopathy likely to interfere with growth, safety, or interpretation of study outcomes, including uncontrolled hyperthyroidism, growth hormone excess, phosphate-wasting osteomalacia, or Cushing syndrome.
8. ALT or AST >3 × upper limit of normal (ULN), total bilirubin >2 × ULN, or other clinically significant hepatic impairment at screening (post-letrozole 14 day wash-out), unless the abnormality is explained, stable, and approved by the Sponsor Medical Monitor.
9. Clinically significant renal impairment, hematologic abnormality, or coagulation abnormality that may increase risk or confound interpretation.
10. History of venous thromboembolism or known hereditary thrombophilia.
11. Significant ophthalmic conditions, including cataracts
12. Known hypersensitivity to endoxifen, tamoxifen, or any formulation excipient.
13. Pregnancy or breastfeeding. Pregnancy testing applies only to post-menarche or otherwise at-risk participants as medically and ethically appropriate.
14. Participation in another interventional clinical study or receipt of another investigational product within 30 days or 5 half-lives, whichever is longer, before first dose, unless approved by the Sponsor.
15. Planned major surgery during the 3-month treatment period that could materially affect safety or endpoint assessment.
16. Any serious concomitant medical, developmental, behavioral, or psychiatric condition that, in the Investigator's judgment, would make participation unsafe, prevent reliable completion of study procedures, or compromise study integrity.