Phase 4 Open-Label Study of Nirogacestat in Premenopausal Females with Desmoid Tumors/Aggressive Fibromatosis to Assess Ovarian Function Recovery Rate

The primary objective of this study is to determine the **ovarian function recovery rate** of ovarian toxicity (OT) treatment emergent adverse events (TEAEs) in adult premenopausal females with Desmoid Tumors/Aggressive Fibromatosis (DT/AF). This is clinically relevant as it addresses the potential impact of nirogacestat on ovarian health, which is a significant concern for premenopausal women undergoing treatment for DT/AF.

Secondary objectives include:

• Determining the incidence of ovarian toxicity.
• Assessing the time to ovarian function recovery in participants who experience OT as a TEAE.
• Evaluating the safety and tolerability of nirogacestat.

The clinical trial involves a total of **3 participants** who are exclusively **female**, postpubertal, and aged between **18 and 40 years**. These participants are premenopausal at baseline and have been diagnosed with **desmoid tumors/aggressive fibromatosis (DT/AF)**, exhibiting symptomatic or progressive disease necessitating systemic treatment. The study population was selected based on specific criteria, including the requirement for participants to not be pregnant or breastfeeding and to use effective contraceptive methods if of childbearing potential. Participants must have an **Eastern Cooperative Oncology Group (ECOG) performance status** of 2 or less and demonstrate adequate organ and bone marrow function. Additionally, they must be capable of swallowing tablets and not have any gastrointestinal conditions that could affect absorption. The trial does not include male subjects, and the population is considered vulnerable. Participants who have undergone prior gonadotoxic chemotherapy or pelvic radiotherapy are excluded from the study. The selection process ensures that participants can comply with the study's requirements and restrictions as outlined in the informed consent form.

The clinical trial is designed as a **single-arm, open-label, Phase 4 study** to evaluate the incidence and recovery rates of ovarian toxicity in postpubertal and premenopausal females with **desmoid tumors/aggressive fibromatosis (DT/AF)** treated with **nirogacestat**. The primary objective is to determine the ovarian function recovery rate of treatment-emergent adverse events (TEAEs) related to ovarian toxicity. The trial is expected to commence recruitment on September 30, 2025, and conclude by September 29, 2028, with a maximum treatment period of 24 months.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, reproductive status, and disease confirmation. The inclusion criteria require participants to be females aged 18 to 40 years, premenopausal, and not pregnant or breastfeeding. They must have histologically confirmed DT/AF requiring systemic treatment and meet specific health and reproductive conditions. The study will exclude those who have received prior gonadotoxic chemotherapy or pelvic radiotherapy.

Following the screening, participants will receive **nirogacestat** tablets orally, with a maximum daily dose of 300 mg. The study will include regular follow-up visits to monitor safety endpoints, including the incidence of TEAEs, changes in laboratory parameters, and vital signs. The primary endpoint is the ovarian function recovery rate, defined by the resumption of menstrual periods and specific hormone levels. Secondary endpoints include the incidence of ovarian toxicity TEAEs and time to ovarian function recovery.

The expected length of participant involvement is up to 24 months, with conditions for early termination including non-compliance with study protocols, withdrawal of consent, or adverse events that necessitate discontinuation. The end-of-study visit will assess the final outcomes and ensure the collection of all necessary data. The trial is not categorized as low intervention and adheres to the criteria of a Category 3 trial as per regulatory guidance.

The clinical trial involves the administration of **Nirogacestat**, an investigational medication, to evaluate its effects on ovarian function recovery in adult premenopausal females with **Desmoid Tumors/Aggressive Fibromatosis**. Nirogacestat is provided in the form of a **tablet** and is intended for **oral use**. The active substance in the medication is **nirogacestat hydrobromide**, which is of chemical origin. The maximum daily dose of Nirogacestat is 300 mg, with a total maximum dose of 300 mg per day. The treatment period is set for a maximum of 24 months. The medication is not formulated for pediatric use and is designated as an orphan drug under the designation number EU/3/19/2214.

In this study, Nirogacestat is the primary investigational product, and no additional non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The trial is designed as a single-arm, open-label study, meaning all participants will receive the investigational medication without a control group for comparison. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the prescribed regimen. The study aims to assess the recovery rate of ovarian function following treatment-emergent adverse events related to ovarian toxicity.

The efficacy of the clinical trial will be assessed by evaluating the **ovarian function recovery rate** of ovarian toxicity (OT) treatment emergent adverse events (TEAEs) in adult premenopausal females with desmoid tumors/aggressive fibromatosis (DT/AF). The primary endpoint is defined as the resumption of two or more consecutive menstrual periods and a follicle-stimulating hormone (FSH) level of less than 30 mIU/mL with concomitant estradiol levels below 80 pg/mL, or the resumption of two or more consecutive menstrual periods and an anti-mullerian hormone (AMH) level within the normal range adjusted for age and pretreatment baseline, or a positive serum beta-human chorionic gonadotropin (β-HCG) pregnancy test.

Secondary endpoints include the incidence of OT TEAEs, where OT is characterized by new onset amenorrhea lasting three or more consecutive menstrual periods, an FSH level of 30 mIU/mL or higher, and a negative β-HCG pregnancy test. Additionally, the time to ovarian function recovery in participants with a TEAE of OT will be measured. Safety endpoints will encompass the incidence of TEAEs, changes in laboratory parameters including hormone levels, vital signs, and physical examination findings. Tolerability will be assessed according to toxicities graded by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.