Nirogacestat for premenopausal women with desmoid tumors

A Single-Arm, Open-Label Phase 4 Study of Nirogacestat in Adult Premenopausal Females With Desmoid Tumors/Aggressive Fibromatosis (DT/AF)

This trial tests whether nirogacestat affects ovarian function in premenopausal women (ages 18–40) with progressing desmoid tumors.

Quick facts

• Phase: PHASE4
• Study type: Interventional
• Enrollment: 50 (estimated)
• Ages: 18 Years to 40 Years
• Sex: Female
• Sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany (industry)
• Locations: 21 sites (Brussels and 20 other locations)
• Trial ID: NCT07176689 on ClinicalTrials.gov

What this trial studies

This open-label Phase 4 trial gives oral nirogacestat to postpubertal, premenopausal women with symptomatic or progressive desmoid tumors to measure ovarian toxicity events and the rates of ovarian function recovery. Participants must meet baseline hormone and menstrual criteria and have adequate organ function and ECOG ≤2. The study will also collect safety, tolerability, and efficacy data while monitoring reproductive hormones and menstrual patterns over time. Sites are located in Europe and the protocol includes regular in-person visits and laboratory assessments.

Who should consider this trial

Good fit: Ideal candidates are premenopausal women aged 18–40 with histologically confirmed, symptomatic or progressive desmoid tumors who meet baseline hormone and menstrual criteria, are not pregnant or breastfeeding, and have ECOG performance status ≤2.

Not a fit: Patients who are postmenopausal, older than 40, pregnant or breastfeeding, have pre-existing severe ovarian dysfunction, or do not have progressive disease requiring systemic therapy are unlikely to benefit from participation.

Why it matters

Potential benefit: If successful, the trial could clarify risks and recovery timelines for ovarian function after nirogacestat, helping patients and clinicians make informed treatment and fertility decisions.

How similar studies have performed: Nirogacestat has shown efficacy in treating desmoid tumors and is approved in the U.S., but focused data on ovarian toxicity incidence and recovery in premenopausal women remain limited.

Eligibility criteria

Inclusion Criteria:

* Participant is female, postpubertal aged ≥18 and ≤40 years of age at the time of signing the informed consent and premenopausal at baseline. Premenopausal is defined as meeting all of the following: Estradiol \>30 pg/mL. Follicle-stimulating hormone (FSH) \<40 IU/L. Regular menses (e.g., menstrual cycle length of 21 to 35 days) for at least 3 menstrual cycles prior to signing informed consent
* Participant uses 1 highly effective non-hormonal contraceptive method, has a negative pregnancy test prior to first dose of study treatment), is not breastfeeding, agrees to not harvest or donate eggs for at least 90 days prior to and during the study
* Participant has histologically confirmed DT/AF with symptomatic or progressive disease requiring systemic treatment
* Participant has an Eastern Cooperative Oncology Group (ECOG) performance status ≤2 at screening
* Participant has adequate organ and bone marrow function.

Exclusion Criteria:

* Participant has known malabsorption syndrome or preexisting gastrointestinal conditions that may impair absorption of nirogacestat
* Participant has experienced any of the following within 6 months of signing informed consent: clinically significant cardiac disease (New York Heart Association Class III or IV), myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident, transient ischemic attack, or symptomatic pulmonary embolism.
* Participant has had lymphoma, leukemia, or any malignancy within the past 5 years at the time of informed consent, except for any locally recurring cancer that has been treated curatively (e.g., resected basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix or breast), with no evidence of metastatic disease for 3 years at the time of informed consent.
* Participant has known hepatic impairment
* Participant previously received or is currently receiving gamma secretase inhibitors or anti-Notch antibody therapy
* Participant is currently using any treatment for DT/AF including tyrosine kinase inhibitors (TKIs) or any investigational treatment 28 days (or 5 half-lives, whichever is longer) prior to the first dose of study treatment
* Participant is currently using or anticipates using food or drugs that are known strong/moderate cytochrome P450 (CYP) 3A4 inhibitors, or strong CYP3A inducers within 14 days prior to the first dose of study treatment.
* Participant has a history of polycystic ovary syndrome, hypothalamic amenorrhea, severe endometriosis involving ovaries, family history of primary ovarian insufficiency, any chromosomal abnormality, mutation, gene variant or medical condition associated with early/premature menopause, including a history of OT while on a TKI
* Participant is currently using or has used hormonal contraception or ovarian suppression within 90 days prior to first dose of study treatment
* Participant has a history of heavy tobacco smoking (≥20 pack years) or is a current smoker (\>1 pack per day)
* Participant has experienced other severe acute or chronic medical or psychiatric conditions within 1 year of signing informed consent.
* Participant is unable to comply with study related procedures (including, but not limited to, the completion of a menstrual diary and electronic patient-reported outcomes and ability to return to clinic for hormone level blood draws timed to the menstrual cycle (days 1-5)

Where this trial is running

Brussels and 20 other locations

• Cliniques Universitaires Saint-Luc (CUSL) — Brussels, Belgium (RECRUITING)
• Universitätsklinikum Mannheim, Mannheim Cancer Center — Mannheim, Germany (RECRUITING)
• Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori" IRCCS IRST. S.r.l. — Meldola, Forli-Cesena, Italy (RECRUITING)
• Fondazione del Piemonte per l'Oncologia Istituto di Candiolo IRCCS — Candiolo, Torino, Italy (RECRUITING)
• IRCCS Istituto Ortopedico Rizzoli — Bologna, Italy (RECRUITING)
• IRCCS Azienda Ospedaliero-Universitaria S. Orsola — Bologna, Italy (RECRUITING)
• Istituto Nazionale Tumori I.R.C.C.S- Fondazione G. Pascale — Naples, Italy (RECRUITING)
• Fondazione Policlinico Unversitario Campus Bio-Medico di Roma — Roma, Italy (RECRUITING)
• Nederlands Kanker Instituut - Antoni van Leeuwenhoek Ziekenhuis (NKI-AVL) — Amsterdam, Netherlands (RECRUITING)
• LUMC — Leiden, Netherlands (RECRUITING)
• Hospital de la Santa Creu i Sant Pau — Barcelona, Spain (RECRUITING)
• Hospital General Universitario Gregorio Maranon — Madrid, Spain (RECRUITING)
• Hospital Universitario Jimenez Diaz — Madrid, Spain (RECRUITING)
• Hospital General Universitario Gregorio Maranon — Madrid, Spain (RECRUITING)
• Hospital Universitario La Paz — Madrid, Spain (RECRUITING)
• Hospital Universitario y Politecnico La Fe — Valencia, Spain (RECRUITING)
• Hospital Universitario Miguel Servet — Zaragoza, Spain (RECRUITING)
• Cambridge University Hospitals NHS Foundation Trust — Cambridge, United Kingdom (RECRUITING)
• University College London Hospitals NHS Foundation Trust — London, United Kingdom (RECRUITING)
• The Royal Marsden NHS Foundation Trust — London, United Kingdom (RECRUITING)
• The Christie NHS Foundation Trust — Manchester, United Kingdom (RECRUITING)

Study contacts

• Principal investigator: Winette van der Graff, MD — The Netherlands Cancer Institute
• Study coordinator: US Medical Information

Conditions: Desmoid Tumor, Aggressive Fibromatosis, Nirogacestat, PF-03084014, GSI, gamma secretase inhibitor, notch pathway, Ogsiveo