An Open-label, Phase 4 Study of Nirogacestat in Adult Premenopausal Females with Desmoid Tumor/Aggressive Fibromatosis (DT/AF).

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Springworks Therapeutics Inc.

Participant type

Patients

Age range

18-64 years

Gender

Female

Therapeutic area

Diseases [C] - Skin and Connective Tissue Diseases [C17]

Trial duration

24 Oct 2025 → ongoing

Decision date (initial)

2025-09-15

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

SpringWorks Therapeutics, Inc.

External identifiers

EU CT number

2024-515215-21-00

WHO UTN

U1111-1318-6025

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Pharmacokinetic

To determine the ovarian function recovery rate of ovarian toxicity (OT) treatment emergent adverse events (TEAEs).

Secondary objectives 3

1. 1.To determine the incidence of Ovarian Toxicity
2. 2.To determine the time to ovarian function recovery in participants with a TEAE of OT.
3. 3.To evaluate the safety and tolerability of nirogacestat.

Conditions and MedDRA coding

DESMOID TUMOURS/AGGRESSIVE FIBROMATOSIS (DT/AF)

Regulatory references

Scientific advice from competent authorities

Food And Drug Administration

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. 1.Participant must be female, postpubertal aged ≥18 and ≤40 years of age at the time of signing the informed consent and premenopausal at baseline.
2. 2.Participant is eligible to participate if she is not pregnant or breastfeeding, and the following conditions apply: - Is of childbearing potential but is abstinent or using at least 1 highly effective contraceptive method. - The participant has not harvested or donated eggs for the purpose of reproduction for at least 90 days prior to the first dose of nirogacestat and agrees to not harvest or donate eggs for the purpose of reproduction during the Treatment and Clinical Follow-up Periods.
3. 3.Participant has histologically confirmed DT/AF with symptomatic or progressive disease requiring systemic treatment.
4. 4.Participants who have received prior chemotherapy or radiation must meet the definition of premenopausal ≥2 weeks after the end of the final cycle of chemotherapy or final radiation treatment. Participants who have received prior gonadotoxic chemotherapy or pelvic radiotherapy are not eligible for this study.
5. 5.Participant has an Eastern Cooperative Oncology Group (ECOG) performance status ≤2 at screening.
6. 6.Participant has adequate organ and bone marrow function.
7. 7.Participant can swallow tablets and has no gastrointestinal conditions affecting absorption.
8. 8.Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form and in this protocol.

Exclusion criteria 14

1. 1.Participant has known malabsorption syndrome or preexisting gastrointestinal conditions that may impair absorption of nirogacestat.
2. 2.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 -Symptomatic pulmonary embolism
3. 3.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 with no evidence of metastatic disease for 3 years at the time of informed consent.
4. 4.Participant has known severe hepatic impairment.
5. 5.Participant previously received or is currently receiving therapy with gamma secretase (GS) inhibitors or anti-Notch antibody therapy.
6. 6.Participant is currently using any treatment for DT/AF including tyrosine kinase inhibitors (TKIs) or any investigational treatment within 28 days (or 5 half-lives, whichever is longer) prior to the first dose of study treatment. All toxicities from prior therapy must be resolved to Grade ≤1 or clinical baseline prior to the first dose of study treatment.
7. 7.Participant is currently using or anticipates using food or drugs that are known strong or moderate cytochrome P450 (CYP) 3A4 inhibitors or strong or moderate CYP3A inducers within 14 days or 5 half-lives (whichever is longer) prior to the first dose of study treatment.
8. 8.Participants 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.
9. 9.Participant is currently using or has used hormonal contraception or ovarian suppression within 90 days prior to the first dose of study treatment.
10. 10.Participant is currently enrolled or was enrolled within 28 days of first dose of study treatment in another clinical study with any investigational drug or device. Participationin observational studies may be permitted with prior approval from the medical monitor/sponsor.
11. 11.Participant has a history of heavy tobacco smoking (defined as ≥20 pack years) and/or is a current smoker (>1 pack per day) at the time of informed consent.
12. 12.Participant has experienced other severe acute or chronic medical or psychiatric conditions, including recent or active suicidal ideation or behavior, or a laboratory abnormality that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the participant inappropriate for entry into this study.
13. 13.Participant has known hypersensitivity to the active substance or to any of the excipients of nirogacestat.
14. 14.Participant is unable to comply with study-related procedures including, but not limited to the following: the completion of a menstrual diary and electronic patient-reported outcomes and the ability to return to the clinic for hormone level blood draws timed to the menstrual cycle (Day 1-5) at the required visits.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Ovarian function recovery rate of OT TEAEs. Ovarian function recovery is defined as achieving the resumption of ≥2 consecutive menstrual periods and an follicle stimulating hormone (FSH) level <30 mIU/mL with concomitant estradiol <80 pg/mL, OR resumption of ≥2 consecutive menstrual periods and anti-mullerian hormone (AMH) level within normal range adjusted for age and pretreatment baseline, OR a positive serum beta-human chorionic gonadotropin (β-HCG) pregnancy test.

Secondary endpoints 3

1. 1.Incidence of OT TEAEs. OT is defined as new onset amenorrhea lasting ≥3 consecutive menstrual periods, FSH level ≥30 mIU/mL, AND a negative β-HCG pregnancy test.
2. 2.Time to ovarian function recovery in participants with a TEAE of OT.
3. 3.Safety endpoints will include incidence of TEAEs, changes in laboratory parameters including hormones, vital signs, and physical examination findings. Tolerability will be assessed according to toxicities graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Springworks Therapeutics Inc.

Sponsor organisation

Springworks Therapeutics Inc.

Address

100 Washington Boulevard

City

Stamford

Postcode

06902-9302

Country

United States

Scientific contact point

Organisation

Springworks Therapeutics Inc.

Contact name

Cindy Garrison

Public contact point

Organisation

Springworks Therapeutics Inc.

Contact name

Cindy Garrison

Third parties 10

Locations

5 EU/EEA countries · 20 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 62 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications