Nirogacestat in Premenopausal Females With Desmoid Tumor/Aggressive Fibromatosis (DT/AF)

Official title

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

Overview

This study is being conducted to study how nirogacestat may affect the ovarian function of adult premenopausal women with progressing desmoid tumors/aggressive fibromatosis.

Detailed description

Desmoid tumors, also referred to as aggressive fibromatosis, are rare, locally invasive, slow growing soft tissue tumors. Although considered benign because of their inability to metastasize, desmoid tumors can cause significant morbidity and occasionally mortality in patients.

Nirogacestat is a tumor inhibitor that works by slowing or stopping the growth of tumor cells. Nirogacestat is a tablet taken by mouth and has been approved in the USA for adult patients with progressing desmoid tumors who require systemic treatment.

This is an open-label study to characterize the incidence and ovarian function recovery rates of ovarian toxicity (OT) events and to evaluate the efficacy, safety, and tolerability of nirogacestat in postpubertal and premenopausal females with desmoid tumors (DT).

Interventions

• Drug Nirogacestat
  Nirogacestat oral tablet

Primary outcome measures

• Ovarian function recovery rate of ovarian toxicity (OT) treatment-emergent adverse events (TEAEs) [Time frame: Up to 24 cycles (each cycle is 28 days) of treatment and up to 2 years in the Clinical Follow-up Period]

Secondary outcome measures (3)

• Incidence of OT TEAEs [Time frame: Up to 24 cycles (each cycle is 28 days) of treatment and up to 2 years in the Clinical Follow-up Period]
• Time to ovarian function recovery in participants with a TEAE of OT [Time frame: Up to 24 cycles (each cycle is 28 days) of treatment and up to 2 years in the Clinical Follow-up Period]
• The incidence of adverse events (AEs) according to toxicities graded by National Cancer Institute (NCI) Common Technology Criteria for Adverse Events (CTCAE) Version 5 [Time frame: Up to 24 cycles (each cycle is 28 days) of treatment and up to 2 years in the Clinical Follow-up Period]

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)

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

Spain · 8 centers

• Hospital de la Santa Creu i Sant Pau — Barcelona
• Institut Catala d'Oncologia — Barcelona
• Hospital General Universitario Gregorio Maranon — Madrid
• Hospital Fundacion Jimenez Diaz — Madrid
• Hospital Universitario 12 de Octubre — Madrid
• Hospital Universitario La Paz — Madrid
• Hospital Universitari i Politecnic La Fe de Valencia — Valencia
• Hospital Universitario Miguel Servet — Zaragoza

Italy · 7 centers

• IRCCS Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori" - IRST S.r.l. — Meldola
• La Fondazione e l'Istituto di Candiolo — Candiolo
• IRCCS Azienda Ospedaliero-Universitaria di Bologna - Policlinico di Sant Orsola — Bologna
• IRCCS Istituto Ortopedico Rizzoli di Bologna — Bologna
• Fondazione IRCCS Istituto Nazionale dei Tumori Milano — Milan
• Istituto Nazionale Tumori I.R.C.C.S- Fondazione G. Pascale — Naples
• Policlinico Universitario Campus Bio-Medico — Roma

United Kingdom · 4 centers

• Cambridge University - Addenbrooke's Hospital — Cambridge
• University College London Hospital — London
• The Royal Marsden NHS Foundation Trust — London
• The Christie NHS Foundation Trust — Manchester

Netherlands · 2 centers

• Nederlands Kanker Instituut - Antoni van Leeuwenhoek Ziekenhuis (NKI-AVL) — Amsterdam
• Academisch Ziekenhuis Leiden — Leiden

Belgium · 1 center

• Cliniques Universitaires Saint-Luc (CUSL) — Brussels

Germany · 1 center

• Universitaetsmedizin Mannheim — Mannheim

Identifiers

NCT: NCT07176689 · NIR-DT-401 · 2024-515215-21-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗