Nirogacestat for Adults With Desmoid Tumor/Aggressive Fibromatosis (DT/AF)

Double-Blind Key Inclusion Criteria:

• Participant has histologically confirmed DT/AF (by local pathologist prior toinformed consent) that has progressed by ≥ 20% as measured by RECIST v1.1 within 12months of the screening visit scan.

• Participant has:

1. Treatment naïve, measurably progressing DT/AF that is deemed not amenable tosurgery without the risk of significant morbidity; OR

2. Recurrent, measurably progressing DT/AF following at least one line of therapy;OR

3. Refractory, measurably progressing DT/AF following at least one line oftherapy.

• Participant has a DT/AF tumor where continued progressive disease will not result inimmediate significant risk to the participant.

• Participant agrees to provide archival or new tumor tissue for re-confirmation ofdisease.

• If participant is currently being treated with any therapy for the treatment ofDT/AF, this must be completed at least 28 days (or 5 half-lives, whichever islonger) prior to first dose of study treatment. All toxicities from prior therapymust be resolved to ≤Grade 1 or clinical baseline.

• Participants who are receiving chronic nonsteroidal anti-inflammatory drugs (NSAIDs)as treatment for conditions other than DT/AF must be receiving them prior to thedocumented DT/AF progressive disease (inclusion criteria 2) and on a stable dose forat least 28 days prior to first dose of study treatment.

• Participant has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2at screening.

• Participant has adequate organ and bone marrow function.

Double-Blind Key Exclusion Criteria:

• Participant has known malabsorption syndrome or preexisting gastrointestinalconditions that may impair absorption of nirogacestat.

• Participant has experienced any of the following within 6 months of signing informedconsent: clinically significant cardiac disease (New York Heart Association ClassIII or IV), myocardial infarction, severe/unstable angina, coronary/peripheralartery bypass graft, symptomatic congestive heart failure, cerebrovascular accident,transient ischemic attack, or symptomatic pulmonary embolism.

• Participant has an abnormal QT interval at screening.

• Participant is using concomitant medications that are known to prolong the QT/QTcFinterval including Class Ia and Class III antiarrhythmics at the time of informedconsent. Non-antiarrhythmic medications which may prolong the QT/QTcF interval areallowed provided the participant does not have additional risk factors for Torsadesde Pointes (TdP)

• Participant has congenital long QT syndrome.

• Participant has a history of additional risk factors for Torsades de Pointes (TdP) (e.g., heart failure, hypokalemia, family history of Long QT Syndrome).

• Participant has had lymphoma, leukemia, or any malignancy within the past 5 years atthe time of informed consent, except for any locally recurring cancer that has beentreated curatively (e.g., resected basal or squamous cell skin cancer, superficialbladder cancer, carcinoma in situ of the cervix or breast), with no evidence ofmetastatic disease for 3 years at the time of informed consent.

• Participant has current or chronic history of liver disease or known hepatic orbiliary abnormalities (except for Gilbert's syndrome or asymptomatic gallstones).

• Participant previously received or is currently receiving therapy with GS inhibitorsor anti-Notch antibody therapy.

• Participant is currently using any treatment for DT/AF including tyrosine kinaseinhibitors (TKIs), NSAIDs (chronic daily use) or any investigational treatment 28days (or 5 half-lives, whichever is longer) prior to the first dose of studytreatment.

OR

Participant has started any treatment for DT/AF after the documented DT/AF progressive disease.

• Participant is currently using or anticipates using food or drugs that are knownstrong/moderate cytochrome P450 3A4 (CYP3A4) inhibitors, or strong CYP3A inducerswithin 14 days prior to the first dose of study treatment.

• Participant has a positive human immunodeficiency virus antibody test.

• Participant has presence of Hepatitis B surface antigen at screening.

• Participant has a positive Hepatitis C antibody or Hepatitis C ribonucleic acid (RNA) test result at screening or within 3 months prior to starting study treatment.

• Participant is unable to tolerate MRI or for whom MRI is contraindicated.

• Participant with active or chronic infection at the time of informed consent andduring the screening period.

• Participant has experienced other severe acute or chronic medical or psychiatricconditions within 1 year of signing informed consent.

• Participant is unable to comply with study related procedures (including, but notlimited to, the completion of electronic patient report outcomes (ePROs), or theePRO questionnaires are not available in the participant's preferred language).

Open-Label Key Inclusion

• Participant is enrolled in the double-blind phase when the estimated number of PFSevents have been observed and the primary PFS analysis has been completed; OR

• Participant is randomized to receive placebo in the double-blind phase and CentralImaging Review determines that the participant has radiographic progressive disease;OR

• Participant is randomized to receive nirogacestat in the double-blind phase andCentral Imaging Review determines that the participant has radiographic progressivedisease but the participant is deriving clinical benefit without significanttoxicity (as determined by the investigator).

• Participant has adequate organ and bone marrow function

Open-Label Key Exclusion

• Participant requires surgery to prevent organ dysfunction.

• Participant has prematurely discontinued from the double-blind phase for any reasonother than radiographic progressive disease (as determined by Central ImagingReview).

• Participant developed a concurrent illness/condition that, in the opinion of theinvestigator, would represent a risk to overall health if they enroll in this study.

• Participant has initiated a new treatment for DT/AF after the Central Imaging Reviewdetermines that a participant has radiographic progressive disease.