Inclusion Criteria: 

• Participant must be at least 18 years of age at the time of signing the informed consent.
• Participant has histologically confirmed DT/AF (by local pathologist prior to informed consent) that has progressed by ≥ 20% as measured by RECIST v1.1 within 12 months of the screening visit scan.
• Participant has:
  • Treatment naïve, measurably progressing DT/AF that is deemed not amenable to surgery without the risk of significant morbidity; OR
  • Recurrent, measurably progressing DT/AF following at least one line of therapy; OR
  • Refractory, measurably progressing DT/AF following at least one line of therapy.
• Participant has a DT/AF tumor where continued progressive disease will not result in immediate significant risk to the participant.
• Participant agrees to provide archival or new tumor tissue for re-confirmation of disease.
• If participant is currently being treated with any therapy for the treatment of DT/AF, this must be completed at least 28 days (or 5 half-lives, whichever is longer) prior to first dose of study treatment. All toxicities from prior therapy must 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 the documented DT/AF progressive disease (inclusion criteria 2) and on a stable dose for at least 28 days prior to first dose of study treatment.  Participant has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 at screening.
• Participant has adequate organ and bone marrow function as defined by the following screening laboratory values:
  • Absolute neutrophil count ≥ 1500 cells/μL;
  • Platelets ≥ 100,000μL;
  • Hemoglobin ≥ 9 g/dL;
  • Total bilirubin ≤ 1.5 × upper limit of normal (ULN) (isolated bilirubin > 1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin < 35%);
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase)/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase) ≤ 2 × ULN; and
  • Serum creatinine ≤ 1.5 × ULN or if creatinine > 1.5 × ULN then calculated creatinine clearance must be ≥ 60 mL/min (using the Cockcroft-Gault formula).
• Participant can swallow tablets and has no gastrointestinal conditions affecting absorption.
• Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Male participants are eligible to participate if they agree to the following during the treatment period and for at least 90 days after the last dose of study treatment:
  • Refrain from donating sperm; PLUS either:
  • Be abstinent from sexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent; OR
  • Must agree to use a male condom when having sexual intercourse with women of childbearing potential (WOCBP). An additional form of contraception should also be used by the female partner, if she is of childbearing potential.
• A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
  • Is not of childbearing potential (not WOCBP); OR
  • Is of childbearing potential but is abstinent or using 1 highly effective contraceptive method during the treatment period and until 30 days after the last dose of study treatment. A second method of contraception is required if the participant is using oral contraception, as coadministration with nirogacestat may alter the plasma concentrations of oral contraceptives resulting in reduced efficacy.  Additionally, the participant agrees not to donate eggs (ova,  oocytes) for the purpose of reproduction during the treatment period and for at least 60 days after the last dose of study treatment. The investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study treatment.
  • A WOCBP must have a negative serum pregnancy test result at screening and a negative urine pregnancy test result at the baseline visit prior to the first dose of study treatment.
  • The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
• Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.

Exclusion Criteria: 

• Participant has known malabsorption syndrome or preexisting gastrointestinal conditions that may impair absorption of nirogacestat (e.g., gastric bypass, lap band, or other gastric procedures that would alter absorption); delivery of nirogacestat via nasogastric tube or gastrostomy tube is not allowed.
• 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 abnormal QT interval corrected by Fridericia’s formula (> 450 msec for male participants, > 470 msec for female participants, or > 480 msec for participants with bundle branch block) after electrolytes have been corrected (triplicate ECG readings, done approximately 2-3 minutes apart and averaged) at screening.
• Participant is using concomitant medications that prolong the QT/QTcF interval at the time of informed consent.
• 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 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 current or chronic history of liver disease or known hepatic or biliary abnormalities (except for Gilbert's syndrome or asymptomatic gallstones).
• Participant previously received or is currently receiving therapy with GS inhibitors or anti-Notch antibody therapy.
• Participant is currently using any treatment for DT/AF including tyrosine kinase inhibitors (TKIs), NSAIDs (chronic daily use) or any investigational treatment 28 days (or 5 half-lives, whichever is longer) prior to the first dose of study treatment.
• 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 known strong/moderate cytochrome P450 3A4 (CYP3A4) inhibitors, or strong CYP3A inducers within 14 days prior to the first dose of study treatment.
• 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. Participation in observational studies may be permitted with prior approval from the medical monitor/sponsor.
• 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.
  • NOTE: Participants with positive Hepatitis C antibody due to prior resolved disease can be enrolled, only if a confirmatory negative Hepatitis C RNA test is obtained.  Test is optional and participants with negative Hepatitis C antibody test are not required to also undergo Hepatitis C RNA testing.
• Participant is unable to tolerate MRI or for whom MRI is contraindicated.
• Participant with active or chronic infection at the time of informed consent and during the screening period.
• Participant has experienced other severe acute or chronic medical or psychiatric conditions, including recent (within 1 year of signing informed consent) 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.
• Participant has known hypersensitivity to the active substance or to any of the excipients of nirogacestat or placebo.
• Participant is unable to comply with study related procedures (including, but not limited to, the completion of electronic patient report outcomes (ePROs), or the ePRO questionnaires are not available in the participant’s preferred language).