⁃ This study will enroll approximately 40 participants diagnosed with DT. Participants must meet the following eligibility criteria to be enrolled:

• Age ≥ 18 years. Individuals younger than 18 years old are excluded. More than 99% of the population evaluated at MDACC with a diagnosis of DT is older than 18. Sixty-three percent of the population with a diagnosis of DT evaluated at MDACC are 10 - 54 years old. The remaining 37 percent are older than 54 years old. Additionally, most of the robust data related to dosing or adverse event data currently available on the use of nirogacestat is in adults

• Histologically documented DT with evidence of radiographic tumor progression (≥ 10% or absolute increase in dimensions of ≥ 10 mm in maximal diameter) in unidimensional measurement within the previous 18 months. Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension as ≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam

∙ Recurrent or primary disease

‣ Symptomatic disease or impending morbidity (as defined by physician) and patient and physician agree treatment would be of benefit

• Treatment naïve or progression on or after any prior therapy for DT. Participant must have discontinued prior therapy for at least 28 days or 5 half-lives of the drug, whichever is greater. All toxicities from prior therapy must be resolved to Grade ≤ 1 or clinical baseline. There is no limit on the number of previous systemic treatments received

• Able to tolerate radiographic progression (up to 20% increase in tumor longest diameter) as determined by treating oncologist based on morbidity and tumor growth is not threatening vital structures

• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2

• Are appropriate for systemic therapy

• Have accessible tumors for serial biopsies

• Agree to provide new tumor tissue. Tumor tissue from the archival (tumor bank) may be used if the biopsy is performed after discontinuation of prior therapy and the participant must have discontinued prior therapy for at least 28 days or five half-lives of the drug, whichever is greater

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated

⁃ Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load

⁃ Adequate organ and bone marrow function as defined by the following screening laboratory values:

• Absolute neutrophil count ≥ 1500 cells/μL;

∙ Platelets ≥ 100,000 μL;

∙ 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

∙ If Creatinine \> 1.5 x ULN then calculated creatinine clearance must be . 60 mL/min (using the Cockcroft-Gault formula).

⁃ Can swallow tablets and have no gastrointestinal conditions affecting absorption

⁃ Agree to the use of adequate contraception during the treatment period and for at least 4 months for men and women after the last dose of the study treatment (see Appendix 1 for more information)

⁃ Have the ability to understand and the willingness to sign a written informed consent document

⁃ English and non-English speaking patients

⁃ Participants with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this study

⁃ Participants with a known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification; to be eligible for this study, participants should be class 2B or better