Study of Cryoablation and Nirogacestat for Desmoid Tumor

Inclusion Criteria:

1. Histologically-confirmed diagnosis of desmoid tumor (DT) that is progressing (byRECIST criteria over the past 12 months) or symptomatic (as defined by change inpain regimen or impairment of activities of daily living (ADLs), or at investigatordiscretion). Note: Must have diagnosis of desmoid tumor on pathology report.

2. Desmoid tumor is 50 to <75% cryoablatable. Tumors that are 50 to <75% (volume) ablatable in a single session are characterizedby:

3. Proximity (< 1 cm) to critical structures, such as nerves, vessels, bowel, orskin, at risk of injury during ablation, despite hydrodissection

4. Large size ( > 100 mL)

5. Complex shape, such that parts of the tumor cannot be reached from a singleapproach or subject position

6. Thin, infiltrative components, where ablation of that portion would damage morenormal anatomy than tumor (e.g., tumor extending along a fascial plane betweenmuscles, such that ablation would damage more muscle than tumor volume)

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

8. Participants who are receiving chronic nonsteroidal anti-inflammatory drugs (NSAIDs)as treatment for conditions other than DT must be on a stable dose for at least 28days prior to first dose of study treatment.

9. Age ≥ 18 years.

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

11. Participant has adequate organ and bone marrow function as defined by the followingscreening laboratory values:

12. Absolute neutrophil count ≥ 1500 cells/μL;

13. Platelets ≥ 100,000μL;

14. Hemoglobin ≥ 9 g/dL;

15. Total bilirubin ≤ 1.5 × upper limit of normal (ULN) (isolated bilirubin > 1.5 ×ULN is acceptable if bilirubin is fractionated and direct bilirubin < 35%);

16. Aspartate aminotransferase (AST) (serum glutamic oxaloacetictransaminase)/alanine aminotransferase (ALT) (serum glutamic pyruvatetransaminase) ≤ 2 × ULN; and

17. Serum creatinine ≤ 1.5 × ULN or if creatinine > 1.5 × ULN then calculatedcreatinine clearance must be ≥ 60 mL/min (using the Cockcroft-Gault formula)

18. Women of childbearing potential must have a negative serum pregnancy test atscreening.

19. Participant can swallow tablets.

20. Participant able to have MRI.

21. Ability to understand and the willingness to personally sign the writtenIRB-approved informed consent document.

22. Contraceptive use by men or women should be consistent with the standard that willbe used at Stanford regarding the methods of contraception for those participatingin clinical studies.

23. Male participants: Male participants are eligible to participate if they agreeto the following during the treatment period and for at least 90 days after thelast dose of study treatment: • Refrain from donating or preserving sperm;PLUS either:

• Be abstinent from sexual intercourse as their preferred and usuallifestyle (abstinent on a long-term and persistent basis) and agree toremain abstinent; OR
• Must agree to use a male condom when having sexual intercourse with womenof childbearing potential (WOCBP). An additional form of contraception asdescribed in Appendix G should also be used by the female partner, if sheis of childbearing potential.Postmenopausal state (not of childbearing potential) is defined as no mensesfor 12 months without an alternative medical cause.

2. Female participants: A female participant is eligible to participate if she isnot pregnant or breastfeeding, and at least one of the following conditionsapplies:

• Is not of childbearing potential (not WOCBP). OR
• Is of childbearing potential but is abstinent or using 1 highly effectivecontraceptive method, as described in Appendix H during the treatmentperiodand for at least 1 week after the last dose of active study treatment. A second method ofcontraception is required if the participant is using hormonalcontraception, as coadministration with nirogacestat may alter the plasmaconcentrations of hormonal contraceptives resulting reduced efficacy.Additionally, the participant agrees not to harvest or donate eggs (ova,oocytes) for the purpose of reproduction during the treatment period andfor at least 6 months after the last dose of active study treatment. Theinvestigator should evaluate the effectiveness of the contraceptive methodin relationship to the first dose of study treatment.
• The investigator is responsible for review of medical history, menstrualhistory, and recent sexual activity to decrease the risk for inclusion ofa woman with an early undetected pregnancy.

Exclusion Criteria:

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

2. Participant is currently using any treatment for DT including tyrosine kinaseinhibitors (TKIs), NSAIDS (chronic daily use - except as in inclusion criterion 4)or any investigational treatment 28 days (or 5 half-lives, whichever is longer)prior to the first dose of study treatment.

3. Participant is currently using or anticipates using food or drugs that are knownstrong or moderate cytochrome P450 3A4 (CYP3A4) inhibitors, or strong CYP3a inducerswithin 14 days prior to the first dose of study treatment.

4. Participant has known hypersensitivity to the active substance or to any of theexcipients of nirogacestat.

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

6. Participant has known malabsorption syndrome or preexisting gastrointestinalcondition that may impair absorption of nirogacestat (e.g., gastric bypass, lapband, or other gastric procedures that would alter absorption); delivery ofnirogacestat via nasogastric tube or gastrostomy tube is not allowed.

7. History of other high-grade malignancy ≤ 2 years previous. Exceptions include prioror concurrent malignancy whose natural history or treatment does not have thepotential to interfere with the safety or efficacy assessment of the investigationalregimen; adequately treated basal cell or squamous cell skin cancer; or adequatelytreated, with curative intent, cancer from which the subject is currently incomplete remission per study Principal Investigator's (PI's) judgment. Specificsituations can be discussed with study PI.

8. Participant has experienced any of the following within 6 months of signing informedconsent:

• Clinically significant cardiac disease (New York Heart Association Class III orIV);

• Myocardial infarction

• Severe / unstable angina

• Coronary / peripheral artery bypass graft

• Symptomatic congestive heart failure

• Cerebrovascular accident

• Transient ischemic attack

• Symptomatic pulmonary embolism

9. Participant has congenital long QT syndrome.

10. Participant has a history of additional risk factors for Torsades de pointes (TdP) (e.g., heart failure, hypokalemia, family history of long QT syndrome).

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

12. Participant is currently enrolled or was enrolled within 28 days of first dose ofstudy treatment in another clinical study with any investigational drug or device.

All subject files must include supporting documentation to confirm subject eligibility. The method of confirmation can include, but is not limited to, laboratory test results, radiology test results, subject self-report, and medical record review.