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

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 (PF-03084014) is a potent, small molecule, selective, reversible, noncompetitive
inhibitor of γ-secretase (GS) with a potential antitumor activity.

Nirogacestat is being investigated for the treatment of desmoid tumors due to its ability to
bind to GS, blocking proteolytic activation of Notch receptors. Previous clinical study data
have shown that Notch signaling plays an important role in cancer development. Hence,
inhibition of Notch signaling is an important strategy for therapeutic treatment.

Key Inclusion Criteria:

- Participant has DT/AF that has progressed by ≥20% as measured by RECIST Version 1.1
Criteria within the 12-month period prior to first dose of study treatment.

- Participant has newly diagnosed, measurably progressing DT/AF that is not amenable to
surgical resection or radiation therapy; OR recurrent, progressing DT/AF following CR
to initial therapy; OR preexisting DT/AF and has previously received therapy and the
residual tumor has progressed.

- Participant agrees to provide archival or new tumor tissue for confirmation of
disease.

- If participant was previously treated with an investigational therapy for treatment of
DT/AF, participant must have completed prior therapy at least 28 days prior to signing
informed consent.

- Participants who are receiving nonsteroidal anti-inflammatory drugs (NSAIDs) as
treatment for conditions other than DT/AF.

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

- Participant has adequate organ and bone marrow function.

Key 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.

- Lymphoma, leukemia, or any malignancy within the past 5 years except for basal cell or
squamous epithelial carcinomas of the skin that have been resected with no evidence of
metastatic disease for 3 years.

- 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 or anticipates using a tyrosine kinase inhibitor within
28 days of study treatment.

- Participant is currently using or anticipates using food or drugs that are known
strong/moderate cytochrome P450 3A4 (CYP3A4) inhibitors or strong inducers within 14
days prior to the first dose of study treatment.

- Participant is currently using or anticipates using chronic daily NSAIDs for treatment
of DT/AF within 28 days of study treatment.

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

- Participant has experienced other severe acute or chronic medical or psychiatric
conditions within 1 year of study start.