A Phase 2 Trial of Nirogacestat in Patients With Recurrent Ovarian Granulosa Cell Tumors
Phase: PHASE2
Conditions: Ovarian Granulosa-Stromal Tumor, Ovarian Granulosa Cell Tumor, Ovarian Cancer
Sponsor: SpringWorks Therapeutics, Inc.

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Protocol NIR-OGT-201 
Amendment 5 (19Mar2024) 
 
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TITLE PAGE 
A PHASE 2 TRIAL OF NIROGACESTAT IN PATIENTS WITH RECURRENT 
OVARIAN GRANULOSA CELL TUMORS  
Protocol Number: NIR-OGT-201 
Amendment Number:  5 
Compound Number: 
PF-03084014 (nirogacestat) 
Study Phase: 
Phase 2 
Short Title: 
Nirogacestat in Ovarian Granulosa 
Cell Tumors 
Sponsor Name: 
SpringWorks Therapeutics, Inc. 
Legal Registered Address: 
100 Washington Blvd, Stamford, CT 
06902, United States 
Regulatory Agency Identifying 
Number(s): 
Registry  
ID 
IND  
159545 
EudraCT 
EU CT 
number 
2022-001816-25 
2023-510239-12-00 
Approval Date 
19Mar2024 
Confidentiality Statement 
The information in this document is confidential information of SpringWorks Therapeutics, Inc. 
and is not to be disclosed without the prior written consent of SpringWorks. You are allowed to 
disclose the contents of this document only to your Institutional Review Board or Independent 
Ethics Committee and study personnel directly involved with conducting this protocol. Persons 
to whom the information is disclosed must be informed that the information is confidential and 
proprietary to SpringWorks and that it may not be further disclosed to third parties or used for 
any other purpose. The disclosure and use of information in this document are subject to a 
written confidentiality agreement between SpringWorks and your institution. 

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Protocol NIR-OGT-201 
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INVESTIGATOR’S AGREEMENT 
I have read the protocol entitled, “A Phase 2 Trial of Nirogacestat in Patients With Recurrent 
Ovarian Granulosa Cell Tumors” dated 19Mar2024 and agree to abide by all provisions set forth 
therein. 
I agree to comply with the International Council for Harmonisation Guidelines for Good Clinical 
Practice and applicable Food and Drug Administration regulations/guidelines and any local 
regulations per country. 
I agree to ensure that the confidential information contained in the protocol will not be used for 
any purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of SpringWorks Therapeutics. 
This protocol has been received for information only and must be implemented before all 
necessary regulatory agency and Ethics Committee / Institutional Review Board approval 
documents have been obtained. 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
Signature of Investigator 
 
 
 
 
Date 
 
The contents of this document are confidential and proprietary to SpringWorks Therapeutics. This document is made available 
for business operations and review by SpringWorks Therapeutics employees, contracting consultants of SpringWorks 
Therapeutics and regulatory agencies. Distribution to third parties without prior permission is prohibited. 

Nirogacestat
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Protocol NIR-OGT-201
Amendment 5 (19Mar2024)
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SIGNATORY
Shinta Cheng, MD
Vice President, Clinical Development
SpringWorks Therapeutics
Date
Nicole Leedom
Vice President, Clinical Operations
SpringWorks Therapeutics
Date
Vincent Amoruccio
Vice President, Biometrics
SpringWorks Therapeutics
Date
Jocelyn Lewis, DO
Medical Director, Clinical Development
SpringWorks Therapeutics
Date

SpringWorks Therapeutics

SpringWorks Therapeutics


SIGNATORY
SpringWorks Therapeutics
	

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Protocol NIR-OGT-201 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Table 1: 
Document History 
Document 
Date 
Amendment 5 
19 March 2024 
Amendment 4 
07 June 2023 
Amendment 3 
31 January 2023 
Amendment 2 
18 July 2022 
Amendment 1 
13 December 2021 
Original Protocol 
09 November 2021 
 
Amendment 5 (19Mar2024) 
Full description of all changes to the protocol can be found in the Summary of Rationale and 
Changes document. 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Protocol NIR-OGT-201 
Amendment 5 (19Mar2024) 
 
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1. 
PROTOCOL SUMMARY 
1.1. 
SYNOPSIS 
Protocol title: A Phase 2 trial of Nirogacestat in Patients with Recurrent Ovarian Granulosa 
Cell Tumors 
Short title: Nirogacestat in Ovarian Granulosa Cell Tumors 
Rationale:  
Epidemiology 
Ovarian granulosa cell tumors (OvGCTs) represent 5-7% of all ovarian cancers (~1.5 to 2k 
newly diagnosed patients/year in the United States (US)) and are the most common subtype of 
ovarian sex cord tumors (70%). The average age at diagnosis for OvGCT is 50 years: 12% of 
OvGCT patients are younger than 30 years and 57% are between the ages of 30 and 59 years 
(Torre et al. 2018). OvGCTs are usually slow growing and often do not lead to mortality, so 
prevalence is high relative to incidence. In a 2018 case series (Dridi et al. 2018), mean overall 
survival (OS) was 13 years (11–15 years) from time at diagnosis with a 10-year OS of 90%. 
OvGCTs tend to recur late after primary surgery and primary platinum-based therapy. The 
recurrence rate in case series was 32% to 44% (longest reported time to recurrence was 
40 years). Median recurrence free survival was 8.4 years (6.8–9.9 years) (Dridi et al. 2018). 
Clinical Description and Presentation 
OvGCTs originate from early ovarian mesenchyma and are composed of granulosa cells, theca 
cells, and fibroblasts.  
Hyperestrogenism is reported in patients with OvGCT and is related to tumor production 
of estrogens, anti-Müllerian hormone (AMH), and inhibin A and B. This hormone 
production differentiates OvGCT from serous ovarian cancer and could serve as a 
tumor-specific pharmacodynamic marker. 
A 2018 case series (Dridi et al. 2018), detailing 31 patients describes that sixty-one percent of 
cases presented with abdominal mass and/or abdominal pain, while postmenopausal bleeding 
was reported in 32% of cases. All cases underwent ultrasound imaging which showed mainly 
cystic unilateral masses in 80% of patients with a mean tumor size of 20cm (4-33cm). 
Significantly elevated levels of CA-125 were reported in 42% of OvGCT patients. 
Histologically, these tumors consisted of micro/macrofollicles with cores “coffee bean” 
(74%), Call-Exner bodies (55%), and necrosis (22%) – mitotic index measured in only 
22 patients was mainly low (64%). Local pelvic recurrence was seen in 70% of cases – only 
9% of recurrences were abdominopelvic, 6% were retroperitoneal, 6% were pelvic and 
retroperitoneal, and 3% were abdominopelvic and retroperitoneal. Metastatic locations were 
mainly liver (67%) and pleura (33%). 
Standard of Care and Unmet Need 
There are currently no Food and Drug Administration (FDA) approved therapies for OvGCT. 
Surgery, possibly with adjuvant chemotherapy, is the mainstay of initial treatment. Adjuvant 

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chemotherapy is typically with a platinum-based regimen: paclitaxel-carboplatin, 
cyclophosphamide-cisplatin, or bleomycin-etoposide-cisplatin. In the relapsed setting, which 
is the subject of this protocol, multiple chemotherapy regimens are used. These chemotherapy 
regimens are predominantly platinum based. After platinum, options are limited. One such 
example is bevacizumab.  Bevacizumab used as single agent or in combination with 
chemotherapy (taxane or doxorubicin) in post-platinum recurrence has only modest activity 
(Gershenson, Okamoto, and Ray-Coquard 2019). A randomized trial in recurrent OvGCT 
evaluating paclitaxel (N=32) vs. paclitaxel + bevacizumab (N=28) showed only modestly 
improved activity with the combination of paclitaxel +bevacizumab. Paclitaxel monotherapy 
had an Objective Response Rate (ORR) of 25% (95% CI: 12-43%). Although the addition of 
bevacizumab increased the ORR to 44% (95% CI: 26-65%) no improvement in Progression 
Free Survival at 6 months (PFS-6) was seen. PFS-6 of paclitaxel + bevacizumab was 72% 
(95% CI: 57-89%) vs. PFS-6 of paclitaxel monotherapy of 71% (95% CI: 53-84%) in the trial 
(Ray-Coquard et al. 2020). Hormonal therapy (HT) has also been used in recurrent OvGCT 
and has shown some activity albeit inferior to that of paclitaxel. A retrospective analysis of HT 
(Meurs et al. 2015) showed an ORR of 18% with PFS and disease specific survival of 10 and 
36 months respectively.  
ORR from any monotherapy in the relapse setting is low. Furthermore, combination therapy in 
the relapse setting has failed to show an improvement in PFS rates. Therefore, there is an 
unmet need in this patient population for an agent with a higher response rate and the potential 
to improve PFS.  
Scientific Rationale 
NOTCH, particularly NOTCH-2 and 3, is an essential pathway for embryonic development of 
the ovary and function of the ovarian follicle (essential for development of mature oocytes and 
production of steroid hormones). Notch expression and function is important throughout 
follicle development and is an integral component of granulosa cell development, proliferation 
and function (Vanorny and Mayo 2017). Knockout or inhibition of Notch or Notch-related 
signaling genes in mice leads to poorly developed ovaries and/or development of primary 
ovarian failure (POF). Mutations in the Notch pathway (NOTCH-2, NOBOX, FOXO1, 
FOXO3, PTEN, WNT4 and FOXL2) have been associated with primary ovarian insufficiency 
(POI) and POF in humans. (Qin et al. 2007; Fortuño and Labarta 2014; Grzechocińska et al. 
2019) Notch activation induces granulosa cell tumor proliferation while decreasing apoptotic 
cell death (Irusta et al. 2013). Inhibition of Notch by DAPT (r N-[N-(3,5- difluorophenacetyl)-L-
alanyl]-S-phenylglycine t-butyl ester), a γ-secretase inhibitor, in KGN cells (steroidogenic human 
granulosa-like tumor cell line harboring the FOXL2 C134W mutation) led to a decrease in 
proliferation and activation of apoptosis pathways via inhibition of PI3K/AKT signaling.   
FOXL2 is the most important gene implicated in the development of OvGCT with more than 
97% of OvGCT having a mutation in FOXL2 [C402G; C134W] (Li et al. 2018). An 
autosomal gene, FOXL2 is a transcription factor and member of the forkhead-winged helix 
family and, is one of the earliest known markers of ovarian differentiation. FOXL2 is required 
for normal development and function of granulosa cells (mainly expressed in undifferentiated 
granulosa cells) and is involved in ovarian granulosa cell proliferation, follicle development 
and ovarian hormones synthesis. The wild-type FOXL2 protein may also act as a tumor 
suppressor under certain circumstances by inducing apoptosis in damaged granulosa cells, 

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increasing DNA repair, slowing the cell cycle and suppressing growth factor signaling 
(Caburet et al. 2012; Benayoun et al. 2010).  Li et al. (2018) has shown that overexpression of 
FOXL2 induces apoptosis in ovarian cells (including granulosa cells). STAT3, a likely 
transcription factor for FOXL2 (Han et al., 2017), is activated in the presence of active Notch 
and the Notch effector proteins hairy and enhancer of split (Hes) which facilitate complex 
formation between JAK2 and STAT3 (Kamakura et al, 2004). Therefore, activation of Notch 
signaling is directly involved in the expression of FOXL2 which may provide a check on 
notch-induced proliferation.    
An in vitro study in granulosa and sertoli cell lines suggested that the ability of FOXL2 
C134W to induce apoptosis in these cells is impaired (compared to WT) (Kim et al. 2011). 
Kim et al propose that the FOXL2 C134W transcription factor exhibits reduced expression of 
“death receptors” TNF-R1, Fas and TRAIL-R1. The reduced “death receptor” expression 
results in lower activation of the caspase apoptosis pathway.  Granulosa cell proliferation and 
differentiation are governed, in part, by TGF-β receptor signaling through multiple SMAD 
proteins. Multiple receptor ligands, activins, inhibins, BMP, and AMH are involved. Both 
Notch Intracellular Domain (NICD) and FOXL2 interact with SMAD proteins to induce gene 
transcription. 
An increase in growth factor (TGFβ) signaling in cells expressing the FOXL2 C134W mutant 
is believed to be due to a gain in SMAD function. In vitro studies indicate that FOXL2 
C134W acquires the ability to bind to SMAD4, forming a complex with SMAD2/3 with a 
unique DNA binding motif leading to activation of TGFβ signaling and possibly driving 
proliferation of GCTs (Weis-Banke et al. 2020; Rosario et al. 2012). 
Active Notch also Promotes Cell Proliferation through PI3K/AKT signaling 
pAKT (via PI3K) is anti-apoptotic through inhibition of FOXO and Bcl-2 expression. 
Uncontrolled PI3K/AKT signaling in oocytes is oncogenic and has been shown to irreversibly 
develop granulosa cell tumors (GCTs). Negative regulation of PI3K occurs partly by the tumor 
suppressor PTEN (Li et al. 2018). PTEN mutation leads to over-phosphorylation and 
activation of AKT, thereby driving cell proliferation. HES1, a transcription product of 
activated Notch, is a repressor of PTEN. In the absence of HES1, PI3K is inactivated by 
PTEN (Li et al. 2018). 
Therefore, treatment with of granulosa cell tumors with a gamma secretase (GS) inhibitor is 
expected to inhibit Notch-induced granulosa cell proliferation by (1) limiting activation of 
growth factor signaling by the FOXL2 mutant protein, (2) inhibiting proliferation signaling 
through NICD and (3) by inducing apoptosis through the pAKT activation.   

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Objectives and Endpoints 
Primary Objectives: 
Primary Endpoints: 
To determine the anti-tumor activity of 
nirogacestat in adult participants with 
relapsed/refractory OvGCT 
Objective response rate, defined as the 
proportion of participants with Complete 
Response (CR) + Partial Response (PR) 
using Response Evaluation Criteria in Solid 
Tumors (RECIST) v1.1  
Secondary Objectives: 
Secondary Endpoints: 
To determine if nirogacestat delays 
progression or death in OvGCT 
Estimate of proportion of participants who 
have not progressed or died at 6 months 
follow-up: PFS-6. Progression is defined by 
RECIST v1.1 
To describe overall survival in participants 
treated with nirogacestat 
Estimate of 2-year overall survival, defined 
as the proportion of participants who have 
not died after 2 years of follow-up after their 
first dose of nirogacestat 
To determine the effect of nirogacestat on 
ovarian cancer symptoms measured by 
Functional Assessment of Cancer Therapy – 
Ovarian Symptom Index (FOSI) 
Change from baseline in FOSI 
To determine the duration of response 
Duration of response (DoR), defined as the 
time from first assessment of response (CR + 
PR using RECIST v1.1) to first disease 
progression defined by RECIST v1.1 or 
death, whichever comes first 
To determine the pharmacokinetics (PK) of 
nirogacestat 
Serum concentrations of nirogacestat will be 
measured to evaluate system exposures 
(Cmax, Ctrough and other PK parameters as data 
allow) 

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Safety Objectives 
Safety Endpoints 
To characterize the safety and tolerability of 
nirogacestat at a dose of 150 mg BID in adult 
participants with relapsed/refractory OvGCT 
Key safety endpoints will include incidence 
of treatment-emergent Adverse Events 
(TEAEs), changes in clinical laboratory 
parameters, vital signs, physical examination 
findings, and electrocardiograms (ECGs) 
Tolerability will be assessed according to 
toxicities graded by National Cancer Institute 
Common Terminology Criteria for Adverse 
Events (CTCAE) v5.0 
Exploratory Objectives 
Exploratory Endpoints 
To detect FOXL2 C134W mutation as well as 
other genomic alterations and correlate these 
with response 
Evaluate Next Generation Sequencing (NGS) 
status in baseline tumor tissue 
To detect NICD and candidate biomarkers of 
response, and to correlate nirogacestat 
exposure with response 
Evaluate change from Baseline:  
• Inhibin A&B, Follicle-stimulating 
hormone (FSH), estradiol, CA-125, 
and Müllerian Inhibiting Substance 
(MIS) / AMH  
• Circulating tumor DNA (ctDNA) 
Baseline NICD expression in tumor tissue 
To describe progression free survival on 
continued nirogacestat treatment post first 
disease progression 
Progression free survival on prolonged 
nirogacestat treatment, defined as time from 
first disease progression per RECIST v1.1 to 
second disease progression on continued  
nirogacestat treatment confirmed by 
investigator discretion or death, whichever 
comes first 
To describe progression free survival on 
subsequent line of anticancer treatment 
Progression free survival 2 (PFS2), defined as 
time from first dose of nirogacestat to second 
disease progression on subsequent line of 
anticancer treatment (after nirogacestat) 
confirmed by investigator discretion at long 
term safety follow-up visit or death, 
whichever comes first 

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Overall design: This is a multi-center, single-arm, Phase 2 open label treatment study to 
determine the efficacy, safety, tolerability, and pharmacokinetics of nirogacestat in adult 
participants with relapsed/refractory OvGCT. Participants must have received at least one 
prior course of systemic therapy for OvGCT and have measurable disease by RECIST v1.1 to 
meet the eligibility criteria.  
Participants will be screened up to 28 days prior to the first dose of study treatment 
(nirogacestat) and full eligibility will be based on the inclusion and exclusion criteria 
(Sections 7.1 and 7.2).  
Eligible participants will be enrolled in the study using the Interactive Response Technology 
(IRT) system following all pre-dose baseline assessments at Cycle 1 Day 1 (C1D1). Following 
C1D1, participants will return to the clinic for scheduled study visits monthly for the first year 
and then every 3 months thereafter until end of study participation.  
Participants who discontinue study treatment early for any reason should return to the clinic 
for an End of Treatment (EOT) visit within 7 days after the Investigator determines study 
treatment will no longer be used and then again for a safety Follow-up (FUP) visit 30 days 
(+7 days) after the last dose of study treatment.  
The estimated study duration is 3 years, and all participants will be followed for at least 2 
years (unless the study is prematurely stopped due to futility). 
A Bayesian strategy allowing continuous monitoring will be used to evaluate the posterior 
distribution of ORR (complete + partial) (J. Lee and Liu 2008; Chen et al. 2019) and the study 
may be stopped for futility if necessary. There will be no pause in accrual for interim 
assessments. 
Disclosure Statement: Single-arm open label treatment study 
Number of participants: Approximately 43 participants 
Treatment groups and duration:  
At C1D1 participants will be enrolled in the study using the IRT system and will receive 
150 mg (orally) BID of study treatment (nirogacestat; 3 × 50 mg tablets), continuously in 
28-day cycles. 
Participants will remain on study treatment until death, disease progression (unless the 
participants meet criteria for continued treatment as defined in Section 9), discontinuation of 
study treatment for any reason, the study is stopped by the Sponsor for any reason, or 
participant qualifies for Sponsor’s Compassionate Use Program. 
Data Monitoring committee: No 

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1.2. 
SCHEMA 
Figure 1: 
Schema 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1Refer to Section 6.1 for more detail on accrual milestones. 
2If the Response Rate falls below 15%, the study may be stopped for futility. See Table 11 for Probability of Early Stopping. 
 
 
N = ~43 
Increase N1 to ~43 
Rule out ORR 
< 15% 
Screening 
and 
Enrollment 
Continuous assessment of futility using 
Bayesian rules with Imaging data collected 
every 2 months for 6 months, then every 3 
months until EOT. There will be no pause in 
accrual for interim assessments2 
Final estimate 
of ORR with 
95% CI, PFS-6 
Baseline 
tumor 
measurements 

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1.3. 
SCHEDULE OF ASSESSMENTS (SOA) 
Table 2: 
Schedule of Assessments 
Cycle Number/Day 
Screening1 
C1D1 
(Baseline)3 
C2D1  
C3D1, 
C4D1, 
C5D1, 
C6D1, 
C7D1 
C8D1, 
C9D1, 
C10D1, 
C11D1, 
C12D1, 
C13D1 
Cycle 16 
& Every 3 
Cycles 
(C16, 
C19, C22, 
etc.)23 
EOT25 
Safety 
FUP26 
2-year 
Survival  
Check-In27 
Visit Week 
 
Week 
1 
Week 
5 
Weeks 
9,13,17, 
21,25 
Weeks 
29,33,37, 
41,45,49 
Weeks 
61,73,85 
& On 
 
 
Week 
104 
Calendar Day 
 
Day  
1 
Day  
29 
Days 
57,85,113, 
141,169 
Days 
197,225, 
253,281,3
09, 337 
Days  
421,505,5
89 & On 
 
 
Day 
722 
(Visit Window) 
(Up to 28 
days before 
Day 1) 
(Up to 48 
hours prior 
to 1st dose) 
( 2 days) 
( 2 days) 
( 2 days) 
( 7 days) 
See 
footnote 
25 for visit 
window 
30 days  
after last 
dose 
(+7 days) 
~2 years after 
first dose 
Informed consent2 
X 
 
 
 
 
 
 
 
 
I/E criteria 
X 
X 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
Medical history including 
menstrual history 
X 
 
 
 
 
 
 
 
 
ECOG performance status4 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical examination 
(including pelvic exam)5 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs6 
X 
X 
X 
X 
X 
X 
X 
X 
 
Weight/height7 
X 
X 
X 
X 
X 
X 
X 
X 
 
Single 12-lead ECG8 
X 
X8a 
(post dose) 
X8b 
(pre-& 
post dose) 
 
 
 
X 
X 
 

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Cycle Number/Day 
Screening1 
C1D1 
(Baseline)3 
C2D1  
C3D1, 
C4D1, 
C5D1, 
C6D1, 
C7D1 
C8D1, 
C9D1, 
C10D1, 
C11D1, 
C12D1, 
C13D1 
Cycle 16 
& Every 3 
Cycles 
(C16, 
C19, C22, 
etc.)23 
EOT25 
Safety 
FUP26 
2-year 
Survival  
Check-In27 
Visit Week 
 
Week 
1 
Week 
5 
Weeks 
9,13,17, 
21,25 
Weeks 
29,33,37, 
41,45,49 
Weeks 
61,73,85 
& On 
 
 
Week 
104 
Calendar Day 
 
Day  
1 
Day  
29 
Days 
57,85,113, 
141,169 
Days 
197,225, 
253,281,3
09, 337 
Days  
421,505,5
89 & On 
 
 
Day 
722 
(Visit Window) 
(Up to 28 
days before 
Day 1) 
(Up to 48 
hours prior 
to 1st dose) 
( 2 days) 
( 2 days) 
( 2 days) 
( 7 days) 
See 
footnote 
25 for visit 
window 
30 days  
after last 
dose 
(+7 days) 
~2 years after 
first dose 
Laboratory 
Tumor biopsy9 
(archival or fresh) 
X 
 
 
 
 
 
 
 
 
Blood for serology10 
X 
 
 
 
 
 
 
 
 
Blood for  
PK sampling11 
 
 
X11a 
(pre - & 
post dose  
X11b 
(pre-dose) 
 
 
 
 
 
Blood for  
ctDNA biomarkers 
 
X 
 
X 
(C3D1)  
 
 
X 
 
 
Blood for  
safety labs12 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood for  
hormone levels13a 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood for  
tumor markers13b 
 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysis14 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood/Urine  
for pregnancy test 
(WOCBP only)15 
X 
(serum)15a 
X 
(urine)15b 
X 
(urine)15c 
X 
(urine)15c 
X 
 
(monthly; urine)15.d 
X 
(urine)15c 
X 
(urine)15c 
 

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Cycle Number/Day 
Screening1 
C1D1 
(Baseline)3 
C2D1  
C3D1, 
C4D1, 
C5D1, 
C6D1, 
C7D1 
C8D1, 
C9D1, 
C10D1, 
C11D1, 
C12D1, 
C13D1 
Cycle 16 
& Every 3 
Cycles 
(C16, 
C19, C22, 
etc.)23 
EOT25 
Safety 
FUP26 
2-year 
Survival  
Check-In27 
Visit Week 
 
Week 
1 
Week 
5 
Weeks 
9,13,17, 
21,25 
Weeks 
29,33,37, 
41,45,49 
Weeks 
61,73,85 
& On 
 
 
Week 
104 
Calendar Day 
 
Day  
1 
Day  
29 
Days 
57,85,113, 
141,169 
Days 
197,225, 
253,281,3
09, 337 
Days  
421,505,5
89 & On 
 
 
Day 
722 
(Visit Window) 
(Up to 28 
days before 
Day 1) 
(Up to 48 
hours prior 
to 1st dose) 
( 2 days) 
( 2 days) 
( 2 days) 
( 7 days) 
See 
footnote 
25 for visit 
window 
30 days  
after last 
dose 
(+7 days) 
~2 years after 
first dose 
Patient-Reported Outcomes (PROs) 
FOSI16 
X 
X 
X 
X 
X 
X 
X 
X 
 
Imaging 
CT or MRI scan  
for tumor measurement  
(using RECIST v1.1)17a 
X 
 
 
X 
(C3D1, 
C5D1, 
C7D1) 
X 
(C10D1, 
C13D1) 
X 
X17c 
 
 
Chest imaging  
CXR/CT scan17b 
X 
 
 
X 
(C3D1, 
C5D1, 
C7D1) 
X 
(C10D1, 
C13D1) 
X 
X17c 
 
 
Enrollment and Study Treatment 
Pre-Enrollment  
Review Form18 
X 
 
 
 
 
 
 
 
 
Enrollment19 
 
X 
 
 
 
 
 
 
 
Study treatment dispensing20 
 
X 
X 
X 
X 
X 
 
 
 
Study treatment 
administration & 
Dosing Diary21 
 
X 
 
 
 

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Cycle Number/Day 
Screening1 
C1D1 
(Baseline)3 
C2D1  
C3D1, 
C4D1, 
C5D1, 
C6D1, 
C7D1 
C8D1, 
C9D1, 
C10D1, 
C11D1, 
C12D1, 
C13D1 
Cycle 16 
& Every 3 
Cycles 
(C16, 
C19, C22, 
etc.)23 
EOT25 
Safety 
FUP26 
2-year 
Survival  
Check-In27 
Visit Week 
 
Week 
1 
Week 
5 
Weeks 
9,13,17, 
21,25 
Weeks 
29,33,37, 
41,45,49 
Weeks 
61,73,85 
& On 
 
 
Week 
104 
Calendar Day 
 
Day  
1 
Day  
29 
Days 
57,85,113, 
141,169 
Days 
197,225, 
253,281,3
09, 337 
Days  
421,505,5
89 & On 
 
 
Day 
722 
(Visit Window) 
(Up to 28 
days before 
Day 1) 
(Up to 48 
hours prior 
to 1st dose) 
( 2 days) 
( 2 days) 
( 2 days) 
( 7 days) 
See 
footnote 
25 for visit 
window 
30 days  
after last 
dose 
(+7 days) 
~2 years after 
first dose 
Study treatment 
accountability 
 
 
X 
X 
X 
X 
X 
 
 
Ongoing Monitoring 
ConMed review 
X 
 
 
AE/AESI/SAE review22 
X 
 
 
Remote monthly  
wellness checks24 
 
 
 
 
X 
 
 
 
 
Survival check-in27 
 
 
 
 
 
 
 
 
X 
AE = adverse event; AESI = adverse event of significant interest; BID = twice daily; ConMed = concomitant medication; ctDNA = circulating tumor DNA; CT = computed 
tomography; CXR = chest x-ray; ECG = electrocardiogram;; ECOG = Eastern Cooperative Oncology Group; EOT = end of treatment; FOSI = Functional Assessment of Cancer 
Therapy – Ovarian Symptom Index; FUP = follow-up; ICF = informed consent form; I/E = inclusion/exclusion; MRI = magnetic resonance imaging; PK = pharmacokinetic; 
PRO = patient-reported outcome; RECIST = Response Evaluation Criteria in Solid Tumors; SAE = serious adverse event; SoA = schedule of assessments; v = version; 
WOCBP = women of child bearing potential. 
Footnotes: 
1. 
Screening visit: Assessments may occur up to 28 days prior to first dose of study treatment. An extension to the screening period may be permitted on a case-by-case basis 
following discussion between the Investigator and the Medical Monitor. The reason(s) for the extension must be clearly documented. 

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2. 
Informed consent process: Includes participant signing the Informed Consent Form (ICF) and must be conducted prior to any study related procedures being performed. The 
date the participant signs the ICF will be Day 1 of the screening period. Refer to Appendix A1-3 for more detail on the ICF process. 
3. 
Baseline visit: Assessments may be performed over a 48-hour period. All Baseline assessments are to be conducted prior to first dose of study treatment. 
4. 
ECOG performance status: At Baseline, assessment must be done prior to first dose of study treatment. Refer to Appendix A4-2 for ECOG scale. 
5. 
Physical examination: At Baseline, assessment must be done prior to first dose of study treatment. A pelvic exam is also required for participants whose disease can be 
evaluated by pelvic exam. Refer to Section 11.2.2 for detail regarding physical examination requirements. 
6. 
Vital signs: Includes blood pressure, respiratory rate, heart rate, and body temperature (should follow at least 5 minutes of rest). At Baseline, assessment must be done prior 
to first dose of study treatment and should be done prior to blood draws when possible. Refer to Section 11.2.3 for more detail. 
7. 
Height/Weight: Height is required at Screening only. A historical height measured within 1 year prior to signing informed consent may be used as the screening height. 
Weight to be collected at applicable study visits as described in the SoA. 
8. 
Single 12-lead ECGs: ECGs will be collected as described in the SoA and read locally at the site. Participants should rest in a semi-recumbent supine position for at least 5 
minutes prior to ECG collection and ECGs should be done after collection of vital signs when possible. Refer to Section 11.2.4 for more detail. 
a. 
C1D1: a single ECG is required 1-hour (±10 minutes) post-dose. 
b. 
C2D1: a single ECG is required pre-dose and 1-hour (±10 minutes) post-dose. 
9. 
Tumor biopsy: At Screening, a core needle fresh biopsy is only required if archival tissue is not available for study procedures. If the archival tumor is used for the baseline 
sample, or if a fresh biopsy is collected, then sufficient tissue should be provided as a Formalin-Fixed Paraffin-Embedded (FFPE) block or FFPE unstained slides. If 
applicable, the fresh biopsy should be collected 7 or more days prior to first dose of study treatment. If tumor biopsy and imaging are performed on the same day, it is 
recommended that the biopsy is performed after imaging. Refer to the central laboratory manual for additional details. 
10. Serology: Only required at Screening and to include testing for hepatitis B virus (hepatitis B surface antigen), hepatitis C virus (hepatitis C antibody [Hepatitis C virus 
polymerase chain reaction, if hepatitis C antibody positive]), and human immunodeficiency virus. Refer to Appendix A4-1 for details.  
11. PK sampling: Refer to Section 11.5 and central laboratory manual for sample processing details. For all pre-dose PK samples, the evening before applicable study visits, 
participants will record the exact time study treatment was taken in the Dosing Diary. Participants will hold their planned morning dose of study treatment the day of the 
applicable pre-dose PK study visit and will take their dose after the pre-dose sample is collected.  
a. 
C2D1: a pre-dose PK sample is required prior to the morning dose of study treatment and a post-dose sample is required approximately 1-hour after the 
morning dose of study treatment.  
b. 
C3-C7: a pre-dose PK sample is required prior to the morning dose of study treatment. 
12. Safety Labs (hematology, serum chemistry): At baseline, must be done prior to first dose of study treatment. Refer to Appendix A4-1 for a complete list of analytes.  
13. Hormone Levels and Tumor Markers: 
a. 
Hormone Levels: Blood for FSH, LH, Estradiol and Progesterone will be obtained at specific times described in the SoA table. Baseline sample must be done 
prior to first dose of study treatment. Refer to the central laboratory manual for sample processing details.  
b. 
Tumor Markers: Blood for Inhibin A, Inhibin B, AMH/MIS and CA-125 will be obtained at specific times described in the SoA table. Baseline sample must be 
done prior to first dose of study treatment. Refer to the central laboratory manual for sample processing details.  
14. Urinalysis: At Baseline, must be done prior to first dose of study treatment. Refer to Appendix A4-1 for a complete list of analytes. Microscopy is to be performed only as 
needed based on positive dipstick test results and only if blood or protein is abnormal. 
15. Serum / Urine pregnancy tests: Only required for WOCBP participants. Throughout the study, serum pregnancy tests may be conducted in place of urine pregnancy tests if 
required by local regulations (sites should follow institutional standards). Refer to Section 11.2.6 for more detail. 
a. 
Screening: serum pregnancy test is required.  
b. 
Baseline (C1D1): urine pregnancy test is required prior to first dose of study treatment to reconfirm eligibility.  
c. 
C1-C13, EOT and FUP: urine pregnancy tests are required at each study visit. 

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d. 
Following C13: In between study visits, participants are required to return to the site for monthly (every 28 days [+/- 2 days]) urine pregnancy tests. If it is 
more convenient for the participant, they may alternatively visit a local laboratory that has been pre-approved by the Sponsor (or designee) for this assessment.  
16. PROs: Participants will complete the FOSI in the clinic at applicable study visits. When possible, the questionnaire should be given as the first assessment during the study 
visit to minimize participant bias. Refer to Section 11.1.2.1. 
17. Tumor imaging: All scans will be performed and read locally. Same modality used at Screening must be used at each subsequent imaging visits. Standard of care scan(s) 
acquired prior to the participant signing ICF may be used as the participant’s screening visit scan(s) if obtained within 28 days of the first dose of study treatment. On 
treatment scans may be performed (-) 7 days prior to the visit or within the study visit window as described in the SoA. Refer to Section 11.1.1 for more detail. 
a. 
Tumor imaging/measurement using RECIST v1.1: CT or MRI scans (contrast required unless contraindicated) will be acquired per the SoA to assess tumor 
changes. Tumor response and progression of cancer under study in real time will be evaluated locally at each study site according to RECIST v1.1. All 
RECIST measurements will be done by the site’s local radiologist. Imaging must be done prior to tumor biopsy if assessments occur on the same day.  
b. 
Chest imaging: CXR or CT (contrast not required) required as described in the SoA and should be obtained per institutional standards.   
c. 
EOT Visit: Scans only required if not performed within the last 6 weeks.  
18. Pre-Enrollment Review Form: This form should be submitted at least 2 days prior to C1D1 in order to allow the Medical Monitor to review and approve eligibility prior to 
the participant being enrolled in the Interactive Response Technology IRT system (refer to the study reference manual for additional details) 
19. Enrollment: Participants will be enrolled during the C1D1 visit, using the IRT system, only after all baseline assessments have been completed and participant has been 
confirmed to meet all eligibility criteria.  
20. Study treatment dispensing: Participants will be dispensed study treatment using the IRT every cycle for the first year (C1-C13) and then every 3 cycles thereafter. 
21. Study treatment administration/Dosing Diary: The first dose of study treatment (3 × 50 mg tablets) will be administered orally at the site at C1D1 followed by a 1-hour 
observation period. Following the first dose, participants will self-administer study treatment at 150 mg (3 × 50 mg tablets) twice daily (BID) (approximately every 12 hours, 
without regard to food) continuously in 28-day cycles throughout the study. Participants should record daily administration of each study treatment dose in the Dosing Diary. 
Refer to Section 8 for more detail. 
22. AEs/AESIs/SAEs: Will be monitored and documented from the time of informed consent up to 30 days after the last dose of study treatment. Participants reporting 
AEs/AESIs/SAEs of reproductive system disorders will have hormone levels assessed every 3 months until event resolution (or for at least 90 days after discontinuing study 
treatment).  
23. Every 3 Cycles and On: Following C13D1 participants will return every 3 cycles for study visits until end of study participation. 
24. Remote Monthly Wellness Checks: Monthly (every 28 days [+/- 2 days]) telephone or email contact is required following C13D1 until EOT. The wellness checks may be 
replaced by a face-to-face interaction when study visits occur, provided the wellness information can be obtained during the visit. Refer to Section 11.2.7 for more detail. 
25. EOT visit: The End of Treatment (EOT) visit should be conducted within 7 days after the Investigator determines that study treatment will no longer be used.  
26. Safety Follow-up (FUP): The Safety FUP visit will be conducted 30 days (+ 7 days) after the last dose of study treatment.  
27. 2-year Survival Check-In: The final 2-year survival check-in will occur approximately 2 years after the first dose of study treatment. If participant discontinues from study 
treatment prior to the 2-year check-in, quarterly telephone or email contact following EOT is required until the 2-year survival data point has been collected. In addition, 
collection of subsequent anticancer therapy after nirogacestat and overall response to this therapy will be recorded. Only information about the subsequent therapy used 
directly after nirogacestat is required along with the final survival outcome at the 2-year check point. Refer to Section 11.2.8 for more detail.  

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2. 
TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
INVESTIGATOR’S AGREEMENT ...............................................................................................2 
SPONSOR’S SIGNATORY ............................................................................................................3 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ..........................................................4 
1. 
PROTOCOL SUMMARY ............................................................................................5 
1.1. 
Synopsis ........................................................................................................................5 
1.2. 
Schema ........................................................................................................................11 
1.3. 
Schedule of Assessments (SoA) .................................................................................12 
2. 
TABLE OF CONTENTS ...........................................................................................18 
LIST OF TABLES .........................................................................................................................23 
LIST OF FIGURES .......................................................................................................................23 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................24 
4. 
INTRODUCTION ......................................................................................................29 
4.1. 
Study Rationale ...........................................................................................................29 
4.2. 
Background .................................................................................................................29 
4.3. 
Benefit/Risk Assessment ............................................................................................32 
5. 
OBJECTIVES AND ENDPOINTS ............................................................................33 
6. 
STUDY DESIGN .......................................................................................................34 
6.1. 
Overall Design ............................................................................................................34 
6.2. 
Scientific Rationale for Study Design ........................................................................35 
6.3. 
Justification for Dose ..................................................................................................36 
6.4. 
End of Study Definition ..............................................................................................36 
7. 
STUDY POPULATION .............................................................................................36 
7.1. 
Inclusion Criteria ........................................................................................................36 
7.2. 
Exclusion Criteria .......................................................................................................38 
7.3. 
Lifestyle Considerations .............................................................................................40 
7.3.1. 
Meals and Dietary Restrictions ...................................................................................41 
7.4. 
Screen Failures ............................................................................................................41 
8. 
STUDY TREATMENT ..............................................................................................41 

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8.1. 
Study Treatment Administered ...................................................................................41 
8.1.1. 
Dosing Administration ................................................................................................43 
8.1.2. 
Preparation/Handling/Storage/Accountability ............................................................43 
8.2. 
Study Treatment Compliance .....................................................................................43 
8.3. 
Concomitant Therapy .................................................................................................44 
8.3.1. 
Known Drug Interactions ...........................................................................................44 
8.3.1.1. 
CYTOCHROME P450 INHIBITORS AND INDUCERS ..................................44 
8.3.1.2. 
CYTOCHROME 3A4 SUBSTRATES ...............................................................44 
8.3.1.3. 
ANTI-EMETIC AND ANTI-DIARRHEAL THERAPY ...................................45 
8.3.1.4. 
OTHER CONCOMITANT THERAPY ..............................................................45 
8.3.2. 
Excluded/Restricted Concomitant Medications and/or Procedures ...........................45 
8.3.3. 
Supportive Care ..........................................................................................................47 
8.3.3.1. 
PHOSPHATE SUPPLEMENTS .........................................................................47 
8.3.3.2. 
PALLIATIVE CARE ..........................................................................................47 
8.4. 
Dose Modification ......................................................................................................47 
9. 
DISCONTINUATION OF STUDY TREATMENT AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................48 
9.1. 
Discontinuation of Study Treatment ...........................................................................50 
9.1.1. 
Liver Chemistry Stopping Criteria .............................................................................50 
9.1.2. 
QTcF Stopping Criteria ..............................................................................................51 
9.1.3. 
Pregnancy ...................................................................................................................51 
9.2. 
Participant Discontinuation/Withdrawal from the Study ...........................................51 
9.3. 
Lost to Follow Up .......................................................................................................52 
10. 
DURATION OF STUDY ...........................................................................................52 
11. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................52 
11.1. 
Efficacy Assessments .................................................................................................53 
11.1.1. 
Tumor Imaging ...........................................................................................................53 
11.1.2. 
Other Objective Parameters ........................................................................................54 
11.1.2.1. 
PATIENT-REPORTED OUTCOMES (PROS) ..................................................54 
11.2. 
Safety Assessments .....................................................................................................54 

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11.2.1. 
Demographics Data and Medical History ...................................................................54 
11.2.2. 
Physical Examinations and Eastern Cooperative Oncology Group Performance 
(ECOG) Status ............................................................................................................55 
11.2.3. 
Vital Signs ..................................................................................................................55 
11.2.4. 
Electrocardiograms .....................................................................................................55 
11.2.5. 
Clinical Safety Laboratory Assessments ....................................................................55 
11.2.6. 
Pregnancy Testing ......................................................................................................56 
11.2.7. 
Remote Monthly Wellness Checks .............................................................................56 
11.2.8. 
2-Year Survival Check-In ...........................................................................................57 
11.3. 
Adverse Events (AEs), Adverse Events of Special Interest (AESIs), Serious Adverse 
Events (SAEs), Special Situations, and Pregnancy ....................................................57 
11.3.1. 
Adverse Events of Special Interest .............................................................................57 
11.3.2. 
Time Period and Frequency for Collecting Safety Event Information .......................59 
11.3.3. 
Method of Detecting AEs/AESIs/SAEs/Special Situations .......................................60 
11.3.4. 
Follow-up of AEs/AESIs/SAEs/Special Situations ....................................................60 
11.3.5. 
Regulatory Reporting Requirements for SAEs ...........................................................60 
11.3.6. 
Pregnancy ...................................................................................................................60 
11.4. 
Treatment of Overdose ...............................................................................................61 
11.5. 
Pharmacokinetics ........................................................................................................61 
11.6. 
Biomarkers ..................................................................................................................62 
12. 
STATISTICAL CONSIDERATIONS .......................................................................62 
12.1. 
Statistical Hypotheses .................................................................................................62 
12.2. 
Sample Size and Design Characteristics .....................................................................63 
12.3. 
Statistical Analyses .....................................................................................................65 
12.3.1. 
Efficacy Analyses .......................................................................................................65 
12.3.2. 
Safety Analyses ..........................................................................................................66 
12.3.3. 
Other Analyses ............................................................................................................67 
12.4. 
Interim Analyses .........................................................................................................67 
12.4.1. 
Data Monitoring Committee .......................................................................................67 
13. 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
 ....................................................................................................................................68 

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APPENDIX 1. REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS ..................................................................................................68 
A1-1. 
REGULATORY AND ETHICAL CONSIDERATIONS ..........................................68 
A1-2. 
FINANCIAL DISCLOSURE .....................................................................................68 
A1-3. 
INFORMED CONSENT PROCESS ..........................................................................69 
A1-4. 
DATA PROTECTION ...............................................................................................69 
A1-5. 
DATA QUALITY ASSURANCE ..............................................................................70 
A1-6. 
SOURCE DOCUMENTS ...........................................................................................70 
A1-7. 
STUDY AND SITE CLOSURE .................................................................................71 
A1-8. 
PUBLICATION POLICY ..........................................................................................71 
APPENDIX 2. PROHIBITED CONCOMITANT MEDICATIONS .........................................72 
APPENDIX 3. RECIST CRITERIA V1.1 ..................................................................................73 
APPENDIX 4. SAFETY ASSESSMENTS ................................................................................76 
A4-1. 
CLINICAL LABORATORY TESTS .........................................................................76 
A4-2. 
EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE .................79 
A4-3. 
LIVER SAFETY: SUGGESTED ACTIONS AND FOLLOW-UP ASSESSMENTS
 ....................................................................................................................................79 
A4-4. 
CORRECTED QT INTERVAL (QTC) PROLONGATION RISK ...........................81 
A4-5. 
CKD-EPI CREATNINE EQUATION .......................................................................81 
APPENDIX 5. ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ......................83 
A5-1. 
DEFINITIONS ...........................................................................................................83 
A5-1.1. 
Adverse Event (AE) ....................................................................................................83 
A5-1.2. 
Adverse Events of Special Interest (AESI) ................................................................84 
A5-1.3. 
Serious Adverse Event (SAE) ....................................................................................84 
A5-1.4. 
Special Situations ........................................................................................................85 
A5-1.5. 
Adverse Drug Reaction (ADR), Serious Adverse Reaction (SAR) and Suspected 
Unexpected Serious Adverse Reaction (SUSAR) ......................................................86 
A5-2. 
RECORDING, EVALUATING AND FOLLOW-UP ...............................................86 
A5-2.1. 
Recording AEs / AESIs / SAEs / Special Situations ..................................................86 
A5-2.2. 
Evaluating AEs / AESIs / SAEs / Special Situations .................................................87 

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A5-2.2.1. Severity .......................................................................................................................87 
A5-2.2.2. Causality .....................................................................................................................87 
A5-2.3. 
Follow Up ...................................................................................................................88 
A5-3. 
REPORTING ..............................................................................................................88 
APPENDIX 6. CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION ........................................................................................................89 
A6-1. 
WOMEN OF CHILDBEARING POTENTIAL (WOCBP) DEFINITION ...............89 
A6-2. 
CONTRACEPTION GUIDANCE .............................................................................90 
A6-3. 
COLLECTION OF PREGNANCY INFORMATION ...............................................91 
APPENDIX 7. GENETICS .........................................................................................................92 
A7-1. 
USE/ANALYSIS OF DEOXYRIBONUCLEIC ACID (DNA) .................................92 
APPENDIX 8. LIST OF CONTACTS FOR STUDY ................................................................93 
A8-1. 
SPONSOR ..................................................................................................................93 
A8-2. 
CONTRACT RESEARCH ORGANIZATION .........................................................93 
A8-3. 
REFER TO THE STUDY REFERENCE MANUAL.MEDICAL MONITORING ..93 
A8-4. 
SERIOUS ADVERSE EVENT REPORTING ...........................................................93 
14. 
REFERENCES ...........................................................................................................94 
 
 
 

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LIST OF TABLES 
Table 1: 
Document History .........................................................................................................4 
Table 2: 
Schedule of Assessments ............................................................................................12 
Table 3: 
Abbreviations and Specialist Terms ...........................................................................24 
Table 4: 
Objectives and Endpoints ...........................................................................................33 
Table 5: 
Study Treatment Administered ...................................................................................42 
Table 6: 
Excluded/Restricted Medications and/or Procedures .................................................46 
Table 7: 
Dose Modifications or Interruptions for Selected Toxicities .....................................48 
Table 8: 
Bundle Branch Block Discontinuation Criteria ..........................................................51 
Table 9: 
Adverse Events of Special Interest (AESI) ................................................................58 
Table 10: AESI/SAE/Special Situation Reporting Timeframes .................................................59 
Table 11: Simulated Probability of Early Stopping under Assumed ORR .................................64 
Table 12: Exact 95% CI Given Observed ORR ..........................................................................65 
Table 13: Statistical Method for Efficacy Analyses ...................................................................66 
Table 14: Protocol-Required Laboratory Assessments ...............................................................77 
 
LIST OF FIGURES 
Figure 1: 
Schema ........................................................................................................................11 
Figure 2: 
Liver Chemistry Stopping Criteria and Increased Monitoring Algorithm .................50 
 
 

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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Table 3: 
Abbreviations and Specialist Terms  
Abbreviation or specialist term 
Explanation 
ADL 
Activities of Daily Living 
ADR 
Adverse drug reaction 
AE 
Adverse event 
AESI 
Adverse event of special interest 
AF 
Aggressive Fibromatosis 
AKT 
Protein Kinase B 
ALT 
Alanine Aminotransferase 
AMH 
Anti-Müllerian Hormone 
ANC 
Absolute Neutrophil Count 
ARAs 
Acid Reducing Agents 
AST 
Aspartate Aminotransferase 
BEP 
bleomycin, etoposide, plus cisplatin  
Bcl-2 
B-cell lymphoma 2 
BID 
Twice daily 
C 
Cycle 
CA 125 
Cancer Antigen 125 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CKD-EPI 
Creatinine Kinase Disease Epidemiology Collaboration 
Cmax 
Maximum plasma concentration 
Ctrough 
Plasma trough concentration 
CONSORT 
Consolidated Standards of Reporting Trials 
COVID-19 
Coronavirus Disease 2019 
CPK 
Creatine phosphokinase 
CR 
Complete response 
CRF 
Case report form 
CSR 
Clinical Study Report 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
Circulating tumor DNA 

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Abbreviation or specialist term 
Explanation 
CXR 
Chest x-ray 
CYP2B6 
Cytochrome P450 2B6 
CYP2C8 
Cytochrome P450 2C8 
CYP2C9 
Cytochrome P450 2C9 
CYP3A4 
Cytochrome P450 3A4 
D 
Day 
DAPT 
r N-[N-(3,5- difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester 
DDI 
Drug-drug interaction 
DNA 
Deoxyribonucleic acid 
DT 
Desmoid tumor 
DTP 
Direct to Patient 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic Data Capture 
eGFR 
Estimated Glomerular Filtration Rate 
EOT 
End of Treatment 
Fas 
Apoptosis antigen 1 
FDA 
Food and Drug Administration 
FFPE 
Formalin-Fixed Paraffin-Embedded 
FIGO 
International Federation of Gynecology and Obstetrics  
FOSI 
Functional Assessment of Cancer Therapy – Ovarian Symptom Index 
FOXL2 
Forkhead box protein L2 
FOXO1 
Forkhead box protein O1 
FOXO3 
Forkhead box protein O3 
FSH 
Follicle-stimulating hormone 
FUP 
Follow-up 
GCP 
Good Clinical Practice 
GCT 
Granulosa cell tumors 
GOG 
Gynecologic Oncology Group 
GS 
γ-secretase 
H2 
Histamine 2 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 

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Abbreviation or specialist term 
Explanation 
HCT 
Hematocrit 
HCV 
Hepatitis C virus 
Hes1 
Hairy and Enhancer of Split 1 
Hes4 
Hairy and Enhancer of Split 4  
HGB 
Hemoglobin 
HIPAA 
Health Insurance Portability and Accountability Act 
HRT 
Hormonal Replacement Therapy 
HT 
Hormonal therapy 
HIV 
Human immunodeficiency virus 
HPLC 
High performance liquid chromatography 
HR 
Heart rate 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent ethics committee 
IgG 
Immunoglobulin G 
IHC 
Immunohistochemistry 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IUD 
Intrauterine device 
IUS 
Intrauterine hormone releasing system 
K-M 
Kaplan-Meier 
LD 
Longest dimension 
LDH 
Lactate dehydrogenase 
LH 
Luteinizing Hormone 
MIS 
Müllerian Inhibiting Substance 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum tolerated dose  
N 
Sample size 
NE 
Not evaluable 
NGS 
Next Generation Sequencing  
NICD 
Notch Intracellular Domain 
No. 
Number 

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Abbreviation or specialist term 
Explanation 
NOBOX 
Newborn ovary homeobox protein 
ORR 
Objective Response Rate 
OS 
Overall survival 
OvGCT 
Ovarian granulosa cell tumors 
PCR 
Polymerase chain reaction 
PD 
Progressive Disease 
PFS 
Progression free survival 
PFS2 
Progression free survival 2 
PFS-6 
Progression free survival at 6 months 
P-gp 
P-glycoprotein 
pH 
potential Hydrogen 
PI3K 
Phosphoinositide 3-kinases 
PK 
Pharmacokinetics 
PPI 
Proton pump inhibitor 
POF 
Primary ovarian failure 
POI 
Primary ovarian insufficiency 
PR 
Partial Response 
PRO 
Patient-reported outcomes 
PTEN 
Phosphatase And Tensin Homolog 
QD 
Once daily 
QRS 
QRS complex 
QT 
Uncorrected QT interval 
QTc 
Corrected QT interval 
QTcF 
Corrected QT interval by Fredericia 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
Ribonucleic acid 
RP2D 
Recommended phase 2 dose  
RSI 
Reference safety information 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SAR 
Serious adverse reaction 
SCST 
Sex cord-stromal tumor 
SD 
Stable disease 
SGOT 
Serum glutamic-oxaloacetic transaminase  

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Abbreviation or specialist term 
Explanation 
SGPT 
Serum glutamic-pyruvic transaminase  
SMAD 
Mothers against decapentaplegic homolog 
SoA 
Schedule of Assessments  
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TdP 
Torsades de Pointes 
TEAE 
Treatment Emergent Adverse Event 
TGF-β 
Transforming growth factor-β 
TKI 
Tyrosine kinase inhibitors 
TNF-R1 
Tumor Necrosis Factor R1 
TRAIL R1 
Tumor Necrosis Factor – Related Apoptosis-Inducing Ligand R1 
ULN 
Upper Limit of Normal 
US 
United States 
WNT4  
Wingless/integrated Family Member 4 
WOCBP 
Woman of Childbearing Potential 

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4. 
INTRODUCTION 
SpringWorks Therapeutics is developing nirogacestat which is a potent, small molecule, 
selective, reversible, non-competitive inhibitor of γ-secretase (GS) for the treatment of desmoid 
tumors (DT). The rationale for developing a GS inhibitor in cancer is supported by emerging 
evidence that Notch signaling, activated by GS cleavage, can drive the growth of a wide range of 
tumors. 
4.1. 
STUDY RATIONALE 
The purpose of this phase 2, single-arm study is to assess the anti-tumor activity of nirogacestat 
in adult participants with relapsed/refractory ovarian granulosa cell tumors (OvGCTs). In 
ongoing clinical trials for desmoid tumors, effects on ovarian function have been reported for 
female participants receiving nirogacestat. High levels of Follicle-stimulating hormone (FSH) 
not typical in pre-menopausal women have been detected in this study and are consistent with 
pituitary response to decreased sex steroid production.  
These effects appear to be the result of NOTCH inhibition in human ovaries by nirogacestat. 
Further support for this suggested mechanism was seen in pre-clinical mouse models. These 
models show that the Notch signaling pathway, particularly the NOTCH 2 protein, is important 
in the differentiation and proliferation of ovarian granulosa cells (Zhang et al. 2011; Prasasya 
and Mayo 2018). The results from the clinical trials for desmoid tumors, strongly support that 
nirogacestat is capable of inhibiting NOTCH function in the growth of desmoid tumors the 
mechanism of which should translate to the development and growth of OvGCTs. 
Standard of care treatment for relapsed/refractory OvGCT is platinum-based chemotherapy 
consisting of bleomycin, etoposide, and cisplatin or carboplatin and paclitaxel. These 
chemotherapy regimens, however, are not associated with durable remissions and most patients 
eventually develop progressive disease (PD) necessitating treatment with experimental agents. In 
prior studies in progressive OvGCTs, experimental agents have shown promise with only modest 
performance. In the Gynecologic Oncology Group (GOG) study of bevacizumab monotherapy, 
the Objective Response Rate (ORR) was 16.7% with a median Progression Free Survival (PFS) 
of 9.3 months (Brown et al. 2014). Combination therapy of bevacizumab with paclitaxel showed 
an improved ORR of 44% compared to 25% for paclitaxel monotherapy but did not improve PFS 
(Ray-Coquard et al. 2020). 
Our hypothesis is that treatment of relapsed/refractory OvGCT with nirogacestat 150 mg twice 
daily (BID) will provide at least ORR of 30% with a secondary objective of improved duration 
of PFS and Overall Survival (OS) compared to bevacizumab monotherapy. Refer to Table 4 for 
study Objectives and Endpoints. 
4.2. 
BACKGROUND 
Granulosa cell tumors (GCT) of the ovary belong to the ovarian sex cord-stromal tumors 
(SCSTs), a group of benign and malignant neoplasms that develop from the sex cord (e.g., 
granulosa cell tumors, Sertoli cell tumors) or stromal cells (e.g., Leydig cell tumors, fibromas) or 

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both. Granulosa cell tumors are the most common type of malignant ovarian SCSTs comprising 
90% of malignant SCSTs and 2 to 5 percent of all ovarian malignant neoplasms (Quirk and 
Natarajan 2005; Young 2005). Granulosa cell tumors of the ovary are divided into adult and 
juvenile types based on different clinical and histopathologic features (Schumer and Cannistra 
2003). The juvenile type represents only 5% of cases and usually occurs in prepubertal girls and 
women younger than 30 years (Young 2005; Powell et al. 1993). The adult type most commonly 
presents during the perimenopausal or early postmenopausal period, with a median age of 
diagnosis between 50 and 54 years (Dridi et al. 2018; Kottarathil et al. 2013). There are no 
widely accepted clinically defined risk factors for this disease. Importantly, unlike epithelial 
ovarian cancer, there seems to be no known inherited predisposition for the development of these 
tumors, i.e. no association with germline mutations in BRCA1 and BRCA2 genes and no 
association with germline mutations in mismatch repair genes (Schumer and Cannistra 2003; 
Färkkilä et al. 2017). 
Abdominal pain and abnormal uterine bleeding are the most common presenting symptoms 
(Koukourakis et al. 2008). Abdominal pain is related to the fact that GCTs can be hemorrhagic 
and large. Given its highly vascular nature, GCTs may occasionally present with hemorrhagic 
rupture of the tumor into the abdominal cavity and development of hemoperitoneum (Schumer 
and Cannistra 2003; Färkkilä et al. 2017; W.-L. Lee et al. 1999). Postmenopausal bleeding is due 
to prolonged exposure of the endometrium to tumor-derived estradiol, resulting in endometrial 
hyperplasia or endometrial adenocarcinoma. In premenopausal women, menstrual irregularity, 
menorrhagia, or even secondary amenorrhea may be the initial manifestation, while rarely, 
infertility (possibly due to increased inhibin secretion) may be the initial manifestation (Dridi et 
al. 2018; Segal, DePetrillo, and Thomas 1995). In premenarchal girls, isosexual precocious 
pseudo-puberty may be the initial presentation (Levin et al. 2018).  
Microscopically, GCTs consist of small, round or oval granulosa cells with characteristic 
“coffee-bean” nuclei (Young 2005; King et al. 1996). Call-Exner bodies are characteristic of 
granulosa cell tumors and appear in 30% to 60% of cases; these constitute small cystic areas of 
fluid and cellular debris surrounded by well-differentiated granulosa cells (Young 2005; 
Ranganath R. et al. 2008). Call-Exner bodies and coffee-bean grooved nuclei are infrequent in 
the juvenile type of granulosa cell tumors (Powell et al. 1993; Ranganath R. et al. 2008). 
Granulosa cell tumors are hormonally active and therefore several tumor markers have been used 
for postoperative surveillance and evaluation of response to therapy. Although estradiol may be 
helpful in monitoring the status of some patients, it is not a reliable marker because of a lack of 
consistent correlation between estradiol levels and tumor burden as well as disease progression; 
of note, absence of estradiol secretion is observed in approximately 30% of patients 
(Schumer and Cannistra 2003; Lappöhn et al. 1989). Inhibin is a more reliable marker of disease 
activity than estradiol and can serve as a useful marker of GCT activity in both pre- and 
postmenopausal women (Lappöhn et al. 1989). The alpha subunit of inhibin may associate with 
one of two distinct beta subunits, leading to the formation of either inhibin A or inhibin B. 
Although both inhibins may serve as tumor markers and should both be evaluated, inhibin B is 
more frequently elevated in patients with this disease (Robertson et al. 1999). Anti-müllerian 

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hormone (AMH), also referred to as Müllerian inhibitory substance (MIS) is another tumor 
marker for GCTs in postmenopausal and post-oophorectomy women (Färkkilä et al. 2017; 
Long et al. 2000). AMH is produced by the granulosa cells in the developing follicles of the 
ovary and AMH levels are elevated in a cyclical fashion throughout reproductive life but become 
undetectable in the postmenopausal period (Long et al. 2000).  
Molecularly, the pathognomonic somatic missense point mutation 402C->G (C134W) in FOXL2 
has been identified in 97% of adult subtype GCTs but only in 1 of 10 juvenile granulosa cell 
tumors (Shah et al. 2009). FOXL2 encodes a transcription factor that is expressed as a nuclear 
protein and is critically important in the development of granulosa cells. The FOXL2 C134W 
mutation leads to increased proliferation and survival of granulosa cells, and promotes hormonal 
changes (Färkkilä et al. 2017; Jamieson and Fuller 2012). The exact mechanism of how the 
FOXL2 mutation causes tumor formation is not completely understood. At the molecular level, 
the C134W mutation is not linked to alterations in the protein structure, but instead causes a 
change in the posttranslational modification (ubiquitination) leading to impaired interactions of 
FOXL2 with other transcription factors leading to subtle changes in the transcription of target 
genes (Färkkilä et al. 2017; Jamieson and Fuller 2012). 
The staging system for GCTs is generally the same International Federation of Gynecology and 
Obstetrics (FIGO) staging used for epithelial ovarian cancer (Prat 2015). Surgery is the 
cornerstone of initial management for patients with GCTs (Schumer and Cannistra 2003; 
Powell et al. 1993; Segal, DePetrillo, and Thomas 1995; Peiretti et al. 2020). Surgery is 
necessary to establish a definitive diagnosis, perform staging, and remove as much tumor as 
possible with surgical principles being essentially identical to those used in the management of 
epithelial ovarian cancer (Peiretti et al. 2020; Abu-Rustum et al. 2006; Kuru et al. 2017; 
Ottolina et al. 2015; Stine, Pierce, and Soper 2014). Surgery typically includes total 
hysterectomy and bilateral salpingo-oophorectomy; conservation of a contralateral ovary and/or 
the uterus (if it has no evidence of disease) is reasonable in younger women with stage IA 
disease who wish to preserve fertility. This fertility-sparing approach recognizes the fact that 
GCTs are unilateral in more than 90% of cases. Surgery alone is acceptable treatment for patients 
with stage IA (Iyibozkurt et al. 2010). For those with stage IC and above, adjuvant chemotherapy 
is recommended, either the bleomycin, etoposide, plus cisplatin (BEP) regimen or the paclitaxel 
plus carboplatin regimen (Schumer and Cannistra 2003; Färkkilä et al. 2017; Iyibozkurt et al. 
2010). For patients with stage IIA to IV disease or those with chemo-naïve disease, an ongoing 
randomized clinical trial (GOG264) is investigating carboplatin/paclitaxel vs BEP as the optimal 
first-line regimen in this disease (NCT01042522). 
Treatment of recurrence involves surgery if the recurrent disease is resectable followed by 
postoperative platinum-based chemotherapy; postoperative radiation or observation can also be 
considered (Wolf et al. 1999; Hauspy et al. 2011). If disease is unresectable or the patients are 
not surgical candidates, platinum-based chemotherapy, endocrine therapy, and antiangiogenic 
therapy have shown activity in that setting. Chemotherapeutic regimens for recurrent disease 
may include BEP or carboplatin/paclitaxel depending on which regimen was used previously. 
However, no chemotherapy regimen is associated with durable remissions and the majority of 

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patients eventually experience progressive disease. Hormonal therapies such as luteinizing 
hormone-releasing hormone agonists (e.g., leuprolide), aromatase inhibitors, tamoxifen alone, 
progesterone alone, or a combination of tamoxifen and progesterone have been associated with 
long-term responses in some patients; however, most patients do not respond or exhibit brief 
responses (Hardy et al. 2005). Finally, antiangiogenic therapy with bevacizumab has shown 
promise; in a GOG phase II trial of bevacizumab in patients with metastatic SCSTs (89% were 
granulosa cell tumors) the objective response rate was 16.7% with stable disease in 77.8 percent 
of patients and a median progression-free survival of 9.3 months (Brown et al. 2014). Overall, 
there are currently no effective salvage therapies for patients with recurrent disease and, unlike 
epithelial ovarian cancer, there are currently no Food and Drug Administration (FDA) approved 
therapies, specific for granulosa cell tumors. Therefore, there is an urgent unmet need for novel 
therapies for granulosa cell tumors, especially targeted therapies based on a deeper 
understanding of the pathogenesis of these tumors and the role of the pathognomonic FOXL2 
mutation. 
4.3. 
BENEFIT/RISK ASSESSMENT 
To date, the safety profile of single agent nirogacestat in participants with advanced cancer has 
been characterized by manageable and reversible toxicities. Currently, important identified risks 
related to nirogacestat include diarrhea, dermatologic reactions (maculopapular rash, 
hidradenitis, and folliculitis), ovarian dysfunction, electrolyte abnormalities (hypophosphatemia 
and hypokalaemia), and elevated liver transaminases. Important potential risks include 
embryofetal toxicity, effects on male fertility and in pediatric patients, epiphyseal disorder. The 
results of the nonclinical toxicology and safety pharmacology studies, together with the clinical 
experience in patients with advanced cancers, support the hypothesis that nirogacestat may 
represent an important therapeutic approach in patients with GCTs. Thus, the projected 
benefit/risk balance is considered favorable for further development in this patient population.  
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of nirogacestat may be found in the Nirogacestat Investigator’s Brochure. 

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5. 
OBJECTIVES AND ENDPOINTS 
Table 4: 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary Objective 
Primary Endpoint 
To determine the anti-tumor activity of 
nirogacestat in adult participants with 
relapsed/refractory OvGCT 
Objective response rate (ORR) defined as the proportion of 
participants with Complete Response (CR) + Partial 
Response (PR) using RECIST v1.1 criteria 
Secondary Objectives 
Secondary Endpoints 
To determine if nirogacestat delays 
progression or death in OvGCT 
Estimate of proportion of participants who have not 
progressed or died at 6 months of follow-up: PFS-6. 
Progression is defined by RECIST v1.1 
To describe overall survival in participants 
treated with nirogacestat  
Estimate of 2-year overall survival, defined as the proportion 
of participants who have not died after 2 years of follow-up 
after their first dose of nirogacestat  
To determine the effect of nirogacestat on 
ovarian cancer symptoms measured by 
Functional Assessment of Cancer Therapy – 
Ovarian Symptom Index (FOSI) 
Change from baseline in FOSI 
To determine the duration of response 
Duration of response (DoR), defined as the time from first 
assessment of response (CR + PR using RECIST v1.1) to 
first disease progression defined by RECIST v1.1 or death, 
whichever comes first  
To determine the pharmacokinetics (PK) of 
nirogacestat 
Serum concentrations of nirogacestat will be measured to 
evaluate system exposures (Cmax, Ctrough and other PK 
parameters as data allow) 
Safety Objectives 
Safety Endpoints 
To characterize the safety and tolerability of 
nirogacestat at a dose of 150 mg BID in adult 
participants with relapsed/refractory OvGCT 
Key safety endpoints will include incidence of treatment 
emergent Adverse Events (TEAEs), changes in clinical 
laboratory parameters, vital signs, physician examination 
findings, and electrocardiograms (ECGs). 
Tolerability will be assessed according to toxicities graded by 
National Cancer Institute Common Terminology Criteria for 
Adverse Events (CTCAE) v5.0 
Exploratory Objectives 
Exploratory Endpoints 
To detect FOXL2 C134W mutation as well as 
other genomic alterations and correlate these 
with response 
Evaluate NGS status in baseline tumor tissue 
To detect NICD and candidate biomarkers of 
response, and to correlate nirogacestat 
exposure with response 
Evaluate change from Baseline:  
• 
Inhibin A&B, Follicle-stimulating hormone (FSH), 
estradiol, CA-125 and Müllerian Inhibiting 
Substance (MIS) / AMH  
• 
Circulating tumor DNA (ctDNA) 
Baseline NICD expression in tumor tissue 

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To describe progression free survival on 
continued nirogacestat treatment post first 
disease progression 
Progression free survival on prolonged nirogacestat 
treatment, defined as time from first disease progression per 
RECIST v1.1 to second disease progression on continued  
nirogacestat treatment confirmed by investigator discretion or 
death, whichever comes first 
To describe progression free survival on 
subsequent line of anticancer treatment 
Progression free survival 2 (PFS2), defined as time from first 
dose of nirogacestat to second disease progression on 
subsequent line of anticancer treatment (after nirogacestat) 
confirmed by investigator discretion at long term safety 
follow-up visit or death, whichever comes first 
6. 
STUDY DESIGN 
6.1. 
OVERALL DESIGN 
This is a multi-center, single-arm, Phase 2 open label treatment study to determine the efficacy, 
safety, tolerability, and pharmacokinetics of nirogacestat in adult participants with 
relapsed/refractory OvGCT. Approximately 43 eligible participants will be enrolled. Participants 
must have received at least one prior course of systemic therapy for OvGCT and have 
measurable disease per RECIST v1.1 to meet eligibility criteria.  
Participants will be screened up to 28 days prior to the first dose of study treatment (nirogacestat) 
and full eligibility will be based on inclusion and exclusion criteria (Sections 7.1 and 7.2). At 
Cycle 1 Day 1 (C1D1), eligible participants will enroll in the study using the Interactive 
Response Technology (IRT) system and will orally administer their first dose of study treatment 
(150 mg; nirogacestat) followed by a 1-hour observation period. Following C1D1, participants 
will orally administer 150 mg of study treatment twice daily (BID), continuously in 28-day 
cycles. Participants will return to the clinic for study visits monthly for the first year (C1-C13) 
and then every 3 months thereafter (C16 and On).  
Participants will remain on study treatment until death, disease progression (unless the 
participants meet criteria for continued treatment as defined in Section 9) discontinuation of 
study treatment for any reason, the study is stopped by the Sponsor for any reason, or participant 
qualifies for Sponsor’s Compassionate Use program (see Section 9 for full discontinuation 
criteria). 
Participants who discontinue study treatment early for any reason should return to the clinic for 
an End of Treatment (EOT) visit within 7 days after the Investigator determines study treatment 
will no longer be used and then again for a safety Follow-up (FUP) visit 30 days (+7 days) after 
the last does of study treatment. 
The estimated study duration is 3 years, and all participants will be followed for at least 2 years 
(unless the study is prematurely stopped due to futility). 
This study will use a Bayesian predictive probability approach with early stopping guidelines 
based on objective tumor response rate (CR+PR) intended to limit the accrual of participants to 
ineffective treatments. There will be no pause in accrual for interim assessments. 

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After accrual of full sample size, estimated ORR will be calculated after the last participant 
completes 6 cycles of therapy and has re-imaging at C7D1. 
Refer to the Schedule of Assessments (SoA) (Section 1.3) for details on assessments and timing 
of study visits.  
Refer to Section 1.2 for the study schema. 
6.2. 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
This study will look for direct evidence of anti-tumor activity of nirogacestat in a slow growing 
tumor by assessment of ORR and PFS-6. Previously studied agents in granulosa cell tumors have 
shown activity by increasing ORR and the proportion of PFS-6 (Brown et al. 2014; Ray-Coquard 
et al. 2020). As almost all participants with recurrence have measurable disease, ORR is a 
quantifiable metric to follow. Without an approved standard of care for relapsed disease, a single 
arm study is considered appropriate to define anti-tumor activity and tolerability in this 
population. This is consistent with the statements of the Fifth Ovarian Cancer Consensus 
Congress, where it was determined that innovative study designs may be required to offset small 
patient numbers (Leary et al. 2017). 
The aim of this study is to determine if nirogacestat is an effective therapy for relapsed/refractory 
OvGCT. ORR using RECIST v1.1 will be used as the primary endpoint as ORR establishes a 
clinically relevant decision criterion for efficacy of the treatment in these patients. Secondary 
endpoints include PFS-6, duration of response, change from baseline FOSI, and OS. As an 
exploratory aim, tumor response assessments by RECIST v1.1 will be compared to serum tumor 
marker levels of CA-125, Inhibin A and Inhibin B, and AMH/MIS for response correlation.  
Interim evaluations of ORR can be used as a criterion for determining whether the therapy is 
effective and worthy of continuation to full accrual thereby ruling out truly inactive agents for 
further investigation. A systemic review of prior studies in recurrent epithelial ovarian cancer 
have shown ORR as a possible surrogate for OS and PFS (Siddiqui et al. 2017). In this review, 
they determine that for every 10% increase in ORR, OS will increase by 2.83 months 
(Siddiqui et al. 2017). A secondary endpoint of two-year overall survival was based on overall 
survival in the ALIENOR/ENGOT-ov7 clinical trial where paclitaxel monotherapy showed a one 
and two year OS of 94% and 87% respectively and combination therapy of paclitaxel and 
bevacizumab resulted in one and two year OS of 93% and 73% respectively . Additionally, other 
non-study related factors such as prior therapy modalities, late effects of these treatments, and 
other underlying medical conditions may confound the PFS and OS of participants receiving 
study therapy justifying ORR as the metric of choice for analysis. Nirogacestat may also exhibit 
delayed anti-cancer responses. In this regard, the response patterns seen with such therapy may 
extend beyond the typical time course of responses seen with chemotherapeutic agents and, may 
manifest as a clinical response after an initial increase in tumor burden or even the appearance of 
new lesions. Therefore, participants are allowed to remain on treatment after disease progression 
if they meet criteria for continued treatment as defined in Section 9.  

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To limit accrual of participants to ineffective treatments, the study will use a Bayesian strategy 
(J. Lee and Liu 2008; Chen et al. 2019) for continuous futility monitoring for early stopping 
based on ORR. Bayesian predictive probability will be used throughout the trial to assess the 
posterior probability of obtaining an ORR of no less than 15%.  
6.3. 
JUSTIFICATION FOR DOSE 
An open-label, non-randomized, Phase I dose finding study (Messersmith et al. 2015) in 
participants with advanced solid tumors was conducted to determine the maximum tolerated dose 
(MTD) and recommended phase 2 dose (RP2D) for future clinical development of nirogacestat. 
In the dose-finding portion of the study, the MTD of nirogacestat administered BID continuously 
for 21 days was established at 220 mg BID. Additional participants were subsequently enrolled 
in the expansion cohort at 150 mg or 220 mg BID. The RP2D in participants with advanced solid 
tumors was determined to be 150 mg BID by comparing the tolerability, PK, and 
pharmacodynamic profile of nirogacestat at these 2 doses. At a dose level of 150 mg BID, the 
most frequently reported AEs were diarrhea (70%), fatigue (44%), nausea (39%), decreased 
appetite (26%), vomiting (26%), and hypophosphatemia (22%). HES4, a target gene of Notch, 
measured in peripheral blood samples showed the most consistent pharmacodynamic response, 
with a greater than 2-fold reduction observed in 17 of 19 evaluable participants with solid 
tumors. Nirogacestat was also investigated as a single agent in a Phase 2 study in 19 participants 
with triple-negative breast cancer at the RP2D of 150 mg BID. Neither efficacy nor PK were 
summarized for this study, but the AE profile was consistent with the Phase 1 study. Lastly and 
importantly, nirogacestat at 150 mg BID was studied in another Phase 2 study conducted by the 
National Cancer Institute in participants with progressing desmoid tumors (Kummar et al. 2017). 
In this study, nirogacestat activity was established with 5 PR (29%) out of 16 evaluable 
participants. On the basis of the dose-finding Phase I study and the activity in the desmoid tumor 
Phase 2, the 150 mg BID dose is currently being utilized in the ongoing randomized, double-
blinded phase 3 study, Nirogacestat for Adults With Desmoid Tumor/Aggressive Fibromatosis 
(DT/AF) (DeFi) (ClinicalTrials.gov Identifier: NCT03785964). 
6.4. 
END OF STUDY DEFINITION 
The end of study is defined as the date of the last scheduled procedure shown in the SoA 
(Section 1.3) has been completed for the last participant in the study globally. 
7. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted. 
7.1. 
INCLUSION CRITERIA 
Participants are eligible to be included in the study only if all the following criteria apply: 

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Age 
1. Participant must be aged ≥ 18 years of age inclusive, at the time of signing the 
informed consent. 
Type of Participant and Disease Characteristics  
2. Participant has histologically confirmed recurrent adult-type granulosa cell tumor of 
the ovary prior to first dose of study treatment and agrees to provide archival or fresh 
tumor tissue. 
3. Participant must have documented radiological evidence of relapse after at least one 
systemic therapy that is not amenable to surgery, or radiation and have measurable 
disease by RECIST v1.1 criteria (see Appendix 3). Prior systemic therapy is not 
limited to therapy type nor is any specific prior line of therapy required.   
4. Participant must have a ECOG performance Grade of 0, 1, or 2 at Screening. 
5. Participant must have adequate bone marrow, renal and hepatic function as defined 
by the following Screening laboratory values: 
a. Absolute neutrophil count (ANC) ≥1,000 cells/μL; 
b. Platelets ≥ 75,000/μL;  
c. Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m2 calculated 
by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 
equation (Grade ≤ 1). Appendix A4-5) 
d. Total bilirubin ≤ 1.5 ×ULN (isolated total bilirubin > 1.5 × ULN is acceptable 
if bilirubin is fractionated and direct bilirubin < 35% of total); 
e. Aspartate aminotransferase (AST) (serum glutamic oxaloacetic 
transaminase)/alanine aminotransferase (ALT) (serum glutamic pyruvate 
transaminase) ≤ 2 x ULN; and 
f. Alkaline phosphatase < 2.5 × ULN. 
6. Participant can swallow tablets (delivery of nirogacestat via nasogastric tube or 
gastrostomy tube is not allowed). 
Sex 
7. A female participant is eligible to participate if not pregnant or breastfeeding, and at 
least one of the following conditions applies: 
a. Is not of childbearing potential (WOCBP); 
OR 
b. Is of childbearing potential but is abstinent or using 1 highly effective contraceptive 
method, as described in Appendix 6 during the treatment period and for at least 1 
week after the last dose of study treatment. A second method of contraception is 

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required if the participant is using hormonal contraception, as coadministration with 
nirogacestat may alter the plasma concentrations of hormonal contraceptives resulting 
in reduced efficacy. 
• Additionally, the participant agrees not to harvest or donate eggs (ova, oocytes) 
for the purpose of reproduction during the treatment period and for at least 1 week 
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 Baseline (C1D1) prior to the first dose of 
study treatment. 
• 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. 
Informed Consent 
8. Participant is capable of giving signed informed consent as described in 
Appendix A1-3 which includes compliance with the requirements and restrictions 
listed in the informed consent form (ICF) and in this protocol. Participants who 
cannot read or understand the ICF and do not have a legally authorized representative 
may not be enrolled in the study. 
7.2. 
EXCLUSION CRITERIA  
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Participant has any of the following: 
• Signs of bowel obstruction who require parenteral nutrition. 
• 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).  
2. 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; 

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• Symptomatic congestive heart failure; 
• Cerebrovascular accident; 
• Transient ischemic attack; or 
• Symptomatic pulmonary embolism. 
3. Participant has abnormal QT interval corrected by Fridericia’s formula (> 470 msec for 
female participants, or > 480 msec for participants with bundle branch block) after 
electrolytes have been corrected at Screening. 
4. Participant has congenital or acquired long QT syndrome or a history of additional risk 
factors for Torsades de Pointes (TdP) (e.g., heart failure, hypokalemia, family history of 
Long QT Syndrome). 
5. Participant has current or chronic history of liver disease or known hepatic or biliary 
abnormalities (except for Gilbert’s syndrome or asymptomatic gallstones). 
6. Participant has had a major surgical procedure, open biopsy, or significant traumatic 
injury within 28 days prior to the first dose of study treatment.  
7. Participant has a history of other invasive malignancies, with the exception of non-
melanoma skin cancer, are excluded if there is any evidence of other malignancy being 
present within the last 5 years. Participants are also excluded if their previous cancer 
treatment contraindicates this protocol therapy. 
8. Participant has CTCAE v5.0 Grade > 1 toxicity from prior therapy (except alopecia, 
anorexia or CTCAE grade 2 peripheral neuropathy). 
9. Palliative radiotherapy with a limited field of radiation within 14 days or with wide field 
of radiation or to more than 30% of bone marrow within 28 days prior to the first dose of 
study treatment. 
Prior/Concomitant Therapy 
10. Participant previously received or is currently receiving therapy with GS inhibitors (i.e., 
nirogacestat) or anti-Notch antibody therapy. 
11. Previous or current treatment for OvGCT: 
a. Participant previously received or is currently receiving bevacizumab (or 
other monoclonal antibody therapy with targeted anti-angiogenic activity) for 
OvGCT within 28 days (or 5 half-lives, whichever is shorter) prior to the first 
dose of study treatment; or  
b. Participant has received the following treatment types for OvGCT within 28 
days (or 5 half-lives, whichever is longer) prior to the first dose of study 
treatment: 
• hormonal therapy; 

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• chemotherapy; 
• immunotherapy; 
• targeted therapy (e.g., tyrosine kinase inhibitors [TKIs], small molecule 
inhibitors); or  
• any other investigational treatment 
12. 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. 
13. Participant is using concomitant medications that are known to prolong the QT/QTcF 
interval including Class Ia (e.g., quinidine, procainamide, disopromide) and Class III 
(e.g., dofetilide, ibutilide, sotalol) antiarrhythmics at the time of informed consent. 
Non-antiarrhythmic medications which may prolong the QT/QTcF interval are allowed 
provided the participant does not have additional risk factors for Torsades de Pointes 
(TdP). 
Prior/Concurrent Clinical Study Experience 
14. Participant is currently enrolled or was enrolled in another clinical study with any 
investigational drug or device within 28 days of first dose of study treatment. 
Participation in observational studies may be permitted with prior approval from the 
Medical Monitor. 
Other Exclusions 
15. Participant with active infection requiring parenteral antibiotics at the time of signing the 
informed consent and during the screening period.  
16. 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. 
17. Participant has known hypersensitivity to the active substance or to any of the excipients 
of nirogacestat (Table 5). 
18. Participant is unable to comply with study related procedures, has any intercurrent 
disease that is likely to prevent participant compliance with therapy or follow up as 
described in the protocol, or whose circumstances do not permit completion of the study 
or the required follow-up.  
7.3. 
LIFESTYLE CONSIDERATIONS 
• No specific lifestyle restrictions are required in this study. 

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• Study treatment may be taken without regard to food. 
• Refer to Section 8.3 for more detail on concomitant therapy including exclusions and 
restrictions. 
7.3.1. 
Meals and Dietary Restrictions 
To avoid CYP3A4 inhibition, participants must refrain from consuming Seville oranges, 
grapefruit or grapefruit juice, pomelos, exotic citrus fruits, or grapefruit hybrids at least 14 days 
prior to the first dose of study treatment and throughout the treatment period. 
7.4. 
SCREEN FAILURES 
Screen failures are defined as participants who consent to participate in the clinical study but do 
not receive study treatment. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure participants to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, reason for screen failure (e.g., eligibility 
requirements failed), and any Serious Adverse Events (SAEs). 
Individuals who do not meet the criteria for participation for the study (screen failures) may be 
rescreened at any time if provided the participant has not screen failed on any of the following 
Exclusion Criteria: #1, 4, 5, 10, or 17.  
Participants do not need to wait the full 28 days of the screening period to rescreen. There is no 
set limit to how many times a participant may be rescreened if the Investigator considers the 
rescreening medically and scientifically appropriate, and the screening assessments continue to 
tolerate for the participant. Rescreened participants must be re-consented and will be assigned a 
new participant number at the time of rescreening. 
8. 
STUDY TREATMENT 
Study treatment for this study is investigational (nirogacestat) and intended to be administered to 
a study participant according to the study protocol.  
8.1. 
STUDY TREATMENT ADMINISTERED 
• Participants will be instructed to swallow tablets whole and not to chew them prior to 
swallowing.  
• No tablet should be ingested if it is broken, cracked, or otherwise compromised (e.g., 
not fully intact).  
• Participants should take their dose BID orally, approximately every 12 hours, without 
regard to food.  
• Participants will be instructed to record their daily administration of each study 
treatment dose in a Dosing Diary.  

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• If a participant misses a scheduled dose of study treatment, and it is within 6 hours of 
the scheduled dose, the participant should immediately administer the missed dose 
and resume study treatment in accordance with the normal administration schedule. If 
more than 6 hours have elapsed since the time of scheduled administration, the 
participant should be instructed not to administer the missed dose and to resume study 
treatment as prescribed.  
• Participants should not take 2 doses together to “make up” for a missed dose.  
• If a participant vomits any time after taking a dose, then they must be instructed not 
to take another dose to “make up” for vomiting, but rather to resume subsequent 
doses as prescribed.  
• If a participant inadvertently takes 1 extra dose, then the participant should not take 
the next scheduled dose of study treatment.  
• Delivery of nirogacestat via nasogastric tube or gastrostomy tube is not allowed. 
Table 5: 
Study Treatment Administered 
Study treatment name 
Nirogacestat 
Dosage formulation 
Tablet 
Unit dose strength(s) 
50 mg  
Dosage level(s) 
150 mg BID 
Route of administration 
Oral 
Sourcing 
Sponsor will provide Sites with study treatment for individual 
participant distribution 
Packaging and labeling 
Study treatment will be provided in 90 count bottles. Each bottle 
will be labeled as required per country requirement 
Former Name 
PF-03084014 
Ingredients 
Opadry® QX Film Coated Tablets:  
Nirogacestat;  
Microcrystalline Cellulose;  
Lactose Monohydrate;  
Sodium Starch Glycolate;  
Magnesium Stearate; 
Macrogol (Polyethylene glycol) Polyvinyl Alcohol Graft 
Copolymer:  
Talc;  
Titanium Dioxide;  
Glyceryl Monocaprylocaprate Type 1;  
Polyvinyl Alcohol – Part Hydrolyzed;  
Yellow #6 / Sunset Yellow FCF Aluminum Lake;  
Iron Oxide Yellow 

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8.1.1. 
Dosing Administration 
Participants will administer 150 mg (3 × 50 mg tablets) of study treatment BID (approximately 
every 12 hours, without regard to food), continuously in 28-day cycles.  
8.1.2. 
Preparation/Handling/Storage/Accountability 
Study treatment will be dispensed to participants during scheduled study visits every cycle 
during the first year and then every 3 cycles thereafter, as described in the SoA (Section 1.3) or 
unscheduled visits if study treatment is damaged/lost or a dose modification (Section 8.4) is 
necessary. 
Participants will be instructed to keep their study treatment in the bottles provided and not 
transfer it to any other containers.  
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported and 
resolved before use of the study treatment. 
Only participants enrolled in the study may receive study treatment and only authorized site staff 
may supply or administer study treatment. All study treatment must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to the Investigator and authorized site staff. Study 
treatment should be dispensed at the study site; however, Direct-to Patient (DTP) shipping may 
be allowed with advance approval from the Sponsor in the event of a public health crisis such as 
COVID-19. Direct-To-Patient shipping is not allowed at the C1D1 study visit. 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (i.e., 
receipt, reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused study treatments are 
provided in the pharmacy manual.  
8.2. 
STUDY TREATMENT COMPLIANCE 
Participant compliance with study treatment will be monitored throughout the study. At each 
applicable study visit (Section 1.3) the participant should be asked whether they have been 
compliant with dosing instructions. Compliance will also be assessed by counting returned 
tablets at the applicable study visits. Any discrepancies will be discussed with the participant and 
will be recorded in the source documentation.  
If the participant is not compliant with study treatment dosing, the site must re-educate the 
participant on proper dosing compliance and its importance. Continued non-compliance may 
lead to withdrawal of the participant from the study after consultation between the Investigator 
and the Medical Monitor. 
In the case of an overdose, refer to Section 11.4 for instructions. 

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8.3. 
CONCOMITANT THERAPY 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of informed consent 
and/or receives during the study through 30 days after the last dose of study treatment must be 
recorded along with: 
• Reason for use; 
• Dates of administration including start and end dates; and 
• Dosage information including dose and frequency. 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
8.3.1. 
Known Drug Interactions 
8.3.1.1. 
Cytochrome P450 Inhibitors and Inducers  
Because inhibition of CYP3A4 isoenzymes may increase nirogacestat exposure leading to 
potential increases in toxicities, the use of known strong/moderate CYP3A4 inhibitors is not 
allowed throughout the study treatment period and must be stopped at least 14 days prior to the 
first dose of study treatment. 
Nirogacestat metabolism may be induced when taking strong CYP3A4 inducers resulting in 
reduced plasma concentrations. Therefore, co-administration of nirogacestat in combination with 
strong/moderate CYP3A4 inducers is not allowed throughout the treatment period and must be 
stopped at least 14 days prior to the first dose of study treatment. 
8.3.1.2. 
Cytochrome 3A4 Substrates 
Nirogacestat has been shown to increase exposure of a sensitive CYP3A4 substrate, midazolam, 
by approximately 50% following multiple daily doses of 95 mg once daily (QD). The potential 
for nirogacestat to inhibit CYP3A4 in vivo following BID dosing at 150 mg has not been 
evaluated in a clinical study. However, using physiological-based pharmacokinetic modeling, 
nirogacestat was predicted to be a moderate inhibitor of CYP3A4 metabolism when administered 
at 150 mg BID resulting in increases in midazolam exposures ranging from 2- to 3.3-fold. 
Therefore, caution should be used when co-administering known CYP3A4 substrates with 
nirogacestat.  
Co-administration of CYP3A4 substrates with a narrow therapeutic index should be avoided if 
possible. If co-administration is unavoidable, the participant should be monitored closely for 
toxicity and investigator should consider reducing or titrating the dose of the substrate as 
necessary. 

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8.3.1.3. 
Anti-Emetic and Anti-Diarrheal Therapy 
The choice of anti-emetic drug(s) and anti-diarrheal drug(s), as well as the duration of treatment, 
is at the discretion of the Investigator assuming there is no known or expected drug-drug 
interaction (DDI). If a DDI is expected, then the drug(s) use must be approved by the Medical 
Monitor.  
8.3.1.4. 
Other Concomitant Therapy 
Nonclinical studies suggest that nirogacestat may induce CYP3A4, CYP2B6, CYP2C8 and 
CYP2C9 enzymes. Drugs which are substrates of these enzymes may have a reduced 
exposure/efficacy when co-administered with nirogacestat. Dose adjustments of these 
medications should be considered when appropriate.  
The effect of nirogacestat on the exposure of hormonal contraceptives has not been evaluated. 
However, induction of these cytochrome P450 enzymes has been associated with reduced plasma 
exposure of various hormonal contraceptives resulting in reduced efficacy. 
Nonclinical studies have indicated that nirogacestat is a substrate for the drug efflux transporter 
P-glycoprotein (P-gp). Therefore, caution should be used when co-administering the study 
treatment with known P-gp inhibitors such as amiodarone, azithromycin, captopril, carvedilol, 
elacridar, felodipine, mibefradil, nitrendipine, quinidine, ranolazine, talinolol, and valspodar.  
Co-administration of gastric Acid Reducing Agents (ARAs) such as proton pump inhibitors (e.g., 
omeprazole, esomeprazole, lansoprazole, etc.) may reduce the absorption of nirogacestat. These 
drugs should be avoided if possible or, when necessary, administered 4 hours following the dose 
of study treatment. Twice daily administration of ARAs is not allowed during the treatment 
period. 
Administration of potential QTC prolonging medications aside from anti-arrhythmics as listed 
below, should be used with caution due to possibility of additive QTC prolongation with 
nirogacestat (See Appendix A4-4). 
8.3.2. 
Excluded/Restricted Concomitant Medications and/or Procedures 
Table 6 describes the concomitant medications and/or procedures that are excluded/restricted 
prior and/or throughout the duration of the study until the termination of study treatment. Contact 
the Medical Monitor with any questions regarding excluded/restricted medications. 

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Table 6: 
Excluded/Restricted Medications and/or Procedures 
Medication/Procedure 
Exclusion/Restriction 
• 
Hormonal therapy, chemotherapy, 
immunotherapy, targeted therapy (e.g., 
TKIs, small molecule inhibitors) 
• 
Any other investigational treatment for 
OvGCT. 
• 
Not allowed within 28 days (or 
5 half-lives, whichever is longer) prior to 
first dose of study treatment; and 
• 
Not allowed throughout the duration of 
the treatment period. 
• 
Bevacizumab (or other monoclonal 
antibody therapy with targeted anti-
angiogenic activity)  
• 
Not allowed within 28 days (or 5 half-
lives, whichever is shorter) prior to first 
dose of study treatment; and 
• 
Not allowed throughout the duration of 
the treatment period. 
• 
Strong/moderate CYP3A4 inhibitors; and 
• 
Strong/moderate CYP3A4 inducers. 
• 
Not allowed within 14 days prior to first 
dose of study treatment. 
• 
Not allowed throughout the duration of 
the treatment period. 
• 
CY3A4 substrates with a narrow 
therapeutic index. 
• 
Should be avoided if possible; and 
• 
If co-administration is unavoidable, the 
participant should be monitored closely 
for toxicity and investigator should 
consider reducing or titrating the dose of 
the substrate as necessary. 
• 
Gastric ARAs such as proton pump 
inhibitors. 
• 
Should be avoided if a reasonable 
alternative is available; and  
• 
If administration is necessary, should be 
administered 4 hours after the dose of 
study treatment. 
• 
Twice daily administration of ARAs is 
not allowed during the treatment period. 
• 
GS inhibitors; 
• 
Anti-Notch antibody therapy; and 
• 
Gastric bypass, lap band, or other gastric 
procedures that would alter absorption. 
• 
No prior use, therapy or procedure is 
allowed; and 
• 
Not allowed throughout the duration of 
the treatment period. 
• 
Major surgical procedure or excisional 
biopsy. 
• 
Not allowed within 28 days prior to first 
dose of study treatment.  
• 
Antiarrhythmic medications that are 
known to prolong the QT/QTcF interval 
including: Class Ia (e.g., quinidine, 
procainamide, disopromide) and Class III 
(e.g., dofetilide, ibutilide, sotalol) 
antiarrhythmics; 
• 
Potentially curative radiotherapy. 
• 
Not allowed within 28 days prior to first 
dose of study treatment; and 
• 
Not allowed throughout the duration of 
the treatment period. 

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Medication/Procedure 
Exclusion/Restriction 
• 
Delivery of nirogacestat via nasogastric 
tube or gastrostomy tube. 
• 
Not allowed throughout the duration of 
the treatment period. 
• 
Enrollment in another clinical study with 
any investigational drug or device.1 
• 
Not allowed within 28 days prior to first 
dose of study treatment; and 
• 
Not allowed throughout the duration of 
the treatment period. 
CYP3A4 = Cytochrome P450 3A4; GS = Gamma-secretase; QT = Uncorrected QT interval; QTcF = Corrected QT 
interval by Fridericia 
1Participation in an observational study may be allowed on a case-by-case basis with prior Medical Monitor 
approval. 
8.3.3. 
Supportive Care 
8.3.3.1. 
Phosphate Supplements 
Nirogacestat has been associated with hypophosphatemia which may require phosphate 
supplementation. The choice of phosphate replacement, as well as the duration, is at the 
Investigator’s discretion. 
8.3.3.2. 
Palliative Care 
Systemic or local therapy to the Granulosa cell tumors is not permitted.  
Medications for the standard management of symptoms or supportive care for the side effects of 
study treatment may be administered at the investigator’s discretion; unless they are excluded 
concomitant medications (Section 8.3.2). 
Palliative radiation therapy may be permitted after consultation with the Medical Monitor. 
Radiation will be limited to non-target lesions only and will be documented in the eCRF. 
Thus, the following therapies are not permitted during the study: 
• Other anti-neoplastic therapy, including cytotoxic agents, small molecule inhibitors, 
targeted agents, endocrine therapy or other antibodies;  
• Potentially curative radiotherapy; 
• Surgical resection of granulosa cell tumors; and 
• Any other investigational therapy. 
8.4. 
DOSE MODIFICATION 
Every effort will be made to administer study treatment (nirogacestat) at 150 mg BID. However, 
dosing will be interrupted and/or dose reduced for the AEs described in Table 7. Study treatment 
may also be modified to manage other AEs in collaboration with the Medical Monitor.  
If an event listed in Table 7 has an alternative etiology and is not considered study treatment 
related, dose modifications may not be required; consult with the Medical Monitor. 

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If a participant experiences an AE as described in Table 7, hold study treatment until the AE is 
resolved to ≤ Grade 1 or baseline.  
• If the AE is resolved within 14 days, then study treatment should be restarted at the 
reduced dose as described in Table 7.  
• If the AE does not resolve to ≤ Grade 1 or baseline after holding study treatment for 
22 days, study treatment may be resumed only after discussion with the Medical Monitor. 
Should the same ≥ Grade 3 AE recur at the reduced dose, and the AE is considered related to the 
study treatment, study treatment may be permanently discontinued following discussion with the 
Medical Monitor.  
An unscheduled visit may be performed at any time during the study. Assessments to be 
performed at the unscheduled visit will be determined by the Investigator.   
Table 7: 
Dose Modifications or Interruptions for Selected Toxicities 
Toxicity (NCI CTCAE v5.0)1 
Intervention 
Gastrointestinal Toxicities 
Grade ≥ 3 diarrhea persisting for ≥ 3 days despite 
maximal medical therapy 
Decrease dose to 100 mg BID 
Grade ≥ 3 nausea persisting for ≥ 3 days despite 
maximal medical therapy 
Decrease dose to 100 mg BID 
Grade ≥ 3 vomiting persisting for ≥ 3 days 
despite maximal medical therapy 
Decrease dose to 100 mg BID 
Other toxicities 
Grade ≥ 3 skin toxicity 
Decrease dose to 100 mg BID 
Grade ≥ 3 hypophosphatemia persisting for 
≥ 7 days despite maximal replacement therapy 
and in the absence of symptoms 
Decrease dose to 100 mg BID 
Any clinically significant Grade ≥ 3 toxicities 
Decrease dose to 100 mg BID 
Anaphylaxis 
Permanently discontinue 
Grade ≥ 3 hypersensitivity reaction 
Permanently discontinue 
Hepatic toxicities 
Refer to Section 9.1.1 
NCI = National Cancer Institute; CTCAE = Common Terminology Criteria for Adverse Events. 
1Refer to the study reference manual for details on managing AEs.  
9. 
DISCONTINUATION OF STUDY TREATMENT AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
It may be necessary for a participant to permanently discontinue study treatment (nirogacestat) 
early. In this case, the participant will return to the site for an EOT visit and a post dose safety 

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follow-up (FUP) visit (refer to SoA; Section 1.3 for a complete list of required assessments to be 
conducted). 
Reasons for discontinuation of study treatment at any time may include: 
• Clinical (including physical examination) or radiographic (using RECIST v1.1) 
evidence of progressive disease (PD); 
o Treatment after Initial Evidence of Disease Progression 
▪ Study treatment may be continued at the investigator’s discretion if the 
participant is clinically stable as defined by the following criteria: 
• Absence of clinical signs and symptoms of disease progression 
• No decline in ECOG performance status 
• Absence of progressive tumor at critical anatomical sites (e.g., 
cord compression) requiring urgent alternative medical 
intervention. 
▪ The participant will be reassessed at the next protocol-defined CT or 
MRI scan for tumor measurement in order to rule out pseudo-
progression.   
• If repeat imaging demonstrates CR, PR, or SD compared to the 
first scan that showed disease progression, treatment with study 
treatment may be continued. 
• If repeat imaging demonstrates PD, defined as ≥10% increase 
in tumor burden compared to the first scan that showed disease 
progression, participants should be discontinued from study 
treatment. 
▪ All decisions to continue study treatment beyond initial progression 
must be discussed with the Medical Monitors and documented in 
source documents. 
• Adverse events requiring removal from protocol therapy as stated in Section 9.1. Any 
SAE (refer to Appendix A5-1.3 for SAE criteria), clinically significant AE (refer to 
QTcF stopping criteria, Section 9.1.2), severe laboratory abnormality (refer to liver 
chemistry stopping criteria, Section 9.1.1), any grade ≥ 3 hypersensitivity reaction, 
anaphylaxis, intercurrent illness, or other medical condition which indicates to the 
Investigator that continued participation is not in the best interest of the participant; 
• The initiation of emergent treatment (e.g., radiotherapy, surgery, or systemic therapy 
including chemotherapy, small molecule inhibitors, immunotherapy, or targeted 
therapy) for granulosa cell tumor; 
• Participants who receive concurrent investigational therapy or anti-cancer therapy; 
• Refusal of further protocol therapy by participant; 
• Treating Physician determines it is the participant’s best interest; 

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• Non-compliance: Participant failure to comply with protocol requirements or study-
related procedures; 
• Occurrence of any medical condition or circumstance that exposes the participant to 
substantial risk and/or does not allow the participant to adhere to the requirements of 
the protocol; 
• Pregnancy (refer to Sections 9.1.3 and 11.3.6 for additional details); 
• Requirement of prohibited concomitant medication or procedure (Section 8.3.2); 
• Withdrawal of consent for any required observations or any further data submission; 
• Termination of the study by the Sponsor or the regulatory authority. 
9.1. 
DISCONTINUATION OF STUDY TREATMENT 
9.1.1. 
Liver Chemistry Stopping Criteria 
Discontinuation of study treatment for abnormal liver function should be considered by the 
Investigator when a participant meets one of the conditions outlined in Figure 2 or if the 
Investigator believes that it is in best interest of the participant.  
Figure 2: 
Liver Chemistry Stopping Criteria and Increased Monitoring Algorithm 
➢ If participant is to be monitored weekly, must refer to Liver Safety: Suggested Actions and 
Follow-up Assessments (Appendix A4-3) 
➢ Must refer to Liver Safety: Suggested Actions and Follow-up Assessments (Appendix A4-3) 
➢ Report as an SAE if possible Hy’s Law case: ALT ≥ 3xULN and Bilirubin ≥ 2xULN (> 35% 
direct) or INR > 1.5, if measured* 
*INR value not applicable to participants on anticoagulants 

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9.1.2. 
QTcF Stopping Criteria 
If a clinically significant finding is identified (including, but not limited to changes from baseline 
in QT interval corrected using Fridericia’s formula [QTcF]), the Investigator or qualified 
designee will determine if the participant can continue in the study and if any change in 
participant management is needed. This review of the ECG printed at the time of collection must 
be documented. Any new clinically relevant finding should be reported as an AE. 
A participant who meets either of the following bulleted criterion should be confirmed with 
triplicate ECGs. If these findings are confirmed based on the average of the triplicate readings, 
the participant will be withdrawn from the study treatment: 
• QTcF > 500 msec  
• Change from baseline of QTcF > 60 msec 
Table 8 describes the discontinuation criteria for participants with underlying bundle branch 
block. 
Table 8: 
Bundle Branch Block Discontinuation Criteria 
Baseline QTcF with Bundle Branch Block 
Discontinuation QTcF Threshold with Bundle 
Branch Block 
< 450 msec 
> 500 msec 
450 to 480 msec 
≥ 530 msec 
QTcF = QT interval corrected using Fridericia’s formula; msec = millisecond 
See the SoA (Section 1.3) for data to be collected at the time of treatment discontinuation and 
follow-up and for any further evaluations that need to be completed. 
9.1.3. 
Pregnancy 
A participant who becomes pregnant will be withdrawn from study treatment. See Section 11.3.6 
for additional details. 
9.2. 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, compliance, or 
administrative reasons. This is expected to be uncommon. 
At the time of discontinuing from the study, if possible, the EOT visit should be conducted. See 
SoA (Section 1.3) for specific data to be collected at the time of study discontinuation, as well as 
follow-up for any further evaluations that need to be completed. 
If the participant withdraws consent for disclosure of future information, the Sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 

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If a participant withdraws from the study, they may request destruction of any samples taken and 
not tested. The Sponsor must be notified if the participant requests destruction of sample, and the 
Investigator must document this in the site study records. 
9.3. 
LOST TO FOLLOW UP 
A participant will be considered lost to follow-up if they repeatedly fail to return for scheduled 
visits and is unable to be contacted by the study site.  
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether the participant wishes to and/or should continue in the 
study. 
• Before a participant is deemed lost to follow up, the Investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
• Should the participant continue to be unreachable, they will be considered to have 
withdrawn from the study.  
Discontinuation of specific sites or of the study as whole is handled as part of Appendix A1-7. 
10. 
DURATION OF STUDY 
The study will continue until at least the date that the survival data needed for the estimate of  
2-year overall survival is obtained, or the study is prematurely stopped due to futility.  
11. 
STUDY ASSESSMENTS AND PROCEDURES 
• Study procedures and their timing are summarized in the SoA (Section 1.3).  
• Protocol waivers or exemptions are not allowed. 
• Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study treatment. 
• Adherence to the study design requirements, including those specified in the SoA is 
essential and required for study conduct. 
• All screening evaluations must be completed using a Pre-Enrollment Review Form, 
which should be provided to the Medical Monitor at least two days prior to C1D1 for 
review to confirm that potential participants meet all eligibility criteria (Section 7.1 and 

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Section 7.2). The electronic data capture (EDC) will capture all participants who sign the 
ICF, including all screen-failures. 
• The amount of blood collected from each participant will be approximately 350 mL each 
year during the study. This does not include any extra assessments that may be required 
for unscheduled assessments or EOT/FUP visits. Repeat or unscheduled samples may be 
taken for safety reasons or for technical issues with the samples. 
• In the event that a study site or participant is unable to complete a study visit or 
procedure due to restrictions caused by a public health emergency such as COVID-19, 
the following accommodations may be allowed temporarily with prior approval from the 
Medical Monitor. Any deviations from the study protocol due to a public health 
emergency should be documented in the source data and electronic Case Report Form 
(eCRF) and reported to the IRB/IEC in accordance with their reporting requirements. 
o If a study participant cannot attend a study visit onsite due to a public health 
emergency, they may be able to attend a local hospital/clinic or arrange for a 
telehealth or home healthcare visit. 
o Clinical laboratory assessments (safety labs and pregnancy tests) may be 
performed locally with results and local laboratory normal values entered into the 
eCRF. 
o Electrocardiograms may be performed locally. If ECGs are performed locally, 
ECG tracings should be collected, and the Investigator (or designee) assessment 
should be documented.  
o Study imaging should be performed per the schedule in the SoA (Section 1.3); 
however, imaging may be performed at another imaging center (locally to the 
participant) with prior Medical Monitor approval. 
11.1. 
EFFICACY ASSESSMENTS  
11.1.1. 
Tumor Imaging 
Tumor response will be assessed by CT or MRI (contrast required unless contraindicated). The 
same imaging modality and radiographic procedure used to assess disease sites at Screening is 
required to be used throughout the study (i.e., the same contrast protocol for scans). Tumor 
response and progression of cancer under study in real time will be evaluated locally at each 
study site according to RECIST v1.1 (Eisenhauer 2009). See Appendix 3 RECIST Criteria 
response definitions. All RECIST measurements will be done by the site’s local radiologist. 
Chest imaging using CXR or CT (contrast not required) will also be required as described in the 
SoA and should be obtained per institutional standards. 

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Standard of care scan(s) acquired prior to the participant signing ICF may be used as the 
participant’s screening visit scans if they were obtained within 28 days of the first dose of study 
treatment.  
On treatment scans may be acquired (-) 7 days prior to the study visit or within the study visit 
window as described in the SoA (Section 1.3). 
Imaging must be done prior to tumor biopsy if assessments occur on the same day. 
Whenever disease progression is suspected (e.g., symptomatic deterioration) throughout the 
study, unscheduled scans may be acquired. 
11.1.2. 
Other Objective Parameters 
11.1.2.1. 
Patient-Reported Outcomes (PROs) 
Patient-reported Outcomes (PROs) will be assessed at each clinic visit using the Functional 
Assessment of Cancer therapy Ovarian Cancer Symptom Index (FOSI). The FOSI is an 8-
question evaluation scored on a Likert scale of 0-4 from not at all to very much. Metrics assessed 
include lack of energy, vomiting, pain, nausea, swelling in stomach area, concern condition will 
get worse, quality of life assessment and stomach cramps. When possible, the participant should 
complete the paper FOSI questionnaire as the first assessment during the applicable study visits 
(refer to the SoA; Section 1.3) to minimize bias. This assessment takes approximately 5 minutes 
to complete and is manually calculated to determine a symptom index score correlating with 
level of patient symptoms (Beaumont et al. 2007). Change from baseline in the FOSI score and 
individual responses will be scored at each applicable study visit, EOT, and the safety FUP. 
11.2. 
SAFETY ASSESSMENTS  
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
11.2.1. 
Demographics Data and Medical History 
Demographic data will include age or date of birth, sex, and self-reported race/ethnicity. 
Medical history includes any history of clinically significant disease, surgery, or cancer history; 
reproductive status (i.e., WOCBP or no WOCBP); history of alcohol or substance abuse and 
collection of concomitant medications.  
The medical history should also include a detailed menstrual history including the date of the last 
menstrual cycle and any history of amenorrhea, menstrual irregularities, or infertility.  
Cancer history will include an assessment of prior surgery, prior radiotherapy, prior drug 
therapy, including start and stop dates, best response and reason for discontinuation. 

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11.2.2. 
Physical Examinations and Eastern Cooperative Oncology Group 
Performance (ECOG) Status 
Physical examinations, as well as height/weight, and assessment of ECOG performance status 
(per Investigator’s assessment) (Appendix A4-2) will be required throughout the study as 
described in the SoA. Height to be measured at Screening only; a historical height measured 
within 1 year prior to signing informed consent may be used as the screening height. 
A physical examination should include, at a minimum, assessments of the Cardiovascular, 
Respiratory, Gastrointestinal, Neurological, Lymphatic, and Skin systems. A pelvic exam will 
also be required for participants whose disease can be evaluated by pelvic exam.  
Investigators must pay special attention to clinical signs related to previous serious illnesses and 
changes from baseline will be recorded in the source documentation. New or worsened clinically 
significant abnormalities must be recorded as AEs on the eCRF page. 
11.2.3. 
Vital Signs 
Body temperature, heart rate, respiratory rate, and blood pressure will be assessed throughout the 
study as described in the SoA (Section 1.3). 
Blood pressure and pulse measurements will be assessed with a completely automated device. 
Manual techniques will be used only if an automated device is not available. 
Blood pressure, respiratory rate, heart rate and body temperature should be preceded by at least 
5 minutes of rest for the participant in a quiet setting without distractions. 
Vital signs can be repeated per clinical judgement. 
11.2.4. 
Electrocardiograms 
Single 12-lead ECG will be obtained, and the following data parameters will be reported: HR, 
PR, QRS, QT, and QTcF intervals at the timepoints described in the SoA (Section 1.3). Prior to 
ECG assessments, participants should rest in a semi-recumbent supine position for at least 
5 minutes. Refer to Section 9.1.2 for QTc withdrawal criteria and any additional QTc readings 
that may be necessary. 
For safety monitoring purposes, the Investigator (or appropriate delegated designee) must review 
and assess any abnormalities for clinical significance, and then sign, and date all ECG tracings. 
Paper or electronic copies of ECG tracings will be kept as part of the source documentation at 
the site.  
Refer to Section 9.1.2 for QTcF withdrawal criteria and any additional QTcF readings that may 
be necessary. 
11.2.5. 
Clinical Safety Laboratory Assessments 
See Appendix A4-1 for the list of clinical laboratory tests to be performed and to the SoA 
(Section 1.3) for the timing and frequency.  

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The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless judged 
by the Investigator to be more severe than expected for the participant's condition. 
All laboratory tests with abnormal values considered to be clinically significant during 
participation in the study or within 30 days after the last dose of study treatment will be repeated 
until the values return to normal or baseline or are no longer considered clinically significant by 
the Investigator or Medical Monitor. If such values do not return to normal/baseline within a 
period of time judged reasonable by the Investigator, the etiology should be identified, and the 
Medical Monitor notified. 
If laboratory values from non-protocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in participant management or are considered 
clinically significant by the investigator (e.g., SAE or AE or dose modification), then the results 
must be recorded in the eCRF, and the local laboratory report must be assessed by the 
Investigator and included in the participant’s medical records.  
11.2.6. 
Pregnancy Testing 
Pregnancy testing will only be required for women of childbearing potential (WOCBP) (refer to 
Appendix 6 for definition of WOCBP and additional details on contraceptive guidelines and 
collection of pregnancy information). 
A negative serum pregnancy test at Screening and a negative urine pregnancy test at Baseline 
(prior to first dose of study treatment) will be required to meet study entry criteria. 
Monthly urine pregnancy tests will be required for WOCBP at each study visit (refer to SoA; 
Section 1.3). Following C13D1, between study visits, participants will be required to return to 
the site for monthly (every 28 days [+/- 2 days]) urine pregnancy tests. If it is more convenient to 
the participant, they may alternatively visit a local laboratory that has been pre-approved by the 
Sponsor (or designee) for this assessment (refer to study reference manual for additional detail). 
Serum pregnancy tests may be conducted in place of urine pregnancy tests throughout the study 
if required by local regulations. 
11.2.7. 
Remote Monthly Wellness Checks 
Remote monthly (every 28 days [+/- 2 days]) telephone or email contact is required following 
C13D1 until EOT. The wellness checks may be replaced by a face-to-face interaction when 
study visits occur provided the information can be obtained during the visit.  
During these wellness checks, site staff should assess, at a minimum, AEs, changes to 
concomitant medications, and dosing compliance. 
A copy of the telephone report or email must be documented in the source documentation. Email 
must not replace direct follow-up by phone or in-clinic visits for clinically significant AEs or 

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other emergent issues. Adverse events and concomitant medication changes will be captured in 
the associated eCRFs. 
11.2.8. 
2-Year Survival Check-In 
Sites will document participant’s survival status approximately 2 years after the participant’s first 
dose of study treatment. If the participant discontinues from study treatment prior to the 2-year 
check-in, quarterly telephone or email contact following EOT is required until the 2-year 
survival data point has been collected. Additionally, collection of subsequent anticancer therapy 
after nirogacestat and overall response to this therapy will be recorded. Only information about 
the subsequent therapy used directly after nirogacestat is required along with the final survival 
outcome at the 2-year check point. 
A copy of the telephone report or email must be documented in the source documentation and 
the survival data point will be captured in the eCRF. 
11.3. 
ADVERSE EVENTS (AES), ADVERSE EVENTS OF SPECIAL INTEREST 
(AESIS), SERIOUS ADVERSE EVENTS (SAES), SPECIAL SITUATIONS, 
AND PREGNANCY 
The definitions of an AE, SAE, AESI, Special Situations, Adverse Drug Reaction (ADR), 
Serious Adverse Reaction (SAR), and Suspected Unexpected Serious Adverse Reaction 
(SUSAR) can be found in Appendix 5. 
An AE will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative).  
The Investigator or any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE/AESI/SAE/Special Situation and remain 
responsible for following up on the events that are serious, considered related to the study 
treatment or study procedures, or that caused the participant to discontinue the study treatment. 
11.3.1. 
Adverse Events of Special Interest 
Adverse events of special interest (AESIs) are selected non-serious and serious AEs that must be 
reported regardless of relationship to study treatment.  
Refer to Table 9 for the AESIs identified for this study. AESIs will be followed until resolution 
or return to baseline. 
Following medical evaluation, Sites may be contacted to provide supplemental information (such 
as medical history, concomitant medications, investigations, etc.) about the event. Please note 
this table lists known AESIs; additional events may be identified during the course of the study. 

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Table 9: 
Adverse Events of Special Interest (AESI) 
Skin Rash (reported as AESI if clinically significant Grade 2 and all Grade > 3. Per CTCAE v5.0) 
Maculopapular rash 
Pruritic rash 
Erythematous rash 
Folliculitis 
Hidradenitis suppurativa 
Elevated Liver Enzymes (reported as AESI if Grade ≥ 2, per CTCAE v5.0)  
AST 
ALT 
Alkaline Phosphatase 
Total bilirubin 
Electrolyte Insufficiency (reported as AESI if Grade ≥ 3, per CTCAE v5.0)  
Hypophosphatemia 
Hypokalemia 
Hypomagnesemia 
Drug Reactions (reported as AESI for any grade)  
Allergic reaction 
Anaphylaxis 
(Drug) hypersensitivity 
Ovarian Toxicity1 (reported as AESI for any grade)  
Ovarian dysfunction 
Ovarian disorder 
Amenorrhea 
Oligomenorrhea 
Premature menopause 
Ovarian failure 
Skin Cancer (reported as AESI for any grade) 
Basal cell carcinoma 
Squamous cell carcinoma (of skin) 
Keratoacanthoma 
Actinic keratosis 
Any other skin cancer 
AESI = Adverse Event of Special Interest; ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; CTCAE = 
Common Terminology Criteria for Adverse Events 
1Participants reporting AEs/AESIs/SAEs of ovarian toxicity will have hormone levels assessed every 3 months until event 
resolution (or for at least 90 days after discontinuing study treatment).  

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11.3.2. 
Time Period and Frequency for Collecting Safety Event 
Information  
• AEs/AESIs/SAEs/Special Situations will be collected from the signing of the ICF until 
30 days after the last dose of study treatment. 
• Pregnancies will be reported from the first dose of study treatment until 30 days after the 
last dose of study treatment. However, if a pregnancy is reported by the participant 30 
days after the last dose of study treatment, the pregnancy should still be reported to 
Safety.  
• Investigators are not obligated to actively seek AE or SAE information after conclusion 
of the study participation. However, if the Investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and they 
consider the event to be reasonably related to the study treatment or study participation, 
the Investigator must promptly notify Safety.  
• All AESIs/SAEs/Special Situations will be reported to the Sponsor’s safety group 
(referred to as ‘Safety’ throughout this document) within the timeframes as described in 
Table 10. 
Table 10: 
AESI/SAE/Special Situation Reporting Timeframes  
Type of Safety Event 
Reporting Timeframe to Safety 
SAE 
Initial SAE report:  must be reported to Safety immediately and 
under no circumstances should exceed 24 hours of awareness. 
Follow-up SAE report:  Investigator will submit any updated SAE 
data to Safety within 24 hours of it being available. 
AESI 
Serious AESIs:  must be reported immediately and under no 
circumstance should this exceed 24 hours. 
Non-serious AESIs:  must be reported to Safety as soon as possible, 
but no later than 5 business days of awareness. 
Special Situation 
If there is an associated SAE with the Special Situation, it must be 
reported immediately and under no circumstance should this exceed 
24 hours. 
If there no associated SAE with the Special Situation, it must be 
reported to Safety as soon as possible, but no later than 5 business 
days of awareness. 
Pregnancy  
If a pregnancy is reported, the Investigator must inform Safety 
within 24 hours of learning of the pregnancy. 
AESI = Adverse Event of Special Interest; SAE = Serious Adverse Event 

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11.3.3. 
Method of Detecting AEs/AESIs/SAEs/Special Situations 
The method of recording, evaluating, and assessing causality of AEs/AESIs/SAEs/Special 
Situations, and the procedures for completing and transmitting reports are provided in 
Appendix A5-2. 
Care will be taken not to introduce bias when detecting AEs/AESIs/SAEs/Special Situations. 
Open-ended and non-leading verbal questioning of the participant is the preferred method to 
inquire about these occurrences.  
11.3.4. 
Follow-up of AEs/AESIs/SAEs/Special Situations 
After the initial AE/AESI/SAE/Special Situation report, the Investigator is required to 
proactively follow each participant at subsequent visits/contacts. All SAEs and AESIs (as 
defined in Table 9), will be followed until resolution, stabilization, the event is otherwise 
explained, or the participant is lost to follow-up (as defined in Section 9.3).  
Refer to Appendix 5 for additional details regarding recording and reporting follow-up 
information. 
11.3.5. 
Regulatory Reporting Requirements for SAEs 
Prompt notification (within 24 hours of learning of the event) by the Investigator to the Sponsor 
of an SAE is essential so that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study treatment under clinical investigation are met.  
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study treatment under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, Institutional Review Boards (IRB)/Independent Ethics Committees 
(IEC), and Investigators and report per Sponsor procedures. SUSARs will be reported directly to 
regulatory authorities’ databases, such as EudraVigilance, or per other method as determined by 
governing regulations. 
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements/Sponsor policy and forwarded to Investigators as necessary. 
An Investigator who receives an investigator safety report describing an SAE or other specific 
safety information (e.g., summary or listing of SAEs) from the Sponsor will review and then file 
it along with the Investigator’s Brochure and will notify the IRB/IEC, if appropriate according to 
local requirements. 
11.3.6. 
Pregnancy 
If a pregnancy is reported, the Investigator must inform Safety within 24 hours of learning of the 
pregnancy and should follow the procedures outlined in Appendix 6.  

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Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs.  
11.4. 
TREATMENT OF OVERDOSE 
For this study, any dose of study treatment greater than a 450 mg daily dose of study treatment 
within a 24-hour time period be considered an overdose. 
In the event of an overdose, the investigator should: 
1. Contact the Medical Monitor immediately (refer to Appendix 8 for contact information). 
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities for at least 
4 days. 
3. Document the quantity of the excess dose as well as the duration of the overdose on the 
Special Circumstances eCRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant. 
11.5. 
PHARMACOKINETICS 
• The following pre- and post-dose PK samples will be collected during the study to allow 
for determination of the pharmacokinetics (PK) of nirogacestat and exploratory exposure-
response analysis.  
Visit 
Timepoint 
C2D1 
Pre-dose (prior to morning dose of study treatment) 
Post-dose (1-hour after morning dose of study treatment) 
C3D1 
Pre-dose (prior to morning dose of study treatment) 
C4D1 
Pre-dose (prior to morning dose of study treatment) 
C5D1 
Pre-dose (prior to morning dose of study treatment) 
C6D1 
Pre-dose (prior to morning dose of study treatment) 
C7D1 
Pre-dose (prior to morning dose of study treatment) 
• For pre-dose PK visits:  
o The evening before the study visit, participants will record the exact time 
study treatment was taken in the Dosing Diary. 
o On the day of the study visit, participants will not take their planned 
morning dose at home. The morning dose will be taken in the clinic 
following the pre-dose PK blood draw. 
• For post-dose PK visit: 
o All efforts should be made to obtain the PK sample as close to the 1-hour 
timepoint following the onsite dose of study treatment. However, if the PK 

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time is captured in the source documents and eCRF, a protocol deviation 
will not be captured. 
• Whole blood samples of approximately 4 mL each will be collected for measurement of 
serum concentrations of nirogacestat. 
• Sites will document the exact date and time (24-hour clock time) each PK sample is taken 
in the source documents.  
• Instructions for the collection, handling, and shipment of PK samples will be included in 
the central laboratory manual. 
11.6. 
BIOMARKERS 
Translational components of this study aim to detect the FOXL2 C134W mutation as well as 
other genomic alterations to correlate with response. Additionally, IHC will be used to assess 
baseline NICD expression to correlate expression levels as a predictive marker for treatment 
response. Archival Formalin-Fixed Paraffin-Embedded (FFPE) specimen (a block or 
15-20 unstained slides) will need to be provided for targeted NGS at a central laboratory. If 
archival tissue is not available, a screening biopsy will be required. Refer to central lab manual 
for additional details. 
Blood samples for circulating biomarkers (hormones, protein, DNA) will be collected and 
shipped to a central laboratory. Baseline and on-treatment samples will be collected to monitor 
levels in response to treatment. 
• FSH, LH, Estradiol, and Progesterone will be assessed at Screening, Baseline, Day 1 of 
every cycle, EOT, and the 30-day follow-up visit 
• Inhibin A, Inhibin B, AMH/MIS and CA-125 will be assessed at Baseline, Day 1 of every 
cycle, EOT, and the 30-day follow-up visit 
• Circulating tumor DNA (ctDNA) will be assessed at Baseline, Cycle 3 Day 1, and EOT 
Additional biomarkers may also be measured, based on emerging clinical and literature data 
pertaining to Notch biology. Full details regarding collection, processing, storage and shipping of 
all biomarker samples will be provided in the central laboratory manual.  
Samples may be stored for a maximum of 10 years (or according to local regulations) following 
the last participant’s last study visit at a facility selected by the sponsor to enable further analysis 
of biomarker responses to nirogacestat. 
12. 
STATISTICAL CONSIDERATIONS 
12.1. 
STATISTICAL HYPOTHESES 
The primary objective of the study is to estimate the objective response rate for participants 
receiving nirogacestat who have relapsed/refractory ovarian granulosa cell tumors and who have 

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measurable disease. Since this is a first-in-human proof of concept study for the indication, no 
formal hypothesis testing is contemplated. 
12.2. 
SAMPLE SIZE AND DESIGN CHARACTERISTICS 
A prior GOG phase 2 trial in previously treated participants with stromal tumors evaluated the 
efficacy and safety of bevacizumab monotherapy in participants with recurrent sex cord stromal 
tumors of the ovary. The ORR in this study was 16.7%. (Brown et al. 2014). Following this 
outcome, the ALIENOR/ENGOT ov7 trial randomized participants to see if the addition of 
bevacizumab to paclitaxel had effect on the PFS rate among participants with relapsed ovarian 
sex cord stromal tumors. While the combination therapy of paclitaxel and bevacizumab showed 
an ORR of 44% over paclitaxel monotherapy, the PFS remained equivocal between the two 
treatment groups (Ray-Coquard et al. 2020). Based on the ORR from the bevacizumab 
monotherapy trial, this study aims for an ORR of 30% with PFS as a secondary endpoint. 
No formal sample size calculation is attempted. The initial goal of accrual for this study is 
43 participants which should provide sufficient sample size for interim evaluations for futility 
with a Bayesian strategy of continuous monitoring. Participant accrual will not be paused during 
the interim evaluations. The Bayesian approach to be used for futility analysis assumes a 
beta-binomial distribution with an uninformative prior of beta distribution (J. Lee and Liu 2008; 
Chen et al. 2019). Assume at an assessment point, the study has accrued X responders out of n 
(≤43) participants. With a prior distribution of beta (a, b), X follows a binomial distribution and 
the posterior distribution of the response rate follows a beta distribution with parameters (a+x, 
b+n-x), where x is the observed value of X. Thus, the number of responses in the potential (43-n) 
future participants, Y, follows a beta-binomial distribution with parameters (43-n, a+x, b+n-x). 
From the observed responders x and a target ORR, the predictive probability of reaching the 
target ORR at the end of study can be calculated with the beta-binomial distribution. If the 
predictive probability is too low, e.g., ≤10%, the study may be terminated for futility. A high 
predictive probability, e.g., >85%, suggests high likelihood of achieving treatment efficacy at the 
end of the study. 
For this study, we assume that a response rate of ≤15% at the end of study is considered 
ineffective for the treatment, and enrollment will stop if the posterior probability of ORR >15% 
is less than 0.1. On the other hand, the treatment is considered promising if the posterior 
probability of ORR >15% is higher than 0.85, that is, if the posterior distribution provides 
𝑃𝑟𝑜𝑏{𝑂𝑅𝑅> 0.15|𝑑𝑎𝑡𝑎} > 0.85. 
For calculating the posterior probability, a prior of beta (0.1, 0.9) could be assumed. These 
parameters (0.1 and 0.9) of the beta prior correspond to the initial assumed distribution of ORR 
with mean equal to 0.1/(0.1+0.9) = 10% (that is, an initial belief of ORR around 10%). The beta 
parameters will be updated according to observed number of responders at each analysis. 
Given the cutoff points of the predictive probability for futility and efficacy, the characteristics 
of the design can be assessed in terms of type I and II errors. For example, if the cutoff points are 
set at 10% for futility and 85% for efficacy, the above Bayesian rule will result in futility 

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stopping boundaries of 1, 2, and 5 or fewer respondents if interim evaluations were to occur at 
enrollment of 10, 20, 30 participants, respectively. If the true rate of ORR is 15%, the chance to 
conclude treatment efficacy at the end of the study is 7% (Type I error). However, the probability 
to stop the trial early is 79%. If the true rate of ORR is 30%, the chance to conclude treatment 
efficacy at the end of the study is 76%. 
A set of simulations using a frequentist framework under the similar interim evaluation schedule 
as above are performed for comparisons. Specifically, the type I and II errors are simulated for 
scenarios where the study ceases for futility when the ORRs are 0%, ≤5%, ≤10%, or 15% when 
10, 20, 30, and 43 participants have been enrolled, respectively. Those conditions correspond to 
stopping for futility when there are fewer than or equal to 0, 1, 3, and 6 respondents in the three 
interim and final analyses, respectively. Table 11 below provides results based on 10,000 
simulations of probability of early stopping for futility and the expected overall sample sizes. 
Table 11: 
Simulated Probability of Early Stopping under Assumed ORR 
Interim Time Point 
(Enrollment at N =) 
10 
20 
30 
43 
Futility at 
First Three 
Looks 
Futility at 
End of 
Study 
Efficacy at  
End of 
Study 
Average 
Overall 
Sample 
Size1 
Stopping Boundary  
(No. of Responders) 
0 
1 
3 
6 
Assumed True 
Underlying ORR 
0.05 
0.60 
0.19 
0.16 
0.05 
0.95 
1.00 
0.00 
11 
0.10 
0.35 
0.13 
0.21 
0.19 
0.69 
0.88 
0.12 
22 
0.15 
0.20 
0.07 
0.13 
0.19 
0.40 
0.59 
0.41 
32 
0.20 
0.11 
0.03 
0.06 
0.10 
0.20 
0.30 
0.70 
38 
0.25 
0.06 
0.01 
0.02 
0.03 
0.09 
0.12 
0.88 
41 
0.30 
0.03 
0.00 
0.01 
0.01 
0.04 
0.04 
0.96 
42 
ORR = Objective Response Rate, N = Sample size; No. = Number 
1Without considering newly enrolled participants while the interim evaluation is ongoing.  
As can be seen from the above table, the probabilities to stop for futility early if true ORR is 
either 5% or 10% are approximately 100% and 88%, respectively. The probabilities to stop for 
futility when true ORR is either 25% or 30% are approximately 12% and 4%, respectively. For 
various criteria to claim efficacy, the exact 95% CI for different corresponding observed ORR 
are listed in Table 12. For example, if the total sample size is 20 at the second interim evaluation, 
the lower bound of the 95% CI will be 27.2% if the observed ORR is 50%. When the total 
sample size is 30 or higher and the observed ORR is 50%, the lower bound of the 95% CI will be 
≥31.3%. 

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Table 12: 
Exact 95% CI Given Observed ORR 
Minimum 
ORR to Claim 
Efficacy 
Sample Size 
Observed No. 
of Responders 
Observed 
ORR (%) 
95% Confidence Interval  
Lower 
Bound 
Upper Bound 
0.25 
10 
3 
30.0 
6.7 
65.3 
20 
5 
25.0 
8.7 
49.1 
30 
8 
26.7 
12.3 
45.9 
43 
11 
25.6 
13.5 
41.2 
0.3 
10 
3 
30.0 
6.7 
65.3 
20 
6 
30.0 
11.9 
54.3 
30 
9 
30.0 
14.7 
49.4 
43 
13 
30.2 
17.2 
46.1 
0.5 
10 
5 
50.0 
18.7 
81.3 
20 
10 
50.0 
27.2 
72.8 
30 
15 
50.0 
31.3 
68.7 
43 
22 
51.2 
35.5 
66.7 
CI = Confidence Interval; ORR = Objective Response Rate 
12.3. 
STATISTICAL ANALYSES 
The statistical analysis plan (SAP) will describe the participant populations to be included in the 
analyses, and procedures for accounting for missing, unused, spurious data, and intercurrent 
events that may affect the assessment of the endpoints. This section is a summary of the planned 
statistical analyses of the primary and secondary endpoints. 
12.3.1. 
Efficacy Analyses 
All efficacy analyses will be based on treated participants. A brief description of the statistical 
method for efficacy analyses is summarized in Table 13. Subset analyses for the primary 
endpoints may be performed for selected baseline characteristics. The details will be described in 
the SAP. 

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Table 13: 
Statistical Method for Efficacy Analyses 
Primary Endpoint 
Statistical analysis methods 
Objective response rate, defined as the 
proportion of participants with CR + PR 
using RECIST v1.1 
The response rate will be calculated, and the exact 95% CI 
will be provided. The proportion and 95% CI of participants 
with CR, PR, Stable Disease (SD), and Progressive disease 
(PD) will also be summarized and listed by visit. 
Secondary Endpoint 
Statistical analysis methods 
Estimate of proportion of participants 
who have not progressed or died at 
6 months of follow-up: PFS-6. 
Progression is defined by RECIST v1.1 
The Kaplan-Meier (K-M) method will be used to estimate 
PFS-6. 
Estimate the 2-year overall survival, 
defined as the proportion of participants 
who have not died after 2 years of 
follow-up after their first dose of 
nirogacestat 
The K-M method will be used to estimate the distribution of 
overall survival 
Change from baseline in FOSI 
Change from baseline in the FOSI score and the individual 
responses will be summarized at each cycle, end of 
treatment, and the follow-up visit. 
DoR, defined as the time from first 
assessment of response (CR + PR using 
RECIST v1.1) to first disease 
progression defined by RECIST v1.1 or 
death, whichever comes first 
The K-M method will be used to estimate the distribution of 
the duration of response including median. 
Exploratory Endpoint 
Statistical analysis methods 
Exploratory endpoint statistical analysis method will be described in the SAP. 
CI = Confidence interval; CR = Complete response; FOSI = Functional Assessment of Cancer Therapy – Ovarian Symptom 
Index; K-M = Kaplan-Meier; ORR = Objective Response Rate; PFS = Progression-Free Survival; PR = Partial Response; 
RECIST v1.1 = Response Evaluation Criteria In Solid Tumors version 1.1; SAP = Statistical Analysis Plan 
12.3.2. 
Safety Analyses 
All safety analyses will be performed on participants who received at least one dose of 
nirogacestat.  
The safety and tolerability of nirogacestat will be evaluated by means of treatment-emergent 
AEs, physical examinations, and laboratory safety evaluations. Adverse Events will be graded by 
the Investigator according to the CTCAE v5.0 and coded using the Medical Dictionary for 
Regulatory Activities.  
The focus on AE summaries will be on Treatment-Emergent AEs, those with initial onset or 
increasing in severity after the first dose of study treatment through 30 days after the last dose of 
study treatment. The number and percentage of participants who experienced an AE, SAE, 

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treatment related AE, and treatment related SAE will be summarized according to worst toxicity 
grades. 
Summaries of clinical laboratory parameters will be summarized by study visit and overall, 
including absolute results and changes from baseline. Tables for the shift in CTCAE severity 
grade of laboratory data from baseline to the worst post-baseline value and from baseline to each 
visit will be presented. 
Vital signs data will be summarized by study visit and overall using descriptive statistics. 
Summaries will be presented for the observed value, the change from baseline value, and the 
change from baseline to the worst post-baseline value during the treatment period. 
The observed ECG values and change from baseline values, and the change from baseline to the 
worst post-baseline value during the treatment period will be summarized descriptively. The 
overall ECG assessments will be summarized categorically (normal, abnormal without clinical 
significance, and abnormal with clinical significance) as a shift table by study visit. 
12.3.3. 
Other Analyses 
Pharmacokinetic, pharmacodynamic, and exploratory analyses will be described in the SAP (to 
be finalized before database lock). The population PK analysis and pharmacodynamic analyses 
will be presented separately from the main Clinical Study Report (CSR).  
12.4. 
INTERIM ANALYSES  
No formal interim analysis is planned. This study will use a Bayesian approach of continuous 
monitoring for early futility stopping based on ORR, intended to limit the accrual of participants 
to an ineffective treatment (Section 12.2). The Statistical Analysis Plan will describe the planned 
continuous monitoring in greater detail. 
12.4.1. 
Data Monitoring Committee 
There is no Data Monitoring Committee for this study. 

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13. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
APPENDIX 1. REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS 
A1-1. 
REGULATORY AND ETHICAL CONSIDERATIONS 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines 
• Applicable International Council for Harmonisation (ICH) Good Clinical Practice (GCP) 
Guidelines 
• Regulation (EU) no. 563/2014 
• Applicable laws and regulations 
The protocol, protocol amendments, Informed Consent Form (ICF), Investigator Brochure, and 
other relevant documents (e.g., advertisements) must be submitted to an Institutional Review 
Board (IRB)/Independent Ethics Committee (IEC) by the Investigator and reviewed and 
approved by the IRB/IEC before the study is initiated.  
Any substantial modifications/amendments to the protocol will require competent authority and 
IRB/IEC approval before implementation of changes made to the study design, except for 
changes necessary to eliminate an immediate hazard to study participants.  
The Investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC; 
• Notifying the IRB/IEC of Serious Adverse Events (SAEs) or other significant safety 
findings as required by IRB/IEC procedures; and 
• Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other applicable local 
regulations 
A1-2. 
FINANCIAL DISCLOSURE 
Principal Investigators and Sub-Investigators will provide the Sponsor with sufficient, accurate 
financial information as requested to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities.  

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Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study. 
A1-3. 
INFORMED CONSENT PROCESS 
The Investigator or his/her representative will explain the nature of the study to the participant or 
her legally authorized representative and answer all questions regarding the study.  
Participants must be informed that their participation is voluntary. Participants will be required to 
sign a statement of informed consent that meets the requirements of 21 CFR 50, local 
regulations, ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center.  
The medical record must include a statement that written informed consent was obtained before 
the participant was enrolled in the study and the date/time the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the Informed Consent Form 
(ICF). 
Participants must be re-consented to the most current version of the ICF(s), as per IRB/IEC 
guidance, during their participation in the study.  
A copy of the ICF(s) must be provided to the participant or the participant’s legally authorized 
representative.  
A1-4. 
DATA PROTECTION 
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names or 
any information which would make the participant identifiable will not be transferred.  
Participants must be informed that their personal study-related data will be used by the Sponsor 
in accordance with local data protection law. The level of disclosure must also be explained to 
the participant.  
Participants must be informed that their medical records may be examined by Quality Assurance 
auditors or other authorized personnel appointed by the Sponsor, by appropriate IRB/IEC 
members, and by inspectors from regulatory authorities. 
Sponsor maintains robust technical security measures in relation to its systems and by 
implementing security procedures concerning the handling of sensitive information. The Sponsor 
maintains data incident response policies governing how to respond  in the event of unauthorized 
access, use, or disclosure of sponsor information or systems each a “Data Issue”. Sponsor, in 
consultation with the DPO, will assess the Data Issue as soon as possible and will undertake 
mitigation measures to contain the Data Issue to prevent further impact, including shutting down 
affected applications or third-party connections, reconfiguring firewalls, changing computer 
access codes, and modifying physical access controls. Sponsor will determine if an intruder has 
exported or deleted any information. Sponsor may use the FRM-0128, Data Incident Reporting 
Form to document the Data Issue and share relevant documentation with the DPO as it pertains 

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to Data Issues affecting EEA, Switzerland or UK Data Subjects. Sponsor will provide notice of 
the Data Issue to impacted data subjects in accordance with Applicable Laws.  
A1-5. 
DATA QUALITY ASSURANCE 
All participant data relating to the study will be entered into the electronic case report forms 
(eCRFs) unless transmitted to the Sponsor or designee electronically (e.g., laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
electronically signing the eCRF.  
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.  
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents.  
Monitoring details describing strategy methods, responsibilities, and requirements, including 
handling of non-compliance issues and monitoring techniques (central, remote, or onsite 
monitoring) will be indicated in the monitoring plan to ensure the protocol and GCP is followed. 
The Sponsor or designee is responsible for the data management of this study including quality 
checking of the data.  
The sponsor assumes accountability for actions delegated to other individuals (e.g., Contract 
Research Organizations). 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the eCRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.  
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the investigator according to specifications in the ICH guidelines, local regulations, 
or as specified in the clinical trial agreement, whichever is longer. No records may be destroyed 
during the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the Sponsor.  
A1-6. 
SOURCE DOCUMENTS 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 
Data entered in the eCRF that are transcribed from source documents must be consistent with the 
source documents or the discrepancies must be explained. The investigator may need to request 
previous medical records or transfer records, depending on the study. Also, current medical 
records must be available.  

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Investigators will maintain records separate from the eCRFs in the form of clinical charts, 
medical records, original laboratory, radiology and pathology reports, pharmacy records, etc. The 
investigator will document in the clinic chart or medical record the date on which the participant 
signed informed consent prior to participation in the study. Source documents must completely 
reflect the nature and extent of the participant’s medical care and must be available for source 
document verification against entries in the eCRFs when the sponsor’s monitor visits the site. In 
order to meet data integrity requirements, source documentation should be attributable, legible, 
contemporaneous, accurate, available/accessible, original, complete and credible. All 
information obtained from these documents will be kept in strict confidentiality. Definition of 
what constitutes source data can be found in the study reference manual. 
A1-7. 
STUDY AND SITE CLOSURE 
The Sponsor (or designee) reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
Study-site closure prior to completion of the study should be avoided. The Investigator and 
Sponsor will agree to the circumstances that could cause early study-site closure. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Conditions that may warrant early study site closure but are not limited to: 
• The discovery of an unexpected, serious, or unacceptable risk to participants participating 
in the study; 
• A negative change in the risk/benefit assessment; 
• Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the Sponsor's procedures, or GCP guidelines 
• Inadequate recruitment of participants by the Investigator; or 
• The decision on the part of the Sponsor to suspend or discontinue nirogacestat 
development. 
A1-8. 
PUBLICATION POLICY 
Following completion of the trial, the data may be considered for publication in a scientific 
journal or for reporting at a scientific meeting. Each Investigator is obligated to keep data 
pertaining to the trial confidential. The Investigator must consult with the Sponsor before any 
trial data are submitted for publication. The Sponsor reserves the right to deny publication rights 
until mutual agreement on the content, format, interpretation of data in the manuscript, and 
journal selected for publication are achieved. 
 

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APPENDIX 2. PROHIBITED CONCOMITANT MEDICATIONS 
A listing of cytochrome P450 (CYP3A4) inhibitors/inducers, P-glycoprotein (P-pg) 
inhibitors/inducers, protein pump inhibitors (PPIs), and H2 receptor antagonist will be provided 
in the Study Reference Manual. Contact the Medical Monitor for questions.  
 
 

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APPENDIX 3. RECIST CRITERIA V1.1 
For full guidelines, see RECIST Criteria v1.1 (Eisenhauer 2009) 
Categorizing lesions at Baseline: 
• Only participants with measurable disease (i.e., at least one measurable lesion) at 
Screening are included.  
Measurable lesion – Lesion that can be accurately measured in at least one dimension (longest 
diameter [LD]) in the plane of measurement is to be recorded) and with longest diameter at least 
twice the slice thickness and at least 10 mm when assessed by computed tomography (CT) or 
magnetic resonance imaging (MRI)  
• Measurable disease will be assessed by CT or MRI. 
• The same method of assessment (CT or MRI) and the same technique will be used to 
characterize each identified and reported lesion at Screening and during follow-up.  
• Target Lesions - up to 2 lesions per organ and 5 lesions in total, representative of all 
involved organs at Baseline. 
• Non-target Lesion - All other lesions (or sites of disease) will be identified as non-target 
lesions and should also be recorded at Baseline. Measurements of these lesions are not 
required, but the presence or absence of each should be noted throughout follow-up. 
Methods of Measurement 
CT or MRI must be used to measure target lesions selected for response assessment. 
Conventional CT and MRI will be performed with cuts of 10 mm or less in slice thickness 
contiguously.  
Recording Tumor Assessments 
All sites of disease must be assessed at Screening. Screening assessment must be done within 
28 days of starting study treatment. For an adequate screening assessment, all required scans 
must be done within 28 days prior to first dose of study treatment and all disease must be 
documented appropriately.  
At follow-up, disease site must be assessed using the method (CT or MRI) and same technique 
as screening, including consistent administration of contrast (CT only) and timing of scanning. If 
a change needs to be made the case must be discussed with the Sponsor. 
Unequivocal new lesions will be recorded at follow-up time points. Measurement of new lesions 
is not required. If a new lesion is equivocal, for example because of its small size, continued 
therapy and follow-up evaluation will clarify if it represents truly new disease. If repeat scans 
confirm there is definitely a new lesion, then progression should be declared using the date of the 
initial scan. 

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Response Criteria:  Evaluation of target lesions 
Complete Response (CR): 
Disappearance of all target lesions. 
Partial Response (PR): 
At least a 30% decrease in the sum of the LD of target lesions, 
taking as reference the baseline sum of LD. 
Progressive Disease (PD): 
At least a 20% increase in the sum of the LD of target lesions, 
taking as reference the smallest sum of LD recorded since the 
treatment started or the appearance of one or more unequivocal 
new lesions. In addition to the relative increase of 20%, the sum 
must also demonstrate an absolute increase of at least 5 mm. 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum 
LD since the treatment started. 
Evaluation of best overall response 
The best overall response is the best response recorded from the start of the study treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements recorded 
since the start of study treatment). The participant's best response assignment will depend on the 
achievement of both measurement and confirmation criteria (defined below).  
Target Lesions 
Nontarget Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR=Complete Response; NE=Not Evaluable; PD=Progressive Disease; PR=Partial Response; SD=Stable Disease. 
Participants with a global deterioration of health status requiring discontinuation of study 
treatment without objective evidence of disease progression at that time will be classified as 

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having “symptomatic deterioration”. Every effort should be made to document the objective 
progression even after discontinuation of treatment.  
Confirmation 
• Confirmation of response: 
o The main goal of confirmation of objective response is to avoid overestimating 
the response rate observed. In cases where confirmation of response is not 
feasible, it should be made clear when reporting the outcome of such studies that 
the responses are not confirmed. 
o To be assigned a status of PR or CR, changes in tumor measurements must be 
confirmed by repeat assessments that will be performed no less than 4 weeks after 
the criteria for response are first met.  
• Confirmation of SD: in the case of SD, follow-up measurements must have met the SD 
criteria at least once after study entry (signing of Informed Consent Form [ICF]) at a 
minimum interval of 8 weeks. 
Duration of overall response 
• 
The duration of overall response is measured from the time measurement criteria are met 
for CR or PR (whichever status is recorded first) until the first date that recurrence or PD 
is objectively documented, taking as reference for PD the smallest measurements 
recorded since the treatment started. 
Duration of stable disease 
• 
SD is measured from the start of the treatment until the criteria for disease progression 
are met, taking as reference the smallest measurements recorded since the treatment 
started.  

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APPENDIX 4. SAFETY ASSESSMENTS 
A4-1. 
CLINICAL LABORATORY TESTS 
The tests detailed in Table 14 will be performed by the local laboratory with the exception of 
follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, progesterone, Inhibin 
A, Inhibin B, Anti-Müllerian hormone/Müllerian inhibiting substance, and CA-125, which will 
be sent to a central laboratory.  
Protocol-specific requirements for inclusion or exclusion of participants are detailed in Section 7 
of the protocol. 
Additional tests may be performed at any time during the study as determined necessary by the 
Investigator or required by local regulations. 
Pregnancy testing (urine as described in the SoA [Schedule of Assessments]; Section 1.3) will be 
conducted at monthly intervals for WOCBP. 
Serum pregnancy tests may be conducted in place of urine pregnancy tests throughout the study 
if required by local regulations. 
Additional serum or urine pregnancy tests may be performed, as determined necessary by the 
Investigator or required by local regulation, to establish the absence of pregnancy at any time 
during the participant’s participation in the study. 
Investigators must document their review of each laboratory report. 

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Table 14: 
Protocol-Required Laboratory Assessments 
Laboratory assessments 
Parameters 
Hematology 
Platelet count 
Hemoglobin 
Hematocrit 
Red blood cell count 
Red blood cell indices: 
• 
Mean cell volume 
• 
Mean cell hemoglobin 
White blood cell count with differential1: 
• 
Neutrophils 
• 
Lymphocytes 
• 
Monocytes 
• 
Eosinophils 
• 
Basophils 
Clinical Chemistry2 
Blood urea nitrogen 
Potassium 
Total and direct bilirubin 
Creatinine 
Sodium 
Aspartate Aminotransferase (AST) or Serum Glutamic-Oxaloacetic 
Transaminase (SGOT) 
Alanine Aminotransferase (ALT) or Serum Glutamic-Pyruvic 
Transaminase (SGPT) 
Gamma-glutamyl transferase 
Total protein  
Albumin 
Chloride 
Bicarbonate 
Glucose (non-fasting) 
Calcium 
Magnesium 
Inorganic phosphorous 
Estimated glomerular filtration rate (eGFR)3 
Uric acid 
Alkaline phosphatase 

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Laboratory assessments 
Parameters 
Routine Urinalysis 
Specific gravity 
potential hydrogen (pH), glucose, protein, blood, ketones, bilirubin, 
urobilinogen, nitrite, leukocyte esterase by dipstick 
Microscopic examination (if blood or protein is abnormal)4 
Other Tests 
Serology5  
• 
HIV antibody 
• 
HBV 
o 
HBsAg 
• 
HCV 
o 
Hepatitis antibody (HCV PCR if hepatitis C antibody positive) 
Hormone Levels6 
• 
FSH 
• 
LH 
• 
Estradiol 
• 
Progesterone 
Tumor Markers 
• 
Inhibin A 
• 
Inhibin B 
• 
AMH/Müllerian inhibiting substance 
• 
CA-125 
ALT = Alanine Aminotransferase; AMH = Anti-Müllerian Hormone; AST = Aspartate Aminotransferase; CA-125 = Cancer 
Antigen 125; FSH = Follicle-stimulating hormone; HBV = Hepatitis B virus; HBsAg = Hepatitis B surface antigen; HCV = 
Hepatitis C virus; HIV = Human immunodeficiency virus; LH = Luteinizing Hormone; PCR = Polymerase chain reaction; 
SGOT = Serum Glutamic-Oxaloacetic Transaminase; SGPT = Serum Glutamic-Pyruvic Transaminase 
1Manual microscopic review is performed only if white blood cell count and/or differential values are out of reference range. 
2Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or monitoring 
event are given in Section 9.1.1 and Appendix A4-3.  
3Only required at Screening to establish eligibility and/or Baseline and permit full investigation of clinical observations on 
study. eGFR is calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. See Appendix 
A4-5. 
4Microscopy examination is performed only if blood or protein is abnormal. 
5Serology only required at Screening 
6Participants reporting Adverse Events (AEs)/Adverse Events of Special Interest (AESIs)/Serious Adverse Events (SAEs) of 
reproductive system disorders will have hormone levels assessed every 3 months until event resolution (or for at least 90 days 
after discontinuing study treatment). 
 
 

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A4-2. 
EASTERN COOPERATIVE ONCOLOGY GROUP 
PERFORMANCE 
Grade Description 
0 
Normal activity. Fully active, able to carry on all pre-disease performance without 
restriction 
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (e.g., light 
housework, office work) 
2 
In bed < 50% of the time. Ambulatory and capable of all self-care, but unable to 
carry out any work activities. Up and about more than 50% of waking hours 
3 
In bed > 50% of the time. Capable of only limited self-care, confined to bed or chair 
more than 50% of waking hours 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally 
confined to bed or chair 
5 
Dead 
Source: (Oken et al. 1982)  
A4-3. 
LIVER SAFETY: SUGGESTED ACTIONS AND FOLLOW-UP 
ASSESSMENTS 
Liver Chemistry Stopping Criteria 
ALT-absolute 
ALT ≥ 5×ULN 
ALT Increase 
ALT ≥ 3×ULN persists for ≥ 4 weeks 
Bilirubin1, 2 
ALT ≥ 3×ULN and total bilirubin ≥ 2×ULN (> 35% direct bilirubin) 
INR2 
ALT 3×ULN and International normalized ratio (INR) > 1.5, if INR measured 
Cannot Monitor 
ALT ≥ 3×ULN and cannot be monitored weekly for 4 weeks 
Symptomatic3 
ALT ≥ 3×ULN associated with symptoms (new or worsening) believed to be related to liver 
injury or hypersensitivity 
Suggested Actions, Follow-up Assessments, and Monitoring  
Actions 
• 
Immediately discontinue study treatment (nirogacestat) 
• 
Report the event to the Sponsor within 24 hours 
• 
Complete the liver event in the electronic Case Report Form (eCRF) and complete the SAE eCRF form if the 
event also met the criteria for an SAE2 
• 
Perform liver chemistry follow-up assessments 
• 
Monitor the participant until liver chemistry test abnormalities resolve, stabilize, or return to baseline (see 
MONITORING) 
• 
Restart/rechallenge is not allowed per protocol and not granted, permanently discontinue study treatment 
and continue participant in the study for any protocol specified follow up assessments 

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Follow-Up Assessments 
• 
Viral hepatitis serology4 
• 
Obtain INR and recheck with each liver chemistry assessment until the transaminase values show downward 
trend 
• 
Serum CPK and LDH 
• 
Fractionate bilirubin, if total bilirubin ≥ 2×ULN 
• 
Obtain complete blood count with differential to assess eosinophilia 
• 
Record the appearance or worsening of clinical symptoms of liver injury, or hypersensitivity, on the AE 
eCRF page 
• 
Record use of concomitant medications (including acetaminophen, herbal remedies, and other over-the-
counter medications) on the concomitant medications eCRF page 
• 
Record alcohol use in the eCRF if AE is related to alcohol use 
If ALT ≥ 3×ULN AND bilirubin ≥ 2×ULN or INR >1.5: 
• 
Anti-nuclear antibody, anti-smooth muscle antibody, Type 1 anti-liver kidney microsomal antibodies, and 
quantitative total Immunoglobulin G (IgG) or gamma globulins 
• 
Serum acetaminophen adduct High performance liquid chromatography (HPLC) assay (quantifies potential 
acetaminophen contribution to liver injury in participants with definite or likely acetaminophen use in the 
preceding week (James, 2009). 
• 
Liver imaging (ultrasound, magnetic resonance, or computerized tomography) and/or liver biopsy to evaluate 
liver disease; complete liver 
• 
Notify the medical monitor within 24 hours of learning of the abnormality to discuss participant safety  
• 
Participant can continue study treatment 
• 
Participant must return weekly for repeat liver chemistry tests (ALT, AST, alkaline phosphatase, bilirubin) 
until the abnormalities resolve, stabilize or return to baseline  
• 
If at any time, the participant meets liver chemistry stopping criteria, proceed as described in Section 9.1.1 
If, after 4 weeks of monitoring, ALT < 3×ULN and bilirubin < 2×ULN, monitor participants twice monthly until 
liver chemistry tests resolve, stabilize, or return to baseline 
Monitoring 
If ALT ≥ 3×ULN AND bilirubin ≥ 2×ULN or INR > 1.5:  
• 
Repeat liver chemistry tests (include ALT, AST, alkaline phosphatase, bilirubin and INR) and perform liver 
event follow-up assessments within 24 hours 
• 
Monitor participant twice weekly until liver chemistry test abnormalities resolve, stabilize, or return to 
baseline 
• 
A specialist or hepatology consultation is recommended 
If ALT ≥ 3×ULN AND bilirubin < 2×ULN and INR ≤ 1.5:  
• 
Repeat liver chemistry tests (include ALT, AST, alkaline phosphatase, bilirubin and INR) and perform liver 
chemistry follow-up assessments within 24 to 72 hours 
• 
Monitor participants weekly until liver chemistry abnormalities resolve, stabilize, or return to baseline 
ALT  3×ULN and < 5×ULN and bilirubin < 2×ULN, without symptoms believed to be related to liver 
injury or hypersensitivity, and who can be monitored weekly for 4 weeks 
AE = Adverse Event; ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; CPK = Creatine phosphokinase; 
eCRF = electronic Case Report Form; HPLC = High Performance Liquid Chromatography; IgG = Immunoglobulin G; INR = 
International normalized ratio; LDH = Lactate dehydrogenase; SAE = Serious Adverse Event; ULN = Upper Limit of Normal;  
1 Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not immediately 
available, discontinue study treatment if ALT  3xULN and bilirubin  2xULN. Additionally, if serum bilirubin fractionation 

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testing is unavailable, record the absence/presence of detectable urinary bilirubin on dipstick which is indicative of direct 
bilirubin elevations suggesting liver injury.  
2 All events of ALT  3xULN and bilirubin ≥ 2xULN (> 35% direct bilirubin) or ALT  3xULN and INR > 1.5 may indicate 
severe liver injury (possible ‘Hy’s Law’) and must be reported as an SAE (excluding studies of hepatic impairment or 
cirrhosis). The INR stated threshold value will not apply to participants receiving anticoagulants. 
3 New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, or jaundice) or hypersensitivity (such as fever, rash or eosinophilia). 
4 Includes: Hepatitis A immunoglobulin M (IgM) antibody; hepatitis B surface antigen and hepatitis B core antibody; hepatitis 
C RNA; cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, heterophile 
antibody or monospot testing); and hepatitis E IgM antibody.  
 
A4-4. 
CORRECTED QT INTERVAL (QTC) PROLONGATION RISK 
Refer to the Study Reference Manual for a list of substances have been reported to show risk of 
QTc interval prolongation in published literature or have been demonstrated to have QT effects 
and risk of effect on cardiac repolarization in clinical studies. 
A4-5. 
CKD-EPI CREATNINE EQUATION  
Recommend use of calculator found at: 
https://www.kidney.org/professionals/kdoqi/gfr_calculator, which corresponds to the equation 
below. 
Expressed as a single equation:  
eGFR =142* min(standardized Scr/K, 1)α *max(standardized Scr/K, 1)-1.200 *0.9938Age *1.012 [if 
female] 
Source: CKD-Epi Creatinine Equation, 2021 
Abbreviations / Units: 
eGFR (estimated glomerular filtration rate) = mL/min/ 1.73 m2 
Scr (serum creatinine) = mg/dL 
K = 0.7 (females) or 0.9 (males) 
α = -0.241 (females) or -0.302 (males) 
min = indicates the minimum of Scr/K or 1 
max = indicates the maximum of Scr/K or 1 
Clinical Use:  
The Recommended method for estimating GFR in adults from the National Kidney 
Foundation is the 2021 CKD-EPI equations. 
Designed for use with laboratory creatinine values that are standardized to IDMS. (See 
"About GFR" button.) 
Estimates GFR from serum creatinine, age and sex 

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More accurate than the MDRD Study equation, particularly in people with higher levels of 
GFR. 
The CKD-EPI equation is modeled using least squares linear regression to relate log 
transformed measured GFR to log-transformed filtration markers, age and sex with two slope 
splines for creatinine. 
Some clinical laboratories are still reporting GFR estimates using the MDRD Study equation. 
The National Kidney Foundation has recommended that clinical laboratories should begin 
using the 2021 CKD-EPI equation to report estimated GFR using creatinine and cystatin C. 

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APPENDIX 5. ADVERSE EVENTS: DEFINITIONS AND PROCEDURES 
FOR RECORDING, EVALUATING, FOLLOW-UP, AND 
REPORTING 
A5-1. 
DEFINITIONS 
A5-1.1. 
ADVERSE EVENT (AE) 
An Adverse Event (AE) is any untoward medical occurrence in a participant or clinical study 
participant, temporally associated with the use of study treatment, whether or not considered 
related to the study treatment. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of study 
treatment. 
Events meeting the AE definition: 
• Any abnormal laboratory test results (hematology, clinical chemistry, hormone levels, or 
urinalysis) or other safety assessments (e.g., electrocardiograms, radiological scans, vital 
signs measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the Investigator (i.e., not related to 
progression of underlying disease). 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study treatment administration even though it 
may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. Overdose per se will not be reported as an 
AE/Serious Adverse Event (SAE) unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of sequelae. 
• "Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as AE or SAE if they fulfil the definition of an AE or SAE.  
 
 

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Events NOT meeting the AE definition: 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the participant’s condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
• Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads 
to the procedure is the AE. Any surgeries and/or procedures that were scheduled prior to 
obtaining the Informed Consent Form (ICF) but occurring afterwards will not be treated 
as an AE or SAE, unless the condition requiring the surgery or procedure worsened.  
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
A5-1.2. 
ADVERSE EVENTS OF SPECIAL INTEREST (AESI) 
Adverse Events of Special Interest (AESIs) are defined as non-serious or serious AEs that is one 
of scientific and/or medical concern specific to the Sponsor’s product for which ongoing 
monitoring and rapid communication by the Investigator to the Sponsor can be appropriate.  
A5-1.3. 
SERIOUS ADVERSE EVENT (SAE) 
If an event is not an AE per definition in Appendix A5-1.1, then it cannot be a Serious Adverse 
Event (SAE) even if serious conditions are met. 
An SAE is defined as any untoward medical occurrence that, at any dose: 
1. Results in death 
2. Is life-threatening 
• The term 'life-threatening' in the definition of 'serious' refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe. 
3. Requires inpatient hospitalization or prolongation of existing hospitalization 
• In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any 

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other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered serious. 
• Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
4. Results in persistent disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g., sprained ankle) which may interfere with 
or prevent everyday life functions but do not constitute a substantial disruption. 
5. Is a congenital anomaly/birth defect 
6. Other situations 
• Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but 
may jeopardize the participant or may require medical or surgical treatment to 
prevent one of the other outcomes listed in the above definition. These events 
should usually be considered serious. 
• Examples of such events include intensive treatment in an emergency room or at 
home for allergic bronchospasm, blood dyscrasias or convulsions that do not 
result in hospitalization. 
A5-1.4. 
SPECIAL SITUATIONS 
Special Situations are defined as Abuse, Misuse, Occupational Exposure 
(inadvertent/accidental), Medication Error study product (with or without participant exposure to 
the study product e.g., study product name confusion). 
• Abuse: Persistent or sporadic, intentional excessive use of medicinal products which is 
accompanied by harmful physical or psychological effects. 
• Misuse: Situations where a medicinal product is intentionally and inappropriately used 
not in accordance with the terms of the protocol. 
• Occupational Exposure: An exposure to a medicinal product as a result of one’s 
professional or non-professional occupation. 
• Medical Error: An unintended failure in the drug treatment process that leads to, or has 
the potential to lead to, harm to the participant. 

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A5-1.5. 
ADVERSE DRUG REACTION (ADR), SERIOUS ADVERSE REACTION 
(SAR) AND SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTION 
(SUSAR) 
• Adverse Drug Reaction (ADR): 
An ADR is any noxious and unintended response to a medical product or procedure, for 
which a causal relationship with the product or procedure is at least a reasonable 
possibility (i.e., the relationship cannot be ruled out). 
• Serious Adverse Reaction (SAR): 
A SAR is an SAE for which a causal relationship with the product or procedure is at least 
a reasonable possibility (i.e., the relationship cannot be ruled out). 
• Suspected Unexpected Serious Adverse Reaction (SUSAR): 
A SUSAR is a SAR that is judged as unexpected. An event is considered “unexpected” if 
it is not listed as expected in the reference safety information (RSI) section of the 
Investigator Brochure (IB) or summary of product characteristics. 
A5-2. 
RECORDING, EVALUATING AND FOLLOW-UP 
A5-2.1. 
RECORDING AES / AESIS / SAES / SPECIAL SITUATIONS 
• All required information pertaining to the AE/AESI/SAE/Special Situation will be 
recorded in the electronic Case Report Form (eCRF). 
• All AESIs, SAEs and Special Situations will require additional information to be reported 
to Safety utilizing paper forms that must be submitted to Safety. Refer to Appendix A5-3 
for reporting details.  
• It is not acceptable for the Investigator to send photocopies of the participant’s 
medical records to Safety in lieu of completion of the AESI/SAE/Special Situation paper 
forms. 
• There may be instances when copies of medical records for certain cases are requested by 
Safety. In this case, all participant identifiers, with the exception of the participant 
number, must be redacted on the copies of the medical records before submission to 
Safety. 
• The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/AESI/SAE/Special Situation. 

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A5-2.2. 
EVALUATING AES / AESIS / SAES / SPECIAL SITUATIONS 
A5-2.2.1. Severity 
• The Investigator will make an assessment of severity for each AE/AESI/SAE/Special 
Situation1 reported during the study and assign it to one of the following categories:  
• Grade refers to the severity of the AE. The Common Terminology Criteria for Adverse 
Events (CTCAE) version 5.0 displays Grades 1 through 5 with unique clinical 
descriptions of severity for each AE based on this general guideline:  
o Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; treatment not indicated. 
o Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental Activities of Daily Living (ADL)2. 
o Grade 3 Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL3. 
o Grade 4 Life-threatening consequences; urgent intervention indicated. 
o Grade 5 Death related to AE. 
• An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE (Appendix A5-1.3), not when it is rated as severe. 
1Special Situation reports may not have an applicable CTCAE Grade and may be reported without a CTCAE Grade 
assigned. 
2Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc. 
3Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden. 
A5-2.2.2. Causality  
• The Investigator is obligated to assess the relationship between study treatment and each 
occurrence of an AE/AESI/SAE/Special Situation. 
• A "reasonable possibility" of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
• The Investigator will use clinical judgment to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study treatment administration 
will be considered and investigated. 
• The Investigator will also consult the Investigator’s Brochure (IB) when making an 
assessment. 

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• For each AE/AESI/SAE/Special Situation, the Investigator must document in the 
medical notes that they have reviewed the AE/AESI/SAE/Special Situation and has 
provided an assessment of causality. 
• There may be situations in which an AESI/SAE/Special Situation has occurred and the 
Investigator has minimal information to include in the initial report to SpringWorks. 
However, it is very important that the Investigator always make an assessment of 
causality for every event with the initial SAE reporting to Safety (refer to 
Appendix A5-3 for reporting details) 
• The Investigator may change their opinion of causality in light of follow-up information 
and send a follow-up report with the updated causality assessment. 
• The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
A5-2.3. 
FOLLOW UP 
• The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Safety to 
elucidate the nature and/or causality of the AE/AESI/SAE/Special Situation as fully as 
possible. This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
• If a participant dies during participation in the study or during a recognized follow-up 
period, the Investigator will provide Safety with a copy of any post-mortem findings 
including histopathology. 
• New or updated information will be recorded in the electronic Case Report Form (eCRF).  
• The Investigator will submit any updated AESI/SAE or Special Situations form to Safety 
within 24 hours of receipt of the information. 
A5-3. 
REPORTING 
• The preferred method of submitting AESI/SAE and Special Situations information to 
Safety is to email the scanned paper forms to PV@springworkstx.com. Facsimile 
transmission is possible. Please refer to the reporting forms for the fax phone numbers for 
USA and Europe. 
• In rare circumstances in the absence of email or facsimile equipment, notification by 
telephone is acceptable with a copy of the AESI/SAE or Special Situations form sent by 
overnight mail or courier service. However, initial notification via telephone does not 
replace the need for the Investigator to complete and sign the AESI/SAE or Special 
Situations form within the designated reporting time frames. 
• The AESI/SAE and Special Situation forms can be found in the Study Reference Manual.  
• Contacts for AESI/SAE/Special Situations reporting can be found in Appendix A8-4. 

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APPENDIX 6. CONTRACEPTIVE GUIDANCE AND COLLECTION OF 
PREGNANCY INFORMATION 
A6-1. 
WOMEN OF CHILDBEARING POTENTIAL (WOCBP) 
DEFINITION 
Women of Childbearing Potential (WOCBP) are defined as women that are considered fertile 
following menarche and until becoming post-menopausal unless permanently sterile (see below). 
For WOCBP, participant must remain abstinent or use 1 highly effective contraceptive method, 
as described below during the treatment period and for at least 1 week after the last dose of study 
treatment. 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study treatment, additional evaluation should be considered. 
Women in the following categories are not considered WOCBP: 
1. Premenarchal 
2. Premenopausal with 1 of the following: 
a. Documented hysterectomy; or 
b. Documented bilateral salpingectomy; or 
c. Documented bilateral oophorectomy. 
For individuals with permanent infertility due to an alternate medical cause other 
than the above, (e.g., Müllerian agenesis, androgen insensitivity), Investigator 
discretion should be applied to determining study entry. Bilateral tubal occlusion 
is not considered to be a permanent form of infertility. 
Note: Documentation can come from the site personnel’s review of the 
participant’s medical records, medical examination, or medical history interview. 
3. Postmenopausal 
d. A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.  
i. A high follicle-stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using 
hormonal contraception or hormonal replacement therapy (HRT). 
However, in the absence of 12 months of amenorrhea, confirmation with 
more than one FSH measurement is insufficient.  
e. Participants on HRT and whose menopausal status is in doubt will be required to 
use one of the non-estrogen hormonal highly effective contraception methods if 
they wish to continue their HRT during the study. Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before study 
enrollment. 

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A6-2. 
CONTRACEPTION GUIDANCE 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
Highly Effective Contraceptive Methodsb That Have Lower User Dependency 
Note: Failure rate of < 1% per year when used consistently and correctly. 
• Implantable progesterone-only hormone contraception associated with inhibition 
of ovulationc 
• Intrauterine device 
• Intrauterine hormone-releasing system 
• Bilateral tubal occlusion 
• Vasectomized partner 
Note: Vasectomized partner is a highly effective contraceptive method provided 
that the partner is the sole sexual partner of the WOCBP and the absence of 
sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. Spermatogenesis cycle is approximately 90 days. 
Highly Effective Methodsb That Are User Dependent 
Note: Failure rate of < 1% per year when used consistently and correctly. 
• Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulationc 
o Oral 
o Intravaginal 
o Transdermal 
o Injectable 
• Progestogen-only hormone contraception associated with inhibition of ovulationc 
o Oral 
o Injectable 
• Sexual abstinence 
Note: Sexual abstinence is considered a highly effective method only if defined 
as refraining from heterosexual intercourse during the entire period of risk 
associated with the study treatment. The reliability of sexual abstinence needs 
to be evaluated in relation to the duration of the study and the preferred and 
usual lifestyle of the participant.) 

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a) Contraceptive use by men or women should be consistent with local regulations 
regarding the use of contraceptive methods for those participating in clinical studies. 
b) Failure rate of < 1% per year when used consistently and correctly. Typical use failure rates 
differ from those when used consistently and correctly. 
c) Barrier methods such as condoms (male or female) or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream or vaginal suppository must be used 
in addition to hormonal contraception. If locally required, in accordance with Clinical Trial 
Facilitation Group (CTFG) guidelines, acceptable contraceptive methods are limited to those 
which inhibit ovulation as the primary mode of action. 
Note: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhea method are not acceptable methods of 
contraception. Male condom and female condom should not be used together (due to risk of failure 
with friction). 
A6-3. 
COLLECTION OF PREGNANCY INFORMATION 
Pregnancy information will be recorded on the appropriate form and submitted to the sponsor 
within 24 hours of learning of a participant's pregnancy.  
The participant will be followed to determine the outcome of the pregnancy. The Investigator 
will collect follow-up information on the participant and the neonate and the information will be 
forwarded to the Sponsor. Generally, follow-up will not be required for longer than 6 to 8 weeks 
beyond the estimated delivery date but could be longer if needed to confirm the health status of 
the neonate. If there are any birth defects identified from the pregnancy, an extended period of 
time for follow-up may be required. Any termination of pregnancy will be reported, regardless of 
fetal status (presence or absence of anomalies) or indication for the procedure. 
While pregnancy itself is not considered to be an Adverse Event (AE) or Series Adverse Event 
(SAE), any pregnancy complication or elective termination of a pregnancy will be reported as an 
AE or SAE. A spontaneous abortion is always considered to be an SAE and will be reported as 
such. Any post-study pregnancy related SAE considered reasonably related to the study 
treatment by the Investigator will be reported to the Sponsor as described in Section 11.3.5. 
While the Investigator is not obligated to actively seek this information in former study 
participants, they may learn of an SAE through spontaneous reporting.  
Any participant who becomes pregnant while participating in the study will discontinue study 
treatment or be withdrawn from the study 

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APPENDIX 7. GENETICS 
A7-1. 
USE/ANALYSIS OF DEOXYRIBONUCLEIC ACID (DNA) 
Genetic variation may impact a participant’s response to study treatment, susceptibility to, 
severity and progression of disease. Therefore, where local regulations and Institutional Review 
Board (IRB)/Independent Ethics Committees (IEC) allow, a tissue sample will be collected for 
DNA analysis from all participants. 
DNA samples will be used for research related to this study treatment or this indication. Genetic 
research may consist of the analysis of one or more candidate genes or the analysis of genetic 
markers throughout the genome (as appropriate). 
DNA samples will be analyzed for mutations that correlate with response to treatment.  
Additional analyses may be conducted if it is hypothesized that this may help further understand 
the clinical data. 
The results of genetic analyses may be reported in the clinical study report (CSR) or in a separate 
study summary. 
The sponsor will store the DNA samples in a secure storage space with adequate measures to 
protect confidentiality. 
The samples will be retained until study closure and for up to 10 years after (or other period as 
per local requirements). 

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APPENDIX 8. LIST OF CONTACTS FOR STUDY 
A8-1. 
SPONSOR 
SpringWorks Therapeutics 
100 Washington Blvd 
Stamford, CT 06902 
United States 
Telephone: 212-421-8012 
A8-2. 
CONTRACT RESEARCH ORGANIZATION 
Refer to the Study Reference Manual. 
A8-3. 
REFER TO THE STUDY REFERENCE MANUAL.MEDICAL 
MONITORING 
Refer to the Study Reference Manual. 
A8-4. 
SERIOUS ADVERSE EVENT REPORTING 
United BioSource Corporation  
920 Harvest Drive, Suite 200 
Blue Bell, PA 19442  
Fax: 866-750-4514  
PV@springworkstx.com 

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14. 
REFERENCES 
Abu-Rustum, N.R., A. Restivo, J. Ivy, R. Soslow, P. Sabbatini, Y. Sonoda, R.R. Barakat, and 
D.S. Chi. 2006. “Retroperitoneal Nodal Metastasis in Primary and Recurrent Granulosa 
Cell Tumors of the Ovary.” Gynecologic Oncology 103 (1): 31–34. 
https://doi.org/10.1016/j.ygyno.2006.01.050. 
Beaumont, J., S. Yount, D. Lalla, D. Lubeck, M. Derynck, B. Karlan, and D. Cella. 2007. 
“Validation of the Functional Assessment of Cancer Therapy-Ovarian (FACT-O) 
Symptom Index (FOSI) in a Phase II Clinical Trial of Pertuzumab in Patients with 
Advanced Ovarian Cancer.” Journal of Clinical Oncology 25 (18_ Suppl): 16021. 
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