Clinical trial NCT03785964
Conditions: Desmoid Tumor Aggressive Fibromatosis
Keywords: PF-03084014 GSI gamma secretase inhibitor notch pathway
Sponsor: SpringWorks Therapeutics, Inc.
Start date: 2019-04-17; Completion date: 2024-10-17
Enrollment: 142 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study evaluates nirogacestat (PF-03084014) in the treatment of desmoid tumor/aggressive fibromatosis (DT/AF). In the double-blind phase, half of the participants will receive nirogacestat while the other half will receive placebo. Once participants are eligible to roll into the open-label phase, they will receive nirogacestat.

Detailed description:
Desmoid tumors, also referred to as aggressive fibromatosis, are rare, locally invasive, slow growing soft tissue tumors. Although considered benign because of their inability to metastasize, desmoid tumors can cause significant morbidity and occasionally mortality in patients.

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

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

Arms: arm 1: Nirogacestat 150 mg by mouth, twice daily arm 2: Placebo by mouth, twice daily arm 3: Nirogacestat 150 mg by mouth, twice daily
Interventions: intervention 1: Nirogacestat oral tablet intervention 2: Placebo Oral Tablet
Intervention descriptions: intervention 1: Nirogacestat tablet intervention 2: Sugar pill manufactured to mimic nirogacestat 50 mg tablet

Protocol documents:
SAP_002.pdf: 
 
 
 
STATISTICAL ANALYSIS PLAN FOR PATIENT-REPORTED OUTCOMES 
An Addendum to NIR-DT-301 Statistical Analysis Plan (PRO Addendum) 
Protocol NIR-DT-301 
 
Protocol Number: 
NIR-DT-301 
Protocol Version and Date: 
Amendment 5: 09 February 2021 
Amendment 4: 07 July 2020 (not released to sites) 
Amendment 3: 27 January 2020 
Amendment 2: 14 October 2019 
Amendment 1: 28 November 2018 
Original: 03 August 2018 
Name of Test Drug: 
PF-03084014 (nirogacestat) 
Phase: 
Phase 3 
Methodology: 
Randomized, Double-Blind, Placebo-Controlled 
Sponsor: 
SpringWorks Therapeutics 
100 Washington Blvd. 
Stamford, CT 06902 
United States 
Sponsor Representative: 
 
Sponsor Biostatistician 
Analysis Plan Date: 
05 Apr 2022 
Analysis Plan Version: 
Final Version 2 
 
Confidentiality Statement 
The information in this document is confidential information of SpringWorks Therapeutics 
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 study personnel directly involved with 
conducting this study and who are bound by obligations of confidentiality in connection with 
their involvement with this study. 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 organization. 
 




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MODIFICATION HISTORY 
 
Unique 
Identifier 
for this 
Version 
Date of the 
Document 
Version 
Author 
Significant Changes from  
Previous Authorized Version 
1.0 
14Oct2021 
 
Not Applicable – First Version 
2.0 
12Jan2022 
 
Clarifications added in response to 
FDA comments and to enhance 
readability. Specifically, the following 
key modifications were performed: 
• 
statistical test was added for the 
proportion of patients with 
improvement at Cycle 10 in section 5.6 
• 
clarification on the seed used in 
the multiple imputation was added in 
section 5.5.2 
• 
clarified that the formal statistical 
testing on PRO-related endpoints is 
conducted at the 1-sided, 0.025 level of 
significance. 
• 
Supplementary analysis added 
where GODDESS Total Symptom 
Score is derived excluding item 2 (dull 
pain) and item 3 (shooting pain)  
• 
Proportion of participants with 
improvement in BPI-SF API score at 
Cycle 10 has been removed from the 
hierarchical testing of secondary 
endpoints and added as an exploratory 
endpoint. 
 
 


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TABLE OF CONTENTS 
Section 
Page 
1. 
Introduction ........................................................................................................... 9 
2. 
Information From the Study Protocol ................................................................. 10 
2.1. 
Study Design and Objectives .................................................................... 10 
2.1.1. 
Synopsis of PRO Data Collection.................................................. 10 
2.1.2. 
PRO Data Collection Procedures................................................... 11 
2.1.3. 
Efficacy Endpoints ....................................................................... 14 
2.2. 
PRO Measures .......................................................................................... 15 
2.2.1. 
The GOunder/DTRF DEsmoid Symptom/Impact Scale (GODDESS)
 .................................................................................................... 15 
2.2.2. 
BPI Short Form (BPI-SF) ............................................................. 16 
2.2.3. 
EORTC QLQ-C30........................................................................ 17 
2.2.4. 
PROMIS PF Short Form 10a + 3 Additional Items from PROMIS 
Item Bank .................................................................................... 18 
2.2.5. 
Patient Global Impression of Severity (PGIS) ................................ 19 
2.2.6. 
Patient Global Impression of Change (PGIC)................................. 19 
3. 
Subject Population ............................................................................................... 20 
3.1. 
Population Definitions .............................................................................. 20 
4. 
General Statistical Methods ................................................................................. 21 
4.1. 
General Methods....................................................................................... 21 
4.2. 
Baseline Definitions................................................................................... 21 
4.3. 
Adjustments for Covariates ...................................................................... 21 
4.4. 
Multiple Comparisons/Multiplicity .......................................................... 21 
4.5. 
Subgroups ................................................................................................. 22 
4.6. 
Withdrawals, Dropouts, Loss to Follow-up .............................................. 23 
4.7. 
Missing, Unused, and Spurious Data ........................................................ 23 
4.8. 
Visit Windows ........................................................................................... 23 
5. 
Study Analyses ..................................................................................................... 24 
5.1. 
Participant Disposition ............................................................................. 24 
5.2. 
PRO Completion ....................................................................................... 24 
5.3. 
Exploration of Missing Data ..................................................................... 25 


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Section 
Page 
5.4. 
Descriptive Analyses ................................................................................. 25 
5.5. 
Longitudinal Analysis of Change from Baseline....................................... 26 
5.5.1. 
Mixed Model Repeated Measures – Main Analysis........................ 26 
5.5.2. 
Pattern Mixture Model – Sensitivity Analysis ................................ 27 
5.6. 
Responder Analysis................................................................................... 30 
5.7. 
Time to Event Analysis ............................................................................. 31 
6. 
Changes to Planned Analyses............................................................................... 34 
7. 
References ............................................................................................................ 35 
8. 
Appendices ........................................................................................................... 36 
8.1. 
The GOunder/DTRF DEsmoid Symptom/Impact Scale (GODDESS) ..... 36 
8.1.1. 
Items of Desmoid Tumor Impact Scale (DTIS) .............................. 36 
8.1.2. 
Items of Desmoid Tumor Symptom Scale (DTSS) ......................... 37 
8.2. 
BPI Short Form ........................................................................................ 38 
8.3. 
EORTC QLQ-C30 .................................................................................... 40 
8.4. 
PROMIS ................................................................................................... 43 
8.4.1. 
PROMIS PF Short Form 10a......................................................... 43 
8.4.2. 
PROMIS PF Short Form 10a Look-Up Table ................................ 44 
8.4.3. 
3 Additional Items from PROMIS Item Banks ............................... 45 
8.5. 
PGIS.......................................................................................................... 46 
8.6. 
PGIC ......................................................................................................... 47 
 


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TABLES INCLUDED IN THE TEXT 
 
Page 
Table 1: Double-Blind Phase: PRO Assessment Administration Schedule (Reproduced from 
Table 1-1 of main SAP) .....................................................................................12 
Table 2: OLE Phase: PRO Assessment Administration Schedule (Reproduced from Table 1-2 
of main SAP) ...................................................................................................13 
Table 3 List of subgroups..........................................................................................................22 
Table 4 Visit Responses for PRO Measures Based on Clinically Meaningful Thresholds ....................30 
 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
AP 
Appetite loss 
API 
Average Pain Intensity 
BPI-SF 
Brief Pain Inventory Short Form 
CDF 
Cumulative Distribution Function 
CF 
Cognitive functioning 
CI 
Confidence interval 
CMH 
Cochran–Mantel–Haenszel 
CO 
Constipation 
CSR 
Clinical Study Report 
DI 
Diarrhea 
DT/AF 
Desmoid Tumors/Aggressive Fibromatosis  
DTIS 
Desmoid Tumor Impact Scale  
DTRF 
Desmoid Tumor Research Foundation 
DTSS 
Desmoid Tumor Symptom Scale  
DY 
Dyspnea 
EF 
Emotional functioning  
EORTC 
European Organisation for Research and Treatment of Cancer 
EORTC QLQ-C30 
European Organisation for Research and Treatment of Cancer Quality of 
Life Questionnaire-Core 30  
FA 
Fatigue 
GHS/QoL 
Global health status/Quality of life  
GODDESS 
GOunder/DTRF DEsmoid Symptom/Impact Scale  
HR 
Hazard Ratio 
ITT 
Intention-to-treat 
LS 
Least squares 
MAR 
Missing at random 
MCMC 
Markov Chain Monte Carlo 
MMRM 
Mixed model repeated measures 
MNAR 
Missing not at random  
NDA 
New Drug Application 
NRS 
Numeric rating scale  
NV 
Nausea and vomiting 
OLE 
Open-label extension  
OR 
Odds ratio 
PA 
Pain 
PF 
Physical functioning  
PGIC 
Patient Global Impression of Change  


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Abbreviation 
Definition 
PGIS 
Patient Global Impression of Severity  
PMM 
Pattern mixture model  
PRO 
Patient-reported outcome  
PROMIS 
Patient-Reported Outcomes Measurement Information System 
PROMIS PF 
Patient-Reported Outcomes Measurement Information System Physical 
Function  
QoL 
Quality of life  
REML 
restricted maximum likelihood 
RF 
Role functioning 
SAP 
Statistical analysis plan  
SF 
Social functioning 
SL 
Insomnia 


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1. 
INTRODUCTION 
This document is a patient-reported outcome (PRO) data analysis addendum to the statistical 
analysis plan (SAP) of NIR-DT-301, a Phase 3, randomized, double-blind, placebo-controlled 
study that compares the efficacy, safety, and tolerability of nirogacestat and placebo in adult 
participants with progressing Desmoid Tumors/Aggressive Fibromatosis (DT/AF).  
To evaluate desmoid tumor symptoms and impacts in patients with progressing DT/AF, the 
following PROs were collected in the study NIR-DT-301:  
1. GOunder/Desmoid Tumor Research Foundation (DTRF) DEsmoid Symptom/Impact 
Scale (GODDESS) 
2. Brief Pain Inventory Short form (BPI-SF) 
3. European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire-Core 30 (EORTC QLQ-C30) 
4. Patient-Reported Outcomes Measurement Information System Physical Function 
(PROMIS PF) short form 10a + 3 additional items from PROMIS item banks 
5. Patient Global Impression of Severity (PGIS) 
6. Patient Global Impression of Change (PGIC) 
This addendum (PRO Addendum) is designed to outline the methods used in the analysis of the 
PRO data. Populations for analysis, data handling rules, statistical methods, and formats for data 
representation follow those specified in the NIR-DT-301 SAP, unless otherwise noted. The 
statistical analyses and summary tabulations described in this addendum will provide the basis 
for the results sections of the PRO analysis of the Clinical Study Report (CSR) for this trial. 


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2. 
INFORMATION FROM THE STUDY PROTOCOL 
2.1. 
Study Design and Objectives 
This is a multi-center, randomized, double-blind, placebo-controlled, parallel group, event-
driven, Phase 3 study to compare the efficacy, safety, and tolerability of nirogacestat and 
placebo in adult participants with progressing DT/AF.  
The primary objective of this study is: 
• To determine the efficacy (as defined by progression-free survival) of nirogacestat in adult 
participants with progressing DT/AF 
One of the secondary objectives of this study, relating to the PRO data, is: 
• To evaluate desmoid tumor symptoms and impacts using the following PROs:  
o GODDESS  
o BPI-SF 
o EORTC QLQ-C30 
Exploratory objectives of this study, relating to the PRO data, are: 
• To evaluate desmoid tumor symptoms and impacts using the following PROs: 
o PROMIS PF short form 10a and 3 additional items from PROMIS item banks 
o PGIS  
o PGIC 
Additional analyses where PRO based outcomes are correlated with clinical data are 
documented in the Main SAP (Section 4.3.3.9 Change in Symptoms by Exposure and Change in 
Tumor Size/Volume). 
2.1.1. 
Synopsis of PRO Data Collection 
This study will consist of two phases: the double-blind phase and the optional, open-label 
extension (OLE) phase.  
The following PRO assessments will be conducted during the double-blind phase: 
• Screening PRO assessment: 
o On Day 1 of the screening visit, participants will receive training by the site staff on 
how to use the home ePRO device and will include a practice questionnaire to be 
completed by the participant prior to leaving the site. 


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o Participants will then begin the screening PROs assessments that same day (more 
details outlined in Table 1).  
o The PGIC is intentionally omitted from the screening PRO assessments. 
• Baseline PRO assessment: 
o The baseline PRO assessments will begin 7 days prior to the Cycle 1 Day 1 visit 
(more details outlined in Table 1).  
o The PGIC is intentionally omitted from the baseline PRO assessments. 
• Monthly PRO assessments are required throughout the study (Cycle 2, 3, 4 and on). 
The following PRO assessments will be conducted during the OLE phase: 
• Monthly PRO assessments are required for the first year (Cycle 2-12). 
• Quarterly PRO assessments are required after the first year (Cycle 13, 16, 19 and on).  
2.1.2. 
PRO Data Collection Procedures 
The schedules of PRO assessments, as outlined in the study protocol, are provided in Table 1 
(double-blind phase) and Table 2 (OLE phase). 
 






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2.1.3. 
Efficacy Endpoints 
The primary efficacy endpoint of the study is progression free survival. It is documented in the 
Main SAP for DeFi clinical data analyses. 
Secondary efficacy endpoints related to the PRO are as follows: 
• Mean change from baseline at Cycle 10 in BPI-SF Average Pain Intensity (API) score 
• Mean change from baseline at Cycle 10 in Desmoid Tumor Symptom Scale (DTSS) 
Total Symptom Score 
• Mean change from baseline at Cycle 10 in Desmoid Tumor Impact Scale (DTIS) Physical 
Functioning Domain Score 
• Mean change from baseline at Cycle 10 in EORTC QLQ-C30 Global health status/Quality 
of life (GHS/QoL) 
• Mean change from baseline at Cycle 10 during the double-phase period in EORTC QLQ-
C30 Physical Functioning 
• Mean change from baseline at Cycle 10 during the double-phase period in EORTC QLQ-
C30 Role Functioning 
Exploratory endpoints related to PRO are as follows: 
• Mean change from baseline at Cycle 10 in DTSS Pain Domain Score 
• Mean change from baseline at Cycle 10 in EORTC QLQ-C30 pain 
• Mean change from baseline at Cycle 10 in PROMIS PF10a (sum score) and PF13 (sum 
score) 
• Proportion of participants with improvement at Cycle 10 in DTSS Total Symptom Score 
and DTSS Pain Domain Score 
• Proportion of participants with improvement at Cycle 10 in DTIS Physical Functioning 
Domain Score 
• Proportion of participants with improvement at Cycle 10 in BPI-SF API score 
• Time to first DT symptom improvement (using DTSS Total Symptom) 
• Time to pain response (using DTSS Pain Domain Score) 
• Time to first control of pain symptoms (using BPI-SF API) 
• Time to pain response (using BPI-SF API ) 
 
 


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2.2. 
PRO Measures 
2.2.1. 
The GOunder/DTRF DEsmoid Symptom/Impact Scale (GODDESS)  
The GODDESS tool was developed to measures signs and symptoms of desmoid tumors and 
their impact on patients’ lives, using two separate scales – the DTSS and the DTIS. The DTSS 
consists of 11 items assessing the severity of key signs and symptoms, including pain, fatigue, 
swelling, muscle weakness, difficulty moving, and tumor location-specific signs/symptoms. 
The DTIS includes 17 items that measure the impact of the symptoms of DTSS on daily life. 
The items from the GODDESS tool are presented in Appendix 8.1. 
2.2.1.1. 
Desmoid Tumor Symptom Scale (DTSS) 
Items of DTSS are evaluated on an 11-point, numeric rating scale (NRS) from 0 to 10 to measure 
severity from “none” to “as bad as you can imagine,” with a 24-hour recall period.  The DTSS 
will also have daily total scores and weekly average scores computed for items 1-7 and 9-11. 
Item 8 refers to the location of the tumor and will not be includied in the scoring. Weekly 
average scores will be computed for the 7-day periods at Screening, Baseline, and the 7 days 
preceding each Cycle using the mean of the period’s total daily scores but only if there are four 
or more days of assessments within that period.  
The following daily scores will be derived for the DTSS for each day of completion: 
• Total Symptom Score:  
o Mean of Pain items (Items 1-3) as a single score, then a mean of this with items 4-7) 
 
((𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼 1+𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼 2+𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼 3)/3)+𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼 4+𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼 5+𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼 6+𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼 7
5
 
• Total Symptom Score-5 Items:  
o Mean of items 1, 4, 5, 6 and 7 
• Total Symptom Score -Average 
o Mean of Items 1-7 
• Pain Domain Score 
o Mean of Items 1-3 
• Extra-abdominal Symptoms Domain Score 
o Mean of Items 5-7 
• Abdominal Symptoms Domain Score 
o Mean of Items 9-11 


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In the case of missing item-level data (not expected, as all items were administered 
electronically, and mandatory) participants will have a missing daily value. 
Weekly summary scores will be created by averaging the daily scores over the 7 days period 
prior to each visit. A weekly score will be derived only if 4 or more out of 7 days period have 
non-missing scores. The weekly summary score will be used in analyses. If no weekly summary 
score is calculable, the participant will have data considered as missing at that visit. 
Higher scores represent worse symptom severity. There is no total score for the DTSS. 
2.2.1.2. 
Desmoid Tumor Impact Scale (DTIS) 
Items of DTIS are evaluated either on an 11-point NRS to measure severity, or a 5-point Likert 
scale ranging from “none of the time” to “all of the time,” to measure frequency with a 7-day 
recall period. 
The following scores will be derived for the DTIS: 
• Physical Function Domain Score  
o Mean of: Item 01 Moving, Item 02 Reaching (Freq), Item 06 Vigorous Activity, Item 
07 Moderate Activity, Item 08 Accomplished Less  
• Sleep Domain Score  
o Mean of: Item 03 Falling Asleep, Item 04 Comfortable in Bed, Item 05 Staying 
Asleep 
• Emotion Domain Score  
o Mean of: Item 12 Fear Tests, Item 13 Fear Growth/Reoccurrence, Item 14 
Hopelessness, Item 15 Anger, Item 16 Anxiety, Item 17 Frustration 
In the case of missing item-level data (not expected as all items were electronically 
administered, and mandatory) participants will have a missing domain value. 
Higher scores represent worse impact severity. 
2.2.2. 
BPI Short Form (BPI-SF) 
The BPI-SF is a measurement tool for assessing clinical pain and allows patients to rate the 
severity of their pain and the degree to which their pain interferes with common dimensions of 
feeling and function. The BPI-SF consists of 9 questions and utilizes an 11-point NRS from 0-
10 (0 being “no pain” and 10 being “highest pain level”) with a 24-hour recall period. BPI-SF 
is presented in Appendix 8.2. 
The BPI-SF assesses pain at its “worst,” “least,” “average,” and “now” (current pain) through 
four pain severity items (items 3, 4, 5 and 6) rated on 0–10 scale, with 0 = “no pain” and 10 = 
“pain as bad as you can imagine”. To measure the average pain severity, a Pain Severity 


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Subscale will be derived both daily and weekly. Daily score will be calculated as the average of 
the 4 items responses for each day, and the weekly score will be calculated as the average of the 
daily scores. All 4 questions must be answered for the daily average pain severity score to be 
computed. A weekly score will be derived only if 4 or more days out of 7 days period have non-
missing scores.  
The BPI-SF also measures how much pain has interfered with seven daily activities, including 
general activity, walking, work, mood, enjoyment of life, relations with others, and sleep 
through seven pain interference items (items 9A to 9G of question 9) rated on 0–10 scales 
(with 0 = “no interference” and 10 = “interferes completely”). To measure average pain 
interference, a Pain Interference Subscale will be derived both daily and weekly. Daily score 
will be calculated as the average of the 7 items responses for each day provided that 4 out of the 
7 items have non-missing responses. The weekly score will be the average of the daily scores 
over the 7 days period prior to each visit. A weekly score will be derived only if 4 or more days 
out of 7 days period have non-missing scores. 
In addition, Average Pain Intensity (API) will be calculated as the average of the daily BPI-SF 
Item 3 “Worst Pain in Past 24 hours” over the 7 day period prior to each visit. API will be 
derived only if 4 to 7 days have non-missing scores.  
2.2.3. 
EORTC QLQ-C30 
The EORTC QLQ-C30 is a quality of life (QoL) questionnaire used for assessing the health-
related quality of life of cancer patients participating in international clinical trials. The items 
from the questionnaire are presented in Appendix 8.3. 
EORTC QLQ-C30 version 3.0 will be used in this study, with a 7-day recall period. It consists 
of 30 questions, with all items scored 1 (“not at all”) to 4 (“very much”) except for the 2 items 
contributing to the global health status/QoL, which are scored 1 (“very poor”) to 7 (“excellent”). 
The recall period for each question is “during the past week”. The instrument yields the 
following scales: 
• GHS/QoL scale with 2 items 
• 5 Functional scales : 
o Physical functioning (PF) with 5 items 
o Role functioning (RF) with 2 items  
o Emotional functioning (EF) with 4 items  
o Cognitive functioning (CF) with 2 items 
o Social functioning (SF) with 2 items 
 
• 3 Symptom scales / single items  : 
o Fatigue (FA) with 3 items  


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o Nausea and vomiting (NV) with 2 items 
o Pain (PA) with 2 items 
o Dyspnea (DY) , insomnia (SL), appetite loss (AP), constipation (CO), diarrhea 
(DI) with 1 item each  
• 
Financial impact of disease with 1 item .  
The EORTC QLQ-C30 scale scores will be calculated using the EORTC QLQ-C30 Scoring 
Manual (Fayers, et al., 2001). Each of the scales will have a raw mean score computed as long 
as at least 50% of the scales’ questions have responses. The raw score will be used in a scoring 
formula described below that will transform the raw score linearly onto a score of 0 to 100. 
Details on computing raw scores and transforming them are found in Appendix 8.3. 
A higher score represents a higher ("better") level of functioning, or a higher ("worse") level of 
symptoms, i.e., a high score for a functional scale (PF, RF, EF, CF, SF) represents a high/healthy 
level of functioning, a high score for the GHS/QoL and FI represents a high QoL or less impact, 
but a high score for a symptom scale (FA, NV, PA, DY, SL, AP, CO, DI) represents a high level 
of symptomatology.  
The financial impact domain will not be included in this PRO Addendum to the DeFi Main SAP 
analysis as it is not related to symptoms, functioning or health-related quality of life, and 
therefore is not relevant for the context of the clinical trial. 
2.2.4. 
PROMIS PF Short Form 10a + 3 Additional Items from PROMIS Item Bank 
The PROMIS PF instruments measure self-reported capability rather than actual performance 
of physical activities. This includes the functioning of one’s upper extremities (dexterity), lower 
extremities (walking or mobility), and central regions (neck, back), as well as instrumental 
activities of daily living, such as running errands.  
The PROMIS PF short form 10a version 2.0 will be used in this study with a 7-day recall period. 
The items from the questionnaire are presented in Appendix 8.4. This PRO assessment consists 
of 10 questions and was constructed with a focus on representing the range of the trait and the 
content of the item bank, as well as mapping the questions in the instrument to qualitative 
evidence of the physical function concepts important to patients. A total sum score will be 
computed using all 10 items. A T-score and standard error of the T-score associated with the 
total score will be assigned based on the short form conversion table accompanying the scale 
and found in Appendix 8.4. A higher PROMIS T-score represents more of the concept being 
measured. For positively-worded concepts like physical function, a T-score of 60 is one SD 
better than average, and a participant with a T-score of 40 is one SD worse than the average 
(PROMIS, s.f.). 
To supplement the PROMIS PF short form 10a, 3 additional questions representing other 
elements of physical function found to be important to patients were selected from the PROMIS 
Physical Function, Upper Extremity, and Ability to Participate item banks.  
• Additional item 1: “Are you able to bend or twist your back”,  


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• Additional item 2: “Are you able to reach into a high cupboard”,  
• Additional item 3: “I have trouble doing my regular daily work around the house”. 
A total score for the PROMIS-PF 10a with these three additional items has been supported by 
further psychometric evaluation. Therefore, a PROMIS PF13 score will be derived as a sum 
score of all 13 items, provided that there are no missing items.  
Due to limitations in available translations in some countries, the additional 3 questions were 
not available at all sites. As such, this analysis only applies to those participants with available 
data at baseline including PROMIS PF short for 10a plus the 3 additional questions. 
2.2.5. 
Patient Global Impression of Severity (PGIS) 
The PGIS is a single-item scale that evaluates the participant’s perception of the overall severity 
of their desmoid related symptoms over the past week on a 4-point scale ranging from “none” 
to “severe.”. The PGIS has a 7-day recall period. The scale is presented in Appendix 8.5.  
2.2.6. 
Patient Global Impression of Change (PGIC) 
The PGIC is a single-item scale that evaluates the participant’s perception of the change in their 
overall status since the start of the study treatment on a 7-point scale ranging from “very much 
better” to “very much worse”. The PGIC has a 7-day recall period. The scale is presented in 
Appendix 8.6.  
 
 


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3. 
SUBJECT POPULATION 
3.1. 
Population Definitions 
The Intent-to-Treat (ITT) Population will be evaluated and used for presentation and analysis 
of the PRO data. The ITT Population will consist of all participants who are enrolled and 
randomized to study treatment (nirogacestat or placebo). Participants will be analyzed according 
to the treatment to which they were randomized and the strata to which they have been assigned. 
Participants who were randomized but did not subsequently go on to receive study treatment 
are included in the ITT population. 
 


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4. 
GENERAL STATISTICAL METHODS 
4.1. 
General Methods 
Continuous variables will be described by the number of participants, mean, median, standard 
deviation, minimum, and maximum. Categorical variables will be described by the number and 
percentage of participants within each category (with a category for missing data). Time-to-
event data will be summarized using Kaplan-Meier methodology using 25th, 50th (median), 
and 75th percentiles with associated 2-sided 95% confidence intervals (CIs), as well as 
percentage of censored observations. Additional conventions for presentation of study data are 
laid out in the main body of the NIR-DT-301 SAP and will be applied for the PRO analyses as 
appropriate. 
Formal statistical hypothesis testing on the PRO-related secondary endpoints listed in section 
2.1.3, for the purpose of New Drug Application (NDA), will be conducted at the 1-sided, 0.025 
level of significance. 
Specific details on analysis of selected PRO measures are laid out in Section 5. All additional 
PRO measures, as well as all data collected after crossover to nirogacestat in the OLE phase of 
the study will be analyzed as described in an exploratory PRO statistical analysis plan and 
reported separately.  
4.2. 
Baseline Definitions 
For all PRO analyses unless specified, baseline for the double-blind phase will be defined as 
the most recent measurement prior to the first administration of study drug. 
For weekly summary scores of the GODDESS and the BPI-SF, the baseline score will be set as 
the weekly average of the Baseline period (e.g., study days -7 through -1) if there are 4 or more 
days of assessments during that Baseline period. If there are less than 4 days of assessments 
during Baseline period, the baseline weekly score will be set to weekly average of the Screening 
visits’ assessments, provided that there are 4 or more days of assessments during that period. 
Otherwise, it will be set as missing. 
Baseline assessments of PGIC do not exist, as PGIC assessments are post-baseline only. 
4.3. 
Adjustments for Covariates 
In general, the stratification factor (as reported in randomization) will be included in the analysis 
of all PRO endpoints. In addition, longitudinal change from baseline models will account for 
the baseline scores.  
4.4. 
Multiple Comparisons/Multiplicity 
Multiplicity will be controlled via hierarchical testing method for the primary and secondary 
endpoints as defined in the main study SAP. 


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4.5. 
Subgroups 
The longitudinal analysis of change from baseline in PRO endpoints and the time to pain 
response will be examined in selected subgroups as listed in Table 3.  
Table 3 List of subgroups 
Subgroup Name 
Subgroup Levels 
Primary tumor location as reported 
in randomization 
Intra-abdominal 
Extra-abdominal 
Baseline worst pain score  
Uncontrolled (API > 4) 
Controlled (API ≤ 4) 
Tumor focality 
Multi-Focal Disease 
Single Tumor 
Desmoid tumor treatment status 
Treatment naïve, measurably progressing DT/AF that is 
deemed not amenable to surgery 
Recurrent, measurably progressing DT/AF following at least 
one line of therapy  
Refractory, measurably progressing DT/AF following at least 
one line of therapy 
Sex  
Male 
Female 
Race  
White 
Non-White 
Geographic region 
North America Sites 
Rest of World Sites 
Age group 
First age quartile 
Second age quartile 
Third age quartile 
Fourth age quartile 
Ethnicity 
Hispanic or Latino 
Not Hispanic or Latino 
 


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4.6. 
Withdrawals, Dropouts, Loss to Follow-up 
Subjects who are withdrawn or discontinue from the study will not be replaced. 
4.7. 
Missing, Unused, and Spurious Data 
In case of missing items, the scale and total scores will be calculated as indicated in the scoring 
manual for the PRO instrument for the existing instruments. For GODDESS all items for a given 
total or domain score should be present in order to create the total or domain score. 
Weekly scores (GODDESS and BPI-SF) will be calculated only if there are 4 or more days of 
assessments with non-missing data within the respective week. 
It is anticipated that the great majority of missing data in this study will have a monotone pattern, 
meaning that once a participant has missing data at one visit, data will be missing at all 
subsequent visits. There may be some small amount of intermittent (non-monotone) missing 
data (when participant skips intermediate visits but returns for evaluations at subsequent visits).  
Missing PRO data will be assumed to be missing at random (MAR) in general and will be 
analyzed using mixed model repeated measures (MMRM) analysis when appropriate. To 
address the possibility that missing data may not be MAR, sensitivity analysis with pattern 
mixture model (PMM) will be conducted. 
4.8. 
Visit Windows 
In line with the clinical SAP, no windowing conventions will be applied for the analysis of the 
PRO data. All data will be tabulated per the evaluation visit as recorded on the eCRF. In the 
case of multiple observations at a specific visit, the first observation will be used. 


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5. 
STUDY ANALYSES 
5.1. 
Participant Disposition 
The participant disposition by treatment arm for all PRO assessment timepoints in the double- 
blind phase will be provided:  
• The number of participants with PRO assessment expected 
• The number and % of participants with PRO assessment not expected due to progression  
• The number and % of participants with PRO assessment not expected due to death 
• The number and % of participants with PRO assessment not expected due to other reasons 
The participant disposition by treatment arm per timepoint will also be provided graphically using 
bar charts. 
A participant is expected to complete the PRO assessment as long as he/she is still alive and 
have not discontinued the study. 
5.2. 
PRO Completion 
PRO completion for all instruments will be examined at each timepoint in the double blind 
phase. Specifically, the following will be examined: 
• Unadjusted completion rate at each timepoint will be calculated as the number of 
participants meeting at least the minimum requirements for scoring of each instrument 
divided by the number of participants in the ITT population.  
• Adjusted completion rate at each timepoint will be calculated among participants who are 
expected to have PRO assessments.  
For the adjusted completion rate described above, the following will be provided: 
• The number and % of participants with all questions completed  
• The number and % of participants meeting at least the minimum requirements for scoring 
of the instrument (see section 2.2 
• The number and % of participants with at least one question completed (for multi-item 
instruments) 
The completion rates (both adjusted and unadjusted) by treatment arm per timepoint will also 
be provided graphically: This will be displayed using grouped bar charts with visit on the x-axis 
and percent completion on the y-axis. Groups will be defined by treatment arm. 


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5.3. 
Exploration of Missing Data 
Tabular summaries for the percentage of participants by the reason for discontinuation of study 
treatment, as well as for withdrawal from the study, are provided in the clinical SAP and will 
not be repeated herein. 
The number of participants with missing PRO data will be summarized by treatment arm and 
timepoint (all scheduled timepoints in the double blind and OLE phases). For this analysis, the 
frequency and percentage of: 
• Informative missingness, versus  
• Non-informative missingness  
The denominator will be the number of participants in the ITT. 
This will be tabulated over time by treatment arm for each PRO endpoint. Informative 
missingness will be based on discontinuation due to an adverse event or due to lack of efficacy.   
A comprehensive evaluation of missing data may warrant a modification to the planned analysis 
Any such modification will be detailed in the CSR.  
5.4. 
Descriptive Analyses 
Descriptive statistics for the observed scores as well as change from baseline scores for all the 
scores resulting from the instruments described in Section 2.2 except PGIS and PGIC will be 
provided for the ITT population by treatment arm at each timepoint in the double blind. 
Graphical representation will be also provided for the observed scores, e.g., box and whisker 
plots will be presented by treatment arm at each timepoint. Number and percentage of 
participants with each response value for PGIS and PGIC will be prestend by treatment arm at 
each timepoint.  
A cumulative distribution function (CDF) plot showing a continuous plot of the  change from 
baseline during the study, with change scores presented on the x-axis and the cumulative percent 
of participants experiencing that change on the y-axis, will be presented by treatment arm at all 
post-baseline timepoints up to and including Cycle 10. The cumulative distribution plot will be 
produced for the following PRO scores:  
• DTSS scores: Total Symptom Score (weekly summary), Total Symptom Score – 5 Items 
(weekly summary), Pain Domain Score (weekly summary) 
• DTIS scores: Physical Functioning Domain Score 
• BPI-SF: API 
• EORTC QLQ-C30: GHS/QoL, PF, RF and PA 
• PROMIS: PF10a (sum score) and PF13 (sum score). 


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In addition, the number and proportion of participants by pain severity at baseline will be 
reported by treatment arms. Pain severity at baseline will be defined using the API score at 
baseline and classified as follows: 
• Controlled pain at baseline: is API ≤ 4 
• Uncontrolled pain at baseline: if API >4. 
5.5. 
Longitudinal Analysis of Change from Baseline 
Change from baseline during the double-blind phase in PRO scores will be analyzed using a 
restricted maximum likelihood (REML) based repeated measures approach (Brown & Prescott, 
2006) (MMRM – Mixed Model Repeated Measures) in a primary analysis and a PMM (O'Kelly 
& Ratitch, 2014) in a sensitivity analysis. The PMM will be used to assess the robustness of the 
MMRM estimate with regard to missing data, when the MAR assumption is replaced by 
assumptions that are likely to be relatively less favorable to the experimental treatment. 
The longitudinal analysis of change from baseline will include only the on-treatment 
assessments (thus excluding the unscheduled, EOT and follow-up visits).  
5.5.1. 
Mixed Model Repeated Measures – Main Analysis 
The primary objective of this analysis is to examine the treatment difference at Cycle 10. Data 
from all PRO assessments at all scheduled timepoints will be reported, although analysis will 
be limited to timepoints at which at least 10 participants have non-missing data in both treatment 
arms through Cycle 10 (i.e, Cycle 11 on will not be included in the model) . 
The response variable will be the change from baseline to each PRO assessment. The model 
will include the treatment arm and timepoint as fixed-effect categorical factors, the baseline 
PRO score and stratification factor (primary tumor location: intra-abdominal vs extra-
abdominal) as fixed effects covariates, and the baseline x time and treatment x time interactions. 
Both main effects and the interaction terms will remain in the model, regardless of significance. 
The model will present least squares (LS) mean estimates, standard errors, 2-sided 95% CIs, 
and 1-sided p-values for mean changes from baseline to each visit.  
A plot of the LS means accompanied by the 2-sided 95% CI will be produced for each PRO 
measure by treatment arm. 
The analysis will be conducted using PROC MIXED in SAS. The model will assume 
unstructured covariance among the within-participant repeated measurements. If the algorithm 
does not converge, a heterogeneous Toeplitz (the TOEPH option in SAS PROC MIXED) will 
be tried first and then heterogenious autoregressive (ARH)(1) as a covariance structure to 
achieve convergence. The Kenward-Roger approximation will be used to estimate denominator 
degrees of freedom. 
The analysis will be performed on the ITT population. Separate models will be considered for 
each of the following PRO score:  
• DTSS scores: Total Symptom Score, Total Symptom Score – 5 Items, Pain Domain Score 


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• DTIS scores: Physical Functioning Domain Score 
• BPI-SF: API 
• EORTC QLQ-C30: GHS/QoL, PF, RF and PA 
• PROMIS: PF10a (sum score) and PF13 (sum score). 
For the subgroup examinations, a separate model will be considered for each subgroup listed in 
Section 4.5. The model will include the treatment arm, and timepoint as fixed-effect categorical 
factors, the baseline PRO score, stratification factor (primary tumor location: intra-abdominal vs 
extra-abdominal, except for the stratification factor subgroup) and the subgroup as fixed effect 
covariates, and the baseline x time, treatment x time and treatment x subgroup interactions. The 
same hierarchy will be used to chose a covariance structure. Subgroup analyses will be run only 
for variables  resulting in subgroups of at least 10 participants in each treatment arm. The 
following will be presented: least squares (LS) mean estimates for the overall treatment effect 
(across all timepoints), standard errors, 2-sided 95% CIs, and 1-sided p-values for mean changes 
from baseline to each visit, as well as the p-value for the treatment by subgroup interaction. 
5.5.2. 
Pattern Mixture Model – Sensitivity Analysis 
The MMRM assumes that the missing observations are MAR. To address the possibility of the 
data being missing not at random (MNAR) (e.g., non-ignorable missing data), a sensitivity 
analysis using a PMM with sequential modelling with multiple imputation and delta-adjustment 
will be used. Change from baseline to Cycle 10 in PRO scale will be analyzed using a pattern-
mixture model using control-based approach by means of sequential modelling with multiple 
imputation as described by O’Kelly (O'Kelly & Ratitch, 2014). The results from this analysis 
will be used to judge the validity of the MAR assumption. Similar conclusions from MMRM 
and PMM would suggest that the results are not overly dependent on the assumptions of the 
primary analysis with regard to the missing data. 
We distinguish between monotone and non-monotone missing values. Non-monotone missing 
values are values missing intermittently, where a participant may miss some PRO assessments 
but has PRO assessments for the same score later on. Monotone missing values are such that 
once a value is missing for a given score, no subsequent values for this score are available. Any 
given participant may have a combination of non-monotone and monotone missing values.  
Non-monotone missing values are assumed to be MAR and will be multiply imputed using a 
Markov Chain Monte Carlo (MCMC) method of Proc MI in SAS. The imputation model will 
include the following: 
• Treatment arms (nirogacestat or placebo) 
• Stratification factors (primary tumor location:intra-abdominal vs extra-abdominal) 
• Age (continuous) 
• Gender (male or female) 


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• Geographic region (North America vs the rest of world) 
• Desmoid Tumor Treatment Status (treatment naïve, recurrent or refractory) 
• Any prior treatment (Yes vs No). 
Non-monotone missing data will be imputed first, followed by the imputation of monotone 
missing data. 
To impute monotone missing values, we define patterns depending on reason and timing of 
missingness as follows: 
• Pattern 1: missing values before or at Cycle 10 due to participant’s death; 
• Pattern 2: missing values before or at Cycle 10 due to adverse events (AEs) or due to 
progression (clinical or radiographic); 
• Pattern 3: missing values before or at Cycle 10 with missingness that does not satisfy 
conditions of patterns 1 to 2. 
The patterns are mutually disjointed, i.e., each participant with monotone missing data belongs 
only to one pattern. 
The following assumptions will be made for the missing data in each pattern: 
For pattern 1, the worst score (e.g., 10 for DTSS Total Symptom Score) will be assigned as a 
penalty for unobservable values up Cycle 10 after participant’s death. This will be applied to 
both treatment arms. 
For pattern 2, control-based approach will be used for the nirogacestat arm. For the placebo 
arm, multiple imputation under MAR assumption will be used. 
For pattern 3, data will be assumed to be MAR in both treatment arms. 
The imputation of monotone missing data will be done sequentially for each scheduled PRO 
assessment visit, k=k1,…,K (where K corresponds to Cycle 10) as follows: 
a) 
Impute monotone missing data in pattern 1 at visit k as the worst possible score for 
the imputed PRO score.  
b) 
For the pattern 3 and for pattern 2 placebo participants only, impute the monotone 
missing values at visit k using an MAR-based multiple imputation regression model (PROC MI 
option MONOTONE REG) including the effects for baseline covariates as listed for the 
imputation model of non-monotone missing data above and PRO values at each schedule 
assessment time point up to (k-1). 
c) 
For the pattern 2 nirogacestat participants only, impute the monotone missing values 
at visit k using multiple imputation regression model including the effects for baseline 
covariates as listed for the imputation model of non-monotone missing data above and PRO 


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values at each schedule assessment time point up to (k-1); at this step we will include all 
participants from the nirogacestat arm with missing at visit k, plus participants from the placebo 
arm with visit k observed. We omit participants from the nirogacestat arm with outcomes 
observed at vist k. Multiple imputation will now estimate regression parameters for visit k using 
data from the placebo arm only. The imputed data for vist k for a participant from the 
nirogacestat arm will look similar to the imputed data for a similar participant from the placebo 
arm. 
The above steps (a)-(c) are performed for each visit k, before proceeding with the imputations 
of the next visit (k+1). 
A total of 50 multiply-imputed datasets will be created for each PRO. The random number 
generator seed for the imputation of non-monotone missing values using MCMC will be 5414, 
and the random seed for imputation of monotone missing values will be 5414+k, for k=1, 2, … 
for each sequential visit with monotone missing data. For monotone missing imputation, the 
specified seed will be used for the first dataset. Data will be sorted so that the 1st dataset for 
each instrument is imputed, followed by the second dataset for each instrument, etc. Instruments 
will be ordered in the following manner:  
• BPI-SF: API 
• DTIS scores: Physical Functioning Domain Score 
• DTSS scores: Total Symptom Score, Total Symptom Score – 5 Items, Pain Domain Score 
• EORTC QLQ-C30: GHS/QoL, PF, RF and PA 
• PROMIS: PF10a (sum score) and PF13 (sum score). 
The MMRM modeling with the identical setup as described above in Section 5.5.1 will be 
performed, i.e., at each timepoint and also overall across all timepoints giving each visit equal 
weight, for each imputed dataset. 
The SAS MIAnalyze procedure will be used to combine the results of these analyses for the 
imputations. For a more detailed description of the implementation MNAR imputation, see 
Ratitch B and O’Kelly M (O'Kelly & Ratitch, 2014). 
The treatment differences will be estimated from the final model with LS-means differences 
and using the REML method. The degrees of freedom will be estimated with the Kenward-
Roger approximation. The LS mean treatment difference, 2-sided 95% CI, and 1-sided p-value 
will be presented. A plot of the LS means accompanied by the 2-sided 95% CI will be produced 
by treatment and at each timepoint. 
The analysis will be performed on the ITT population. Separate models will be considered for 
each of the following PRO scores:  
• DTSS scores: Total Symptom Score, Total Symptom Score – 5 Items 
• DTIS scores: Physical Functioning Domain Score 




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assumption. Specifically, multiple imputation under the MNAR assumption as described in 
Section 5.5.2 will be performed first to impute the continuous PRO scores. Next, a visit response 
(responder vs non-responder) at Cycle 10 will be derived as described above for each PRO score 
for each of the 50 datasets generated in the imputation procedure. The analysis will include only 
those patients with a baseline score ≥ threshold value used to define improvement (see Table 4 
for GODDESS, for BPI-SF a value of 2 will be used). 
Each of the multiply-imputed data sets with the response visit status at Cycle 10 will be analysed 
using the CMH test adjusted by primary tumor location (intra-abdominal or extra-abdominal) 
used.  Statistical inference obtained from all imputed data will be combined using Rubin’s rule 
(Ratitch, et al., 2013). The odds ratio will be log-transformed and the Wilson-Hilferty 
transformation will be applied to the CMH statistitic prior to combining all results with PROC 
MIANALYZE. The visit response by treatment arm (average, minimum and maximum percent 
responder), odds ratio (OR) as well as the corresponding 2-sided 95% CI will be provided along 
with the 1-sided p-values.  
A descriptive analysis will also be performed. The number and proportion of participants who 
are responders vs. non-responders (as defined in the Table 4 above) will be summarized at each 
post-baseline timepoint (the double-blind phase only) by treatment arm. The proportions will 
be derived in two ways. In the first analysis, the denominator will be the number of participants 
with non-missing data at specific cycle. In a second analysis, the denominator will be the 
number of participants in the ITT population for whom a PRO is expected (i.e., including 
participants with missing data) at specific cycle. Participants with missing data at specific cycle 
will be considered non-responders in this second analysis. The proportion of participants who 
are responders vs non-responders in the second analysis described above will be presented 
graphically using bar charts.  
      In addition, for the DTSS Total Symptom Score, Pain Domain Score, and BPI-SF API, a 
symptom improvement rate will be defined as the number and proportion of participants who 
are responders at two or more consecutive timepoints during the double-blind period (see Table 
4). This analysis will be performed only among those particpants with uncontrolled pain at 
baseline (e.g., with a baseline API ≥4) and will use all the available datapoints during double-
blind phase. The improvement rate will be compared using a logistic regression stratified by 
primary tumor location (intra-abdominal or extra-abdominal). Additional covariates, such as 
age and gender, will also be examined and included as appropriate. The results of the analysis 
will be presented in terms of an OR together with its associated 2-sided 95% CI and 1-sided p-
value.  
5.7. 
Time to Event Analysis 
Time to event analyses will include all PRO assessments during the double-blind phase (thus 
any unscheduled and EOT visits) and will be performed separately for the following PRO 
scores: 
• DTSS scores: Total Symptom Score, Pain Domain Score 
• DTIS scores: Physical Functioning Domain Score 
• BPI-SF: API. 


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The following time to event endpoints will be defined: 
• Time to first DT symptom improvement (using DTSS Total Symptom) 
• Time to first control of pain symptoms (using BPI-SF API) 
• Time to pain response (using BPI-SF API, DTSS Pain Domain Score) 
• Time to first improvement in functioning (using DTIS: Physical Functioning Domain 
Score) 
Time to first DT symptom improvement will be defined as the duration of time from the date 
of randomization to the date of the first time reduction of at least a X points in DT symptoms 
using the DTSS Total Symptom Score (X is the threshold value which is provided in Table 4) 
as compared to the baseline score. The primary threshold as well as both sensitivity thresholds 
will be used. Participants without observed symptom improvement at the time of analysis will 
be censored at the date of last available PRO assessment (i.e., date of the last non-missing value) 
on or before the analysis data cutoff date. Participants who were randomized but with no 
baseline or whose baseline scores do not allow for further improvement will be censored on the 
date of randomization. Participants with a baseline score but no post-baseline assessments will 
be censored at the baseline assessment date. 
Time to first control of pain symptoms will be defined as the time from randomization to first 
time the BPI-SF API score is ≤ 4. The analysis will include only those participants whose BPI-
SF API baseline scores are > 4. Participants without observed control of pain symptoms at the 
time of analysis will be censored at the date of last pain assessment on or before the analysis 
data cutoff date. Participants who were randomized but with no baseline score will be censored 
on the date of randomization. Participants with a baseline score but no post-baseline assessments 
will be censored at the baseline assessment date. 
Time to pain response will be defined using the BPI-SF API and DTSS Pain Domain Score as 
follows: time to pain response is defined as the time from randomization to first occurence of 
pain response (using 2 points for BPI-SF API and the values in Table 4 for DTSS Pain Domain 
Score). Participants without observed pain response at the time of analysis will be censored at 
the date of last pain assessment on or before the analysis data cutoff date. Participants who were 
randomized but with no baseline or whose baseline scores do not allow for further reduction in 
pain will be censored on the date of randomization. Participants with a baseline score but no 
post-baseline assessments will be censored at the baseline assessment date. 
Time to first improvement in functioning will be defined using the DTIS Physical 
Functioning Domain Score as follows: time to clinically meaningful improvement is defined as 
the time from randomization to first occurrence of improvement (e.g., response, see Table 4). 
Participants without observed improvement at the time of analysis will be censored at the date 
of last PRO assessment on or before the analysis data cutoff date. Participants who were 
randomized but with no baseline or whose baseline scores do not allow for further improvement 
will be censored on the date of randomization. Participants with a baseline score but no post-
baseline assessments will be censored at the baseline assessment date. 
For all time to event analyses, the time to event will be analyzed in months and will be presented 


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by treatment arm. Kaplan-Meier curves will be presented. The hazard ratio (HR) and the 95% 
CI will be estimated using a Cox proportional hazards model controlling for stratification factor 
(primary tumor location [intra-abdominal or extra-abdominal]). Additional covariates, such as 
age or gender, will also be examined and included as appropriate. 
A 1-sided stratified log-rank test on the time to event will be performed using SAS PROC 
LIFETEST with method=PL option (Kaplan-Meier estimates, also known as the product-limit 
estimates). The HR with 2-sided 95% CI will be estimated from the stratified Cox proportional 
hazards model using SAS PHREG procedure with ties=EXACT option in the model. In this 
analysis, the baseline hazard function will be allowed to vary across strata; i.e., the MODEL 
statement will include the treatment arm variable as the only covariate and the STRATA 
statement will include the prespecified variable. The assumption of proportionality will be 
tested by producing plots of complementary log-log (event times) versus log(time). 
Kaplan-Meier plots of the survival distribution function will be presented and include the 
number of participants at risk over time by treatment arm.  
The time to pain response will also be examined in selected subgroups (see Section 4.5). For 
the subgroup examinations, separate unstratified Cox models will be employed for each 
subgroup listed in Section 4.5. The model will include the treatment arm, the subgroup and 
treatment x subgroup interaction. Subgroup analyses will be run only if at least 10 events 
occurred in one of the subgroups across treatment groups. The following will be presented for 
each subgroup: the number of participants, events and censored cases, the median time to event 
and the corresponding 2-sided 95% CI , HR with 2-sided 95% CI and the 1-sided p-value 
corresponding to the stratified log-rank test, as well as the 2-sided p-value obtained from the 
unstratified Cox for the treatment by subgroup interaction. 
 
 


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6. 
CHANGES TO PLANNED ANALYSES 
As of this date, there have been one notable change between the protocol-defined statistical 
analyses of the PRO data and those presented in this statistical analysis plan: 
“Patient-Reported Outcomes Measurement Information System Physical Function (PROMIS 
PF) short form 10a plus 3 additional items from PROMIS item banks” has been moved from 
secondary to exploratory endpoint, due to duplications to other PROs instruments. 
 


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7. 
REFERENCES 
Brown, H. & Prescott, R., 2006. Applied Mixed Models in Medicine. s.l.:John Wiley and Sons Ltd. 
Dworkin , R., Turk, D. & Wyrwich, K., 2008. Interpreting the clinical importance of treatment outcomes 
in chronic pain clinical trials: IMMPACT recommendations. Pain, Volume 9, pp. 105-21. 
Farrar, J. et al., 2000. Defining the clinically important difference in pain outcome measures. Pain, 
Volume 88, pp. 287-94. 
Fayers, P. et al., 2001. EORTC QLQ-C30 Scoring Manual (3rd ed.). EORTC. 
O'Kelly, M. & Ratitch, B., 2014. Clinical Trials with Missing Data: A Guide for Practitioners.. s.l.:John 
Wiley & Sons Ltd. 
PROMIS, n.d. Physical functioning: A brief guide to the PROMIS Physical Function instruments. 
Patient-Reported Outcomes Measurement Information System (PROMIS). 
Ratitch, B., Lipkovich, I. & O’Kelly, M., 2013. Combining Analysis Results from Multiply Imputed 
Categorical Data. [Online]  
Available at: https://www.lexjansen.com/pharmasug/2013/SP/PharmaSUG-2013-SP03.pdf 
[Accessed 17 December 2021]. 
 
 
 
 
 


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8. 
APPENDICES 
8.1. 
The GOunder/DTRF DEsmoid Symptom/Impact Scale (GODDESS)  
8.1.1. 
Items of Desmoid Tumor Impact Scale (DTIS) 
Item # 
Question 
Scale 
Range 
During the past 7 days 
 
 
1 
How often have you had difficulty moving (for example twisting or 
bending) near your tumor? 
5  
None - All the time 
2 
How often have you had difficulty with reaching up, such as reaching 
shelves that were above your head? 
5  
None - All the time 
3 
How often have you had trouble falling asleep? 
5  
None - All the time 
4 
How often have you had difficulty getting comfortable in bed? 
5 
None - All the time 
5 
How often have you had trouble staying asleep at night? 
5 
None - All the time 
6 
How often have you had difficulty doing vigorous activities (such as 
running, lifting heavy objects, or participating in strenuous sports)? 
5 
None - All the time 
7 
How often have you had difficulty doing moderate activities (such as 
pushing a vacuum cleaner, playing with children, or taking a long 
walk)? 
5 
None - All the time 
8 
How often have you accomplished less than you would like when 
doing work or other regular daily activities? 
5 
None - All the time 
9 
How often have you avoided people because of the way you feel about 
your appearance? 
5 
None - All the time 
10 
What was your worst difficulty with reaching up, such as reaching 
shelves that were above your head? 
11 
0 - 10 
11 
Have you been dissatisfied about your appearance? 
11 
0 - 10 
12 
How much fear of future diagnostic tests did you have? 
11 
0 - 10 
13 
How much fear of recurrence / growth of your desmoid tumor(s) did 
you have? 
11 
0 - 10 
14 
How much hopelessness did you have? 
11 
0 - 10 
15 
How much anger did you have? 
11 
0 - 10 
16 
How much anxiety did you have? 
11 
0 - 10 
17 
How much frustration did you have? 
11 
0 - 10 
 
 
 


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Statistical Analysis Plan for Patient-Reported Outcomes, Protocol NIR-DT-301 
05 Apr 2022, Final Version 2 
 
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37 
8.1.2. 
Items of Desmoid Tumor Symptom Scale (DTSS) 
Item # 
Question 
Scale Range 
Note 
During the past 24 hours 
 
 
1 
How bad was your worst feeling of pain? 
11 
0 - 10 
2 
How bad was your worst feeling of dull pain? 
11 
0 - 10 
3 
How bad was your worst feeling of shooting pain? 
11 
0 - 10 
4 
How bad was your worst feeling of fatigue? 
11 
0 - 10 
5 
What was your worst swelling around your tumor(s)? 
11 
0 - 10 
6 
What was your worst muscle weakness around your 
tumor(s)? 
11 
0 - 10 
7 
At its worst, how difficult was moving (for example 
twisting or bending) near your tumor(s)? 
11 
0 - 10 
8 
Please indicate the location(s) of your desmoid 
tumor(s). Select all that apply. 
 
 
Gate Q for Q9 - Q11 
9 
How bad was your worst feeling of abdominal pain? 
11 
0 - 10 
If Abdominal Wall in Q8 
10 
How bad was your worst feeling of nausea? 
11 
0 - 10 
If Abdominal Wall in Q8 
11 
How bad was your worst feeling of fullness after 
beginning to eat? 
11 
0 - 10 
If Abdominal Wall in Q8 
 
 
 


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05 Apr 2022, Final Version 2 
 
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8.2. 
BPI Short Form  
 
 
 


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05 Apr 2022, Final Version 2 
 
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8.4. 
PROMIS  
8.4.1. 
PROMIS PF Short Form 10a 
 


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8.4.2. 
PROMIS PF Short Form 10a Look-Up Table 
 
 


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8.4.3. 
3 Additional Items from PROMIS Item Banks 
 
 
 
 
 


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05 Apr 2022, Final Version 2 
 
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8.5. 
PGIS  
Please choose the response below that best describes the severity of your desmoid related symptoms over 
the past week. 
□ None 
□ Mild 
□ Moderate 
□ Severe 
 
 


SpringWorks Therapeutics 
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05 Apr 2022, Final Version 2 
 
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47 
8.6. 
PGIC  
Please choose the response below that best describes the overall change in your general state of health 
since you started taking your study medication. 
□ Very much Better 
□ Moderately Better 
□ A Litter Better 
□ No Change 
□ A Little Worse 
□ Moderately Worse 
□ Very much Worse 
 

Prot_000.pdf: 
SpringWorks Therapeutics 
 
Protocol NIR-DT-301
 
 
Amendment 5 (09Feb2021) 
CONFIDENTIAL 
Page 1 
TITLE PAGE 
Protocol Title: A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial of Nirogacestat 
Versus Placebo in Adult Patients with Progressing Desmoid Tumors/Aggressive Fibromatosis 
(DT/AF). 
Protocol Number: NIR-DT-301 
Amendment Number: 5 
Compound Number: PF-03084014 (nirogacestat) 
Study Phase: Phase 3 
Short Title: A Placebo-Controlled, Phase 3 Study of Nirogacestat in Adults with Desmoid 
Tumor/Aggressive Fibromatosis (DT/AF). 
 
Acronym: DeFi 
Sponsor Name: SpringWorks Therapeutics 
Legal Registered Address: 100 Washington Blvd, Stamford, CT 06902, United States 
Regulatory Agency Identifier Number(s) 
Registry 
ID 
EudraCT 
2018-001991-39 
IND 
138207 
 
Approval Date: 09 February 2021 
 
Confidentiality Statement 
The information in this document is confidential information of SpringWorks Therapeutics 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.


SpringWorks Therapeutics
Protocol NIR-DT-301
Amendment 5 (09Feb2021)
CONFIDENTIAL 
Page 2


SpringWorks Therapeutics 
 
Protocol NIR-DT-301
 
 
Amendment 5 (09Feb2021) 
CONFIDENTIAL 
Page 3 
Protocol Amendment Summary of Changes Table 
DOCUMENT HISTORY 
Document 
Date 
Comment 
Amendment 5 
09 February 2021 
Global 
Amendment 4 
07 July 2020 
Not implemented and not 
released to sites 
Amendment 3 
27 January 2020 
Global 
Amendment 2 / CAN-2.1 
04 February 2020 
Canada only 
Amendment 2 / GBR-2.2 
17 January 2020 
Great Britain only 
Amendment 2 
14 October 2019 
Global 
Amendment 1 / ITA-1 
19 March 2019 
Italy only 
Amendment 1 
27 November 2018 
Global 
Original Protocol 
03 August 2018 
Global 


SpringWorks Therapeutics 
 
Protocol NIR-DT-301
 
 
Amendment 5 (09Feb2021) 
CONFIDENTIAL 
Page 4 
TABLE OF CONTENTS 
1. 
Protocol Summary ..........................................................................................................8 
 
Synopsis ............................................................................................................................8 
 
Schema ............................................................................................................................12 
 
Schedule of Activities (SoA) ..........................................................................................13 
1.3.1. 
Double-Blind Phase SoA ................................................................................................13 
1.3.2. 
Open-Label Extension Phase SoA ..................................................................................19 
2. 
Introduction ...................................................................................................................24 
 
Study Rationale ...............................................................................................................24 
 
Background .....................................................................................................................24 
2.2.1. 
Desmoid Tumors/Aggressive Fibromatosis ....................................................................24 
2.2.2. 
Diagnosis.........................................................................................................................25 
2.2.3. 
Treatment ........................................................................................................................26 
 
Rationale for Nirogacestat in Desmoid Tumors .............................................................29 
 
Rationale for Participant Population and Placebo Arm ..................................................29 
 
Benefit/Risk Assessment ................................................................................................30 
3. 
Objectives and Endpoints ............................................................................................31 
4. 
Study Design ..................................................................................................................33 
 
Overall Design ................................................................................................................33 
4.1.1. 
Overall Design for the Double-Blind Phase: ..................................................................33 
4.1.2. 
Overall Design for the Optional OLE Phase: .................................................................34 
 
Scientific Rationale for Study Design ............................................................................35 
 
Justification for Dose ......................................................................................................35 
 
End of Study Definition ..................................................................................................36 
5. 
Study Population ...........................................................................................................37 
 
Inclusion Criteria ............................................................................................................37 
 
Exclusion Criteria ...........................................................................................................39 
 
Lifestyle Considerations .................................................................................................41 
5.3.1. 
Meals and Dietary Restrictions .......................................................................................42 
 
Screen Failures ................................................................................................................42 
6. 
Study Treatment ...........................................................................................................43 
 
Study Treatment Administered .......................................................................................43 
6.1.1. 
Double-Blind Phase Dosing Administration ..................................................................45 
6.1.2. 
Open-Label Phase Dosing Administration .....................................................................45 
6.1.3. 
Study Treatment Errors ...................................................................................................45 
 
Preparation/Handling/Storage/Accountability ................................................................46 
 
Measures to Minimize Bias: Randomization and Blinding ............................................46 
6.3.1. 
Randomization ................................................................................................................46 
6.3.2. 
Blinding...........................................................................................................................47 
 
Study Treatment Compliance .........................................................................................49 
 
Concomitant Therapy .....................................................................................................49 
6.5.1. 
Concomitant Medications and/or Procedures .................................................................49 
 
Dose Modification ..........................................................................................................53 
 
Treatment after the End of the Double-Blind Study .......................................................54 
6.7.1. 
Optional Open-Label Extension Phase ...........................................................................54 
6.7.2. 
Inclusion Criteria - Open-Label Extension Phase ...........................................................54 


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Protocol NIR-DT-301
 
 
Amendment 5 (09Feb2021) 
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6.7.3. 
Exclusion Criteria - Open-Label Extension Phase ..........................................................55 
7. 
Discontinuation of Study Treatment and Participant 
Discontinuation/Withdrawal........................................................................................56 
 
Discontinuation of Study Treatment ...............................................................................56 
7.1.1. 
Liver Chemistry Stopping Criteria ..................................................................................56 
7.1.2. 
QTcF Stopping Criteria...................................................................................................57 
7.1.3. 
Pregnancy ........................................................................................................................58 
 
Participant Discontinuation/Withdrawal from the Study ................................................58 
 
Lost to Follow up ............................................................................................................58 
8. 
Study Assessments and Procedures.............................................................................60 
 
Efficacy Assessments .....................................................................................................72 
8.1.1. 
Tumor Imaging ...............................................................................................................72 
8.1.2. 
Definition and Assessment of Clinical Progression........................................................74 
8.1.3. 
Patient-Reported Outcomes ............................................................................................74 
8.1.4. 
Tumor Biopsy .................................................................................................................79 
 
Safety Assessments .........................................................................................................80 
8.2.1. 
Demographics Data and Medical History .......................................................................80 
8.2.2. 
Physical Examinations and Eastern Cooperative Oncology Group 
Performance status ..........................................................................................................80 
8.2.3. 
Electrocardiograms .........................................................................................................80 
8.2.4. 
Vital Signs .......................................................................................................................81 
8.2.5. 
Clinical Safety Laboratory Assessments ........................................................................81 
8.2.6. 
Pregnancy Testing ...........................................................................................................81 
8.2.7. 
Monthly Wellness Checks ..............................................................................................82 
 
Adverse Events and Serious Adverse Events .................................................................82 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE 
Information .....................................................................................................................82 
8.3.2. 
Method of Detecting AEs and SAEs ..............................................................................83 
8.3.3. 
Follow-up of AEs and SAEs ...........................................................................................83 
8.3.4. 
Regulatory Reporting Requirements for SAEs ...............................................................83 
8.3.5. 
Pregnancy ........................................................................................................................84 
8.3.6. 
Adverse Events of Special Interest .................................................................................84 
 
Treatment of Overdose ...................................................................................................85 
 
Pharmacokinetics ............................................................................................................85 
 
Pharmacodynamics .........................................................................................................86 
 
Genetics ..........................................................................................................................87 
 
Biomarkers ......................................................................................................................87 
8.8.1. 
RNA Transcriptome Research ........................................................................................88 
8.8.2. 
RNA Expression Research of a Subset of RNA Species ................................................88 
8.8.3. 
Proteome Research..........................................................................................................88 
 
Health Economics OR Medical Resource Utilization and Health 
Economics .......................................................................................................................88 
9. 
Statistical Considerations .............................................................................................89 
 
Statistical Hypotheses .....................................................................................................89 
 
Sample Size Determination ............................................................................................89 
 
Populations for Analyses ................................................................................................89 


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Protocol NIR-DT-301
 
 
Amendment 5 (09Feb2021) 
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Statistical Analyses .........................................................................................................90 
9.4.1. 
Efficacy Analyses ...........................................................................................................90 
9.4.2. 
Safety Analyses ...............................................................................................................92 
9.4.3. 
Other Analyses ................................................................................................................92 
 
Interim Analyses .............................................................................................................92 
9.5.1. 
Data Monitoring Committee ...........................................................................................93 
10. 
Supporting Documentation and Operational Considerations ..................................94 
 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................94 
10.1.1. Regulatory and Ethical Considerations ...........................................................................94 
10.1.2. Financial Disclosure........................................................................................................94 
10.1.3. Informed Consent Process ..............................................................................................95 
10.1.4. Data Protection................................................................................................................95 
10.1.5. Committees Structure......................................................................................................95 
10.1.6. Data Quality Assurance ..................................................................................................96 
10.1.7. Source Documents ..........................................................................................................96 
10.1.8. Study and Site Closure ....................................................................................................97 
 
Appendix 2: Clinical Laboratory Tests ...........................................................................98 
 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................................100 
10.3.1. Definition of Adverse Event (AE) ................................................................................100 
10.3.2. Definition of SAE .........................................................................................................101 
10.3.3. Recording and Follow-Up of AE and/or SAE ..............................................................102 
10.3.4. Reporting of SAEs ........................................................................................................104 
10.3.5. Definition of AR, SAR and SUSAR .............................................................................105 
 
Appendix 4: Contraceptive Guidance and Collection of 
Pregnancy Information .................................................................................................106 
 
Appendix 5: Genetics....................................................................................................110 
 
Appendix 6: Liver Safety: Suggested Actions and Follow-up 
Assessments  .................................................................................................................111 
 
Appendix 7: Eastern Cooperative Oncology Group Performance................................114 
 
Appendix 8: RECIST (Response Evaluation Criteria in Solid 
Tumors) Version 1.1 Guidelines ...................................................................................115 
 
Appendix 9: Abbreviations ...........................................................................................119 
 
Appendix 10: List of Contacts for Study ......................................................................122 
10.10.1. Sponsor .........................................................................................................................122 
10.10.2. Contract Research Organization ...................................................................................122 
10.10.3. Medical Monitoring ......................................................................................................122 
10.10.4. Serious Adverse Event Reporting .................................................................................122 
10.10.5. Biological Specimens....................................................................................................122 
11. 
REFERENCES............................................................................................................123 


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Protocol NIR-DT-301
 
 
Amendment 5 (09Feb2021) 
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List of Figures 
Figure 1 
Liver Chemistry Stopping Criteria and Increased Monitoring Algorithm ........ 57 
 
 
 
List of Tables 
Table 1 
Study Objectives and Endpoints ....................................................................... 31 
Table 2 
Study Treatments Administration ..................................................................... 44 
Table 3 
Restricted/Excluded Medications and/or Procedures ........................................ 51 
Table 4 
Dose Modifications or Interruptions for Selected Toxicities ............................ 53 
Table 5 
Bundle Branch Block Discontinuation Criteria ................................................ 58 
Table 6 
Double-Blind Phase Study Visits ...................................................................... 61 
Table 7 
Open-Label Phase Study Visits ......................................................................... 68 
Table 8 
Double-Blind Phase: PRO Assessment Administration Schedule .................... 76 
Table 9 
OLE Phase: PRO Assessment Administration Schedule .................................. 77 
Table 10 
Adverse Events of Special Interest (AESI) ....................................................... 84 
Table 11 
PK Blood Draw Schedule ................................................................................. 86 
Table 12 
Protocol-Required Safety Laboratory Assessments .......................................... 99 


SpringWorks Therapeutics 
 
Protocol NIR-DT-301
 
 
Amendment 5 (09Feb2021) 
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1. 
PROTOCOL SUMMARY 
 
Synopsis 
Protocol Title: A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial of Nirogacestat 
Versus Placebo in Adult Patients with Progressing Desmoid Tumors/Aggressive Fibromatosis 
(DT/AF). 
Short Title: A Placebo-Controlled, Phase 3 Study of Nirogacestat in Adults with Desmoid 
Tumor/Aggressive Fibromatosis (DT/AF). 
Rationale: 
The NIR-DT-301 Phase 3, double-blind, placebo-controlled study is being conducted to 
determine the efficacy and safety of nirogacestat in participants with progressing desmoid 
tumors. A Phase 1 solid tumor study provided preliminary efficacy (Messersmith, 2015), 
including long-term durable responses and safety of nirogacestat in desmoid participants 
(Villalobos, 2018). These encouraging results led to a Phase 2 study in participants with 
progressing desmoid tumors (Kummar, 2017). This study demonstrated that nirogacestat resulted 
in a 29% response rate, significant tumor shrinkage as measured by magnetic resonance imaging 
(MRI) and no participants progressed while on therapy. Importantly, participants in the 
responder group had failed previous systemic therapies (imatinib or sorafenib) indicating a need 
for alterative therapeutic options for this patient population. These results support the further 
study of nirogacestat in this population. 
Objectives and Endpoints 
Key Objectives 
Key Endpoints 
Primary 
Primary 
To determine the efficacy (as 
defined by progression-free 
survival [PFS]) of nirogacestat in 
adult participants with 
progressing DT/AF. 
PFS defined as the time from randomization until the date 
of assessment of progression or death by any cause will be 
determined.  
Progression will be determined radiographically using 
Response Evaluation Criteria In Solid Tumors (RECIST) 
version (v)1.1 (Eisenhauer, 2009; Section 10.8) or 
clinically as assessed by the investigator. 
Clinical progression is defined as the onset or worsening 
of symptoms resulting in a global deterioration of health 
status causing the permanent discontinuation from study 
treatment and the initiation of emergent treatment (e.g., 
radiotherapy, surgery, or systemic therapy including 
chemotherapy or tyrosine kinase inhibitors) for DT/AF. 


SpringWorks Therapeutics 
 
Protocol NIR-DT-301
 
 
Amendment 5 (09Feb2021) 
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Page 9 
Key Objectives 
Key Endpoints 
Secondary 
Secondary 
To evaluate the safety and 
tolerability of nirogacestat in 
adult participants with 
progressing DT/AF as measured 
by the incidence of adverse 
events (AEs); 
Safety endpoints will include incidence of treatment-
emergent AEs, changes in 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;  
To determine the overall 
response rate (complete response 
[CR] + partial response [PR]) of 
nirogacestat in participants with 
progressing DT/AF;  
Overall response rate, defined as the proportion of 
participants with CR + PR assessed via central reader 
using RECIST v1.1 Criteria;  
To determine the duration of 
response; 
Duration of response for participants whose best response 
is CR or PR; 
To compare tumor volume 
changes measured by MRI in 
participants with progressing 
DT/AF; and 
Change in tumor volume from baseline as assessed by 
MRI volumetric; and 
To evaluate desmoid tumor 
symptoms and impacts using 
patient-reported outcomes 
(PROs). 
Symptoms and impacts will be assessed by evaluating 
change from baseline on the following PROs: 
• GOunder/Desmoid Tumor Research Tumor 
Foundation (DTRF) DEsmoid Symptom/Impact Scale 
(GODDESS); 
• Brief Pain Inventory (BPI) short form; 
• Patient-Reported Outcomes Measurement Information 
System Physical Function (PROMIS PF) short form 
10a plus 3 additional items from PROMIS item banks; 
and 
• European Organisation for Research and Treatment of 
Cancer Quality of Life Questionnaire-Core 30 
(EORTC) QLQ-C30. 


SpringWorks Therapeutics 
Protocol NIR-DT-301
Amendment 5 (09Feb2021) 
CONFIDENTIAL 
Page 10 
Overall Design: 
This is a multi-center, randomized, double-blind, placebo-controlled, event-driven, Phase 3 study 
to compare the efficacy, safety, and tolerability of nirogacestat and placebo in adult participants 
with progressing DT/AF. This study will consist of 2 phases, a double-blind and an optional 
open-label extension (OLE) phase.  
Participants will be screened up to 28 days prior to the first dose of study treatment (nirogacestat 
or placebo) in the double-blind phase and eligibility will be based on the inclusion and exclusion 
criteria (Sections 5.1 and 5.2). Refer to the double-blind schedule of activities (SoA) 
(Section 1.3.1) for the required assessments and Table 6 for additional details regarding each 
scheduled study visit. 
If Central Imaging Review determines that a participant has progressive disease (using RECIST 
v1.1) during the double-blind phase of the study, the site will be notified by the central imaging 
core laboratory. The participant will return to the site for an end of treatment (EOT) visit within 
14 days of the notification. During the EOT visit, the participant will be unblinded and have the 
option to enter the OLE phase, if eligible (Section 6.7.1).  
Participants who discontinue due to reasons other than radiographic disease progression as 
determined via central review will not be unblinded and will not be eligible for participation in 
the optional OLE phase of the study. 
At the completion of the double-blind phase (once the required number of events have been 
observed and the primary PFS analysis has been completed), the remaining participants in the 
double-blind phase will have their study treatment assignment unblinded and if eligible, will 
have the option to enroll in the optional OLE phase (Section 6.7.1). Refer to OLE SoA (Section 
1.3.2) for the required assessments and for additional details regarding each scheduled study 
visit. 
See Section 1.2 for study schema. 
Disclosure Statement: This is a randomized, parallel treatment study with 2 arms that is 
participant and investigator blinded. There is an optional OLE phase for eligible participants. 
Number of Participants: 
Approximately 135 participants will be screened (assessed for eligibility) to achieve 
118 participants randomly assigned (1:1) to study treatment (placebo or nirogacestat). It is 
estimated that 51 observed progression events will be needed to meet the primary PFS analysis. 
Refer to Section 9.2 for sample size determination. 
Treatment Groups and Duration: 
Double-blind phase: 
At Cycle 1 Day 1 (baseline), participants will be randomized (stratified by primary tumor 
location [Section 6.3.1]) to study treatment (nirogacestat or placebo) in a 1:1 ratio and will 
receive 150 mg twice daily (BID) of study treatment, continuously in 28-day cycles. Participants 


SpringWorks Therapeutics 
 
Protocol NIR-DT-301
 
 
Amendment 5 (09Feb2021) 
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Page 11 
will remain in the double-blind phase until death, disease progression, they prematurely 
discontinue study treatment for any reason, the study is stopped by the sponsor for any reason, or 
the required number of PFS events have been observed and the primary PFS analysis has been 
completed (based on current statistical assumptions, this is anticipated to be approximately 
2 years after the first participant is randomized). 
Open-label phase: 
Eligible participants (refer to Sections 6.7.2 and 6.7.3 for OLE eligibility criteria) may enroll in 
the optional OLE phase to receive 150 mg BID of nirogacestat (open-label study treatment), 
continuously in 28-day cycles. Participants will remain in the OLE phase until death, disease 
progression, they prematurely discontinue study treatment for any reason, the study is stopped by 
the sponsor for any reason, participant qualifies for Sponsor’s Continued Access Plan, or 
nirogacestat is commercially available. 
Data Monitoring Committee: Yes


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Protocol NIR-DT-301
 
 
Amendment 5 (09Feb2021) 
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Schema 
 
DT/AF = desmoid tumor/aggressive fibromatosis. 
1All eligible participants must have histologically confirmed DT/AF (by local pathologist prior to informed consent) 
that has progressed by ≥ 20% as measured by RECIST v1.1 within 12 months of the screening visit scan (inclusion 
criteria 2). 
2Participants discontinuing study treatment due to clinical progression are not eligible for participation in the OLE.


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Protocol NIR-DT-301
 
 
 
              Amendment 5 (09Feb2021) 
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Schedule of Activities (SoA) 
1.3.1. 
Double-Blind Phase SoA 
Double-Blind Phase 
Cycle Number 
Screening1 
Cycle 1 
Cycle 2 
Cycle 4 
Cycle 7 & 
Every 3 Cycles26 
EOT27 
Follow-
Up28 
Cycle Day 
 
Day 1 
Baseline3 
Day 8 
Day 15 
Day 22 
Day 28 
Day 1 
Day 1 
Visit Week 
 
Week 1 
Week 2 
Week 3 
Week 4 
Week 8 
Week 13 
Week 25 & On 
 
 
See footnote 
27 for visit 
window 
 
 
30 days  
after last dose 
(+7 days) 
Calendar Day 
 
(up to 28 days 
before Day 1) 
Day 1 
Day 8 
Day 15 
Day 22 
Day 56 
Day 85 
Day 169 & On 
(Visit Window) 
(up to 48 hours 
prior to 1st dose) 
(± 2 days) 
(± 2 days) 
(± 2 days) 
(± 2 days) 
(± 7 days) 
(± 7 days) 
Informed consent2 
X 
 
 
 
 
 
 
 
 
 
I/E criteria 
X 
X 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
Medical history including 
menstrual history for women 
X 
 
 
 
 
 
 
 
 
 
ECOG performance status4 
X 
X 
 
 
 
X 
X 
X 
X 
X 
Physical examination5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight/height7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG8 
X 
X8a 
(pre-& post dose) 
X8b 
(post dose) 
 
 
X 
X 
X 
X 
X 
Laboratory 
 
 
 
 
 
 
 
 
 
 
Tumor biopsy9 
X9a 
 
 
 
 
 
 
 
X9b 
(optional) 
 
Blood for serology10 
X 
 
 
 
 
 
 
 
 
 
Blood for serum pregnancy 
test (WOCBP only)11 
X 
 
 
 
 
 
 
 
 
 
Blood for PK sampling12 
 
X12a 
(serial) 
X12b 
(trough) 
X12b 
(trough) 
X12b 
(trough) 
X12b 
(trough) 
X12b 
(trough) 
X12b 
(trough) 
 
 
Blood for 
pharmacogenomics13 
 
X 
(optional) 
 
 
 
 
 
 
 
 
Blood for genotyping14 
 
X 
 
 
 
 
 
 
 
 
Blood for safety labs15 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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              Amendment 5 (09Feb2021) 
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Double-Blind Phase 
Cycle Number 
Screening1 
Cycle 1 
Cycle 2 
Cycle 4 
Cycle 7 & 
Every 3 Cycles26 
EOT27 
Follow-
Up28 
Cycle Day 
 
Day 1 
Baseline3 
Day 8 
Day 15 
Day 22 
Day 28 
Day 1 
Day 1 
Visit Week 
 
Week 1 
Week 2 
Week 3 
Week 4 
Week 8 
Week 13 
Week 25 & On 
 
 
See footnote 
27 for visit 
window 
 
 
30 days  
after last dose 
(+7 days) 
Calendar Day 
 
(up to 28 days 
before Day 1) 
Day 1 
Day 8 
Day 15 
Day 22 
Day 56 
Day 85 
Day 169 & On 
(Visit Window) 
(up to 48 hours 
prior to 1st dose) 
(± 2 days) 
(± 2 days) 
(± 2 days) 
(± 2 days) 
(± 7 days) 
(± 7 days) 
Blood for female hormone 
levels15 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
Blood for male hormone 
levels15 
 
X 
 
 
 
 
X 
X 
X 
X 
Urinalysis16 
X 
X 
 
 
 
X 
X 
X 
X 
X 
Urine pregnancy test 
(WOCBP only)17 
 
X 
 
 
X 
X 
 
(monthly)17a 
X 
X 
Patient-Reported Outcomes (PROs)18 
 
 
 
 
 
 
 
 
 
Home ePRO device training 
X 
 
 
 
 
 
 
 
 
 
GODDESS (symptom scale) 
 
(refer to Table 8) 
 
 
 
(monthly assessment, refer to Table 8) 
 
 
(refer to  
Table 8) 
BPI short form 
 
PROMIS PF short form 10a 
plus 3 additional items from 
PROMIS item banks 
 
 
 
 
GODDESS (impact scale) 
 
 
 
 
EORTC QLQ-C30 
 
 
 
 
PGIS 
 
 
 
 
PGIC 
 
 
 
 
 
 
Imaging and RECIST 
 
 
 
 
 
 
 
 
 
 
Pre-Randomization RECIST 
v1.1 Calculation Worksheet19 
X 
 
 
 
 
 
 
 
 
 
CT or MRI scan for tumor 
measurement (using RECIST 
v1.1)20 
X20a 
 
 
 
 
 
X20b 
X20b 
X20c 
 
MRI scan for tumor volume 
assessment20 
X 
 
 
 
 
 
 
X20b 
(every 6 cycles) 
X20c 
 
Local RECIST v1.1 read20  
X20a 
 
 
 
 
 
X 
X20b 
X20c 
 


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Double-Blind Phase 
Cycle Number 
Screening1 
Cycle 1 
Cycle 2 
Cycle 4 
Cycle 7 & 
Every 3 Cycles26 
EOT27 
Follow-
Up28 
Cycle Day 
 
Day 1 
Baseline3 
Day 8 
Day 15 
Day 22 
Day 28 
Day 1 
Day 1 
Visit Week 
 
Week 1 
Week 2 
Week 3 
Week 4 
Week 8 
Week 13 
Week 25 & On 
 
 
See footnote 
27 for visit 
window 
 
 
30 days  
after last dose 
(+7 days) 
Calendar Day 
 
(up to 28 days 
before Day 1) 
Day 1 
Day 8 
Day 15 
Day 22 
Day 56 
Day 85 
Day 169 & On 
(Visit Window) 
(up to 48 hours 
prior to 1st dose) 
(± 2 days) 
(± 2 days) 
(± 2 days) 
(± 2 days) 
(± 7 days) 
(± 7 days) 
Enrollment and Study Treatment 
 
 
 
 
 
 
 
 
 
Randomization21 
 
X 
 
 
 
 
 
 
 
 
Study treatment dispensing22 
 
X 
 
 
 
 
X 
X 
 
 
Study treatment 
administration/diary23 
 
 
 
 
Study treatment 
accountability 
 
 
 
 
 
 
X 
X 
X 
 
Ongoing Monitoring 
 
 
 
 
 
 
 
 
 
 
Monthly wellness checks24 
 
 
 
ConMed review 
 
AE/SAE review25 
 
AE = adverse event; BID = twice daily; BPI = brief pain inventory; ConMed = concomitant medication; CT = computed tomography; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology 
Group; eCRF = electronic case report form; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30; EOT = end of treatment; ePRO = 
electronic patient-reported outcome; FU = follow-up; GODDESS = GOunder/DTRF DEsmoid Symptom/Impact Scale; ICF = informed consent form; I/E = inclusion/exclusion; IRT = interactive response 
technology; MRI = magnetic resonance imaging;  OLE = open-label extension; PFS = progression free survival; PGIS = patient global impression of severity; PGIC = patient global impression of change; PK 
= pharmacokinetic; PRO = patient-reported outcome; PROMIS PF= Patient-Reported Outcomes Measurement Information System Physical Function; RECIST = Response Evaluation Criteria in Solid 
Tumors; SAE = serious adverse event; SoA = scheduled of activities; v = version; WOCBP = women of child bearing potential.. 
1. Screening visit: Assessments may occur up to 28 days prior to first dose of study treatment with a minimum screening period of 14 days to allow for 
participant completion of the screening and baseline PRO assessments (refer to Table 8 for PRO administration schedule). An extension to the screening period 
may be permitted on a case-by-case basis following discussion between the investigator and the medical monitor/sponsor. The reason(s) for the extension must 
be clearly documented. 
2. Informed consent process: Includes participant signing the 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 Section 10.1.3 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 except 
for the following assessments: post-dose 12-Lead ECGs and post-dose blood draws for pharmacokinetic (serial PK) sampling. 
4. ECOG performance status: At baseline, assessment must be done prior to first dose of study treatment. Refer to Section 10.7 for ECOG scale. 


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5. Physical examination: At baseline, assessment must be done prior to first dose of study treatment. Refer to Section 8.2.2 for detail regarding physical 
examination requirements. 
6. Vital signs: Includes blood pressure, respiratory rate, pulse rate, and body temperature (following at least 5 minutes of rest). At baseline, assessment must be 
done prior to first dose of study treatment. Refer to Section 8.2.4 for more detail. 
7. Height: Required at screening only. Weight to be collected at all visits. 
8. 12-lead ECGs: Will be administered in triplicate (approximately 2-3 minutes apart and averaged) and read locally at the site. Participants should rest in semi-
recumbent supine position for at least 5 minutes prior to ECG collection. Refer to Section 8.2.3 for more detail. 
8a. At baseline, triplicate ECGs are required at two timepoints: (1) prior to the first dose of study treatment and (2) approximately 1-hour post-dose. 
8b. At Cycle 1 Day 8, triplicate ECGs are required 1-hour (±10 minutes) post-dose. 
9. Tumor (core needle) biopsy: If tumor biopsy and MRI are performed during the same study visit, the biopsy must be done after MRI. Refer to Section 8.1.3 
and central laboratory manual for sample processing details. 
9a. At screening, tumor biopsy is only required if archival tissue is not available for study procedures. Tumor biopsy will be reviewed centrally to 
reconfirm diagnosis, but participant enrollment is not dependent on central review. 
9b. At EOT, tumor biopsy will be optional and additional pharmacogenomic consenting is required (10.1.3). 
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 Section 10.2 and central laboratory manual 
for sample processing details. 
11. Serum pregnancy test: Only required at screening for women of childbearing potential (WOCBP). Refer to Sections 8.3.5 and 10.4, and central laboratory 
manual for sample processing details. 
12. PK sampling: Refer to Section 8.5 and Table 11, and central laboratory manual for sample processing details. 
12a. Serial PK: Required on Cycle 1 Day 1 at the following timepoints: pre-dose and 0.25-, 0.5-, 1-, 1.5-, 2- and 3-hours post-dose. All efforts will be 
made to obtain the sample within 10% of the nominal time (e.g., within 6 minutes of a 60-minute sample) from dosing. Out of window PK draws 
will not be captured as deviations if the exact time of the sample collection is noted on the source documents and eCRF. 
12b. Trough PK: The evening before applicable study visits, participants will record the exact time study treatment was taken in the eDiary using the 
home ePRO device. Participants will not take their planned morning dose the day of the study visit. The morning dose will be taken following the 
pre-dose PK blood draw. 
13. Pharmacogenomics: Blood sample will be optional and additional pharmacogenomic consenting is required (Section 10.1.3). At baseline, blood sample must 
be drawn prior to first dose of study treatment. Refer to Sections 8.8 and 10.5, and central laboratory manual for sample processing details.  
14. Genotyping: Required blood sample for all participants unless prohibited by local regulations. At baseline, blood sample must be drawn prior to first dose of 
study treatment. Refer to Section 8.7 and central laboratory manual for sample processing details. 


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15. Safety Labs (hematology, serum chemistry, and hormone levels): At baseline, must be done prior to first dose of study treatment. Refer to Section 10.2 for 
a complete list of analytes and central laboratory manual for sample processing details. The time of hormone level blood draws should also be recorded. 
16. Urinalysis: At baseline, must be done prior to first dose of study treatment. Refer to Section 10.2 for a complete list of analytes and the central laboratory 
manual for sample processing details. Microscopy is to be performed only as needed based on positive dipstick test results and only if blood or protein is 
abnormal. 
17. Urine pregnancy tests: Only required for WOCBP. At baseline, urine pregnancy test must be done prior to first dose of study treatment to reconfirm 
eligibility. Refer to Sections 8.2.6 and 10.4 for more detail.  
17a. Following the Cycle 4 Day 1 study visit, all WOCBP participants will be required to return to the site for a monthly urine pregnancy test. 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 (refer to the study reference manual for additional details). 
18. PROs: Participants will complete the questionnaires and record study treatment administration in the eDiary using a home ePRO device (Section 8.1.2). Refer 
to Table 8 for the PRO administration schedule.  
19. Pre-Randomization RECIST v1.1 Calculation Worksheet (Section 8.1.1.1): As part of documenting that participants have satisfied inclusion criteria 2, sites 
are required to complete a worksheet (provided by the sponsor). The worksheet must be submitted to the sponsor’s designee during the screening period as 
soon as the data are available to complete the worksheet. All worksheets must be received no later than 7 days prior to C1D1 to allow for review prior to 
randomization (refer to study reference manual for additional details). 
20. Tumor imaging: All scans will be submitted to the central imaging core laboratory and read by Central Imaging Review throughout the study. Refer to 
Section 8.1.1and imaging manuals for more detail.  
Tumor measurement using RECIST v1.1 assessment (Section 8.1.1.2): CT scans (contrast required unless contraindicated) or MRI scans (no contrast 
required) will be acquired to assess tumor changes. The modality (CT or MRI) for tumor assessment is to be determined by the investigator. The imaging 
modality used to assess the tumor at screening must be used at each subsequent visit. All scans will be submitted to the central imaging core laboratory and 
reviewed by Central Imaging Review, but participant enrollment is not dependent on central review. Tumor measurement will also be performed locally per 
RECIST v1.1 using the same target lesion(s) identified on the Pre-Randomization RECIST v.1.1 Calculation Worksheet. 
Tumor volumetric assessment (Section 8.1.1.3): MRI scans (no contrast required) will be acquired to assess tumor volume. All scans will be submitted to the 
central imaging core laboratory and assessed by Central Imaging Review.  
If applicable, CT and MRI assessments may be conducted on the same day. However, MRI with no contrast must be performed prior to CT with contrast. MRI 
must be done prior to tumor biopsy if assessments occur on the same visit. 
20a. Screening visit scans: 
• 
MRI and CT scans obtained during the screening visit will serve as the participant’s baseline scan for the study (CT scan only required if it’s 
the chosen modality for RECIST v1.1 tumor measurement). Scans should be submitted to central imaging core laboratory as early in the 
screening period as possible to confirm scan quality is acceptable for analysis prior to randomization.  
• 
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 and the quality of the scans are acceptable for analysis (as determined by the central 


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imaging core laboratory). These scans will then be collected, stored, and documented as the screening visit scan(s). No other pre-enrollment 
images will be collected for central reading. 
20b. On study treatment scans: Starting at cycle 4, MRI or CT scans for tumor assessment (RECIST v1.1) will be obtained every 3 cycles. Starting at 
cycle 7, MRI for tumor volume assessment will be obtained every 6 cycles. 
20c. EOT visit scans: only required if not performed within the past 3 months. 
21. Randomization: Participants will not be randomized to study treatment using IRT until all I/E criteria (Sections 5.1 and 5.2) have been confirmed and all pre-
randomization baseline study assessments have been completed.  
22. Study treatment dispensing: Participants will be dispensed study treatment using the IRT every 3 cycles at applicable study visits. 
23. Study treatment administration/diary: The first dose of study treatment (3 × 50 mg tablets) will be administered orally at the site at Cycle 1 Day 1 followed 
by a 3-hour observation period. Participants will 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 
eDiary using the home ePRO device. Refer to Section 6.1 for more detail. 
24. Monthly wellness checks: Monthly telephone or email contact is required throughout the study (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 8.2.7 for more detail. 
25. AEs/SAEs: Will be monitored and documented from the time of informed consent up to 30 days after the last dose of study treatment. Refer to Section 8.3 for 
more detail. Females reporting AEs/AESIs/SAEs of primary ovarian insufficiency (POI) and/or amenorrhea will have hormone levels assessed every 3 months 
until event resolution (or for at least 90 days after discontinuing study treatment). 
26. Every 3 cycles and on: Following Cycle 7 Day 1, participants will return every 3 cycles for study visits until death, progressive disease, discontinuation of 
study treatment for any reason, study is stopped by the sponsor for any reason, or required number of PFS events have been observed and primary PFS analysis 
has been completed. 
27. EOT visit: EOT visit should be conducted prior to study treatment discontinuation to avoid a gap in study treatment for participants entering the OLE phase. 
All EOT assessments must be conducted prior to unblinding (if applicable refer to Section 6.3.2.1). 
If Central Imaging Review determines that a participant has progressive disease (using RECIST v1.1) the participant will be encouraged to return to the site as 
soon as possible to complete the EOT visit assessments (but no later than 14 days of becoming aware of the progression). 
If the participant discontinues study treatment for any reason other than progressive disease (as determined by Central Imaging Review using RECIST v1.1), 
they will be encouraged to return to the site as soon as possible to complete the EOT visit assessments prior to study treatment discontinuation or as close as 
possible to the last dose of study treatment. 
28. Follow-up visit: Only required for participants who are not continuing into the optional OLE phase and will occur 30 days (+7 days) after the last dose of 
study treatment. 


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1.3.2. 
Open-Label Extension Phase SoA 
OLE Phase 
 
Cycle Number 
Cycle 15 
(Applicable only to participants previously randomized to 
placebo in the double-blind phase) 
Cycle 25 
Cycles 4, 7, 10 
Cycle 13 &  
Every 3 Cycles 
EOT20 
Follow-Up21 
Cycle Day 
Day 1 
Baseline3 
Day 8 
Day 15 
Day 22 
Day 28 
Day 1 
Day 1 
Visit Week 
Week 1 
Week 2 
Week 3 
Week 4 
Week 8 
Weeks 13, 25, 37 
Week 49 & On 
See 
footnote 
20 for visit 
window 
30 days after last 
dose 
(+ 7 days) 
Calendar Day 
Day 1 
Day 8 
Day 15 
Day 22 
Day 56 
Days 85, 169, 253 
Day 337 & On 
(Visit Window) 
Same day as, 
or up to 24 
hours after, 
double-blind 
EOT 
(± 2 days) 
(± 2 days) 
(± 2 days) 
(± 2 days) 
(± 7 days) 
(± 7 days) 
Informed consent1 
X 
 
 
 
 
 
 
 
 
I/E criteria2 
X 
 
 
 
 
 
 
 
 
ECOG performance status6 
Same as 
double-blind 
EOT 
 
 
 
X 
X 
X 
X 
X 
Physical examination7 
Same as 
double-blind 
EOT 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs8 
Same as 
double-blind 
EOT 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
Same as 
double-blind 
EOT 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG9 
X9a 
(post dose) 
X9b 
(post dose) 
 
 
X 
X 
X 
X 
X 
Laboratory 
 
 
 
 
 
 
 
 
 
Blood for PK sampling10 
X 
(serial)10a 
X 
(trough)10b 
X 
(trough)10b 
X 
(trough)10b 
X 
(trough)10b 
X 
(trough)10b 
X 
(trough)10b 
 
 
Blood for safety labs11 
X11a 
X 
X 
X 
X 
X 
X 
X 
X 
Blood for female hormone 
levels11 
X11a 
 
 
X 
X 
X 
X 
X 
X 
Blood for male hormone 
levels11 
X11a 
 
 
 
 
X 
X 
X 
X 
Urinalysis12 
Same as 
double-blind 
EOT 
 
 
 
X 
X 
X 
X 
X 


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OLE Phase 
 
Cycle Number 
Cycle 15 
(Applicable only to participants previously randomized to 
placebo in the double-blind phase) 
Cycle 25 
Cycles 4, 7, 10 
Cycle 13 &  
Every 3 Cycles 
EOT20 
Follow-Up21 
Cycle Day 
Day 1 
Baseline3 
Day 8 
Day 15 
Day 22 
Day 28 
Day 1 
Day 1 
Visit Week 
Week 1 
Week 2 
Week 3 
Week 4 
Week 8 
Weeks 13, 25, 37 
Week 49 & On 
See 
footnote 
20 for visit 
window 
30 days after last 
dose 
(+ 7 days) 
Calendar Day 
Day 1 
Day 8 
Day 15 
Day 22 
Day 56 
Days 85, 169, 253 
Day 337 & On 
(Visit Window) 
Same day as, 
or up to 24 
hours after, 
double-blind 
EOT 
(± 2 days) 
(± 2 days) 
(± 2 days) 
(± 2 days) 
(± 7 days) 
(± 7 days) 
Urine pregnancy test  
(WOCBP only)13 
Same as 
double-blind 
EOT 
 
 
X 
X 
 
(Monthly)13a 
X 
X 
Patient-Reported Outcomes (PROs)14 
 
 
 
 
 
 
 
 
GODDESS (symptom scale) 
 
 
 
 
(Monthly assessment, 
refer to Table 9) 
(Quarterly 
assessment,  
refer to Table 9) 
 
(Refer to  
Table 9) 
BPI short form 
 
 
 
 
 
PROMIS PF short form 10a 
plus 3 additional items from 
PROMIS item banks 
 
 
 
 
 
GODDESS (impact scale) 
 
 
 
 
 
EORTC QLQ-C30 
 
 
 
 
 
PGIS 
 
 
 
 
 
PGIC 
 
 
 
 
 
Imaging and RECIST 
 
 
 
 
 
 
 
 
 
CT or MRI scan for tumor 
measurement (using RECIST 
v1.1)15 
Same as 
double-blind 
EOT 
 
 
 
 
X 
X15a 
(Cycle 13 and then 
every 6 cycles) 
X15b 
 
Local RECIST v1.1 read15 
Same as 
double-blind 
EOT 
 
 
 
 
X 
X15a 
(Cycle 13 and then 
every 6 cycles) 
X15b 
 
Enrollment and Study Treatment 
 
 
 
 
 
 
 
 
Enrollment/first dose of open-
label study treatment4 
X 
 
 
 
 
 
 
 
 
Study treatment dispensing16 
X 
 
 
 
 
X 
X 
 
 


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OLE Phase 
 
Cycle Number 
Cycle 15 
(Applicable only to participants previously randomized to 
placebo in the double-blind phase) 
Cycle 25 
Cycles 4, 7, 10 
Cycle 13 &  
Every 3 Cycles 
EOT20 
Follow-Up21 
Cycle Day 
Day 1 
Baseline3 
Day 8 
Day 15 
Day 22 
Day 28 
Day 1 
Day 1 
Visit Week 
Week 1 
Week 2 
Week 3 
Week 4 
Week 8 
Weeks 13, 25, 37 
Week 49 & On 
See 
footnote 
20 for visit 
window 
30 days after last 
dose 
(+ 7 days) 
Calendar Day 
Day 1 
Day 8 
Day 15 
Day 22 
Day 56 
Days 85, 169, 253 
Day 337 & On 
(Visit Window) 
Same day as, 
or up to 24 
hours after, 
double-blind 
EOT 
(± 2 days) 
(± 2 days) 
(± 2 days) 
(± 2 days) 
(± 7 days) 
(± 7 days) 
Study treatment 
administration/diary17 
 
 
 
Study treatment accountability 
 
 
 
 
 
X 
X 
X 
 
Ongoing Monitoring 
 
 
 
 
 
 
 
 
 
Monthly wellness checks18 
 
 
 
ConMed review 
 
AE/SAE review19 
 
AE = adverse event; BID = twice daily; BPI = brief pain inventory; ConMed = concomitant medication; CT = computed tomography; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology 
Group; eCRF = electronic case report form; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30; EOT = end of treatment; ePRO = 
electronic patient-reported outcome; FU = follow-up; GODDESS = GOunder/DTRF DEsmoid Symptom/Impact Scale; ICF = informed consent form; I/E = inclusion/exclusion; IRT = interactive response 
technology;  MRI = magnetic resonance imaging;  OLE = open-label extension; PFS = progression free survival; PGIS = patient global impression of severity; PGIC = patient global impression of change; PK 
= pharmacokinetic; PRO = patient-reported outcome; PROMIS PF= Patient-Reported Outcomes Measurement Information System Physical Function; RECIST = Response Evaluation Criteria in Solid Tumors; 
SAE = serious adverse event; SoA = scheduled of activities; v = version; WOCBP = women of child bearing potential. 
1. Informed consent process: Includes participant signing the ICF (exclusive to the OLE study phase) and must be conducted prior to administration of the first 
dose of open-label study treatment. Refer to Section 10.1.3 for more detail on the process. 
2. I/E criteria: Exclusive to the OLE phase. Refer to Sections 6.7.2 and 6.7.3 for participant eligibility criteria specific to the OLE phase. 
3. Baseline visit: The C1D1 visit of the OLE phase should be conducted on the same day as, or within 24 hours after, the double-blind EOT visit. A longer 
window between the double-blind EOT and OLE C1D1 visit may be allowed with prior medical monitor approval; however, repeat assessments may be 
required with medical monitoring guidance depending on the length of time between double-blind EOT and OLE C1D1. All double-blind EOT visit 
assessments, as described in the double-blind SoA (Section 1.3.1), will be conducted prior to unblinding the participant’s study treatment and prior to 
administration of the first dose of open-label study treatment.  
4. Enrollment and first dose of open-label study treatment: Participants will be enrolled in the OLE phase using the IRT only after (1) all ongoing AEs/SAEs 
from the double-blind phase have been assessed for causality in a blinded manner by the investigator or qualified designee, and (2) all AE/SAE causality 
assessments have been entered into the eCRF. All double-blind EOT visit assessments must be completed prior to unblinding and taking first dose of open-
label study treatment.  


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Participants who were randomized to receive placebo in the double-blind phase will receive their first dose of study treatment at the site followed by a 3-hour 
observation period.  
Participants who were randomized to nirogacestat in the double-blind phase may take their first dose of open-label study treatment at home (observation 
period is not required). 
5. Study visits at Cycle 1 (Day 8, 15 and 22) and Cycle 2 (Day 28): Only applicable for participants who were previously randomized to receive placebo in the 
double-blind phase. If a participant was randomized to receive nirogacestat in the double-blind phase, these study visits will not be conducted, and the 
participant will not be required to return to the site until Cycle 4 Day 1 visit.  
6. ECOG performance status: Refer to Section 10.7 for the ECOG scale. 
7. Physical examination: Refer to Section 8.2.2 for more detail regarding physical examination requirements. 
8. Vital signs: Includes blood pressure, respiratory rate, pulse rate, and body temperature (following at least 5 minutes of rest). Refer to Section 8.2.4 for more 
detail. 
9. 12-lead ECGs: Will be administered in triplicate (approximately 2-3 minutes apart and averaged) and read locally at the site. Participants should rest in semi-
recumbent supine position for at least 5 minutes prior to ECG collection. Refer to Section 8.2.3 for more detail. 
9a. At baseline, triplicate ECGs are required approximately 1-hour post-dose (open-label study treatment). Applicable only to participants who were 
previously randomized to receive placebo in the double-blind study phase. 
9b. At Cycle 1 Day 8 visit, triplicate ECGs are required 1-hour (±10 minutes) post-dose. Applicable to participants who were previously randomized to 
receive placebo in the double-blind study phase only. 
10. PK sampling: Refer to Section 8.5 and central laboratory manual for sample processing details.  
10a. Serial PK: Only applicable to participants who were previously randomized to receive placebo in the double-blind study phase. PK samples should 
be collected on OLE Cycle 1 Day 1 at the following timepoints: pre-dose and 0.25-, 0.5-, 1-, 1.5-, 2- and 3-hours post-dose. All efforts will be 
made to obtain within 10% of the nominal time (e.g., within 6 minutes of a 60-minute sample) from dosing. Out of window PK draws will not be 
captured as deviations if the exact time of the sample collection is noted on the source documents and eCRF. 
10b. Trough PK: The evening before applicable study visit, participants will record the exact time study treatment was taken in the eDiary using the 
home ePRO device. Participants will not take their planned morning dose the day of the study visit. The morning dose will be taken following the 
pre-dose PK blood draw. 
11. 
Safety labs (hematology, serum chemistry, and hormone levels): Refer to Section 10.2 for a complete list of analytes and central laboratory manual for 
sample processing details. The time of hormone level blood draws should also be recorded. 
11a. At baseline, blood draws for hematology, serum chemistry, and hormone levels will be done as part of the double-blind EOT visit (prior to 
unblinding). However, if hematology and serum chemistry safety labs have not been conducted within the 14 days prior to C1D1, an additional 
blood draw will be required for same day local laboratory processing to reconfirm adequate organ and bone marrow function (refer to OLE 
inclusion criteria 2) and must be done prior to first dose of open-label study treatment. 


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12. 
Urinalysis: Refer to Section 10.2 for a complete list of analytes and the central laboratory manual for sample processing details. Microscopy is to be 
performed only as needed based on positive dipstick test results and only if blood or protein is abnormal. 
13. 
Urine pregnancy tests: Only required for WOCBP. Refer to Sections 8.2.6 and 10.4 for more detail. 
13a. Following Cycle 4 Day 1 study visit, all WOCBP participants will be required to return to the site for a monthly urine pregnancy test. 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 (refer to study reference manual for additional details). 
14. 
PROs: Participants will complete the questionnaires using a home ePRO device (Section 8.1.2). Refer to Table 9 for the PRO administration schedule. 
15. 
Tumor imaging: CT (contrast required unless contraindicated) or MRI (no contrast required) using RECIST v1.1 (modality to be determined by the 
investigator) is required. Whichever imaging modality is used to measure the tumor by RECIST v1.1 at screening in the double-blind phase must be used at 
each subsequent visit throughout the OLE phase. All scans will be submitted to the central imaging core laboratory and reviewed by Central Imaging 
Review. Tumor measurement will also be performed locally per RECIST v1.1 using the same target lesion(s) identified on the Pre-Randomization RECIST 
v.1.1 Calculation Worksheet. 
15a. Scan is required every 3 cycles until Cycle 13 Day 1, and then every 6 cycles thereafter. 
15b. At EOT, scan is only required if not performed within the past 3 months. 
16. 
Study treatment dispensing: Participants will be dispensed study treatment using the IRT every 3 cycles during study visits. 
17. 
Study treatment administration/diary: Participants will self-administer study treatment at 150 mg (3 × 50 mg tablets) 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 eDiary using the home ePRO device. (Section 6.1). 
18. 
Monthly wellness checks: Monthly telephone or email contact is required throughout the study (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 8.2.7 for more detail. 
19. 
AEs/SAEs: Will be monitored and documented from the time of informed consent and up to 30 days after the last dose of study treatment. Refer to 
Section 8.3 for more detail. Females reporting AEs/AESIs/SAEs of POI and/or amenorrhea will have hormone levels assessed every three months until event 
resolution (or for at least 90 days after discontinuing study treatment). 
20. 
End of treatment (EOT) visit: Should be conducted prior to study treatment discontinuation or as close as possible to the last dose of open-label study 
treatment.  
21. 
Follow-up visit: Only required for participants who are not transitioning directly to commercial nirogacestat (or sponsor’s Continued Access Plan) at time of 
discontinuation. The follow-up visit will occur 30 days (+7 days) after the last dose of study treatment. 
 


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2. 
INTRODUCTION 
Nirogacestat (PF-03084014) is a potent, small-molecule, selective, reversible, noncompetitive 
inhibitor of gamma secretase (GS). Nirogacestat is being investigated for the treatment of 
desmoid tumors/aggressive fibromatosis (DT/AF). 
 
Study Rationale 
The NIR-DT-301 Phase 3, double-blind, placebo-controlled study is being conducted to 
determine the efficacy and safety of nirogacestat in participants with progressing desmoid 
tumors. A Phase 1 study in patients with solid tumors provided preliminary efficacy 
(Messersmith, 2015), including long-term durable responses and safety of nirogacestat in 
desmoid participants (Villalobos, 2018). These encouraging results lead to a Phase 2 study in 
participants with progressing desmoid tumors (Kummar, 2017). This study demonstrated that 
nirogacestat resulted in a 29% response rate, significant tumor shrinkage as measured by 
magnetic resonance imaging (MRI) and no participants progressing while on therapy. 
Importantly, participants in the responder group had failed previous systemic therapies (imatinib 
or sorafenib) indicating a need for alterative therapeutic options for this patient population. These 
results support the further study of nirogacestat in this population. 
 
Background 
2.2.1. 
Desmoid Tumors/Aggressive Fibromatosis 
Desmoid tumors, also referred to as aggressive fibromatosis, are rare, locally invasive, slow 
growing soft tissue tumors. According to the World Health Organization, desmoid tumors are 
defined as “clonal fibroblastic proliferations that arise in the deep soft tissue and are 
characterized by infiltrative growth and a tendency toward local recurrence but an inability to 
metastasize” (Kasper, 2011). Desmoid tumors are considered benign; however, they cause 
significant morbidity by infiltrating or exerting mass effects on vital structures (Lewis, 1999; 
Smith, 2000). Desmoid tumors include soft tissue masses arising in any part of the body in 
different varieties of connective tissue, including muscle and fascia aponeurosis. The most 
common primary tumor sites include abdominal walls, limbs, girdles, and mesenteric areas. 
Desmoid tumors infiltrate surrounding structures and spread along plains and muscle, which can 
lead to severe pain, functional impairment, and more rarely, life-threatening conditions (Penel, 
2017). Despite the benign nature of desmoid tumors, they can behave aggressively, causing 
significant morbidity, with elevated rates of local recurrence (as high as 60%) despite wide 
excisions (Penel, 2017). Mortality is occasionally observed owing to the local aggressive nature 
of some desmoid tumors that occur in the mesentery (Smith, 2000). 
Desmoid tumors most commonly occur in individuals between the ages of 15 to 60 years, more 
often in young adults, with the peak age of about 30 years, and a 2- to 3-fold predominance in 
females (de Camargo, 2010; Skubitz, 2017). The incidence of desmoid tumors is about 2 to 4 
cases per million per year in the general population, with fewer than 1000 cases diagnosed in the 
United States per year (Hosalkar, 2006).  


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The incidence of desmoid tumors is reported to be about 800- to 1000-fold higher in patients with 
familial adenomatous polyposis (FAP [Gardner Syndrome]), in which the adenomatous polyposis 
coli (APC) tumor suppressor gene is mutated (Skubitz, 2017). Familial adenomatous polyposis-
associated desmoid tumor is more frequently associated with abdominal tumors, especially in the 
Gardner variant of FAP, which is associated with intestinal polyposis, osteomas, fibromas, and 
epidermal inclusion cysts (Skubitz, 2017). Intra-abdominal desmoid tumors are one of the leading 
causes of death in patients with FAP (Quintini, 2012). Although common in patients with FAP, 
most cases of desmoid tumors occur spontaneously in adults and are associated with a mutation in 
β-catenin (CTNNB1) (Lazar, 2008; Tejpar, 1999; Bo, 2012). β-catenin is an integral component 
of the Wnt/β-catenin/T-cell transcription factor signaling pathway, which is frequently 
dysregulated in cancer. Patients with desmoid tumors carrying β-catenin have a worse 5-year 
recurrence-free survival rate than patients with wild-type tumors (Kummar, 2017). 
Histologically, desmoid tumors appear as poorly circumscribed proliferation of myofibroblastic 
cells with variable collagen deposition, and tumor margins are difficult to assess at the time of 
surgery. Desmoid tumors are morphologically heterogeneous and may exhibit striking 
morphological intratumoral and intertumoral heterogeneity (Skubitz, 2017). In some areas, 
tumors may resemble fibroblasts of inactive fibrous tissue, whereas other areas may resemble the 
active fibroblasts of wound healing. 
The clinical course of desmoid tumor may be unusual and heterogeneous, characterized not only 
by tumor growth, proliferation, and disease progression, but also by stabilization and 
spontaneous remission (Kasper, 2011). Desmoid tumors can present almost anywhere throughout 
the body, and there are different factors by which desmoid tumors develop. They can have wide 
range of clinical symptoms, such as bloating, pain, or rectal bleeding, in the case of abdominal 
desmoid tumors; or extremity pain, decreased range of motion, and swelling, in the case of 
extremity desmoid tumors. Given the heterogeneity of desmoid tumor, predicting the desmoid 
tumor behavior and determining which treatment option is appropriate for a patient remains 
challenging. 
2.2.2. 
Diagnosis 
There are several guidelines published on diagnosis, treatment, and follow-up of participants 
with soft tissue sarcomas (STS), including desmoid tumors. According to the clinical practice 
guidelines published in 2018 by the European Sarcoma Network Working Group, the basic 
principles for the diagnosis of STS applies to desmoid tumors (Casali, 2018). Because of the 
ubiquitous nature of sarcomas and their site of origin, a multidisciplinary (e.g., radiologist, 
pathologist, surgeon, medical oncologist, etc.) approach to the diagnosis and management is 
warranted. Once a sarcoma mass is suspected, non-invasive imaging by MRI or computed 
tomography (CT) is performed. Additionally, a biopsy is performed, if feasible. Once the 
primary diagnosis of desmoid tumor is confirmed, the potential treatment options outlined below 
are evaluated. 


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2.2.3. 
Treatment 
Treatment options vary for each patient depending on the size, location and morbidity associated 
with the tumor. The wait-and-see policy is currently recommended as the first approach in 
desmoid tumors (Kasper, 2015). In a prospective study comparing surgical versus non-surgical 
approaches in primary desmoid tumors conducted by the French Sarcoma Group (Penel, 2017), 
the wait-and-see policy was implemented regardless of primary tumor location. For all patients, 
the 2-year event free survival (EFS) rate was 56%. The 2-year EFS was 63% and 70% for 
patients managed by wait-and-see approach and for surgery with tumors in favorable locations 
(abdominal wall, intra-abdominal, breast, digestive viscera and lower limb), respectively. 
However, in patients with unfavorable tumor locations (chest wall, head and neck, upper limb) 
the 2-year EFS was significantly improved in participants initially managed with the wait-and-
see approach (52%) vs surgery (25%). The authors concluded that the wait-and-see approach 
may be preferred to surgical resection. 
Previously, surgery was the therapeutic option of choice for localized, extra-abdominal, small 
volume desmoid tumors. However, surgery is no longer regarded as the cornerstone of desmoid 
tumor treatment given the high rate of relapse after surgery, which exceeds 60% in larger studies, 
and the frequent observation of spontaneous disease regression and stabilization (Penel, 2017). 
Variables associated with local recurrence post-surgery include tumor location, age of the 
participant, and quality of the surgical resection (Kasper, 2011). 
Radiotherapy has been used both in the adjuvant setting after surgery and in the primary setting, 
mainly for extra-abdominal tumors (Kasper, 2011).  Radiotherapy after surgery is an independent 
positive prognostic factor for local recurrence and overall survival, and radiotherapy alone or in 
combination with surgery led to significantly lower recurrence rates (Kasper, 2011).  
Modalities studied in clinical studies include hormonal therapy since virtually all desmoid 
tumors express nuclear estrogen receptor-β, albeit at low receptor levels (Janinis, 2003); and 
nonsteroidal anti-inflammatory drugs, such as indomethacin and sulindac; however, limited 
responses have been observed with these agents.  
In the case of unresectable, rapidly growing and/or symptomatic and/or life-threatening desmoid 
tumors, traditional chemotherapy may be considered. Kasper et al. (2011), provided an overview 
of chemotherapy regimens that have been studied in participants with advanced disease  
For patients with relapsed or recurrent desmoid tumors, or for patients with desmoid tumors that 
are not amenable to surgery or radiotherapy, or if surgery is potentially mutilating, various 
systemic therapy have been studied, although little in controlled clinical studies. Schöffski et al 
conducted a survey of physician’s preference for systemic treatment for patients with advanced 
desmoid tumors using a structured questionnaire (Schöffski, 2018). Results indicated that disease 
progression and failure of local therapy were typical indications for the use systemic therapy. 
Thus, clinical studies with systemic agents should ideally select a homogenous population with 
advanced, progressive, and symptomatic desmoid tumors and/or functional impairment after 
failure of observation only strategies and/or local treatments such as surgery or radiotherapy. 


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Due to the spontaneous regression observed in participants with desmoid tumors, studies should 
ideally be randomized, with physician’s choice or placebo as potential comparators. 
Meaningful responses have been observed with tyrosine kinase inhibitors, such as imatinib 
(Kasper, 2017) and sorafenib. Recently, the results from a Phase 3 study of sorafenib compared 
to placebo were published in The New England Journal of Medicine (Gounder, 2018). The study 
enrolled 87 participants with progressive, symptomatic or recurrent desmoid tumors that were 
randomized 2:1 to sorafenib (n=50) or placebo (n=37). The median PFS for placebo was 
11.3 months (95% CI [5.7, not evaluable]) and was not reached for sorafenib (HR = 0.13, 95% 
CI [0.05, 0.31], p < 0.001). The objective response rate (ORR) for sorafenib was 33% (95% CI, 
20 to 48) and for placebo was 20%, (95%CI, 8 to 37). Spontaneous regressions are known to 
occur in desmoid patients. This study confirmed the need for a control group (Schöffski, 2018) in 
desmoid tumor clinical studies particularly given the spontaneous response rate in the placebo 
group. 
Additional targeted agents such as sirolimus and pazopanib are also being studied in participants 
with desmoid tumors (NCT01265030 and NCT01876082, respectively). 
2.2.3.1. 
Clinical Studies with Nirogacestat 
 Study A8641014A: Phase 1 study of PF-03084014 in participants with advanced 
solid tumor malignancy and T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma 
Messersmith and colleagues conducted a Phase 1, dose-finding study to determine the 
maximum tolerated dose (MTD), the recommended Phase 2 dose (RP2D), and to evaluate 
safety of continuous administration of nirogacestat in participants with advanced solid 
tumors (Messersmith, 2015). Sixty-four participants received doses of nirogacestat and the 
MTD was determined to be 220 mg, administered twice daily (BID). The RP2D was 
determined to be 150 mg BID, given comparable NOTCH related target inhibition. The most 
common reason for discontinuation from nirogacestat was objective progression or relapse 
of disease (32 participants). The most common primary diagnosis was desmoid tumor 
(9 participants), with a mean duration since diagnosis of 7.7 years. All participants received 
surgeries and about half of the participants received radiation therapy. The majority (60 
[93.8%] participants) received previous systemic therapies and more than half (35 [54.7%] 
participants) had systemic therapies for > 3 regimens. 
Of the 64 participants with solid tumors, 62 experienced at least 1 adverse event (AE), and 
54 experienced at least 1 treatment-related AE (1 participant with a Grade 1 AE of upper 
respiratory infection was excluded from the analysis due to a database error). The most 
common treatment-related AEs were diarrhea, nausea, fatigue, hypophosphatemia, vomiting, 
rash, and decreased appetite. The majority of these AEs were Grade 1 to Grade 3. Dose 
reductions due to treatment-related AEs were infrequent and were reported in 9 (14%) 
participants at various times during treatment (from Cycle 1 to Cycle 10). Across dose 
levels, 5 (7.8%) participants had Grade 2 or Grade 3 diarrhea that resolved with dose 
reduction. Temporary discontinuation occurred in 21 (32.8%) participants, 13 (20.3%) of 
which were for a treatment-related AE. All treatment-related AEs that led to temporary 
discontinuation (diarrhea, hypophosphatemia, rash, nausea, vomiting, and fatigue) or dose 


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reduction were Grade 1 to Grade 3, and most resolved following temporary discontinuation 
or dose reduction. Seven (10.9%) participants permanently discontinued treatment primarily 
owing to an AE; of these, 4 (6.3%) participants discontinued for a treatment-related AE: one 
each for Grade 4 anaphylactic shock (100 mg BID) (an event thought to be related to co-
administration of IV morphine), Grade 1 visual impairment (150 mg BID), Grade 3 drug 
hypersensitivity (220 mg BID), and Grade 3 rash (330 mg BID). The hypersensitivity 
reaction (rash associated with chest tightening and shortness of breath) resolved with 
intravenous steroid therapy after discontinuation of study treatment. 
There were 46 participants with solid tumors evaluable for response. Overall, ORR was 
13.0% (95% CI [94.9, 26.3]) for these participants. Six participants had an ORR with 1 
complete response (CR) (participant with thyroid cancer) and 5 partial responses (PRs). All 
5 PRs were reported by participants with desmoid tumors, who accounted for 71.4% (95% 
CI [29.0, 96.3]) of the 7 participants with desmoid tumors evaluable for response. At the 
time of data cutoff, all 6 responders were censored in the calculation of duration of response. 
All 5 responders with desmoid tumors had not progressed and were censored at the time of 
data cutoff, with 4 still on study and 1 discontinued due to noncompliance. The participant 
with thyroid cancer with CR later had recurrence of disease but was censored at the last 
disease assessment of CR due to missed tumor assessments. 
Overall, nirogacestat was well tolerated with an MTD determined to be 220 mg BID and a 
RP2D to be 150 mg BID. The best tumor responses were 5 PRs out of 7 evaluable 
participants with desmoid tumors. 
Villalobos and colleagues reported the long-term follow-up of the 7 participants with 
desmoid tumors from the Phase 1 study (Villalobos, 2018). As previously described, 5 of the 
7 participants with desmoid tumors had a PR with a mean time to response of 11.9 months. 
All participants that achieved a PR continued to maintain response between 48 and 73+ 
months. Four participants who discontinued therapy remained free of progression between 
11 and 53+ months. One participant had a PFS of > 42 months, with a 17% decrease in the 
target lesion. Prolonged disease control was observed for 6 out of 7 of the participants with 
desmoid tumors treated with nirogacestat. 
 National Cancer Institute Protocol 14-C-0007: Phase 2 study of gamma secretase 
inhibitor PF-03084014 in adults with desmoid tumors/aggressive fibromatosis 
(NCT01981551) 
A Phase 2 study was conducted by investigators at the National Cancer Institute (NCI) to 
evaluate the ORR after therapy with nirogacestat in participants with recurrent, refractory, 
progressive desmoid tumors (Kummar, 2017). Seventeen participants received daily doses 
of nirogacestat at 150 mg BID continuously in 3-week cycles. Response to treatment was 
evaluated at Cycle 1 and every 6 cycles (18 weeks) thereafter by Response Evaluation 
Criteria in Solid Tumors (RECIST) version (v)1.1. Of the 17 participants treated in the 
study, 15 had mutations in APC or CTNNB1 genes. Sixteen participants were evaluable for 
response; 5 participants experienced a confirmed PR and had been on study for more than 2 
years, and the remaining 11 participants had stable disease. No participant progressed on 


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study. The AE profile was consistent with previous reports (Messersmith, 2015) and 
consisted of all participants experiencing at least 1 Grade 1 or Grade 2 AE; and the most 
commonly reported AEs were diarrhea and skin disorders. Four participants had a dose 
reduction while on study. Two participants received a reduced dose of 100 mg BID as a 
result of persistent Grade 3 nausea and diarrhea, 1 participant developed urticaria 
nonresponsive to dose reduction and came off study, and 1 participant developed a Grade 2 
maculopapular rash, which resolved with dose reduction. The only Grade 3 AE attributable 
to study treatment was hypophosphatemia, reported in 8 participants, and is a known class 
effect of GS inhibitors. 
 
Rationale for Nirogacestat in Desmoid Tumors 
Emerging evidence in recent years presents the Notch pathway as a promising target for 
treatment of solid tumors. It has been reported that aberrant Notch activation and deregulated 
expression of Notch ligands and targets are associated with a broad panel of solid tumors. At 
least 3 Notch members (NOTCH1, NOTCH3, and NOTCH4) have been found to be involved in 
solid tumors.  
The molecular mechanism for the oncogenic activity of Notch intracellular domain (NICD) may 
include inhibiting differentiation, promoting survival, or accelerating proliferation. Potential 
oncogenic targets of NOTCH1 include Myc, cyclin D1, and several other factors. In the case of 
Myc, evidence demonstrates that Myc is a direct target gene of NOTCH1 and essential for 
development of both T-cell leukemia and mammary tumors in mice (Sharma, 2006; Klinakis, 
2006).   
Recent studies suggest crosstalk between the Wnt and Notch pathways (Rodilla, 2009; 
Rampazzo, 2013). It has been shown that Notch activity is increased in colorectal cancer cells 
through upregulation of JAG1 mediated by β-catenin, and levels of hairy and enhancer of split-1 
(Hes1) messenger ribonucleic acid are significantly upregulated in APCmin/+ mouse intestinal 
cancer models (Ungerback, 2011). Expression of NOTCH1 and Hes1 have been observed in 
mesenchymal stromal cells found in desmoid tumor, suggesting that the Notch pathway is 
possibly related to desmoid tumorigenesis (Shang, 2015). Importantly, nirogacestat has been 
shown to inhibit the Notch pathway in desmoid tumors by inhibiting NICD and Hes1 expression 
and this blockade results in grow arrest rather than apoptotic cell death in desmoid tumors 
(Shang, 2015). 
This collective data suggests that Notch signaling plays an important role in cancer development. 
Hence, inhibition of Notch signaling is an important strategy for therapeutic treatment. 
 
Rationale for Participant Population and Placebo Arm 
Desmoid tumors most commonly occur in individuals between the ages of 15 to 60 years, more 
often in young adults, with the peak age of about 30 years, and a 2- to 3-fold predominance in 
females (de Camargo, 2010; Skubitz, 2017). This Phase 3 study will enroll participants 
≥ 18 years old. The pharmacokinetics (PK) and optimal dosing of nirogacestat in younger 
participants has not been established. A future study in pediatric participants is planned. 


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There is no FDA-approved therapeutic option for the treatment of desmoid tumors, nor is there 
an accepted standard of care for patients with advanced progressing tumors. The population will 
be assessed by a wait-and-see approach and depending on the tumor growth and location, 
different therapeutic options may be considered. The recently analyzed Phase 3 study of 
sorafenib versus placebo (Gounder, 2018) showed a significant improvement in PFS in the 
sorafenib arm, but also demonstrated objective responses in the placebo group highlighting the 
need for this control in Phase 3 studies. 
 
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. The most frequently reported AEs 
were diarrhea, fatigue, nausea, vomiting, hypophosphatemia, cough, and rash. The majority of 
the events were mild-to-moderate in intensity. Additionally, a Phase 2 (investigator-initiated) 
study in adult participants with desmoid tumors showed a similar AE profile (Kummar, 2017). 
All participants in the study experienced at least one Grade 1 or Grade 2 AE; with the most 
commonly reported events being diarrhea and skin disorders. 
Based on the mechanism of action and nonclinical/clinical study data, the important identified 
risks associated with nirogacestat administration include notch-related effects on reproductive 
function and fertility, notch-related effects on hematopoietic (immune) function, notch-related 
effects on gastrointestinal function, skin rash, and hypophosphatemia. Important potential risks 
include effects on the hepatic system, including potential liver cholestasis. These risks will be 
assessed by routine pharmacovigilance measures.  
Additionally, measures are in place to minimize potential risks to study participants, and review 
of safety data will be conducted on an ongoing basis in order to identify new safety signals that 
may arise during the program. 
The results of the nonclinical toxicology and safety pharmacology studies, together with the 
clinical experience in participants with advanced cancers (Sections 2.2.3.1.1 and 2.2.3.1.2), 
support the hypothesis that nirogacestat may represent an important therapeutic approach in 
patients with desmoid tumors. 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 Investigator’s Brochure. 
The study will utilize an independent data monitoring committee (DMC) and will operate 
according to an established Charter (Section 9.5.1). In addition, a protocol steering committee 
was established to support the development of nirogacestat for the treatment of desmoid 
tumor/aggressive fibromatosis. The purpose and provisions of the DMC will be specified in the 
DMC Charter. 


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3.
OBJECTIVES AND ENDPOINTS
Table 1 
Study Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
Primary 
To determine the efficacy (as defined by 
PFS) of nirogacestat in adult 
participants with progressing DT/AF. 
PFS defined as the time from randomization until 
the date of assessment of progression or death by 
any cause. Progression will be determined 
radiographically using RECIST v1.1 (Eisenhauer, 
2009; Section 10.8) or clinically as assessed by the 
investigator.  
Clinical progression is defined as the onset or 
worsening of symptoms resulting in a global 
deterioration of health status causing the permanent 
discontinuation from study treatment and the 
initiation of emergent treatment (e.g., radiotherapy, 
surgery, or systemic therapy including 
chemotherapy or tyrosine kinase inhibitors) for 
DT/AF. 
Secondary 
Secondary 
To evaluate the safety and tolerability of 
nirogacestat in adult participants with 
progressing DT/AF as measured by the 
incidence of AEs; 
Safety endpoints will include incidence of 
treatment-emergent AEs, changes in laboratory 
parameters, vital signs, physical examination 
findings, and electrocardiograms (ECGs). 
Tolerability will be assessed according to toxicities 
graded by NCI Common Terminology Criteria for 
Adverse Events v5.0;  
To determine the overall response rate 
(CR + PR) of nirogacestat in 
participants with progressing DT/AF; 
Overall response rate, defined as the proportion of 
participants with CR + PR assessed by central 
reader using RECIST v1.1 Criteria; 
To determine the duration of response; 
Duration of response for participants whose best 
response is CR or PR; 
To compare tumor volume changes 
measured by MRI in participants with 
progressing DT/AF; and 
Change in tumor volume from baseline as assessed 
by MRI volumetric; and 
To evaluate desmoid tumor symptoms 
and impacts using patient-reported 
outcomes (PROs). 
Symptoms and impacts will be assessed by 
evaluating change from baseline on the following 
PROs: 


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• GOunder/Desmoid Tumor Research Tumor 
Foundation (DTRF) DEsmoid Symptom/Impact 
Scale (GODDESS); 
• Brief Pain Inventory short form; 
• Patient-Reported Outcomes Measurement 
Information System Physical Function 
(PROMIS PF) short form 10a plus 3 additional 
items from PROMIS item banks; and 
• European Organisation for Research and 
Treatment of Cancer Quality of Life 
Questionnaire-Core 30 (EORTC) QLQ-C30. 
Exploratory 
Exploratory 
To evaluate desmoid tumor symptoms 
and impacts using PROs; 
Symptoms and impacts will be assessed by 
evaluating changes using the Patient Global 
Impression of Severity (PGIS) and the Patient 
Global Impression of Change (PGIC); 
To perform genotyping for germline and 
somatic mutation in APC and CTNNB1 
genes; 
Assess the frequency and distribution of each 
mutation; 
To assess modulation of the Notch 
pathway by evaluating NOTCH 
response genes in tumor biopsies at 
screening and disease progression or 
end of treatment (EOT); 
Change in expression pre- and post-dose on Notch 
pathway genes; 
To assess MRI T2 hyperintensity at 
baseline and post-drug administration; 
Assess the percent change in MRI T2 intensity; 
To inform development of a population 
PK model of nirogacestat; and 
To optimally collect sparse PK samples to increase 
precision of model parameters; and  
To perform exposure-response analysis 
using a final population PK/PD 
(PopPK/PD) model. 
To determine the relationship between exposure 
and primary, secondary, and/or exploratory efficacy 
and safety endpoints. 
To evaluate the effect of nirogacestat on 
clinical events related to disease specific 
desmoid tumor co-morbidity. 
Summarize the incidence and frequency of events 
which may include hospitalization due to small 
bowel obstruction, hospitalization due to desmoid 
tumor-related pain, surgery for desmoid tumor. 
 


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4. 
STUDY DESIGN 
 
Overall Design 
This is a multi-center, randomized, double-blind, placebo-controlled, parallel group, event-
driven, Phase 3 study to compare the efficacy, safety, and tolerability of nirogacestat and placebo 
in adult participants with progressing DT/AF. Approximately 118 eligible participants will be 
randomized to study treatment (nirogacestat or placebo) in a 1:1 ratio. Randomization will be 
stratified by primary tumor location (intra-abdominal or extra-abdominal [Section 6.3.1]).  
This study will consist of 2 phases: the double-blind phase and the optional open-label extension 
(OLE) phase. Refer to the schedule of activities (SoA; Sections 1.3.1 and 1.3.2) for details on 
assessments and timing of study visits. 
Refer to Section 1.2 for the study schema. 
4.1.1. 
Overall Design for the Double-Blind Phase:  
Participants will be screened up to 28 days prior to the first dose of study treatment and 
eligibility will be based on inclusion and exclusion criteria (Sections 5.1 and 5.2). Participants 
will be randomized to study treatment at Cycle 1 Day 1 using interactive response technology 
(IRT), and will orally administer 150 mg BID, continuously in 28-day cycles.  
Following the baseline visit (Cycle 1 Day 1), participants will return to the clinic for study visits 
at Cycle 1 (Days 8, 15, 22), Cycle 2 (Day 28), Cycle 4 (Day 1) and then on Day 1 of every 
3 cycles thereafter.  
Participants will remain in the double-blind phase until: 
• Participant experiences death; 
• Central Imaging Review determines that the participant has radiographic progressive 
disease (using RECIST v1.1);1 
• The investigator determines the participant is experiencing clinical progression which is 
defined as the onset or worsening of symptoms resulting in a global deterioration of 
health status causing the permanent discontinuation from study treatment and the 
initiation of emergent treatment (e.g., radiotherapy, surgery, or systemic therapy 
including chemotherapy or tyrosine kinase inhibitors) for DT/AF; 2 
• Participant prematurely discontinues study treatment for any reason; 
• The study is stopped by the sponsor for any reason; or 
• The required number of PFS events have been observed and the primary PFS analysis has 
been completed (based on current statistical assumptions, this is anticipated to be 
approximately 2 years after the first participant is randomized).3 
1If Central Imaging Review determines that a participant has radiographic progressive disease (using RECIST v1.1) 
during the double-blind phase of the study, the site will be notified by the central imaging core laboratory. The 
participant will return to the site for an end of treatment (EOT) visit within 14 days of the notification from the 


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central imaging core laboratory. During the EOT visit, the participant will be unblinded and have the option to enter 
the OLE phase if eligible (Section 6.7.1). 
2If a participant has clinical progression as determined by the investigator; the participant will return to the site for 
an end of treatment (EOT) visit within 14 days of the date of clinical progression. During the EOT visit, the 
participant will NOT be unblinded; and will NOT be eligible to enter the optional OLE phase. 
3When the required number of PFS events have been observed and the primary PFS analysis has been completed, all 
remaining participants in the double-blind phase will be unblinded. And if eligible, they will have the option to enter 
the OLE phase. 
4.1.2. 
Overall Design for the Optional OLE Phase: 
Only eligible participants may enroll in the OLE phase of the study. Refer to Sections 6.7.2 and 
6.7.3 for the OLE phase eligibility criteria.  
The Cycle 1 Day 1 visit of the OLE phase should be conducted on the same day as, or within 
24 hours after, the double-blind EOT visit. A longer window between the double-blind EOT and 
OLE C1D1 visit may be allowed with prior medical monitor approval; however, repeat 
assessments may be required with medical monitoring guidance depending on the length of time 
between double-blind EOT and OLE C1D1. 
Participants will be enrolled in the OLE phase using the IRT only after (1) all ongoing 
AEs/SAEs from the double-blind phase have been assessed for causality in a blinded manner by 
the investigator or qualified designee, and (2) all AE/SAE causality assessments have been 
entered into the electronic case report form (eCRF). In addition, all double-blind EOT visit 
assessments must be completed prior to unblinding and administering the first dose of open-label 
study treatment. Refer to Section 6.3.2.1 for more detail on the required unblinding criteria.  
Participants who were randomized to receive placebo in the double-blind phase will receive their 
first dose of study treatment at the site followed by a 3-hour observation period.  
Participants who were randomized to nirogacestat in the double-blind phase may take their first 
dose of open-label study treatment at home (observation period is not required). 
Following the OLE baseline visit (Cycle 1 Day 1), participants who were previously randomized 
to receive placebo in the double-blind phase will return to the clinic for study visits at Cycle 1 
(Day 8, 15, 22) and Cycle 2 (Day 28). Participants who were previously randomized to 
nirogacestat in the double-blind phase will not return to the clinic until the Cycle 4 Day 1 visit. 
All participants will have study visits at Cycle 4 Day 1 and then on Day 1 of every 3 cycles 
thereafter. 
Participants will remain in the OLE phase until: 
• Participant experiences death; 
• Central Imaging Review determines that the participant has radiographic progressive 
disease (using RECIST v1.1); 
• The investigator determines the participant to have clinical progression which is defined 
as the onset or worsening of symptoms resulting in a global deterioration of health status 


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causing the permanent discontinuation from study treatment and the initiation of 
emergent treatment (e.g., radiotherapy, surgery, or systemic therapy including 
chemotherapy or tyrosine kinase inhibitors) for DT/AF; 
• Participant prematurely discontinues study treatment for any reason; 
• The study is stopped by the sponsor for any reason;  
• Participant qualifies for sponsor’s Continued Access Plan; or 
• Nirogacestat is commercially available. 
 
Scientific Rationale for Study Design 
Based on the promising, prolonged tumor responses and overall tolerability with nirogacestat 
observed in the Phase 1 and Phase 2 studies, this Phase 3 double-blind, placebo-controlled study 
is being proposed to determine the efficacy and safety in participants with unresectable, recurrent 
or relapsed progressing desmoid tumors. Progression-free survival was selected as the primary 
endpoint based on the previous clinical studies with nirogacestat in desmoid participants with 
progressing tumors and the observation that only one participant progressed after 15 months on 
therapy (1 out of 24 participants) (Villalobos, 2018 and Kummar, 2017). The rate of progression 
in untreated desmoid patients is about 11 months (Gounder, 2018). A placebo group was chosen 
because of the known spontaneous regressions that can occur with desmoid tumors. Progressing 
desmoid tumors can be unrelenting to patients particularly when they are unresectable or 
unresponsive to systemic treatment and halting progression, particularly when paired with tumor 
shrinkage, is a significant outcome for patients. Because of the size and location of desmoid 
tumors they can often be associated with pain, loss of range of motion, and impact on daily 
living. This study incorporates outcome tools to assess change from baseline in these outcome 
measures, as changes in pain, for example, have been observed in participants treated with 
nirogacestat that had significant tumor shrinkage (Kummar, 2017). 
Given the unique characteristics of DT/AF, applying RECIST v1.1 alone is not always an 
adequate means of capturing the entirety of the disease progression and its clinical impact on 
participants. In particular, DT/AF tumors have been shown to grow in an asymmetric nature that 
can infiltrate multiple layers of fascia, neurovascular bundles and complex joint spaces 
(Gounder, 2017; Villalobos, 2017). This asymmetric growth also impacts the plane in which 
RECIST v1.1 measurements are performed such that the plane selected for review at the 
beginning of the study may not match the plane which ultimately shows progressive disease. To 
address the complexities of evaluating DT/AF lesions, progression will be determined both 
radiographically using Response Evaluation Criteria In Solid Tumors (RECIST) version (v)1.1 
(Eisenhauer, 2009; Section 10.8) and clinically as assessed by the investigator.  
 
Justification for Dose 
An open-label, non-randomized, Phase I dose finding study (Messersmith, 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-


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finding portion of the study, the MTD of nirogacestat administered BID continuously for 21 days 
was established at 220 mg BID in participants with advanced solid tumors. 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%). 
Analysis of whole blood samples demonstrated that HES4 showed the most consistent PD 
response, with a greater than 2-fold down-modulation observed in 17 of 19 evaluable participants 
with solid tumors. Additionally, in participants with advanced desmoid tumors, there appeared to 
be a clear response to nirogacestat treatment. 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 NCI in participants with progressing desmoid tumors 
(Kummar, 2017). In this study, nirogacestat activity was established with 5 PR (29%) out of 16 
evaluable participants. The dose of 150 mg BID was chosen for this Phase 3 clinical study based 
on the safety profile at this dose as well as the encouraging tumor responses in participants with 
desmoid tumors. 
 
End of Study Definition 
The end of the study is defined as the date of the last scheduled procedure shown in the SoA 
(Section 1.3) (including telephone contact) for the last participant in the study globally. 


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5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
 
Inclusion Criteria 
The inclusion criteria apply to the double-blind phase of the study only. The inclusion criteria for 
the OLE phase can be found in Section 6.7.2. 
Participants are eligible to be included in the double-blind phase only if all the following criteria 
apply: 
Age 
1. Participant must be at least 18 years of age at the time of signing the informed consent. 
Type of Participant and Disease Characteristics 
2. Participant has histologically confirmed DT/AF (by local pathologist prior to informed 
consent) that has progressed by ≥ 20% as measured by RECIST v1.1 within 12 months of 
the screening visit scan. 
3. Participant has: 
a. Treatment naïve, measurably progressing DT/AF that is deemed not amenable to 
surgery without the risk of significant morbidity; 
OR 
b. Recurrent, measurably progressing DT/AF following at least one line of therapy; 
OR 
c. Refractory, measurably progressing DT/AF following at least one line of therapy. 
4. Participant has a DT/AF tumor where continued progressive disease will not result in 
immediate significant risk to the participant. 
5. Participant agrees to provide archival or new tumor tissue for re-confirmation of disease. 
6. If participant is currently being treated with any therapy for the treatment of DT/AF, this 
must be completed at least 28 days (or 5 half-lives, whichever is longer) prior to first 
dose of study treatment. All toxicities from prior therapy must be resolved to ≤ Grade 1 
or clinical baseline. 
7. Participants who are receiving chronic nonsteroidal anti-inflammatory drugs (NSAIDs) 
as treatment for conditions other than DT/AF must be receiving them prior to the 
documented DT/AF progressive disease (inclusion criteria 2) and on a stable dose for at 
least 28 days prior to first dose of study treatment.  


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8. Participant has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 
at screening (refer to Section 10.7 for ECOG performance status scale). 
9. Participant has adequate organ and bone marrow function as defined by the following 
screening laboratory values: 
a. Absolute neutrophil count ≥ 1500 cells/µL; 
b. Platelets ≥ 100,000µL; 
c. Hemoglobin ≥ 9 g/dL; 
d. Total bilirubin ≤ 1.5 × upper limit of normal (ULN) (isolated bilirubin > 1.5 x 
ULN is acceptable if bilirubin is fractionated and direct bilirubin < 35%); 
e. Aspartate aminotransferase (AST) (serum glutamic oxaloacetic 
transaminase)/alanine aminotransferase (ALT) (serum glutamic pyruvate 
transaminase) ≤ 2 × ULN; and 
f. Serum creatinine ≤ 1.5 × ULN or if creatinine > 1.5 × ULN then calculated 
creatinine clearance must be ≥ 60 mL/min (using the Cockcroft-Gault formula); 
10. Participant can swallow tablets and has no gastrointestinal conditions affecting 
absorption. 
Sex 
11. Male or Female 
Contraceptive use by men or women should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies. 
a. Male participants: 
Male participants are eligible to participate if they agree to the following during 
the treatment period and for at least 90 days after the last dose of study treatment: 
• Refrain from donating or preserving sperm;  
PLUS either: 
• Be abstinent from sexual intercourse as their preferred and usual lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent;  
OR 
• Must agree to use a male condom when having sexual intercourse with women 
of childbearing potential (WOCBP). An additional form of contraception as 
described in Section 10.4 should also be used by the female partner, if she is of 
childbearing potential. Refer to Section 10.4 for definition of WOCBP.  
b. Female participants: 
A female participant is eligible to participate if she is not pregnant or 
breastfeeding, and at least one of the following conditions applies: 
• Is not of childbearing potential (not WOCBP). 


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OR 
• Is of childbearing potential but is abstinent or using 1 highly effective 
contraceptive method, as described in Section 10.4 during the treatment 
period and until 6 months after the last dose of active study treatment. A 
second method of contraception is 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 6 months after the last dose of active study treatment. The 
investigator should evaluate the effectiveness of the contraceptive method in 
relationship to the first dose of study treatment.  
• A WOCBP must have a negative serum pregnancy test result at screening and 
a negative urine pregnancy test result at the baseline visit prior to the first 
dose of study treatment. 
• The investigator is responsible for review of medical history, menstrual 
history, and recent sexual activity to decrease the risk for inclusion of a 
woman with an early undetected pregnancy. 
Informed Consent 
12. Capable of giving signed informed consent as described in Section 10.1.3 which includes 
compliance with the requirements and restrictions listed in the informed consent form 
(ICF) and in this protocol. 
 
Exclusion Criteria 
These criteria only apply to the double-blind phase of the study. The exclusion criteria for the 
OLE phase can be found in Section 6.7.3. 
Participants are excluded from the double-blind phase if any of the following criteria apply: 
Medical Conditions 
1. Participant has known malabsorption syndrome or preexisting gastrointestinal conditions 
that may impair absorption of nirogacestat (e.g., gastric bypass, lap band, or other gastric 
procedures that would alter absorption); delivery of nirogacestat via nasogastric tube or 
gastrostomy tube is not allowed. 
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;  


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• coronary/peripheral artery bypass graft;  
• symptomatic congestive heart failure;  
• cerebrovascular accident;  
• transient ischemic attack; or  
• symptomatic pulmonary embolism. 
3. Participant has abnormal QT interval corrected by Fridericia’s formula (> 450 msec for 
male participants, > 470 msec for female participants, or > 480 msec for participants with 
bundle branch block) after electrolytes have been corrected (triplicate ECG readings, 
done approximately 2-3 minutes apart and averaged) at screening.  
4. 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). 
5. Participant has congenital long QT syndrome. 
6. Participant has a history of additional risk factors for Torsades de Pointes (TdP) (e.g., 
heart failure, hypokalemia, family history of Long QT Syndrome). 
7. Participant has had lymphoma, leukemia, or any malignancy within the past 5 years at the 
time of informed consent, except for any locally recurring cancer that has been treated 
curatively (e.g., resected basal or squamous cell skin cancer, superficial bladder cancer, 
carcinoma in situ of the cervix or breast), with no evidence of metastatic disease for 3 
years at the time of informed consent. 
8. Participant has current or chronic history of liver disease or known hepatic or biliary 
abnormalities (except for Gilbert’s syndrome or asymptomatic gallstones). 
Prior/Concomitant Therapy 
9. Participant previously received or is currently receiving therapy with GS inhibitors or 
anti-Notch antibody therapy. 
10. Participant is currently using any treatment for DT/AF including tyrosine kinase 
inhibitors (TKIs), NSAIDs (chronic daily use – except as in inclusion criterion 7) or any 
investigational treatment 28 days (or 5 half-lives, whichever is longer) prior to the first 
dose of study treatment.  
OR 
Participant has started any treatment for DT/AF after the documented DT/AF progressive 
disease (inclusion criteria 2). 


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11. 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. 
Prior/Concurrent Clinical Study Experience 
12. Participant is currently enrolled or was enrolled within 28 days of first dose of study 
treatment in another clinical study with any investigational drug or device. Participation 
in observational studies may be permitted with prior approval from the medical 
monitor/sponsor. 
Diagnostic assessments 
13. Participant has a positive human immunodeficiency virus antibody test. 
14. Participant has presence of Hepatitis B surface antigen at screening. 
15. Participant has a positive Hepatitis C antibody or Hepatitis C ribonucleic acid (RNA) test 
result at screening or within 3 months prior to starting study treatment. 
NOTE: Participants with positive Hepatitis C antibody due to prior resolved disease can 
be enrolled, only if a confirmatory negative Hepatitis C RNA test is obtained. 
Test is optional and participants with negative Hepatitis C antibody test are not 
required to also undergo Hepatitis C RNA testing. 
Other Exclusions 
16. Participant is unable to tolerate MRI or for whom MRI is contraindicated. 
17. Participant with active or chronic infection at the time of informed consent and during the 
screening period. 
18. 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. 
19. Participant has known hypersensitivity to the active substance or to any of the excipients 
of nirogacestat or placebo (Table 2). 
20. Participant is unable to comply with study related procedures (including, but not limited 
to, the completion of electronic patient report outcomes (ePROs), or the ePRO 
questionnaires are not available in the participant’s preferred language) 
 
Lifestyle Considerations 
1. No specific lifestyle restrictions are required in this study. 
2. Study treatment may be taken without regard to food. 


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3. Refer to Section 6.5 for more detail on concomitant therapy including exclusions and 
restrictions. 
5.3.1. 
Meals and Dietary Restrictions 
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 double-blind and open-label phase. 
 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomized to study treatment (nirogacestat or placebo). 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 publishing requirements and 
to respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this 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, 5, 6, 8, 9, 13, or 19. 
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 
be tolerable for the participant. Rescreened participants must be re-consented and will be 
assigned a new participant number at the time of rescreening, which can be found on a new 
screening laboratory requisition form and will need to be entered into the IRT. 


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6. 
STUDY TREATMENT 
Study treatment for this study is investigational (nirogacestat or placebo) and intended to be 
administered to a study participant according to the study protocol. 
 
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 an eDiary using a home electronic patient report outcome (ePRO) device, which 
will be provided by the sponsor.  
• 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. 


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Table 2 
Study Treatments Administration 
ARM Name 
Experimental 
Control 
Treatment Name 
Nirogacestat  
Placebo 
Type 
Drug 
Drug 
Dose Formulation 
Tablet1 
Tablet 
Unit Dose Strength(s) 
50 mg 
50 mg 
Dosage Level(s) 
150 mg BID 
150 mg BID 
Route of 
Administration 
Oral 
Oral 
Sourcing 
Sponsor will provide sites with 
study treatment for individual 
participant distribution 
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 
Study treatment will be 
provided in 90 count bottles. 
Each bottle will be labeled as 
required per country 
requirement 
Former Name 
PF-03084014 
Not Applicable 
Ingredients 
Uncoated Tablets: 
PF-03084014-04; 
Microcrystalline Cellulose; 
Lactose Monohydrate; 
Sodium Starch Glycolate; and 
Magnesium Stearate. 
 
Opadry® QX Film Coated 
Tablets: 
Macrogol (PEG) Polyvinyl 
Alcohol Graft Copolymer, 
Talc, 
Titanium Dioxide, 
GMCC Type 1, 
 
Microcrystalline Cellulose; 
Lactose Monohydrate; 
Sodium Starch Glycolate; and 
Magnesium Stearate. 


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Polyvinyl Alcohol – Part 
Hydrolyzed, 
Yellow #6 / Sunset Yellow FCF 
Aluminum Lake, 
Iron Oxide Yellow 
1 Nirogacestat tablets may be uncoated or coated with a non-functional aqueous film coat (Opadry® QX) in the OLE 
phase of the study. In the double-blinded phase of the study, nirogacestat will only be dispensed in an uncoated 
tablet.  
6.1.1. 
Double-Blind Phase Dosing Administration 
The first dose of double-blind study treatment (3 × 50 mg tablets) will be administered at the site 
on Cycle 1 Day 1 followed by a 3-hour observation period. To minimize time required onsite, the 
observation period may be shortened to 2 hours temporarily during a public health emergency 
(e.g., COVID-19) with prior medical monitor / sponsor approval. 
Throughout the double-blind phase, participants will administer 150 mg (3 × 50 mg nirogacestat 
tablets or placebo) of study treatment BID (approximately every 12 hours, without regard to 
food), continuously in 28-day cycles. 
6.1.2. 
Open-Label Phase Dosing Administration 
Participants who were randomized to receive placebo in the double-blind phase will receive their 
first dose of open-label study treatment at the site followed by a 3-hour observation period.  
Participants who were randomized to nirogacestat in the double-blind phase may take their first 
dose of open-label study treatment at home. An observation period at the site is not required. 
Throughout the OLE phase, 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. To minimize time required onsite, the observation period may be shortened to 2 hours 
temporarily during a public health emergency (e.g., COVID-19) with prior medical monitor / 
sponsor approval. 
6.1.3. 
Study Treatment Errors 
Study treatment errors may result from the administration or consumption of the wrong study 
treatment, by the wrong participant, at the wrong time, or at the wrong dosage strength. Such 
study treatment errors are to be captured on the AE page of the eCRF and on the SAE form when 
appropriate. In the event of a dosing error, the medical monitor/sponsor should be notified 
immediately. 
Study treatment errors are reportable irrespective of the presence of an associated AE/SAE, 
including errors involving participant exposure to the product.  
Missed doses are not considered dosing errors. 
 


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Preparation/Handling/Storage/Accountability 
• Study treatment will be dispensed to participants every 3 cycles during scheduled study 
visits as described in the SoA (Section 1.3) or unscheduled visits if study treatment is 
damaged/lost or a dose modification (Section 6.6) 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 shipments received and any 
discrepancies are reported and resolved before use of the study treatment. 
• Only participants randomized in the IRT may receive study treatment and only authorized 
site staff may supply 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 
participant (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 participant shipping is not 
allowed at the C1D1 visit in the double blind or OLE phase of the study. 
• 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).  
• Study treatment returned by the participant will not be re-dispensed. 
• Further guidance and information about the handling, storage, and final disposition of 
unused study treatment (bottles/tablets) are provided in the pharmacy manual. 
 
Measures to Minimize Bias: Randomization and Blinding 
6.3.1. 
Randomization 
• Prior to participants being randomized to study treatment, the following activities must be 
completed: 
1. Participant must sign the ICF (Section 10.1.3) and complete all screening 
assessments (Section 1.3.1). 
2. Site must submit the Pre-Randomization RECIST v1.1 Calculation Worksheet at 
least 7 days prior to Cycle 1 Day 1 (Section 8.1.1.1). 
3. Site must submit the screening visit scan(s) to the central imaging core laboratory 
as early in the screening period as possible to confirm scan quality (Section 8.1.1). 
4. Site must confirm that the participant meets all study entry criteria (Sections 5.1 
and 5.2). 


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5. Participant must complete all pre-randomization baseline visit assessments. Refer 
to Section 1.3.1 and Baseline and Cycle 1 Day 1 (double-blind phase) for 
additional details. 
• At Cycle 1 Day 1, once all of the above activities have been completed, participants will 
be centrally assigned to randomized study treatment (nirogacestat or placebo) using the 
IRT. Before the study is initiated at a site, instructions and log-in information for the IRT 
will be provided to appropriate site personnel. 
• Randomization will be stratified based on the following tumor locations: 
1. Intra-abdominal (including mesentery and pelvis); 
OR 
2. Extra-abdominal (including head/neck, para-spinal, extremities, abdominal wall, 
chest wall, and other locations). 
If the participant has multiple target tumors that are located both in the intra- and extra-
abdominal location, the tumor should be classified as intra-abdominal. 
• The tumor location used for stratification should be the same as the reported target 
lesion(s) used for assessment of the primary endpoint. The location of the target tumor(s) 
will be selected by the investigators as the basis for inclusion in the study and will be 
documented on the Pre-Randomization RECIST v1.1 Calculation Worksheet 
(Section 8.1.1.1). 
6.3.2. 
Blinding 
For the double-blind phase, the participant, investigator, and all other clinical site personnel will 
be blinded to the assigned treatment allocation. All sponsor personnel will also be blinded except 
for the sponsor’s quality assurance designee(s), safety designee(s), and clinical supply material 
designee(s).  
If Central Imaging Review determines that a participant has radiographic progressive disease 
(using RECIST v1.1) during the double-blind phase of the study, the site will be notified by the 
central imaging core laboratory. The participant will then return for the EOT visit which will be 
conducted in a completely blinded fashion. All EOT assessments and all ongoing AEs/SAEs 
must (1) be assessed for causality by the investigator or qualified designee in a blinded manner 
and (2) recorded in the eCRF prior to the unblinding of the study treatment allocation (Section 
6.3.2.1). 
Study participants who discontinue due to clinical progression will NOT be unblinded and will 
NOT be eligible to enroll into the optional OLE phase of the study. These participants should be 
discontinued from the study after completing an EOT and FUP visit as specified in applicable 
SoA table. 
If a participant discontinues study treatment for any reason other than radiographic progressive 
disease as determined via central review, the study treatment allocation will not be unblinded.  


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6.3.2.1. 
Breaking the Blind 
Sites will be provided instructions on how to break the blind in the IRT prior to study initiation. 
The study treatment blind is not to be broken unless one of the following criteria apply 
(unblinding at the clinical site for any other reason will be considered a protocol deviation and 
the unblinded participant will be permanently discontinued from the study): 
1. Emergency situations: 
• In case of an emergency, the investigator has the sole responsibility for 
determining if unblinding of a participant’s study treatment assignment is 
warranted. 
• Participant safety must always be the first consideration in making such a 
determination. 
• If the investigator decides that unblinding is warranted, the investigator will make 
every effort to contact the medical monitor/sponsor prior to unblinding a 
participant’s study treatment assignment unless this could delay emergency 
treatment of the participant. Refer to Section 10.10.3 for the medical monitor 
contact information. 
• The sponsor or medical monitor must be notified within 24 hours after breaking 
the blind. The date and reason that the blind was broken must be recorded in the 
source documentation and eCRF, as applicable.  
• If the blind is broken for emergency reasons, the unblinded participant will be 
permanently discontinued from the study and it not eligible to enter the OLE 
phase. 
2. Central Imaging Review determines that a participant has radiographic progressive 
disease (using RECIST v1.1); 
• Prior to unblinding in this situation, the following criteria must be met: 
o All double-blind EOT study assessments have been completed in a blinded 
manner (refer to SoA table Section 1.3.1 for complete list of assessments). 
o All ongoing AEs/SAEs from the double-blind phase have been assessed 
for causality by the investigator or qualified designee in a blinded manner 
and recorded in the eCRF. 
o Sponsor designee has confirmed that the criteria above have been met and 
only then will the IRT allow the study treatment to be unblinded. 
• If eligible, participants may enter the OLE phase (Sections 6.7.2 and 6.7.3). 
3. The required number of PFS events have been observed and the primary PFS analysis 
has been completed. 
• If eligible, all ongoing participants at this time may enter the OLE phase. 


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Study Treatment Compliance 
Participant compliance with study treatment will be monitored throughout the study. At each 
applicable study visit (Sections 1.3.1 and 1.3.2), the participant should be asked whether he or 
she has 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. The number of tablets dispensed, 
and the number of tablets returned will be recorded in the eCRF.  
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/sponsor. 
In the case of an overdose, refer to Section 8.4 for instructions. 
 
Concomitant Therapy 
6.5.1. 
Concomitant Medications and/or Procedures 
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/sponsor should be contacted if there are any questions regarding 
concomitant or prior therapy. Refer to Section 10.10.3 for the medical monitor contact 
information. 
6.5.1.1. 
Known Drug Interactions 
 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 double-blind and OLE study phases and must be stopped at least 14 
days prior to the first dose of double-blind 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 CYP3A4 inducers is not allowed throughout the double-blind and OLE study 
phases and must be stopped at least 14 days prior to the first dose of double-blind study 
treatment. 


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 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 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. 
 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 up to 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/sponsor.  
 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 CYP 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. Nonclinical studies have indicated that nirogacestat may also be an inhibitor 
of P-gp and may increase the exposure of some P-gp substrates like digoxin, dabigatran, and 
fexofenadine; participants receiving these medications should be closely monitored. 
Co-administration of gastric acid reducing agents 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 2 to 4 hours 
following the morning dose of study treatment. 


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6.5.1.2. 
Excluded/Restricted Concomitant Medications and/or Procedures 
Table 3 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/sponsor with any questions regarding excluded/restricted medications. 
Table 3 
Restricted/Excluded Medications and/or Procedures 
Medication/Procedure 
Restriction/Exclusion Timeframe 
• Chronic daily use of NSAIDS for treatment 
of DT/AF;1  
• Tyrosine kinase inhibitors; 
• Other antineoplastic therapy, including 
cytotoxic agents, targeted agents, endocrine 
therapy or other antibodies; and 
• Any investigational treatment for DT/AF. 
• Not allowed after the documented DT/AF 
progressive disease (inclusion criteria 2) or 
within 28 days (or 5 half-lives, whichever 
is longer) prior to first dose of double-blind 
study treatment; and 
• Not allowed throughout the duration of the 
treatment period during the double-blind or 
OLE phases. 
• Strong/moderate CYP3A4 inhibitors; and 
• Strong CYP3A4 inducers. 
• Not allowed within 14 days prior to first 
dose of double-blind study treatment; and 
• Not allowed throughout the duration of the 
treatment period during the double-blind or 
OLE phases. 
• CYP3A4 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 acid reducing agents such as proton 
pump inhibitors. 
• Should be avoided if a reasonable 
alternative is available; and 
• If administration is necessary, should be 
administered 2 to 4 hours after the morning 
dose of study treatment. 
• 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 during the double-blind or 
OLE phases. 
• 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; and 
• Surgical resection of DT/AF tumors. 
• Not allowed at the time of informed 
consent; and 
• Not allowed throughout the duration of the 
treatment period during the double-blind or 
OLE phases. 


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Medication/Procedure 
Restriction/Exclusion Timeframe 
• Delivery of nirogacestat via nasogastric 
tube or gastrostomy tube. 
• Not allowed throughout the double-blind or 
OLE phases. 
• Enrollment in another clinical study with 
any investigational drug or device.2 
• Not allowed within 28 days prior to first 
dose of study treatment; and 
• Not allowed throughout the duration of the 
double-blind or OLE phases. 
1Participants who are receiving chronic NSAIDs as treatment for conditions other than DT/AF must be receiving 
them prior to the documented DT/AF progressive disease (inclusion criteria 2) and must be on a stable dose for 
28 days prior to first dose of study treatment. 
Occasional use (defined as ≤ 3 days per week) of NSAIDs for the treatment of pain or as an anti-inflammatory in 
conditions such as headache, arthritis, etc., is allowed throughout the treatment period during the study. 
Dose increases of NSAIDs will not be permitted during the treatment period during the double-blind phase of the 
study. 
2Participation in an observational study may be allowed on a case-by-case basis with prior medical monitor/sponsor 
approval. 
6.5.1.3. 
Supportive Care 
 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. 
 Palliative Care 
During the double-blind and OLE phase of the study, systemic therapy or local therapy to 
the DT/AF tumors are not permitted.  
Medications for the standard management of symptoms or supportive care for the 
management of the effects of study treatment may be administered at the investigator’s 
discretion; unless they are excluded concomitant medications (Section 6.5.1.2). 
Palliative radiation therapy may be permitted in the OLE phase of the study after 
consultation with the medical monitor/sponsor. Radiation will be limited to non-target 
lesions only and will be documented in the eCRF and on the Pre-Randomization RECIST 
v1.1 Calculation Worksheet. 
Thus, the following therapies are not permitted during the double-blind or OLE phases of 
the study: 
• Other anti-neoplastic therapy, including cytotoxic agents, targeted agents, endocrine 
therapy or other antibodies;  
• Potentially curative radiotherapy; 
• Surgical resection of DT/AF tumors; and 
• Any other investigational therapy. 


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Dose Modification 
Every effort will be made to administer study treatment (nirogacestat or placebo) at 150 mg BID. 
However, dosing will be interrupted and/or dose reduced for the AEs described in Table 4. Study 
treatment may also be modified to manage other AEs in collaboration with the medical monitor. 
If a participant experiences an AE as described in Table 4, 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 4.  
• 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/sponsor. Refer to Section 10.10.3 for the medical monitor contact details. 
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/sponsor.  
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 4 
Dose Modifications or Interruptions for Selected Toxicities 
Toxicity (NCI CTCAE) 
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 
Reproductive system toxicities 
Grade ≥ 2 premature menopause / primary 
ovarian insufficiency 
Decrease dose to 100 mg BID2 
Other toxicities 
Grade ≥ 3 skin toxicity1 
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 non-
hematological toxicities 
Decrease dose to 100 mg BID 
Grade ≥ 3 hematological toxicities 
Decrease dose to 100 mg BID. 


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Toxicity (NCI CTCAE) 
Intervention 
Anaphylaxis 
Permanently discontinue 
Grade ≥ 3 hypersensitivity reaction 
Permanently discontinue 
Hepatic toxicities 
Refer to Section 7.1.1 
1Refer to the study reference manual for guidelines on managing the AE of skin rash. 
2A dose reduction is not required for events of premature menopause / primary ovarian insufficiency but may be 
considered for symptomatic participants based on the individual benefit / risk profile. A dose interruption is not 
required prior to a dose reduction for reproductive system toxicities. 
 
 
Treatment after the End of the Double-Blind Study 
6.7.1. 
Optional Open-Label Extension Phase 
Eligible participants will have the option to enter the OLE phase of the study. Refer to the OLE 
SoA (Section 1.3.2) for study visits and timing of assessments, and Section 4.1.2 and Table 7 for 
overall design and additional details of the OLE phase. 
6.7.2. 
Inclusion Criteria - Open-Label Extension Phase 
Participants are eligible to be included in the OLE phase only if all the following criteria apply: 
1. Participant is enrolled in the double-blind phase when all the required number of PFS 
events have been observed and the primary PFS analysis has been completed; 
OR 
Participant is randomized to receive placebo in the double-blind phase and Central 
Imaging Review determines that the participant has radiographic progressive disease 
(using RECIST v1.1); 
OR 
Participant is randomized to receive nirogacestat in the double-blind phase and Central 
Imaging Review determines that the participant has radiographic progressive disease 
(using RECIST v1.1) but the participant is deriving clinical benefit without significant 
toxicity (as determined by the investigator). 
2. Participant has adequate organ and bone marrow function as outlined in the double-blind 
inclusion criteria 9 (based off hematology and serum chemistry results within 14 days 
prior to enrollment in the OLE phase). 
3. Participant agrees to use contraception as outlined in the double-blind inclusion 
criteria 11. 
4. Participant is capable of giving signed informed consent specific to the OLE phase, as 
described in Section 10.1.3, which includes compliance with the requirements and 
restrictions listed in the ICF and in this protocol. 


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6.7.3. 
Exclusion Criteria - Open-Label Extension Phase 
Participants are excluded from the OLE phase of the study if any of the following criteria apply: 
1. Participant requires surgery to prevent organ dysfunction. 
2. Participant has prematurely discontinued from the double-blind phase for any reason 
other than radiographic progressive disease (as determined by Central Imaging Review 
using RECIST v1.1). 
3. Participant developed a concurrent illness/condition that, in the opinion of the 
investigator, would represent a risk to overall health if they enroll in this study. 
4. Participant has initiated a new treatment for DT/AF including tyrosine kinase inhibitors, 
other antineoplastic therapy, including cytotoxic agents, targeted agents, endocrine 
therapy or other antibodies; and/or any investigational treatment for DT/AF after the 
Central Imaging Review determines that a participant has radiographic progressive 
disease (using RECIST v1.1). 


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7. 
DISCONTINUATION OF STUDY TREATMENT AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
 
Discontinuation of Study Treatment 
It may be necessary for a participant to permanently discontinue study treatment (nirogacestat or 
placebo) early. In this case, the participant will return to the site for an EOT visit and a post dose 
follow-up visit (refer to SoA tables in Section 1.3 for a complete list of required assessments to 
be conducted). 
Reasons for discontinuation of study treatment early may include: 
• Central Imaging Review determines that a participant has radiographic progressive 
disease (using RECIST v1.1) in the double-blind phase and the participant does not enter 
the OLE phase; 
• Central Imaging Review determines that a participant has radiographic progressive 
disease (using RECIST v1.1); 
• The investigator determines the participant is experiencing clinical progression which is 
defined as the onset or worsening of symptoms resulting in a global deterioration of 
health status causing the permanent discontinuation from study treatment and the 
initiation of emergent treatment (e.g., radiotherapy, surgery, or systemic therapy 
including chemotherapy or tyrosine kinase inhibitors) for DT/AF; 
• 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; 
• Participant’s study treatment is unblinded for safety reasons or any reason other than 
radiographic progressive disease as determined via central review (Section 6.3.2.1); 
• Any SAE (refer to Section 10.3.2 for SAE criteria), clinically significant AE (refer to 
QTcF stopping criteria, Section 7.1.2), severe laboratory abnormality (refer to liver 
chemistry stopping criteria, Section 7.1.1), any grade ≥ 3 hypersensitivity reaction, 
anaphylaxis, Section 6.6), intercurrent illness, or other medical condition which indicates 
to the investigator that continued participation is not in the best interest of the participant; 
• Pregnancy (refer to Sections 8.3.5 and 10.4 for additional details); 
• Requirement of prohibited concomitant medication or procedure (Section 6.5.1.2); 
• Participant failure to comply with protocol requirements or study-related procedures; or  
• Termination of the study by the sponsor or the regulatory authority. 
7.1.1. 
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 1 or if the 
investigator believes that it is in the best interest of the participant. 


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Figure 1 
Liver Chemistry Stopping Criteria and Increased Monitoring Algorithm 
 
Abbreviations: ALT = alanine transaminase; INR = international normalized ratio; SAE = serious adverse event; ULN = upper 
limit of normal. 
7.1.2. 
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] after enrollment), 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 ECGs printed at the time of collection 
must be documented. Any new clinically relevant finding must be reported as an AE. 
A participant who meets either of the following bulleted criterion based on the average of 
triplicate ECG readings will be withdrawn from study treatment: 
• QTcF > 500 msec  
• Change from baseline of QTcF > 60 msec 
Table 5 describes the discontinuation criteria for participants with underlying bundle branch 
block. 
 If participant is to be monitored weekly, must refer to Liver Safety: Suggested Actions and 
Follow-up Assessments (Section 10.6) 
 Must refer to Liver Safety: Suggested Actions and Follow-up Assessments (Section 10.6) 
 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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Table 5 
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 
See the SoA for data to be collected at the time of study treatment discontinuation and follow-up, 
and for any further evaluations that need to be completed. 
7.1.3. 
Pregnancy  
A female participant who becomes pregnant will be withdrawn from study treatment. See 
Section 10.4 and Section 8.3.5 for additional details. 
 
Participant Discontinuation/Withdrawal from the Study 
• A participant may withdraw from the study at any time at their 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 a 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. 
• 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. 
 
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 site for a required study 
visit: 
• 
The site must attempt to contact the participant and reschedule the missed visit as soon 
as possible, 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 


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equivalent methods). These contact attempts must 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 a whole is handled as part of Section 10.1.8. 


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8. 
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 medical monitor/sponsor 
immediately upon occurrence or awareness to determine if the participant should 
continue or discontinue study treatment (nirogacestat or placebo). 
• 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 and reviewed to confirm that potential 
participants meet all eligibility criteria (Sections 5.1, 5.2, 6.7.2, and 6.7.3). 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 218 mL each 
year throughout the double-blind phase and 180 mL each year throughout the OLE 
phase. This does not include any extra assessments that may be required for unscheduled 
assessments. 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 / sponsor. Any deviations from the study protocol due to a public health 
emergency should be documented in the source data and eCRF and reported to the 
IRB/EC 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 may be performed locally with results and local 
laboratory normal values entered into the eCRF. 
o  
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. Every effort should be made to perform ECGs in 
triplicate; however, a single ECG will be allowed if necessary due to a public 
health emergency. 
o Study imaging including CT and/or MRI should be performed per the schedule in 
the SoA at a qualified imaging facility; however, local imaging may be allowed 


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with prior sponsor approval. Local imaging will need to be uploaded for Central 
Imaging Review.   
Table 6 
Double-Blind Phase Study Visits 
This table supplements the SoA and highlights key study visit reminders. Refer to the double-
blind phase SoA table (Section 1.3.1) for the complete list of study assessments, and the study 
reference manual for study visit checklists which will include the recommended sequence of 
assessments for each study visit. 
Screening (double-blind phase) 
Operational visit reminders: 
• Refer to the SoA table for a complete list of required study assessments (Section 1.3.1). 
• Screening assessments may occur up to 28 days prior to first dose of study treatment 
with a minimum screening period of 14 days to allow for participant completion of the 
screening and baseline ePRO assessments.  
• An extension to the screening period may be permitted on a case-by-case basis 
following discussion between the investigator and the medical monitor / sponsor (refer 
to Section 10.10.3 for medical monitor contact information). The reason(s) for the 
extension must be clearly documented. 
• The date the participant signs the ICF will be Day 1 of the screening period. 
• The participant will be assigned a study identification number at the screening visit. 
This number can be found on the screening laboratory requisition form in the Subject 
Requisition Binder and will be entered into the IRT at the screening visit. This 
participant identification number will be utilized for the duration of the study.  
ePRO reminders: 
• On Day 1 of the screening period, participants will receive training on how to use the 
home ePRO device (provided by the sponsor), which will include a practice 
questionnaire to be completed prior to the participant leaving the site. The participant 
will then begin the screening PRO assessments later that same day. Refer to Table 8 for 
details on the ePRO assessment administration schedule. 
• If the participant screen fails during the screening period, they should be reminded to 
return the device back to the site. 
Imaging reminders: 
Pre-randomization scans: 
• To meet inclusion criteria 2, participants must have had two scans (MRI or CT) that 
show ≥ 20% disease progression as measured by RECIST v1.1 within 12 months of the 


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screening visit scan (which will serve as the participant’s baseline scan for the study). 
Pre-randomization scans will be evaluated locally (not subject to central review). 
• As part of documenting that participants have satisfied inclusion criteria 2, sites are 
required to complete a Pre-Randomization RECIST v1.1 Calculation Worksheet 
(provided by the sponsor) (Section 8.1.1.1). The worksheet must be submitted to the 
sponsor’s designee during the screening period as soon as the data are available to 
complete the worksheet. All worksheets must be received no later than 7 days prior to 
C1D1 to allow for review prior to randomization (refer to study reference manual). 
Screening visit scan(s): 
• An MRI scan (no contrast required) will be acquired during the 28-day screening 
period, prior to the participant’s first dose of study treatment.  
• A CT scan (contrast required unless contraindicated) is only required if CT is the chosen 
modality for RECIST v1.1 tumor assessment (modality to be determined by the 
investigator). If CT is the chosen modality for RECIST v1.1, then a CT scan must be 
acquired during the 28-day screening period, prior to the participant’s first dose of study 
treatment. 
• Whichever modality is used at screening (CT or MRI) for tumor assessment (RECIST 
v1.1), the same modality must continue to be used at each subsequent visit throughout 
the study. 
• If applicable, CT and MRI assessments may be conducted on the same day. However, 
MRI with no contrast must be performed prior to CT with contrast. 
• The scan(s) conducted at the screening visit will serve as the participant’s baseline for 
the study. Therefore, scans should be submitted to the central imaging core laboratory 
as early in the screening period as possible to confirm scan quality is acceptable for 
analysis prior to randomization. The scan(s) conducted at the screening visit should also 
be read locally.  
• Standard of care scan(s) acquired prior to participant signing ICF may be used as 
screening visit scan(s) if obtained within 28 days of the first dose of study treatment and 
the quality of the scans are acceptable for analysis (as determined by central imaging 
core laboratory). These standard of care scans will then be collected, stored, and 
documented as the screening visit scan(s). No other pre-enrollment images will be 
collected for central reading. 
Tumor biopsy reminders: 
• Core needle biopsy is only required if archival tissue is not available for study 
procedures (Section 8.1.3). 
• If tumor biopsy and MRI are performed during the same study visit, the biopsy must be 
done after MRI. 


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• Tumor biopsy will be reviewed centrally to reconfirm diagnosis, but participant 
enrollment is not dependent on central review. 
Baseline and Cycle 1 Day 1 (double-blind phase) 
Operational visit reminders: 
• Refer to the SoA table for a complete list of required study assessments (Section 1.3.1). 
• The baseline visit may occur up to 48 hours prior to first dose of study treatment 
(nirogacestat or placebo).  
• Cycle 1 Day 1 will be defined as the first dose of study treatment.  
• The following baseline assessments are to be conducted prior to the first dose of study 
treatment: 
o Physical examination and ECOG performance status (Section 8.2.2); 
o Vital signs and weight (Section 8.2.4); 
o Pre-dose 12-Lead ECGs (Section 8.2.3); 
o Urinalysis and urine pregnancy for women of childbearing potential (WOCBP) 
(Section 8.2.6); 
o Blood draws for safety lab parameters, hormone levels, (Sections 8.2.5 and 
10.2), genotyping (Section 8.7) and optional pharmacogenomic sample (Sections 
8.8 and 10.5); 
o Concomitant medication and AE/SAE review; and 
o Single pre-dose PK blood draw. 
• After all of the pre-dose baseline assessments (as noted above) have been completed 
and the participant’s eligibility has been confirmed (Sections 5.1 and 5.2), the 
participant will be randomized and the first dose of study treatment (150 mg) will be 
administered at the site.  
• The following baseline assessments are to be conducted after the first dose of study 
treatment: 
o Triplicate 12-Lead ECGs (Section 8.2.3) to be conducted approximately 1-hour 
post-dose; 
o PK sampling (Section 8.5) to be conducted at 0.25-, 0.5-, 1-, 1.5-, 2-, 3-hours 
post-dose; and 
o 3-hour observation period following the first dose of study treatment. 


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ePRO reminders: 
• Baseline ePRO assessments will begin 7 days prior to the scheduled Cycle 1 Day 1 
study visit. 
• Refer to Table 8 for details on the ePRO assessment administration schedule. 
Cycle 1 Day 8, 15, 22, and Cycle 2 Day 28 (double-blind phase) 
Operational visit reminders: 
• Refer to the SoA table for a complete list of required study assessments (Section 1.3.1). 
• Visit windows are ± 2 days. 
• At Cycle 1 Day 8, triplicate 12-Lead ECGs are required 1-hour (± 10 minutes) post-
dose. Therefore, study treatment must be taken in the clinic at this visit. 
• A trough PK sample is required at each study visit. Therefore, the evening before the 
study visit, the participant will record the exact time study treatment was taken in the 
home ePRO device. Participant will not take their planned morning dose the day of the 
study visit. The morning dose will be taken following the pre-dose PK blood draw. 
• Urine pregnancy tests for participants of WOCBP must be performed at Cycle 1 Day 22 
and Cycle 2 Day 28. 
Cycle 4 Day 1, Cycle 7 Day 1 and Every 3 Cycles (double-blind phase) 
 Operational visit reminders: 
• Refer to the SoA table for a complete list of required study assessments (Section 1.3.1). 
• Visit windows are ± 7 days. 
• A trough PK sample is required at each study visit. Therefore, the evening before the 
study visit, the participant will record the exact time study treatment was taken in the 
home ePRO device. Participant will not take their planned morning dose the day of the 
study visit. The morning dose will be taken following the pre-dose PK blood draw. 
• The site should submit scans to the central imaging core laboratory for Central Imaging 
Review as soon as possible following the study visit. Scans should also be read locally 
per RECIST v1.1.  
• MRI for tumor volume is required starting with Cycle 7 and then every 6 cycles 
throughout the study. If MRI for tumor volume assessment and CT for tumor 
assessment (RECIST v1.1) are conducted on the same day, MRI with no contrast must 
be performed prior to CT with contrast. 
• Beginning at the Cycle 4 Day 1 visit, participants will return all used / unused study 
treatment, and will be dispensed new study treatment using the IRT at every applicable 


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study visit. Accountability must by counting the returned study treatment tablets and 
document compliance in the eCRF. 
End of Treatment (EOT) (double-blind phase) 
The EOT visit will occur when: 
1. A participant has met the study endpoint of radiographic progression using 
RECIST v1.1 (determined by Central Imaging Review) or is experiencing clinical 
progression as assessed by the investigator; 
2. Participant prematurely discontinues study treatment for any other reason; 
3. Study is stopped by the sponsor for any reason; or 
4. All required number of PFS events have been observed and the primary PFS analysis 
has been completed. 
Operational visit reminders: 
If Central Imaging Review determines that a participant has radiographic progressive disease 
(using RECIST v1.1) during the double-blind phase of the study, the following steps will occur: 
1. Site will be notified by the central imaging core laboratory that Central Imaging Review 
has as determined the participant has radiographic progressive disease (using RECIST 
v1.1). 
2. Participant will return to the site for an EOT visit within 14 days of the site receiving 
the radiographic progressive disease notification from the central imaging core 
laboratory. 
3. Participant should be instructed to remain on study treatment until the EOT visit (if 
possible). 
4. All double-blind EOT study assessments will be completed in a blinded manner (refer 
to SoA table Section 1.3.1 for complete list of assessments). 
5. All ongoing AEs/SAEs from the double-blind phase will be assessed for causality by 
the investigator (or qualified designee) in a blinded manner and recorded in the eCRF. 
6. Sponsor designee will confirm that the above criteria have been met and only then will 
the IRT allow the participant’s study treatment assignment to be unblinded. 
7. Eligible participants may enter the OLE phase at this time. The EOT visit should be 
conducted on the same day as, or 24 hours prior to, the C1D1 visit for the OLE phase. A 
longer window between the double-blind EOT and OLE C1D1 visit may be allowed 
with prior medical monitor approval; however, repeat assessments may be required with 
medical monitoring guidance depending on the length of time between double-blind 
EOT and OLE C1D1. 


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If a participant discontinues study treatment for any reason other than radiographic progressive 
disease as determined via central review the following steps will occur: 
1. Participant will return to the site for an EOT visit as soon as possible. 
2. Participant should be instructed to remain on study treatment until the EOT visit (if 
possible). 
3. All double-blind EOT study assessments will be completed in a blinded manner (refer 
to SoA table Section 1.3.1 for complete list of assessments). 
4. The participant’s study treatment allocation will not be unblinded. 
Imaging reminders: 
5. Scan(s) only required if not performed within the past 3 months. 
Tumor biopsy reminders: 
6. Tumor biopsy at EOT visit is optional if the participant consented for pharmacogenomic 
research (Section 8.1.3). 
7. If tumor biopsy and MRI are performed during the same study visit, the biopsy must be 
done after MRI. 
Follow-Up (double-blind phase) 
Visit is applicable only if participant is not continuing onto the optional OLE phase. 
Operational visit reminders: 
• Participant will return to the site for the follow-up visit 30 days (+7 days) after the last 
dose of study treatment. 
• 
ePROs are to be completed 7 days prior to the scheduled follow-up visit (Table 8). 
• 
Participant will return the home ePRO device. 
Monthly Wellness Checks (double-blind phase) 
• 
Monthly telephone or email contact is required throughout the study. 
• 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 8.2.7. 
Monthly Urine Pregnancy Tests (double-blind phase) 
• 
Assessment applicable to women of child-bearing potential (WOCBP) only. 


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• In between study visits, participants will be required to return to the site for a monthly 
urine pregnancy test. 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 (refer to study reference manual for additional details). 
• 
Refer to Section 8.2.6. 
Monthly PRO Assessments (double-blind phase) 
• The home ePRO device (supplied by the sponsor) will be programmed to prompt the 
participant to complete the questionnaires monthly throughout the study, and always 
prior to a study visit when applicable. 
• 
Refer to Section 8.1.2 and Table 8. 
Unscheduled Visits (double-blind phase) 
Additional tests may be performed at any time during the study as determined necessary by the 
investigator or required by local regulations. 


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Table 7 
Open-Label Phase Study Visits 
This table supplements the SoA and highlights key study visit reminders. Refer to the OLE phase 
SoA table (Section 1.3.2) for the complete list of study assessments, and the study reference 
manual for study visit checklists which will include the recommended sequence of assessments 
for each study visit. 
Cycle 1 Day 1 (OLE phase) 
The OLE phase allows eligible participants to receive open-label study treatment (nirogacestat). 
Refer to Sections 6.7.2 and 6.7.3 for OLE specific eligibility criteria. 
The OLE Cycle 1 Day 1 visit should be conducted on the same day as, or within 24 hours after, 
the double-blind EOT visit. A longer window between the double-blind EOT and OLE C1D1 
visit may be allowed with prior medical monitor approval; however, repeat assessments may be 
required with medical monitoring guidance depending on the length of time between double-
blind EOT and OLE C1D1. 
Operational visit reminders: 
• All double-blind EOT visit assessments described in the double-blind SoA (Section 
1.3.1) will be conducted prior to unblinding the participant’s study treatment assignment 
and prior to the first dose of open-label study treatment. The following OLE baseline 
assessments must be conducted prior to administration of the first dose of open-label 
study treatment: 
o Obtain participant’s consent using OLE phase specific ICF; 
o Confirm participant meets all I/E criteria specific to the OLE phase (refer to 
Sections 6.7.2 and 6.7.3); 
o Draw blood for hematology and serum chemistry safety assessments for local lab 
processing (only if labs not done within the past 14 days); hormone levels do not 
need to be repeated if performed at EOT for the double-blind phase of the study. 
o Note: if hematology and serum chemistry safety labs have not been 
conducted within the past 14 days prior to baseline, an additional blood 
draw will be required for same day local laboratory processing to reconfirm 
adequate organ and bone marrow function (refer to OLE inclusion 
criteria  2) 
o Enroll participant in the OLE phase using the IRT and dispense study treatment; 
o Draw a single pre-dose PK blood draw (only applicable for participants who were 
previously randomized to placebo in the double-blind phase); 
• After the OLE pre-dose baseline assessments (as noted above) have been completed, the 
first dose of open-label study treatment will be administered at the site for participants 


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who were previously randomized to placebo in the double-blind phase. Participants who 
were randomized to nirogacestat may take their first dose at home. 
• The following OLE baseline assessments will be conducted after the first dose (only 
applicable for participants who were previously randomized to placebo in the double-
blind phase): 
o Conduct serial PK sampling at 0.25-, 0.5-, 1-, 1.5-, 2-, and 3-hours post-dose;  
o Conduct triplicate 12-Lead ECGs approximately 1-hour post-dose; and 
o Complete the 3-hour observation period following the first dose of study treatment. 
Cycle 1 Day 8, 15, 22 and Cycle 2 Day 28 (OLE phase) 
Visits are applicable only to participants who were previously randomized to receive placebo in 
the double-blind phase. 
Operational visit reminders: 
• Refer to the SoA table for a complete list of required study assessments (Section 1.3.2). 
• Visit windows are ± 2 days. 
• At Cycle 1 Day 8, triplicate 12-Lead ECGs are required 1-hour (± 10 minutes) post-
dose. Therefore, study treatment must be taken in the clinic at this visit. 
• A trough PK sample is required at each study visit. Therefore, the evening before the 
study visit, the participant will record the exact time study treatment was taken in the 
home ePRO device. Participant will not take their planned morning dose the day of the 
study visit. The morning dose will be taken following the pre-dose PK blood draw. 
• Urine pregnancy tests for participants of WOCBP must be performed at Cycle 1 Day 22 
and Cycle 2 Day 28. 
Cycle 4 Day 1 and Every 3 Cycles (OLE phase) 
Visits are applicable to all participants. 
Operational visit reminders: 
• Refer to the SoA table for a complete list of required study assessments (Section 1.3.2). 
• Visit windows are ± 7 days. 
• CT or MRI scan required every 3 cycles until Cycle 13 Day 1, and then required every 
6 cycles thereafter. 
• A trough PK sample is required at each study visit. Therefore, the evening before the 
study visit, the participant will record the exact time study treatment was taken in the 
home ePRO device. Participant will not take their planned morning dose the day of the 
study visit. The morning dose will be taken following the pre-dose PK blood draw. 


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• The site should submit scans to the central imaging core laboratory for Central Imaging 
Review as soon as possible following the study visit. Scans should also be read locally 
per RECIST v1.1. 
• Beginning at the Cycle 4 Day 1 visit, participants will return all used / unused study 
treatment, and will be dispensed new study treatment using the IRT at every applicable 
study visit. Accountability must be performed on the returned tablets. 
End of Treatment (EOT) (OLE phase) 
The EOT visit will occur when: 
• A participant has met the study endpoint of radiographic progression using 
RECIST v1.1 (determined by Central Imaging Review); 
• The investigator determines that the participant is experiencing clinical progression 
defined as the onset or worsening of symptoms resulting in a global deterioration of 
health status causing the permanent discontinuation from study treatment and the 
initiation of emergent treatment (e.g., radiotherapy, surgery, or systemic therapy 
including chemotherapy or tyrosine kinase inhibitors) for DT/AF; 
• Participant discontinues study treatment for any reason; 
• Study is stopped by the sponsor for any reason; 
• Participant qualifies for Sponsor’s Continued Access Plan; or 
• Nirogacestat becomes commercially available. 
Operational visit reminders: 
• Participants will be encouraged to return to the site as soon as possible to complete 
the EOT visit assessments (Section 1.3.2). 
• If possible, participants should be encouraged to remain on study treatment until the 
EOT visit. 
Follow-Up (OLE phase) 
Visit is applicable only if participant is not transitioning directly to commercial nirogacestat (or 
sponsor’s Continued Access Plan) at the time of discontinuation. 
Operational visit reminders: 
• Participant will return to the site for the follow-up visit 30 days (+7 days) after the last 
dose of study treatment. 
• ePROs to be completed 7 days prior to the scheduled follow-up visit (Table 9). 
• Participant will return the home ePRO device. 
Monthly Wellness Checks (OLE phase) 


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• 
Monthly telephone or email contact is required throughout the study. 
• 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 8.2.7. 
Monthly Urine Pregnancy Tests (OLE phase) 
• 
Assessment applicable to women of child-bearing potential (WOCBP) only. 
• In between study visits, participants will be required to return to the site for a monthly 
urine pregnancy test. 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 (refer to the study reference manual for additional detail). 
• 
Refer to Section 8.2.6. 
Monthly / Quarterly PRO Assessments (OLE phase) 
• 
The home ePRO device (supplied by the sponsor) will be programmed to prompt the 
participant to complete the questionnaires monthly for the first year and then quarterly 
thereafter, and always prior to a study visit when applicable. 
• 
Refer to Section 8.1.2 and Table 9. 
Unscheduled Visits (OLE phase) 
Additional tests may be performed at any time during the study as determined necessary by the 
investigator or required by local regulations. 


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Efficacy Assessments 
Planned time points for all efficacy assessments are provided in the SoA (Section 1.3). 
8.1.1. 
Tumor Imaging 
Central Core Imaging Laboratory: 
Sites will submit all CT and MRI scans to the central imaging core laboratory for Central 
Imaging Review. The purpose of the Central Imaging Review is to provide an independent, 
unbiased and objective review of the CT and MRI data throughout the study. 
Sites will be provided an Imaging Acquisition Manual and an Imaging Submission Manual, 
which describe the imaging methods and submission process that must be followed.  
All image data submitted to the central imaging core laboratory must be de-identified prior to 
submission. The participant identifiers on the image data must be consistent with all study-
related documents throughout the study. See imaging manuals for details on the de-identification 
requirements.  
Site Qualification and Training: 
Before sites are activated and able to enroll participants, they will be trained on the protocol 
imaging requirements and provided guidance on how to submit scans.  
In addition, all sites are required to submit qualification scans to the central imaging core 
laboratory prior to study initiation. These qualification scans will be evaluated for image quality 
and adherence to study protocol parameters. Once the site qualification scans have passed image 
quality control, a site qualification certificate will be issued. The site must file this certificate 
with their site study documents.  
On Study Scans: 
It is important for the site to make every effort to use the same scanner(s) that have been 
qualified (as described above) throughout the double-blind and OLE phases of the study. If the 
same scanner is unavailable, another qualified scanner of the same model should be used with 
the same settings. Study imaging including MRI and/or CT should be performed per the schedule 
in the SoA at a qualified imaging facility; however, 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, local imaging may be allowed with prior sponsor approval.  
The screening visit scans will be submitted to the central imaging core laboratory and reviewed 
by Central Imaging Review. However, participant enrollment will not be dependent on central 
review.  
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 
double-blind study treatment administration. The scan(s) will then be collected, stored, and 
documented as the screening visit scans. No other pre-enrollment images will be collected for 
central reading.  


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All scans should be submitted to the central imaging core laboratory as soon as possible after 
acquisition. This will allow the central imaging core laboratory to assess the scans for quality and 
query the site if necessary. If the scans are deemed unacceptable for analysis, the site will be 
queried, and a replacement scan will be requested. 
If necessary, both CT and MRI assessments may be conducted on the same day, but MRI with no 
contrast must be performed prior to the CT with contrast. 
Whenever disease progression is suspected (e.g., symptomatic deterioration) throughout the 
study, unscheduled scans may be acquired and submitted to the central imaging core laboratory 
for Central Imaging Review. 
8.1.1.1. 
Pre-Randomization RECIST v1.1 Calculation Worksheet  
As part of documenting that participants have satisfied inclusion criteria 2 for the double-blind 
phase, sites are required to complete the Pre-Randomization RECIST v1.1 Calculation 
Worksheet (provided by the sponsor). The worksheet must be submitted to the sponsor’s 
designee during the screening period as soon as the data are available to complete the worksheet, 
and no later than 7 days prior to C1D1 to allow for review prior to randomization.  
8.1.1.2. 
Tumor Assessment Using RECIST Version 1.1 Criteria 
Tumor assessment for primary and secondary endpoints (PFS and ORR, respectively) as 
measured by CT (contrast required unless contraindicated) or MRI (no contrast required), will be 
evaluated by Central Imaging Review for all participants using RECIST v1.1 (Eisenhauer, 2009) 
at the following timepoints: 
• At the double-blind and OLE phases as specified in the SoA (Sections 1.3.1 and 1.3.2); 
and  
• Whenever disease progression is suspected (e.g., symptomatic deterioration).  
The imaging modality will be determined by the investigator and the same imaging modality 
used to measure the identified and reported lesion at screening in the double-blind phase must be 
used at each subsequent visit throughout the double-blind and OLE phases.  
The location of the target tumor(s) will be selected by the investigator as the basis for inclusion 
in the trial and will be documented on the Pre-Randomization RECIST v1.1 Calculation 
Worksheet. The target tumor(s) will be provided to Central Imaging Review and will be used for 
assessment of the primary endpoint. 
While tumor assessments performed by Central Imaging Review will be used for primary and 
secondary endpoints, tumor measurements will also be performed locally using RECIST v1.1 
using the same target lesion(s) identified on the Pre-Randomization RECIST v.1.1 Calculation 
Worksheet as specified in the SoA (Sections 1.3.1 and 1.3.2) and whenever disease progression 
is suspected (e.g., symptomatic deterioration).  


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8.1.1.3. 
Volumetric Assessment 
Tumor volume assessment and T2 hyperintensity imaging will be acquired only by MRI and 
only applicable in the double-blind phase of the study as specified in the SoA (Section 1.3.1). 
Refer to the Imaging Acquisition Manual for details. 
8.1.2. 
Definition and Assessment of Clinical Progression 
Clinical progression is defined as the onset or worsening of symptoms resulting in a global 
deterioration of health status causing the permanent discontinuation from study treatment and the 
initiation of emergent treatment (e.g., radiotherapy, surgery, or systemic therapy including 
chemotherapy or tyrosine kinase inhibitors) for DT/AF. 
The date of clinical progression will be the earliest date of onset or worsening of symptoms 
resulting in a global deterioration of health status. In addition, AEs and SAEs associated with 
clinical progression and concomitant medications and procedures initiated for the treatment of 
DT/AF within 30 days of the last dose of study treatment will be documented in the eCRF. A 
clinical progression narrative will also be developed by the PI for events of clinical progression 
which will be documented in EDC and include a description of onset or worsening of symptoms 
resulting in a global deterioration of health status, the location of progressing lesions, and 
evidence of vital structure involvement (as reported by the PI), as applicable.  
When disease progression is suspected (e.g., symptomatic deterioration), imaging should be 
performed and submitted to the central imaging core laboratory for Central Imaging Review. If 
progressive disease is not determined radiologically via central review of RECIST v1.1 per 
Section 8.1.1.2, but the participant meets the definition of clinical progression, the participant 
may be discontinued for clinical progression. Study participants who discontinue due to clinical 
progression will NOT be unblinded at the EOT visit and will NOT be eligible for participation in 
the optional OLE phase.  
Imaging data from participants who discontinue due to clinical progression will be evaluated for 
changes in tumor characteristics or involvement of vital organ structure at the site of progression, 
which may include: 
1. Individual tumor measurements including all available planes of measurement 
2. Volumetric MRI, if available  
3. T2 hyperintensity, if available 
Events of clinical progression will be adjudicated by an independent blinded central clinical 
review committee which will qualify events of clinical progression for inclusion in the primary 
analysis of PFS prior to study unblinding according to a Central Clinical Review Charter.  
8.1.3. 
Patient-Reported Outcomes 
Participants will complete the PRO questionnaires using their home ePRO devices (supplied by 
the sponsor). These home ePRO devices will be provided to participants at the screening visit 
and will be returned to the site at the end of study participation.  
The home ePRO device will be programmed to always administer the PROs in a particular order 
and at specific timepoints throughout the study (refer to Table 8 and Table 9). 


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The following PRO assessments will be conducted during the double-blind phase: 
• Screening PRO assessment: 
o On Day 1 of the screening visit, participants will receive training by the site 
staff on how to use the home ePRO device, which will include a practice 
questionnaire to be completed by the participant prior to leaving the site. 
o Participants will then begin the screening PROs assessments that same day.  
o The Patient Global Impression of Change (PGIC) is intentionally omitted 
from the screening PRO assessments. 
• Baseline PRO assessment: 
o The baseline PRO assessments will begin 7 days prior to the Cycle 1 Day 1 
visit.  
o The PGIC is intentionally omitted from the baseline PRO assessments. 
• Monthly PRO assessments are required throughout the study (Cycle 2, 3, 4 and on). 
The following PRO assessments will be conducted during the OLE phase: 
• Monthly PRO assessments are required for the first year (Cycle 2-12). 
• Quarterly PRO assessments are required after the first year (Cycle 13, 16, 19 and on). 
 


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Table 8 Double-Blind Phase: PRO Assessment Administration Schedule  
PROs 
Screening PRO Assessments 
First 7 days of screening period  
 
Baseline PRO Assessments 
7 day prior to baseline visit 
 
Base-
line 
Visit 
Monthly PRO Assessments 
7 days prior to Cycle X/FU 
(X = Cycles 2, 3, 4 & on) 
 
Cycle 
X/FU 
Visit 
d 
1 
d 
2 
d 
3 
d 
4 
d 
5 
d 
6 
d 
7 
d 
-7 
d 
-6 
d 
-5 
d 
-4 
d 
-3 
d 
-2 
d 
-1 
 
d 
-7 
d 
-6 
d 
-5 
d 
-4 
d 
-3 
d 
-2 
d 
-1 
 
GODDESS (symptom scale) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
BPI short form 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
PROMIS PF short form 10a plus 3 
additional items from the PROMIS 
item banks 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
GODDESS (impact scale) 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
EORTC  
QLQ-C30 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
PGIS 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
PGIC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
BPI = brief pain inventory; d = day; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30; FU = 
follow-up; GODDESS = GOunder/DTRF DEsmoid Symptom/Impact Scale; PGIC = patient global impression of change; PGIS = patient global impression of severity; 
PRO = patient-reported outcome; PROMIS PF= Patient-Reported Outcomes Measurement Information System Physical Function  


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Table 9 OLE Phase: PRO Assessment Administration Schedule 
PROs 
Monthly PRO Assessments 
7 days prior to Cycle X  
(X = Cycles 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) 
 
Cycle 
X 
Quarterly PRO Assessments 
7 day prior to Cycle X 
(X = Cycles 13, 16, 19, 22 & on) 
 
Cycle 
X 
Follow-Up PRO Assessments 
7 days prior to the FU visit 
FU 
Visit 
d 
-7 
d 
-6 
d 
-5 
d 
-4 
d 
-3 
d 
-2 
d 
-1 
d 
-7 
d 
-6 
d 
-5 
d 
-4 
d 
-3 
d 
-2 
d 
-1 
d 
-7 
d 
-6 
d 
-5 
d 
-4 
d 
-3 
d 
-2 
d 
-1 
GODDESS  
(symptom scale) 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
BPI short form 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
PROMIS PF short 
form 10a plus 3 
additional items from 
the PROMIS item 
banks 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
GODDESS  
(impact scale) 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
EORTC QLQ-C30 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
PGIS 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
PGIC 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
BPI = brief pain inventory; d = day; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30; FU = follow-
up; GODDESS = GOunder/DTRF DEsmoid Symptom/Impact Scale; PGIS = patient global impression of severity; PRO = patient-reported outcome; PROMIS PF= Patient-
Reported Outcomes Measurement Information System Physical Function  
 


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8.1.3.1. 
 GODDESS 
The GOunder/DTRF DEsmoid Symptom/Impact Scale (GODDESS) tool was developed by 
Memorial Sloan Kettering Cancer Center (MSKCC) and Desmoid Tumor Research Foundation 
(DTRF) to measure signs and symptoms of desmoid tumors and their impact on patients’ lives. 
The tool consists of items assessing the severity of key signs and symptoms (11 items), including 
pain, fatigue, swelling, muscle weakness, difficulty moving, and tumor location-specific 
signs/symptoms; the impact of these symptoms on functioning and daily living (17-items).  
The signs and symptoms items are evaluated on an 11-point numeric rating scale (NRS) from 0-
10 to measure severity from “none” to “as bad as you can imagine,” with a 24-hour recall period. 
The impact items are evaluated either on an 11-point NRS to measure severity, or a 5-point 
Likert Scale ranging from “none of the time” to “all of the time” to measure frequency, with a 7-
day recall period.  
8.1.3.2. 
BPI Short Form 
The Brief Pain Inventory (BPI) short form is a measurement tool for assessing clinical pain and 
allows patients to rate the severity of their pain and the degree to which their pain interferes with 
common dimensions of feeling and function. The short form version of the BPI consists of 
9 questions and will utilize an 11-point NRS from 0-10 with a 24-hour recall period.  
8.1.3.3. 
PROMIS PF Short Form 10a Plus 3 Additional Items from PROMIS Item Banks  
The Patient-Reported Outcomes Measurement Information System Physical Function (PROMIS 
PF) instruments measure self-reported capability rather than actual performance of physical 
activities. This includes the functioning of one’s upper extremities (dexterity), lower extremities 
(walking or mobility), and central regions (neck, back), as well as instrumental activities of daily 
living, such as running errands.  
The PROMIS PF short form 10a version 2.0 will be used in this study with a 7-day recall period. 
This PRO assessment consists of 10 questions and was constructed with a focus on representing 
the range of the trait and the content of the item bank, as well as mapping the questions in the 
instrument to qualitative evidence of the physical function concepts important to patients. To 
supplement the PROMIS PF short form 10a, 3 additional questions representing other elements 
of physical function found to be important to patients, were selected from the PROMIS Physical 
Function, Upper Extremity, and Ability to Participate item banks. 
8.1.3.4. 
EORTC QLQ-C30  
The European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire-Core 30 (EORTC QLQ-30) is a quality of life (QoL) questionnaire used for 
assessing the health-related quality of life of cancer patients participating in international clinical 
trials.  
EORTC QLQ-C30 version 3.0 will be used in this study with a 7-day recall period. It consists of 
30 questions overall with a 4-point scale and incorporates 5 functional scales (physical, role, 
cognitive, emotional and social), 3 symptom scales (fatigue, pain, and nausea and vomiting), a 
global health status/QoL scale, and a number of single items assessing additional symptoms 


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commonly reported by cancer patients (dyspnea, loss of appetite, insomnia, constipation and 
diarrhea) and perceived financial impact of disease.  
8.1.3.5. 
PGIS 
The Patient Global Impression of Severity (PGIS) is a single item scale that evaluates the 
participant’s perception of the overall severity of their desmoid related symptoms over the past 
week on a 4-point scale ranging from “none” to “severe.” The PGIS will have a 7-day recall 
period. 
8.1.3.6. 
PGIC 
The Patient Global Impression of Change (PGIC) is a single item scale that evaluates the 
participant’s perception of the overall change in their overall status since the start of the study 
treatment on a 7-point scale ranging from “very much better” to “very much worse.” The PGIC 
will have a 7-day recall period. 
8.1.4. 
Tumor Biopsy 
For all participants: 
• Tumor samples will be used to reconfirm desmoid diagnosis for all participants. 
However, participant enrollment will not be dependent on central review.  
• Additionally, archival or fresh tumor biopsies collected at screening will be used for 
somatic genotyping (unless prohibited by local regulations) (Section 8.7). 
• Ideally, 2 cores will be collected during the screening period (prior to study treatment 
initiation).  
• Archival tissue may be used in place of fresh tumor biopsies only if the tissue has been 
well preserved and there is a sufficient amount of tissue available1.  
• When applicable, fresh tumor biopsies must be taken after MRI if both of these 
assessments occur at the same visit. 
 For participants consenting to optional pharmacogenomics research: 
• For participants consenting to the optional pharmacogenomics research, an additional 
tumor biopsy will be collected at the EOT visit. 
• Refer to Section 8.8 for details on biomarkers. 
1Tumor specimens will be stored as formalin-fixed, paraffin embedded (FFPE) blocks at room 
temperature. If the FFPE block cannot be made available, approximately 20 unstained slides 
should be used in place of 2 cores.  
Instructions for handling, processing and shipment of tumor biopsies are provided in the central 
laboratory manual.


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Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
8.2.1. 
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 consumption (i.e., presence 
or absence); and collection of concomitant medications. For women, 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. Any history of infertility in male 
participants should also be recorded as part of the medical history. 
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. 
Radiographic studies performed prior to study entry may be collected for review by the 
investigator. 
8.2.2. 
Physical Examinations and Eastern Cooperative Oncology Group Performance 
status 
Physical examinations, as well as height/weight, and assessment of ECOG performance status 
(Section 10.7) will be required throughout the study as described in the SoA. Height to be 
measured at screening only. 
A physical examination should include, at a minimum, assessments of the Skin, Cardiovascular, 
Respiratory, Gastrointestinal and Neurological systems.  
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.  
Refer to Section 8.3 regarding AE definitions and reporting and follow-up requirements. 
8.2.3. 
Electrocardiograms 
Triplicate 12-Lead ECGs readings (approximately 2-3 minutes apart and averaged) will be 
obtained using an ECG machine that automatically calculates the heart rate and measures PR, 
QRS, QT, and QTcF intervals, at the timepoints described in the SoA. Prior to the ECG 
assessments, participants should rest in a semi-recumbent supine position for at least 5 minutes. 
For safety monitoring purposes, the investigator must review, 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 7.1.2 for QTcF withdrawal criteria and any additional QTcF readings that may 
be necessary. 


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8.2.4. 
Vital Signs 
Body temperature, pulse rate, respiratory rate, and blood pressure will be assessed throughout the 
study as described in the SoA.  
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, pulse rate and body temperature should be preceded by at least 
5 minutes of rest for the participant in a quiet setting without distractions (e.g., television, cell 
phones). 
8.2.5. 
Clinical Safety Laboratory Assessments 
All protocol-required, central laboratory assessments as defined in Section 10.2, must be 
conducted in accordance with the central laboratory manual and the SoA. Please note, ALL 
participants, regardless of their gender or childbearing potential, are required to have hormone 
level assessments per the SOA (Section 1.3). 
In the event of a public health emergency, clinical laboratory assessments may be performed 
locally with results and local laboratory normal values entered into the eCRF. 
The investigator must review the central laboratory report, document this review, and record any 
clinically relevant changes occurring during the study on the AE page 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 should 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 sponsor 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. 
8.2.6. 
Pregnancy Testing  
Pregnancy testing will only be required for women of childbearing potential (WOCBP) (refer to 
Section 10.4 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 double-blind study treatment) will be required to meet study entry criteria.  


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Monthly urine pregnancy tests will be required for WOCBP throughout the duration of the 
double-blind and OLE phases. In between study visits, participants will be required to return to 
the site for a monthly urine pregnancy test. 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.  
8.2.7. 
Monthly Wellness Checks 
Monthly telephone or email contact is required throughout the double-blind and OLE phases of 
the study and may be replaced by a face-to-face interaction when study visits occur and the 
information can be obtained during the visit.  
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 
other emergent issues. Adverse events and concomitant medications changes will be captured in 
the associated eCRFs. 
 
Adverse Events and Serious Adverse Events 
The definitions of an AE, SAE, adverse reaction (AR), suspected adverse reaction (SAR), and a 
suspected unexpected serious adverse reaction (SUSAR) can be found in Section 10.3. 
An AE will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up on AEs that are serious, considered related to the study treatment or study procedures, or that 
caused the participant to discontinue the study treatment (Section 7). 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information 
All SAEs and AEs will be collected from the time of signing ICF until 30 days after the last dose 
of study treatment at the time points specified in the SoA (Section 1.3) throughout the double-
blind and OLE study phases. 
Medical occurrences that begin before the start of study treatment but after obtaining informed 
consent will be recorded as AEs. 
All SAEs will be recorded and reported to the sponsor’s safety group (‘Safety’) immediately and 
under no circumstance should this exceed 24 hours, as indicated in Section 10.3.4. The 
investigator will submit any updated SAE data to Safety within 24 hours of it being available. 
To report the SAE, a paper SAE form must be completed, scanned and emailed to Safety at 
PV@springworkstx.com. The paper SAE form can be found in the study reference manual. Refer 
to Section 10.3.4 for more details on reporting SAEs to the sponsor. 


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Refer to Section 8.3.6 for details on AEs of special interest (AESI) reporting guidelines. 
Investigators are not obligated to actively seek AEs and/or SAEs 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 considers the event to be reasonably related 
to the study treatment or study participation, the investigator must promptly notify the sponsor. 
8.3.2. 
Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AEs and/or SAEs, and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3.3. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.3.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs and adverse events of special interest (AESI) (as defined 
in Section 8.3.6) will be followed until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to follow-up (as defined in Section 7.3).  
Within 24 hours of receipt of SAE follow-up information, the investigator must complete a paper 
follow-up SAE form and submit any supporting documentation if requested to Safety. Further 
information on follow-up procedures is given in Section 10.3.3. 
8.3.4. 
Regulatory Reporting Requirements for SAEs 
Prompt notification 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.  
Investigator safety reports must be prepared for Suspected Unexpected Serious Adverse 
Reactions according to local regulatory requirements and 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. 


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8.3.5. 
Pregnancy 
Details of all pregnancies in female participants and female partners of male participants will be 
collected after the start of study treatment and until 30 days after the last dose of study treatment. 
If a pregnancy is reported, the investigator must inform the sponsor within 24 hours of learning 
of the pregnancy by completing a paper pregnancy form and submitting to Safety (refer to 
Section 10.4 for reporting details). 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
8.3.6. 
Adverse Events of Special Interest 
Adverse events of special interest (AESI) are selected non-serious and serious AEs that must be 
reported regardless of relationship to study treatment. Refer to Table 10 for the AESIs identified 
for this study. AESIs will be followed until resolution or return to baseline.  
Serious AESIs must be reported to Safety immediately and under no circumstance should this 
exceed 24 hours, as indicated in Section 10.3.4. 
Non-serious AESIs must be reported to the sponsor (by entering the AESI into the eCRF and 
submitting a paper SAE/AESI report form to Safety) as soon as possible, but no later than 
5 business days of awareness.  
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 AESI; additional events may be identified during the course of the study. 
 
Table 10 
Adverse Events of Special Interest (AESI) 
Skin Rash (reported as AESI if clinically significant Grade 2 and all Grade ≥ 3, per 
CTCAE v. 5) 
1. Maculopapular rash 
2. Pruritic rash 
3. Erythematous rash 
4. Folliculitis 
5. Hidradenitis suppurativa 
Elevated Liver Enzymes (reported as AESI if Grade ≥ 2, per CTCAE v. 5) 
1. AST 
2. ALT 
3. Alkaline Phosphatase 


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Electrolyte Insufficiency (reported as AESI if Grade ≥ 3, per CTCAE v. 5) 
1. Hypophosphatemia 
2. Hypokalemia 
3. Hypomagnesemia 
Drug Reactions (reported as AESI for any grade) 
1. Allergic reaction 
2. Anaphylaxis 
Reproductive System Disorders (reported as AESI if ≥ 2, per CTCAE v. 5)1 
1. Amenorrhea 
2. Premature menopause / Primary ovarian insufficiency  
1  Females reporting AEs/AESIs/SAEs of primary ovarian insufficiency (POI) and/or amenorrhea will have hormone 
levels assessed every 3 months until event resolution (or for at least 90 days after discontinuing study treatment). 
 
Treatment of Overdose 
For this study, any dose of study treatment greater than 450 mg daily dose of study treatment 
within a 24-hour period will be considered an overdose. 
In the event of an overdose, the investigator will: 
1. Contact the medical monitor immediately (refer to Section 10.10.3 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 in the 
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. 
 
Pharmacokinetics 
• Serial and trough PK samples will be collected during the study, as described in the SoA 
(Section 1.3) to inform development of a population PK model of nirogacestat. Refer to 
Table 11 for PK blood draw schedule. To minimize the amount of time a participant is 
required to remain onsite during a public health emergency such as COVID-19, the 3-
hour C1D1 PK sample may be omitted with prior medical monitor / sponsor approval. 
• Whole blood samples of approximately 4 mL each will be collected for measurement of 
serum concentrations of nirogacestat as specified in the SoA. 
• 
The actual date and time (24-hour clock time) of each sample will be recorded. 


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• 
Instructions for the collection, handling, and shipment of pharmacokinetic samples will 
be in the central laboratory manual. 
• 
Samples will be used to evaluate the PK of nirogacestat and associated metabolites. 
• 
Genetic analyses will not be performed on these samples.  
• 
Participant confidentiality will be maintained. 
• 
Drug concentration information that would unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded. 
• 
Any changes in the timing or addition of time points for any planned study assessments 
must be documented and approved by the relevant study team member and then 
archived in the sponsor and site study files but will not constitute a protocol 
amendment. The IRB/IEC will be informed of any safety issues that require alteration 
of the safety monitoring scheme or amendment of the ICF. 
Table 11 
PK Blood Draw Schedule 
Visit 
Timepoint 
Cycle 1 Day 13 
Serial PK1 (pre-dose, 0.25-, 0.5-, 1-, 1.5-, 2-, and 3-hour post dose) 
Cycle 1 Day 83 
Trough PK2 (pre-dose) 
Cycle 1 Day 153 
Trough PK2 (pre-dose) 
Cycle 1 Day 223 
Trough PK2 (pre-dose) 
Cycle 2 Day 283 
Trough PK2 (pre-dose) 
Cycle 4 Day 1 and  
Every 3 cycles 
Trough PK2 (pre-dose) 
1Serial PK:  
• 
Double-blind phase: required for all participants. 
• 
OLE phase: required for participants who were previously randomized to placebo in the double-blind phase 
only. 
• 
All efforts will be made to obtain the pharmacokinetic samples at the exact nominal time relative to dosing. 
However, samples obtained within 10% of the nominal time (e.g., within 6 minutes of a 60-minute sample) 
from dosing will not be captured as protocol deviations if the exact time of the sample collection is noted 
on the source document and eCRF. 
2Trough PK: 
• 
Required for all participants. 
• 
The evening before the study visit, participant will record the exact time study treatment was taken in the 
home ePRO device. Participant will not take their planned morning dose the day of the study visit. The 
morning dose will be taken following the pre-dose PK blood draw. 
3OLE Cycle 1 and 2 PK assessment are not applicable for participants who were previously randomized to 
nirogacestat in the double-blind phase. 
 
Pharmacodynamics 
Optional blood and tumor samples will be collected for the evaluation of pharmacodynamic 
biomarkers (refer to Section 8.8). 


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Genetics 
• 
A blood sample and tumor biopsy (archival sample may be used; Section 8.1.3) will be 
collected from all participants (unless prohibited by local regulations) prior to the first 
dose of study treatment to perform genotyping for germline and somatic mutation in 
APC and CTNNB1 genes to determine the frequency of these mutations in desmoid 
tumors. Response to study treatment based on mutational status may be evaluated. 
• 
In the event of DNA extraction failure, a replacement genetic blood sample may be 
requested from the participant. 
• 
Details on processes for collection and shipment and destruction of these samples can 
be found 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. 
• 
Refer to Section 10.5 for information regarding genetic research. 
 
Biomarkers 
• 
Participation is optional for genetic research and those who do not wish to participate 
may still enroll in the study. 
• 
The following optional tumor and blood samples for biomarker research will be 
collected from consenting participants only, as specified in the SoA (Section 1.3). 
o Before study treatment initiation samples: 
 Pharmacogenomic blood sample  
 Archival or fresh tumor tissue sample (Section 8.1.3) 
o After study treatment initiation sample: 
 Fresh tumor tissue sample 
• 
Analyses may include the following: (1) expression analysis of genes and proteins 
associated with the Notch pathway, (2) molecular analysis of genomic alterations 
associated with Notch signaling (for example, Notch 1 mutations), (3) levels of NICD, 
(4) molecular profiling of tumor cells to identify potential markers of 
response/resistance to nirogacestat.  
• 
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 PD biomarker samples will be provided in the central laboratory 
manual. 
• 
Samples may be tested for expression on Notch pathway genes to evaluate their 
association with the observed clinical responses (e.g., PFS or ORR) to study treatment. 


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• 
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. 
8.8.1. 
RNA Transcriptome Research 
Transcriptome studies may be conducted using microarray and/or alternative equivalent 
technologies, which facilitates the simultaneous measurement of the relative abundances of 
thousands of RNA species resulting in a transcriptome profile for each blood and tumor sample. 
This will enable the evaluation of changes in transcriptome profiles that may correlate with 
biological response relating to desmoid tumors or the action of nirogacestat. 
The same samples may also be used to confirm findings by application of alternative 
technologies. 
8.8.2. 
RNA Expression Research of a Subset of RNA Species 
RNA expression studies may be conducted using quantitative reverse transcriptase polymerase 
chain reaction, and/or alternative equivalent technologies, which can facilitate the simultaneous 
measurement of the relative abundances of RNA species resulting in an RNA expression profile 
for each blood and tumor sample. The RNAs assayed may be those involved with the 
pathogenesis of desmoid; the absorption, distribution, metabolism, or excretion of nirogacestat; 
or in the participant’s response to nirogacestat. In addition, continuing research may identify 
other proteins or regulatory RNAs that may be involved in the response to nirogacestat or the 
pathogenesis of desmoid. The RNAs that code for these proteins and/or regulatory RNAs may 
also be studied. This will enable the evaluation of changes in RNA expression profiles that may 
correlate with biological response relating to desmoid or the action of nirogacestat. 
8.8.3. 
Proteome Research 
Plasma and tumor proteome studies may be performed by 2-D gel separation, and/or peptide 
mass mapping, or an alternative equivalent procedure. Proprietary algorithms and standard 
statistical techniques, such as analysis of variance and analysis of covariance, may be used to 
identify individual proteins exhibiting statistically significantly different changes in their levels 
between samples and/or between groups of samples. These differentially expressed proteins will 
be identified by mass spectrometry or equivalent technology. This will enable the evaluation of 
changes in proteome profiles that may correlate with biological response relating to desmoid and 
medically related conditions or the action of nirogacestat. 
The samples may also be used to confirm findings by application of alternative technologies. 
 
Health Economics OR Medical Resource Utilization and Health 
Economics 
Health Economics/Medical Resource Utilization and Health Economics parameters are not 
evaluated in this study. 
 


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9. 
STATISTICAL CONSIDERATIONS 
 
Statistical Hypotheses 
Nirogacestat treatment will increase the time to progression compared to placebo in participants 
with desmoid tumors.  
The following hypothesis will be tested using a stratified log-rank test: 
H0: PFS(t)placebo = PFS(t)nirogacestat 
Ha: PFS(t)placebo < PFS(t) nirogacestat 
where PFS(t) represents the progression free survivorship function at time, t 
 
Sample Size Determination 
The study sample size is based on the PFS endpoint. A total of 51 events will provide 90% 
power and a 1-sided type 1 error rate of 0.025 (1-side hypothesis) to detect a difference between 
nirogacestat and placebo, assuming the median PFS in the nirogacestat group is 20 months and 
8 months in the placebo group (corresponding to a hazard ratio of 0.4 relative to placebo). 
Assuming a 10% dropout rate and a 20% spontaneous regression rate, 118 participants will be 
randomized in a 1:1 ratio to observe the required number of events. 
The assumptions selected for sample size estimate are based partially on the results reported in 
Gounder, 2018. As outlined in Section 2.2.3, a randomized double-blind Phase 3 study was 
conducted in desmoid participants comparing sorafenib to placebo. The study established a 
median PFS of 11.3 months for the placebo participants; but the population enrolled was a more 
heterogeneous desmoid population with only approximately 43% of the placebo participants 
having progressing tumors. The NIR-DT-301 study will only enroll progressing participants; 
therefore, a shorter median of 8 months PFS for placebo was used to calculate the sample size. 
 
Populations for Analyses 
For purposes of analysis, the following populations are defined: 
Population 
Description 
Enrolled  
All participants who sign the ICF. 
Intent-to-Treat (ITT) 
The Intent-to-Treat (ITT) Population will consist of all 
participants who are enrolled and randomized to study treatment 
(nirogacestat or placebo). Participants will be analyzed according 
to the treatment they were randomized to and the strata to which 
they have been assigned. Participants who were randomized but 
did not subsequently go on to receive study treatment are 
included in the ITT population. 


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Population 
Description 
Per-Protocol Population 
The Per-Protocol Population will be defined for supportive 
analysis and will consist of those participants who have no major 
protocol deviations, including mis-randomizations or mis-
stratifications. Participants will be analyzed according to the 
study treatment actually received (i.e., at least 1 dose of the study 
treatment). 
Safety 
The Safety Population will consist of all participants randomly 
assigned to study treatment and who take at least 1 dose of study 
treatment. Participants will be analyzed according to the 
treatment they actually received. 
 
Statistical Analyses 
The statistical analysis plan (SAP) will be developed and finalized before database lock and will 
describe the participant populations to be included in the analyses, and procedures for accounting 
for missing, unused, and spurious data. Detailed methodology for summary and statistical 
analyses of the data collected in this study will be documented. In addition, strategies on dealing 
with protocol deviations due to COVID-19 will be detailed in the SAP. This section is a 
summary of the planned statistical analyses of the primary and secondary endpoints. 
9.4.1. 
Efficacy Analyses 
Endpoint 
Statistical Analysis Methods 
Primary 
The primary efficacy endpoint is PFS, which is defined as the time from 
randomization until the date of assessment of progression or death by any 
cause (whichever occurs first). Progression will be determined 
radiographically by independent, blinded Central Imaging Review using 
RECIST v1.1 (Eisenhauer, 2009) as described in Section 8.1.1 or clinically by 
an investigator whose assessment is qualified via independent blinded central 
clinical review as described in Section 8.1.2. Participants who have not 
progressed or died will be censored at the date of the last response assessment. 
Participants who do not have any response assessments will be censored at the 
date of randomization. Sensitivity analysis utilizing alternative censoring 
methods will be described in the SAP.  
The primary efficacy endpoint, PFS, will be analyzed using a 1-sided 
stratified log-rank test to compare the distributions between nirogacestat and 
placebo at a 1-sided alpha level of 0.025.  
The primary analysis of PFS will be performed on the ITT Population, 
defined as all participants who are randomized to study treatment after the 


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required number of PFS events have been observed. Participants in the ITT 
Population will be analyzed in the study treatment arm to which they are 
randomized. 
Progression-free survival data will be summarized with Kaplan-Meier 
methodology. Two-sided 95% CIs for the median time-to-event in each study 
treatment arm, the event rates at specific time points, and the hazard rate ratio 
will be computed. 
There will be a Central Reader Agreement provided to Central Imaging 
Review and an Imaging Review Charter provided to the sponsor that will 
clearly detail the entire process. 
Secondary 
Secondary endpoints include: 
• Overall response rate, defined as the proportion of participants with 
CR + PR assessed via central reader using RECIST v1.1; 
• Change in tumor volume from baseline as assessed by MRI volumetric; 
• Change in PRO measures (GODDESS [symptom scale], BPI short 
form, PROMIS PF 10a short form plus 3 additional items from the 
PROMIS item banks, GODDESS [impact scale] and EORTC QLQ-
C30) from baseline; and 
• Duration of response for participants whose best response is CR or PR. 
In order to preserve the total type I error for the study, secondary endpoints 
will be evaluated in a hierarchical fashion according to the order that will be 
outlined in the SAP. Testing will only be performed if the null hypothesis of 
the primary endpoint is rejected. 
Overall response rate will be calculated for each treatment arm and the 
proportions will be compared using the Cochran-Mantel-Haenszel test 
stratified by randomization factor. Duration of response will be calculated as 
the time from the first response until progression or the last date of response 
assessment and will be summarized descriptively. 
Change in tumor volume assessed by MRI will be analyzed using a repeated 
measures model adjusting for baseline tumor volume and randomization 
strata.  
The change from baseline in total score for PRO assessment endpoints listed 
above will be analyzed using a repeated measures mixed model adjusting for 
fixed and random factors. Total scores will be calculated according to the 
published guidance for each specific scale if available. In addition, the change 
from baseline in the QLQ-C30 questions regarding rating of overall health 
and overall quality of life will be compared between treatment groups. The 


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total scores and sub-scores at each time-point will be summarized with 
descriptive statistics and displayed graphically.  
All data collected after crossover to nirogacestat (for participants who were 
previously randomized to placebo in the double-blind phase and receive 
nirogacestat in the OLE phase after radiographic disease progression) will be 
analyzed and reported separately. 
Exploratory 
Will be described in the SAP finalized before database lock. 
9.4.2. 
Safety Analyses 
All safety analyses will be performed on the Safety Population. 
Endpoint 
Statistical Analysis Methods 
Safety 
Endpoints 
The safety and tolerability of nirogacestat will be evaluated by means of study 
treatment-related AE reports, 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 of 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 any AE, SAE, treatment related 
AE, and treatment related SAE will be summarized according to worst 
toxicity grades.  
Clinical laboratory parameters, vital signs, and ECG parameters will be 
summarized by treatment group and study visit. Descriptive statistics for the 
actual values (and/or change from baseline) or frequencies of clinical 
laboratory parameters over time. Incidence of abnormalities and shift tables 
will be presented. 
9.4.3. 
Other Analyses  
Sensitivity analyses, pharmacokinetic, pharmacodynamic, and biomarker exploratory analyses 
will be described in the statistical analysis plan finalized before database lock. The population 
PK analysis and pharmacodynamic analyses will be presented separately from the main clinical 
study report. 
 
Interim Analyses  
One interim analysis may be performed after 26 PFS events (corresponding to approximately 
50% of the total events) have been observed. Progression will be determined by independent, 
blinded Central Imaging Review determination for this analysis. A Lan-DeMets alpha-spending 


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function with an O’Brien-Fleming stopping boundary will be used for the interim analysis of 
PFS. The study may be stopped for overwhelming efficacy or futility.  
At the interim analysis, the study may be stopped for futility if the observed hazard ratio is 
greater than 0.91 or stopped for overwhelming efficacy if the hazard ratio is less than or equal to 
0.31 in favor of nirogacestat. This is equivalent to a Z-score greater than -0.252 for futility or less 
than -2.96 for efficacy.  The alpha spent for the interim testing is 0.002 and the remaining 0.023 
alpha will be allocated to the final analysis.   
The analysis will be conducted by an independent committee consisting of at least 1 statistician. 
Results of the interim analysis will not be disseminated among investigators or anyone directly 
involved in study conduct. 
The interim analysis plan will describe the planned interim analyses in greater detail. 
9.5.1. 
Data Monitoring Committee 
The study will utilize an independent data monitoring committee (DMC) and will operate 
according to an established Charter. The committee will be composed of approximately 3 to 
4 members including physicians knowledgeable in the treatment of desmoid tumors and an 
independent statistician knowledgeable about statistical methods for clinical trials and sequential 
analysis of trial data. Sponsor employees will not be voting members of the DMC. The DMC 
will be responsible for ongoing monitoring of the unblinded safety and benefit/risk profile of 
participants in the study. Reviews will include aggregate safety, targeted medical events of 
special interest, serious AE data and aggregate endpoint data. 
Following each data review, the DMC may recommend 1) no changes to the study are needed, 
2) changes to the protocol or informed consent based on clinical safety findings, or 3) early 
termination of the study based on safety analyses. The recommendations made by the DMC to 
alter the conduct of the study will be forwarded to the sponsor for final decision. Additionally, 
the DMC may be asked to assist the sponsor in evaluating the impact of data from other 
company-sponsored studies or other published studies.   
The DMC Charter will outline the frequency of meetings and detail all aspects of DMC’s scope 
of review and procedures. 


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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
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 
International Ethical Guidelines; 
• Applicable International Council for Harmonisation (ICH) Good Clinical Practice (GCP) 
Guidelines; and 
• 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/independent ethics committee (IRB/IEC) by the investigator and reviewed and approved 
by the IRB/IEC before the study is initiated. 
Any amendments to the protocol will require 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 event 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. 
10.1.2. 
Financial Disclosure 
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. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 


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10.1.3. 
Informed Consent Process 
• 
The investigator or their representative will explain the nature of the study to the 
participant or their 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 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 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) during their 
participation in the study as required by the IRB/IEC. 
• 
Consent is required for the collection of pharmacogenomic samples (blood and tumor 
biopsies). 
• 
A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative. 
10.1.4. 
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 Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
10.1.5. 
Committees Structure 
The study will utilize an independent data monitoring committee (DMC) and will operate 
according to an established Charter (Section 9.5.1). In addition, a steering committee will be 
established to support the development of nirogacestat for the treatment of desmoid 
tumor/aggressive fibromatosis. The purpose and provisions of the DMC will be specified in the 
DMC Charter. 


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10.1.6. 
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 noncompliance issues and monitoring techniques (central, remote, 
or on-site 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. 
10.1.7. 
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 reported 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. 
10.1.8. 
Study and Site Closure 
The sponsor 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. 
Conditions that may warrant early study-site closure or study termination may include, 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. 
Should the study be terminated, and/or the site closed for whatever reason, all documentation 
and study treatment pertaining to the study must be returned to the sponsor or its representative, 
and the Investigators, IRB/IEC and Regulatory Authorities will be promptly informed of the 
termination and the reason for the decision. The Investigator should promptly inform the 
participants and assure appropriate therapy and follow-up. 
 
 


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Appendix 2: Clinical Laboratory Tests 
• The tests detailed in Table 12 will be performed by the central laboratory. 
• Local laboratory results are only required in the event that the central laboratory results 
are not available in time for either study treatment (nirogacestat or placebo) 
administration and/or response evaluation. If a local sample is required, it is important 
that the sample for central analysis is obtained at the same time. Additionally, if the local 
laboratory results are used to make either a study treatment decision or response 
evaluation, the results must be entered into the electronic case report form. In the event of 
a public health emergency, clinical laboratory assessments may be performed locally with 
results and local laboratory normal values entered into the eCRF. 
• Protocol-specific requirements for inclusion and exclusion of participants are detailed in 
Section 5 and Sections 6.7.2 and 6.7.3 protocol. 
• Additional tests, as part of unscheduled visits, may be performed at any time during the 
study as determined necessary by the investigator or required by local regulations. 
• Pregnancy testing (urine or serum as described in the SoA; Section 1.3) will be conducted 
at monthly intervals during the double-blind and OLE study treatment phases. 
• Urine pregnancy testing (will be conducted at monthly intervals during the double-blind 
and OLE study treatment phases for women of child-bearing potential. Refer to Section 
8.2.6 for more details on the monthly pregnancy testing requirements.  
• 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 safety report.


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Table 12 
Protocol-Required Safety Laboratory Assessments 
Hematology 
Chemistry2 
Urinalysis 
Serology5 
Hormone Levels6 
• 
HGB 
• 
HCT 
• 
PLT count 
• 
RBC count 
• 
RBC Indices: 
o 
MCV 
o 
MCH 
• 
% Reticulocytes 
• 
WBCC with 
Differential1: 
o neutrophils 
o lymphocytes 
o monocytes 
o eosinophils 
o basophils 
• 
AST/SGOT 
• 
ALT/SGPT 
• 
D-BIL 
• 
TBIL 
• 
GGT 
• 
Sodium 
• 
Chloride 
• 
Potassium 
• 
Bicarbonate 
• 
Inorganic 
phosphorus 
• 
Alkaline 
phosphatase 
• 
Creatinine3 
• 
Estimated 
glomerular 
filtration 
rate 
• 
BUN 
• 
Glucose 
(non-
fasting) 
• 
Uric acid 
• 
Albumin 
• 
Total protein 
• 
Specific 
gravity 
• 
Bilirubin 
• 
Glucose 
• 
Leukocyte 
esterase 
• 
Nitrite 
• 
Protein 
• 
Urobilinogen 
• 
Blood 
• 
Ketones 
• 
pH 
• 
Microscopy4 
• 
HIV antibody 
• 
HBV 
o 
HBsAg 
• 
HCV 
o 
hepatitis C 
antibody 
(HCV PCR 
if hepatitis C 
antibody 
positive) 
Females: 
• 
TSH7 
• 
Prolactin7 
• 
AMH 
• 
LH 
• 
FSH 
• 
Estradiol 
• 
Progesterone 
 
Males: 
• 
Total testosterone 
• 
Free testosterone 
• 
Progesterone 
• 
FSH 
• 
LH 
ALT = alanine aminotransferase; AMH = anti-müllerian hormone; AST = aspartate aminotransferase; BUN = blood urea 
nitrogen; D-BIL = direct bilirubin; FSH = follicle stimulating hormone; GGT = gamma-glutamyl transferase; HBsAg = 
hepatitis B surface antigen; HBV = hepatitis B virus; HCT = hematocrit; HCV = hepatitis C virus; HGB = hemoglobin; HIV = 
human immunodeficiency virus; LH = luteinizing hormone; MCH = mean cell hemoglobin; MCV = mean cell volume; PCR 
= polymerase chain reaction; PLT = platelet; RBC = red blood cell; SGOT = serum glutamic-oxaloacetic transaminase; SGPT 
=serum glutamic-pyruvic transaminase; TBIL = total bilirubin; TSH = thyroid stimulating hormone; WBCC = white blood 
cell count 
1) Manual microscopic review is performed only if white blood cell count and/or differential values are out of 
reference range. 
2) Details of liver stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Sections 7.1.1 and 10.6. 
3) If creatinine > 1.5 × ULN then calculated creatinine clearance must be ≥ 60 mL/min (using the Cockcroft-
Gault formula). 
4) Microscopy examination is performed only if blood or protein is abnormal. 
5) Serology only required at screening. 


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Hematology 
Chemistry2 
Urinalysis 
Serology5 
Hormone Levels6 
6) Hormone level assessments for both females and males are required per the SoA in Section 1.3. Females 
reporting AEs/AESIs/SAEs of primary ovarian insufficiency (POI) and/or amenorrhea will have hormone levels 
assessed every 3 months until event resolution (or for at least 90 days after discontinuing study treatment). 
7) Female hormone levels for TSH and prolactin are only required at Screening and EOT.  
 
 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
10.3.1. 
Definition of Adverse Event (AE) 
AE Definition 
• An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study treatment, whether or not considered 
related to the study treatment. 
• NOTE: 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 
or 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. 
• 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. 
10.3.2. 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (e.g., hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
A SAE is defined as any untoward medical occurrence that, at any dose: 
Results in death 
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. 
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 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. 


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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. 
Is a congenital anomaly/birth defect 
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 invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency or 
drug abuse. 
10.3.3. 
Recording and Follow-Up of AE and/or SAE 
AE and SAE Recording 
• When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event. 
• All required information pertaining to the AE/SAE will be recorded in the electronic 
case report form (eCRF). SAEs will require additional information to be reported to 
Safety utilizing a paper SAE form that must be scanned and emailed or faxed to Safety 
immediately, without undue delay, under no circumstances later than 24 hours after  
becoming aware of the event (refer to Section 10.3.4 for further SAE 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 SAE eCRF page/paper SAE form. 
• There may be instances when copies of medical records for certain cases are requested 
by Safety for reported SAEs. In this case, all participant identifiers, with the exception 
of the participant number, will be redacted on the copies of the medical records before 
submission to Safety. 


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• 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/SAE. 
Assessment of Intensity 
The intensity of all SAEs/AEs will be graded according to the Common Terminology Criteria 
for Adverse Events (CTCAE) version 5.0. For those SAEs/AEs not listed in the CTCAE, the 
following grading system will be used:  
• CTCAE Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; treatment not indicated. 
• CTCAE Grade 2 Moderate; minimal, local or noninvasive treatment indicated; 
limiting age-appropriate instrumental activities of daily living (ADL)*. 
• CTCAE Grade 3 Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL**. 
• CTCAE Grade 4 Life-threatening consequences; urgent treatment indicated. 
• CTCAE Grade 5 Death related to AE. 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, 
taking medications, and not bedridden. 
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE (Section 10.3.2), not when it is rated as severe. 
Assessment of Causality 
• The investigator is obligated to assess the relationship between study treatment 
(nirogacestat or placebo) and each occurrence of each AE/SAE. 
• 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, when making an 
assessment. 




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• 
In rare circumstances in the absence of email or facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE 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 SAE form within the designated reporting time 
frames. 
• After the study is completed at a given site, the eCRF system will be locked to prevent 
the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the eCRFs have been locked, then the site can 
report this information on a paper SAE form to the Safety by telephone/email/fax. 
• Contacts for SAE reporting can be found in Section 10.10.4. 
10.3.5. 
Definition of AR, SAR and SUSAR 
Adverse Reaction (AR): 
An AR 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. 
 
 
 


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Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information 
Definitions: 
Women of Childbearing Potential (WOCBP) is defined as a woman that is considered fertile 
following menarche and until becoming post-menopausal unless permanently sterile (see below). 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study treatment (nirogacestat or placebo), additional evaluation 
should be considered. 
Women in the following categories are not considered WOCBP: 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
• 
Documented hysterectomy; or 
• 
Documented bilateral salpingectomy; or 
• 
Documented bilateral oophorectomy. 
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (e.g., Mullerian 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 female 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.  
• 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 required.  
• Females 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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Contraception Guidance: 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
Highly Effective Methodsb That Have Low User Dependency Failure rate of < 1% per 
year when used consistently and correctly. 
• Implantable progestogen-only hormone contraception associated with inhibition of 
ovulationc 
• Intrauterine device  
• Intrauterine hormone-releasing system  
• Bilateral tubal occlusion 
• Vasectomized partner 
(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 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 
(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.) 
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. 


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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) 


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Collection of Pregnancy Information: 
Male participants with partners who become pregnant 
• 
The investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This 
applies only to male participants who receive study treatment. 
• 
After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the investigator will record pregnancy information on the appropriate form and 
submit it to the sponsor within 24 hours of learning of the partner’s pregnancy. The female 
partner will also be followed to determine the outcome of the pregnancy. Information on the 
status of the mother and child will be forwarded to the sponsor. Generally, the follow-up 
will be no longer than 6 to 8 weeks following the estimated delivery date. Any termination 
of the pregnancy will be reported regardless of fetal status (presence or absence of 
anomalies) or indication for the procedure.  
Female Participants who become pregnant 
• The investigator will collect pregnancy information on any female participant who becomes 
pregnant while participating in this study. 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. 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 AE or 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 8.3.4. While the 
investigator is not obligated to actively seek this information in former study participants, he 
or she may learn of an SAE through spontaneous reporting. 
• Any female participant who becomes pregnant while participating in the study will 
discontinue study treatment or be withdrawn from the study. 
 
 


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Appendix 5: Genetics 
Use and analysis of deoxyribonucleic acid (DNA): 
• 
Genetic variation may impact a participant’s response to study treatment (nirogacestat 
or placebo), susceptibility to, and severity and progression of disease. Variable response 
to study treatment may be due to genetic determinants that impact drug absorption, 
distribution, metabolism, and excretion; mechanism of action of the drug; disease 
etiology; and/or molecular subtype of the disease being treated. Therefore, where local 
regulations and institutional research boards/independent ethic committees allow, DNA 
analysis will be collected from participant’s blood sample (referred to as the optional 
pharmacogenetic blood sample in the SoA [Section 1.3.1]) and participant’s tumor 
biopsy required for disease confirmation at baseline if archival tissue not available, and 
optional tumor biopsy at the EOT visit will be collected from consenting participants. 
• 
DNA samples will be used for research related to nirogacestat or desmoid and related 
diseases. They may also be used to develop tests / assays including diagnostic tests 
related to nirogacestat or treatments of this drug class and desmoid. Genetic research 
may consist of the analysis of one or more candidate genes or the analysis of genetic 
markers throughout the genome. 
• 
DNA samples will be analyzed for the presence of known mutations. Additional 
analyses may be conducted if it is hypothesized that this may help further understand 
the clinical data. 
• 
The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to nirogacestat or study treatments of this class to understand 
study disease or related conditions. 
• 
The results of genetic analyses may be reported in the clinical study report 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 while research on nirogacestat continues but no longer 
than 10 years or other period as per local requirements. 
 


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Appendix 6: Liver Safety: Suggested Actions and Follow-up 
Assessments  
Liver Chemistry Stopping Criteria and Follow-Up Assessments 
 
 
Liver Chemistry Stopping Criteria 
ALT-absolute 
ALT ≥ 5xULN 
ALT Increase 
ALT ≥ 3xULN persists for ≥ 4 weeks 
Bilirubin1, 2 
ALT ≥ 3xULN and bilirubin ≥ 2xULN (> 35% direct bilirubin) 
INR2 
ALT ≥3xULN and INR > 1.5, if INR measured 
Cannot 
Monitor 
ALT ≥ 3xULN and cannot be monitored weekly for 4 weeks 
Symptomatic3 
ALT ≥ 3xULN associated with symptoms (new or worsening) believed to 
be related to liver injury or hypersensitivity 
Suggested Actions and Follow-up Assessments  
Actions 
Follow-Up Assessments 
• Immediately discontinue study treatment 
(nirogacestat or placebo) 
• Report the event to the sponsor within 24 
hours 
• Complete the liver event in the 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 
assessmentsMONITORING: 
If ALT ≥ 3xULN AND bilirubin ≥ 2xULN or 
INR > 1.5:  
• Repeat liver chemistry tests (include ALT, 
AST, alkaline phosphatase, bilirubin and INR) 
• Viral hepatitis serology4 
• 
Obtain INR and recheck with each 
liver chemistry assessment until the 
transaminases values show downward 
trend 
• Serum CPK and LDH 
• Fractionate bilirubin, if total bilirubin 
≥ 2xULN 
• 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. 


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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 ≥ 3xULN AND bilirubin < 2xULN 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. 
• Record alcohol use on the liver event 
alcohol intake eCRF 
ALT ≥ 3xULN AND bilirubin ≥ 2xULN 
or INR >1.5: 
• Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total IgG or gamma 
globulins. 
• Serum acetaminophen adduct 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 
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 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.  


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Liver Chemistry Increased Monitoring Criteria with Continued Study Treatment 
Liver Chemistry Increased Monitoring Criterion and Follow-Up 
Criterion 
Actions 
ALT ≥ 3xULN and < 5xULN and 
bilirubin < 2xULN, without 
symptoms believed to be related to 
liver injury or hypersensitivity, and 
who can be monitored weekly for 4 
weeks 
• 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 7.1.1. 
• If, after 4 weeks of monitoring, ALT < 3xULN 
and bilirubin < 2xULN, monitor participants 
twice monthly until liver chemistry tests resolve, 
stabilize, or return to baseline. 
References 
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee WM. Pharmacokinetics of 
Acetaminophen-Adduct in Adults with Acetaminophen Overdose and Acute Liver Failure. Drug Metab Dispos 
2009; 37:1779-1784. 
 
 


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Appendix 7: 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 MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative 
Oncology Group. Am J Clin Oncol. 1982; 5:649-655 


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Appendix 8: RECIST (Response Evaluation Criteria in Solid 
Tumors) Version 1.1 Guidelines 
Adapted from E.A. Eisenhauer, et al: New response evaluation criteria in solid tumours: 
Revised RECIST guideline (version 1.1). European Journal of Cancer 45 (2009) 228–247 
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 Lesion - The investigator will select up to 5 target 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. Spiral CT should be performed using a 5 mm contiguous reconstruction algorithm.  
This applies to tumors of the chest, abdomen and pelvis. Head and neck tumors and those of 
extremities usually require specific protocols. 
Recording Tumor Assessments 
All sites of disease must be assessed at screening. Screening assessment must be done within 
28 days of starting study treatment (nirogacestat or placebo). 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. Participants must have progressive disease 
(PD) within a 12-month period prior to the screening visit scan. 
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. 


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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. 
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).  


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Time point response: patients with target disease 
Target lesions 
Non-Target lesions 
New Lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Incomplete 
response/SD 
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 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
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 
having “symptomatic deterioration”. Every effort should be made to document the objective 
progression even after discontinuation of treatment.  
Confirmation 
• Confirmation of progression: assessment of PD will be confirmed and documented by 
Central Imaging Review (an independent, blinded central radiological review 
committee).  
• 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 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 


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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.  
o The clinical relevance of the duration of SD varies for different tumor types 
and grades. Therefore, it is highly recommended that the protocol specifies the 
minimal time interval required between two measurements for determination 
of SD. This time interval should consider the expected clinical benefit that 
such a status may bring to the population under study.  
 


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Appendix 9: Abbreviations 
Abbreviation 
Definition 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ADL 
Activities of daily living 
ALT 
Alanine aminotransferase 
AMH 
Anti-müllerian hormone 
APC 
Adenomatous polyposis coli 
AR 
Adverse reaction 
AST 
Aspartate aminotransferase 
BID 
Twice daily 
BPI 
Brief pain inventory 
BUN 
Blood urea nitrogen 
C1D1 
Cycle 1 Day 1 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
ConMed 
Concomitant medication 
CPK 
Creatine phosphokinase 
CR 
Complete response 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTFG 
Clinical Trial Facilitation Group 
CTNNB1 
β-catenin 
CYP3A4 
Cytochrome P450 3A4 
D-BIL 
Direct bilirubin 
DDI 
Drug-drug interaction 
DMC 
Data monitoring committee 
DNA 
Deoxyribonucleic acid, 
DT/AF 
Desmoid tumors/aggressive fibromatosis 
DTP 
DTRF 
Direct to participant 
Desmoid Tumor Research Foundation 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EFS 
Event free survival 
EORTC QLQ-30 
European Organisation for Research and Treatment of Cancer 
Quality of Life Questionnaire-Core 30  
EOT 
End of treatment 
ePRO 
Electronic patient report outcome  
FAP 
Familial adenomatous polyposis 
FDA 
Food and Drug Administration 
FFPE 
formalin-fixed, paraffin embedded 
FSH 
Follicle stimulating hormone 
FU 
Follow-up 
GCP 
Good Clinical Practice 


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Abbreviation 
Definition 
GGT 
Gamma-glutamyl transferase; 
GODDESS 
GOunder/DTRF DEsmoid Symptom/Impact Scale 
GS 
Gamma-secretase 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCT 
Hematocrit 
HCV 
Hepatitis C virus 
Hes1 
Hairy and enhancer of split-1 
HGB 
Hemoglobin 
HIV 
Human immunodeficiency virus 
HPLC 
High performance liquid chromatography 
HR 
Hazard ratio 
HRT 
Hormonal replacement therapy 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
I/E 
Inclusion/exclusion 
IEC 
Independent Ethics Committee 
IgM 
Immunoglobulin M 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IRT 
Interactive response technology 
ITT 
Intent-to-Treat 
LD 
Longest diameter 
LDH 
Lactate dehydrogenase 
LH 
Luteinizing hormone 
MCH 
Mean cell hemoglobin 
MCV 
Mean cell volume 
MRI 
Magnetic resonance imaging 
MSKCC 
Memorial Sloan Kettering Cancer Center 
MSK/DTRF DTIS 
Memorial Sloan Kettering/Desmoid Tumor Research 
Foundation Desmoid Tumor Impact Scale 
MSK/DTRF DTSS 
Memorial Sloan Kettering/Desmoid Tumor Research 
Foundation Desmoid Tumor Symptom Scale 
MTD 
Maximum tolerated dose 
NCI 
National Cancer Institute 
NICD 
Notch intracellular domain 
NIR 
nirogacestat 
NSAIDs 
Nonsteroidal anti-inflammatory drug 
OLE 
Open-label extension 
ORR 
Objective response rate 
PCR 
Polymerase chain reaction 
PD 
Progressive disease 
PFS 
Progression-free survival 
P-gp 
P-glycoprotein 
PGIC 
Patient global impression of change 


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Abbreviation 
Definition 
PGIS 
Patient global impression of severity 
PK 
Pharmacokinetic 
PLT 
Platelet 
POI 
Primary ovarian insufficiency 
PopPK 
Population pharmacokinetic 
PR 
Partial response 
PRO 
Patient-reported outcome 
PROMIS PF 
Patient-Reported Outcomes Measurement Information System 
Physical Function 
QoL 
Quality of life 
QT 
Uncorrected QT interval 
QTcF 
Corrected QT interval by Fridericia 
QRS 
QRS Complex 
RBC 
Red blood cell 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RNA 
Ribonucleic acid 
RP2D 
Recommended Phase 2 dose 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAR 
Serious adverse reaction 
 
SD 
Stable disease 
SGOT 
Serum glutamic-oxaloacetic transaminase 
SGPT 
Serum glutamic-pyruvic transaminase 
SoA 
Schedule of activities 
STSs 
Soft-tissue sarcomas 
SUSAR 
Suspected unexpected serious adverse reaction 
TdP 
Torsades de Pointes 
TBIL 
Total bilirubin 
TKI 
Tyrosine kinase inhibitors 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit of normal 
v 
Version 
WBCC 
White blood cell count 
WOCBP 
Women of childbearing potential 
 


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Amendment 5 (09Feb2021) 
CONFIDENTIAL 
Page 122 
 
Appendix 10: List of Contacts for Study 
10.10.1. 
Sponsor 
SpringWorks Therapeutics 
100 Washington Blvd 
Stamford, CT 06902 
United States 
Telephone: 212-421-8012 
Fax: 646-609-8816 


SpringWorks Therapeutics 
 
Protocol NIR-DT-301
 
 
Amendment 5 (09Feb2021) 
CONFIDENTIAL 
Page 123 
11. 
REFERENCES 
Bo N, Wang D, et al. Analysis of β-catenin expression and exon 3 mutations in pediatric 
sporadic aggressive fibromatosis. Pediatr Dev Pathol. 2012 May Jun;15(3):173-8. 
Casali PG, Abecassis N, et al.; ESMO Guidelines Committee and EURACAN. Soft tissue and 
visceral sarcomas: ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment and 
follow-up. Ann Oncol. 2018; Epub ahead of print, May 28. 
de Camargo VP, Keohan ML, et al. Clinical outcomes of systemic therapy for patients with deep 
fibromatosis (desmoid tumor). Cancer. 2010 May 1;116(9):2258-65. 
Eisenhaur EA, Therasse P, et al. New response evaluation criteria in solid tumours: Revised 
RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. 
Gounder, M., Mahoney M, et al. Phase III, randomized, double-blind, placebo-controlled trial of 
sorafenib in desmoid tumors J Clin Oncol 36, 2018 (suppl; abstr 11500). 
Hosalkar, H, Fox EJ, et al. Desmoid Tumors and Current Status of Management. Orthop Clin N 
Am 2006(37):53-63. 
Janinis J, Patriki M, et al. The pharmacological treatment of aggressive fibromatosis: a 
systematic review. Ann Oncol. 2003 Feb;14(2):181-90. 
Kasper B, Baumgarten C, et al.; Desmoid Working Group. Management of sporadic desmoid 
type fibromatosis: a European consensus approach based on patients' and professionals' 
expertise- a sarcoma patients EuroNet and European Organisation for Research and Treatment of 
Cancer/Soft Tissue and Bone Sarcoma Group initiative. Eur J Cancer. 2015 Jan;51(2):127 36. 
Kasper B, Gruenwald V, et al. Imatinib induces sustained progression arrest in RECIST 
progressive desmoid tumours: Final results of a phase II study of the German Interdisciplinary 
Sarcoma Group (GISG). Eur J Cancer. 2017 May; 76:60-67. 
Kasper B, Ströbel P, et al. Desmoid tumors: clinical features and treatment options for advanced 
disease. Oncologist. 2011;16(5):682-93. 
Klinakis A, Szabolcs M, et al. Myc is a Notch1 transcriptional target and a requisite for Notch1-
induced mammary tumorigenesis in mice. Proc Natl Acad Sci USA. 2006 Jun 13;103(24):9262-
67. 
Kummar S, O'Sullivan Coyne G, et al. Clinical activity of the γ-secretase inhibitor PF-03084014 
in adults with desmoid tumors (Aggressive Fibromatosis). J Clin Oncol. 2017 May 
10;35(14):1561-69. 
Lazar AJ, Tuvin D, et al. Specific mutations in the beta-catenin gene (CTNNB1) correlate with 
local recurrence in sporadic desmoid tumors. Am J Pathol. 2008 Nov;173(5):1518-27. 
Lewis JJ, Boland PJ, et al. The enigma of desmoid tumors. Ann Surg. 1999 Jun;229(6):866-72. 


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Protocol NIR-DT-301
 
 
Amendment 5 (09Feb2021) 
CONFIDENTIAL 
Page 124 
Messersmith WA, Shapiro GI, et al. A Phase I, dose finding study in patients with advanced 
solid malignancies of the oral γ-secretase inhibitor PF-03084014. Clin Cancer Res. 2015 Jan 
1;21(1):60-7. 
Penel N, Le Cesne A, et al. Surgical versus non-surgical approach in primary desmoid-type 
fibromatosis patients: A nationwide prospective cohort from the French Sarcoma Group. Eur J 
Cancer. 2017 Sep; 83:125-31. 
Quintini C, Ward G, et al. Mortality of intra-abdominal desmoid tumors in patients with familial 
adenomatous polyposis: a single center review of 154 patients. Ann Surg. 2012 Mar;255(3):511-
6. 
Rampazzo E, Persano L, et al. Wnt activation promotes neuronal differentiation of glioblastoma. 
Cell Death Dis. 2013 Feb 21;4: e500. 
Rodilla V, Villanueva A, et al. Jagged1 is the pathological link between Wnt and Notch 
pathways in colorectal cancer. Proc Natl Acad Sci USA. 2009 Apr 14;106(15):6315-20. 
Schöffski P, Requilé A, et al. Assessment of physician's systemic treatment preferences for 
patients with advanced desmoid-type fibromatosis: experience-based medicine in the absence of 
high-level evidence. Oncol Res Treat. 2018;41(4):214-19. 
Shang H, Braggio D, et al. Targeting the Notch pathway: a potential therapeutic approach for 
desmoid tumors. Cancer. 2015 Nov 15;121(22):4088-96. 
Sharma VM, Calvo JA, et al. Notch1 contributes to mouse T cell leukemia by directly inducing 
the expression of c-myc. Mol Cell Biol. 2006 Nov;26(21):8022-31. 
Skubitz KM. Biology and Treatment of aggressive fibromatosis or desmoid tumor. Mayo Clin 
Proc. 2017 Jun;92(6):947-64. 
Smith AJ, Lewis JJ, et al. Surgical management of intra-abdominal desmoid tumours. Br J Surg. 
2000 May;87(5):608-13. 
Tejpar S, Nollet F, et al. Predominance of beta-catenin mutations and beta-catenin dysregulation 
in sporadic aggressive fibromatosis (desmoid tumor). Oncogene. 1999 Nov 11;18(47):6615-20. 
Ungerbäck J, Elander N, et al. The Notch-2 gene is regulated by Wnt signaling in cultured 
colorectal cancer cells. PLoS One. 2011 Mar 18;6(3): e17957. 
Villalobos VM, Hall F, et al. Long-term follow-up of desmoid fibromatosis treated with PF-
03084014, an oral gamma secretase inhibitor. Ann Surg Oncol. 2018 Mar;25(3):768-75. 

SAP_001.pdf: 
SpringWorks Therapeutics 
Statistical Analysis Plan, Protocol NIR-DT-301 
12 May 2022 Final Version 2.0 
 
 
CONFIDENTIAL 
1 
 
STATISTICAL ANALYSIS PLAN 
A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial of 
Nirogacestat Versus Placebo in Adult Patients with Progressing Desmoid 
Tumors/Aggressive Fibromatosis (DT/AF) 
 
Protocol Number: 
NIR-DT-301 
Protocol Version and Date: 
Amendment 5: 09 February 2021 
Amendment 4: 07 July 2020 (not released to sites) 
Amendment 3: 27 January 2020 
Amendment 2:  14 October 2019 
Amendment 1:  09 July 2019 
Original:  03 August 2018 
Name of Test Drug: 
Nirogacestat 
Phase: 
Phase 3  
Methodology: 
Randomized, Double-Blind, Placebo-Controlled 
Sponsor: 
SpringWorks Therapeutics 
100 Washington Blvd. 
Stamford, CT 06902 
United States 
Sponsor Representative: 
 
Sponsor Biostatistician  
Analysis Plan Date: 
12 May 2022 
Analysis Plan Version: 
Final Version 2.0 
 
Confidentiality Statement 
The information in this document is confidential information of SpringWorks Therapeutics 
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 study personnel directly involved with 
conducting this study and who are bound by obligations of confidentiality in connection with 
their involvement with this study. 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 organization. 


SpringWorks Therapeutics 
Statistical Analysis Plan, Protocol NIR-DT-301 
12 May 2022 Final Version 2.0 
 
 
CONFIDENTIAL 
2 
Author: 
 
 
 
 
 
 
PharPoint Research, Inc 
 
Date 
 
 
 
 
 
 
 
Sponsor Signatory 
 
 
 
 
 
SpringWorks Therapeutics, Inc 
 
Date 
 
 
 
 
 
 
 
 
 
 
SpringWorks Therapeutics, Inc 
 
Date 
 
 
 
 
 
 
 
 


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Statistical Analysis Plan, Protocol NIR-DT-301 
12 May 2022 Final Version 2.0 
 
 
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TABLE OF CONTENTS 
Section 
Page 
TABLE OF CONTENTS ......................................................................................................3 
LIST OF TABLES................................................................................................................7 
1. 
INFORMATION FROM THE STUDY PROTOCOL ...............................................10 
1.1. 
Introduction and Objectives ..........................................................................10 
1.1.1. 
Introduction ...................................................................................10 
1.1.2. 
Study Objectives ............................................................................11 
1.2. 
Study Design................................................................................................12 
1.2.1. 
Synopsis of Study Design ...............................................................12 
1.2.2. 
Randomization Methodology..........................................................12 
1.2.3. 
Stopping Rules and Unblinding ......................................................13 
1.2.4. 
Study Procedures ...........................................................................13 
1.2.5. 
Efficacy and Safety Endpoints ........................................................27 
1.2.5.1. Primary Efficacy Endpoint ...............................................27 
1.2.5.2. Secondary Efficacy Endpoints ..........................................27 
1.2.5.3. Exploratory Endpoints......................................................28 
1.2.5.4. Safety Parameters ............................................................28 
2. 
SUBJECT POPULATION .......................................................................................29 
2.1. 
Population Definitions ..................................................................................29 
2.2. 
Protocol Deviations ......................................................................................29 
2.3. 
Impacts from COVID-19 ..............................................................................30 
3. 
GENERAL STATISTICAL METHODS ..................................................................31 
3.1. 
Sample Size Justification ..............................................................................31 
3.2. 
General Methods ..........................................................................................31 
3.3. 
Computing Environment ..............................................................................32 
3.4. 
Baseline Definitions .....................................................................................32 
3.5. 
Methods of Pooling Data ..............................................................................32 
3.6. 
Adjustments for Covariates...........................................................................33 
3.7. 
Multiple Comparisons/Multiplicity ...............................................................33 
3.8. 
Subgroups ....................................................................................................33 
3.9. 
Withdrawals, Dropouts, Loss to Follow-up....................................................35 


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Section 
Page 
3.10. Missing, Unused, and Spurious Data .............................................................35 
3.11. Visit Windows .............................................................................................36 
4. 
STUDY ANALYSES ..............................................................................................37 
4.1. 
Disposition...................................................................................................37 
4.2. 
Demographics, Baseline Characteristics, and Medical History .......................37 
4.2.1. 
Prior Therapy.................................................................................38 
4.3. 
Efficacy Evaluations.....................................................................................38 
4.3.1. 
Primary Efficacy Evaluation...........................................................38 
4.3.1.1. Analysis of Progression Free Survival...............................40 
4.3.1.2. Sensitivity Analyses of PFS..............................................40 
4.3.1.3. Subgroup Analysis ...........................................................41 
4.3.2. 
Secondary Efficacy Evaluations......................................................41 
4.3.2.1. Objective Response Rate (ORR) .......................................41 
4.3.2.2. Analysis of PRO Assessment data ....................................42 
4.3.3. 
Exploratory and Other Supportive Efficacy Analyses ......................43 


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4.3.3.1. Best Overall Response (BOR) ..........................................43 
4.3.3.2. Disease Control Rate (DCR).............................................44 
4.3.3.3. Time to Tumor Progression (TTP) ....................................44 
4.3.3.4. PFS at Month 6 (PFS6), Month 12 (PFS12) and Month 24 
(PFS24) of Treatment Period ............................................44 
4.3.3.5. DOR at Month 6 (PFS6), Month 12 (PFS12) and Month 24 
(PFS24) of Treatment Period ............................................44 
4.3.3.6. Time to Response.............................................................44 
4.3.3.7. Change in Tumor Volume Assessed by MRI .....................44 
4.3.3.8. Change in Sum of Largest Diameter of Tumor Assessed by 
RECIST...........................................................................45 
4.3.3.9. Tumor Response by Exposure ..........................................45 
4.3.3.10.Change in Tumor Volume by Tumor Response .................46 
4.3.3.11.Change in Symptoms by Exposure and Change in Tumor 
Size/Volume ....................................................................46 
4.3.3.12.PFS by Mutation Status in APC and CTNNB1 Genes........47 
4.3.3.13.Other Prognostic Factors ..................................................47 
4.3.3.14.Change in Expression of Notch Genes ..............................47 
4.3.3.15.Change in MRI T2 intensity .............................................47 
4.3.3.16.Change in MRI T2 intensity by Tumor Response ..............47 
4.3.3.17.DT Specific Comorbidity .................................................47 
4.3.3.18.Local vs Central RECIST v1.1 Readings...........................48 
4.4. 
Safety Analyses............................................................................................48 
4.4.1. 
Study Drug Exposure and Compliance............................................48 
4.4.2. 
Adverse Events ..............................................................................49 
4.4.2.1. Selected Treatment Emergent Adverse Events ..................50 
4.4.2.2. Adverse Events of Special Interest ....................................52 
4.4.2.3. DT Specific Comorbidity .................................................52 
4.4.3. 
Clinical Safety Laboratory Assessments..........................................52 
4.4.4. 
Physical Examinations and Eastern Cooperative Oncology Group 
Performance Status ........................................................................54 
4.4.5. 
Electrocardiogram..........................................................................54 
4.4.6. 
Vital Signs .....................................................................................55 


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Section 
Page 
4.4.7. 
Concomitant Medications and Procedures .......................................55 
4.5. 
Pharmacokinetic and Pharmacodynamic Analyses .........................................55 
5. 
CHANGES TO PLANNED ANALYSES.................................................................56 
6. 
REFERENCES........................................................................................................57 
7. 
APPENDICES ........................................................................................................58 
7.1. 
Handling of Missing/Partial Dates for AEs ....................................................58 
7.2. 
Handling of Missing/Partial Dates for Concomitant Therapies/Medications....58 
7.3. 
Handling of Missing Dates for Disease History and Prior Therapies...............59 
7.4. 
Consolidated Medication Coding ..................................................................59 
7.5. 
Preferred Terms for Adverse Event Analyses ................................................61 
7.5.1. 
Ovarian Dysfunction (OD) .............................................................61 
7.5.2. 
Rash, Hidradenitis, Hair Follicle AEs .............................................62 
7.5.2.1. Rash ................................................................................62 
7.5.2.2. Hidradenitis .....................................................................64 
7.5.2.3. Hair Follicle AEs .............................................................64 
8. 
CLINICAL STUDY REPORT APPENDICES .........................................................66 
8.1. 
Statistical Tables, Figures and Listings to be Generated .................................66 
 
 


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LIST OF TABLES 
Table 1. 
Schedule of Assessments (SoA) – Double-Blind Phase..................................... 14 
Table 2. 
Schedule of Assessments (SoA) – Open-Label Extension Phase ....................... 21 
Table 3. 
Subgroup for Efficacy Analyses ...................................................................... 34 
Table 4. 
Subgroup Definition for Safety Analyses ......................................................... 35 
Table 5. 
Primary PFS Censoring Methodology .............................................................. 39 
Table 6. 
BOR Determination Table ............................................................................... 43 
Table 7. 
Eastern Cooperative Oncology Group Performance Status Grades .................... 54 
Table 8. 
Broad Summary of Preferred Terms to Describe Ovarian Dysfunction 
in WOCBP ..................................................................................................... 61 
Table 9. 
Broad Summary of Preferred Terms to Describe Rash ...................................... 63 
Table 10. 
Broad Summary of Preferred Terms to Describe Rash ...................................... 64 
Table 11. 
Broad Summary of Preferred Terms to Hair Follicle Adverse Events ................ 65 
 


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12 May 2022 Final Version 2.0 
 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
AE 
Adverse event 
AESI 
Adverse events of special interest 
APC 
Adenomatous polyposis coli 
BOR 
Best Overall Response 
BPI 
Brief Pain Inventory 
CI 
Confidence interval 
CR 
Complete response 
CSR 
Clinical study report 
CT 
Computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DB 
Double-blind 
DOR 
Duration of response 
DT/AF 
Desmoid Tumors/Aggressive Fibromatosis 
DTIS 
Desmoid Tumor Symptom Scale 
DTSS 
Desmoid Tumor Impact Scale 
EAC 
Endpoint Adjudication Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EORTC 
European Organization for Research and Treatment of Cancer 
EOT 
End of treatment 
FAP 
Familial adenomatous polyposis  
FUP 
Follow-up 
GODDESS 
GOunder/Desmoid Tumor Research Foundation DEsmoid 
Symptom/Impact Scale 
HR 
Hazard ratio 
IRT 
Interactive response technology 
ITT 
Intent-to-Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
OD 
Ovarian dysfunction 
OLE 
Open-label extension 
ORR 
Objective Response Rate 
PD 
Progressive Disease 
PFS 
Progression-free survival 
PGIC 
Patient Global Impression of Change 
PGIS 
Patient Global Impression of Severity 
PK 
Pharmacokinetic 


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Abbreviation 
Definition 
PP 
Per-Protocol 
PR 
Partial response 
PRO 
Patient-reported outcome 
PROMIS 
Patient-Reported Outcomes Measurement Information System Physical 
Function 
PT 
Preferred Term 
QLQ-C30 
Quality of Life Questionnaire-Core 30 
RECIST 
Response Evaluation Criteria In Solid Tumors 
SAE 
Serious Adverse Event 
SAP 
SI  
Statistical Analysis Plan 
International System of Units 
SD 
Stable Disease 
SOC 
System Organ Class 
TEAE 
Treatment-emergent adverse event 
WHO 
World Health Organization 
 
 


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12 May 2022 Final Version 2.0 
 
 
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1. 
INFORMATION FROM THE STUDY PROTOCOL 
1.1. 
Introduction and Objectives 
1.1.1. 
Introduction 
This document is the statistical analysis plan (SAP) for NIR-DT-301, a Phase 3, randomized, 
double-blind, placebo-controlled study to compare the efficacy, safety, and tolerability of 
nirogacestat and placebo in adult participants with progressing Desmoid Tumors/Aggressive 
Fibromatosis (DT/AF). It is based on Protocol Amendment 5, dated 09 February 2021. The 
safety and efficacy for the double-blind phase of NIR-DT-301 will be discussed in two parts:  
1. The main body of the SAP (Main SAP) will detail the statistical analyses to be conducted 
using clinical data for the primary analysis data cut after approximately 51 events have 
occurred and a final double-blind phase analysis after last-participant last visit (LPLV) 
for the double-blind phase of the study and  
2. A patient-reported outcome (PRO) Addendum for analysis of PRO data.  
As with the study’s Main SAP, the PRO Addendum will be finalized before the unblinding of the 
clinical database once the target number of events have been observed. Analysis of 
pharmacokinetic (PK) data from samples collected during the study will be described in a 
separate PK SAP that documents the integrated PK analyses (including data from early phase 
studies) for nirogacestat. An End of open-label extension (OLE) SAP will be developed for the 
OLE phase data.  
The primary analysis of safety, efficacy, and tolerability is planned after approximately 51 events 
have occurred in the double-blind phase of the study (primary analysis data cut). A clinical study 
report will be developed using the primary analysis data cut. A final analysis of the double-blind 
phase of the study will be performed after the last participant last visit has occurred for the 
double-blind phase of the study; this final analysis will inform safety and nominal p-values will 
be presented for efficacy endpoints, but no interpretation will be made on these results. Unless 
otherwise specified, the analysis covered by this document will include only clinical data 
collected during the double-blind (DB) phase of the study. The various SAP components for 
study NIR-DT-301 are summarized below: 
SAP Component 
Focus 
SAP Completion 
Date 
Main SAP 
Analysis of safety and efficacy based on clinical data collected during 
the DB phase of the study including the primary analysis after 
approximately 51 events have occurred and end of double-blind phase 
analysis after (LPLV)  
Prior to unblinding 
PRO Addendum 
Analysis of PRO data based on data collected during the DB phase of the 
study 
Prior to unblinding 
PK SAP 
Integrated analysis of nirogacestat PK data, including PK samples 
collected in NIR-DT-301  
Prior to unblinding 
End of OLE SAP 
Analyses for long-term outcomes based on clinical and PRO data 
collected during the DB and OLE phases of the study 
Prior to the End of the 
OLE phase 
 


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12 May 2022 Final Version 2.0 
 
 
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1.1.2. 
Study Objectives 
This SAP is designed to outline the methods to be used in the analysis of study data in order to 
answer the study objective(s). Populations for analysis, data handling rules, statistical methods, 
and formats for data presentation are provided. The statistical analyses and summary tabulations 
described in this SAP will provide the basis for the results sections of the clinical study report 
(CSR) for this trial. 
This SAP will also outline any differences in the currently planned analytical objectives relative 
to those planned in the study protocol. 
The primary objective of this study is: 
• To determine the efficacy (as defined by progression-free survival [PFS]) of nirogacestat in 
adult participants with progressing DT/AF 
The secondary objectives of this study are: 
• To evaluate the safety and tolerability of nirogacestat in adult participants with progressing 
DT/AF as measured by the incidence of AEs 
• To determine the Objective Response Rate (complete response [CR] + partial response [PR]) 
of nirogacestat in participants with progressing DT/AF 
o To describe the duration of response (DOR) and duration of stable disease 
(DOSD) when data is available 
• To evaluate desmoid tumor symptoms and impacts using the following patient-reported 
outcomes (PROs):  
o GOunder/Desmoid Tumor Research Tumor Foundation (DTRF) DEsmoid 
Symptom/Impact Scale (GODDESS) 
o Brief Pain Inventory (BPI) short form 
o European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire-Core 30 (EORTC) QLQ-C30 
The exploratory objectives of this study are: 
• To compare tumor volume changes measured by magnetic resonance imaging (MRI) in 
participants with progressing DT/AF 
• To evaluate desmoid tumor symptoms and impacts using the following PROs: 
o Patient Global Impression of Severity (PGIS)  
o Patient Global Impression of Change (PGIC) 
• To perform genotyping for germline and somatic mutation in adenomatous polyposis coli 
(APC) and β-catenin genes (CTNNB1) 
• To assess modulation of the Notch pathway by evaluating NOTCH response genes in tumor 
biopsies at screening and disease progression or end of treatment (EOT) 


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• To assess MRI T2 hyperintensity at baseline and post-drug administration  
• To inform development of a population pharmacokinetic (PK) model of nirogacestat 
• To perform exposure-response analysis using a final population PK/PD (PopPK/PD) model 
• To evaluate the effect of nirogacestat on clinical events related to disease specific desmoid 
tumor co-morbidity 
1.2. 
Study Design 
1.2.1. 
Synopsis of Study Design 
This is a multi-center, randomized, double-blind, placebo-controlled, parallel group, 
event-driven, Phase 3 study to compare the efficacy, safety, and tolerability of nirogacestat and 
placebo in adult participants with progressing DT/AF. 142 eligible participants were randomized 
to study treatment (nirogacestat or placebo) in a 1:1 ratio. Randomization was stratified by 
primary tumor location (intra-abdominal or extra-abdominal). 
This study will consist of 2 phases: the double-blind phase and the optional OLE phase. Refer to 
the schedule of activities (SoA Table 1 and Table 2) for details on assessments and timing of 
study visits.  
Participants will be screened up to 28 days prior to the first dose of study treatment and 
eligibility will be based on inclusion and exclusion criteria provided in Section 5.1 and 5.2 of the 
protocol. Participants will be randomized to study treatment at Cycle 1 Day 1 using interactive 
response technology (IRT) and will orally administer 150 mg twice daily, continuously in 28-day 
cycles.  
Following the baseline visit (Cycle 1 Day 1), the participants will return to the clinic for study 
visits at Cycle 1 (Days 8, 15, 22), Cycle 2 (Day 28), Cycle 4 (Day 1), and then on Day 1 of every 
3 cycles thereafter.  
1.2.2. 
Randomization Methodology 
Randomization will be stratified based on the following tumor locations: 
1. Intra-abdominal (include mesentery and pelvis)  
OR 
2. Extra-abdominal (including head/neck, para-spinal, extremities, abdominal wall, chest 
wall, and other locations). 
If the participant has multiple target tumors that are located both in the intra- and 
extra-abdominal location, the tumor should be classified as intra-abdominal. 


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12 May 2022 Final Version 2.0 
 
 
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1.2.3. 
Stopping Rules and Unblinding 
For the double-blind phase, the participant, investigator, and all other clinical site personnel will 
be blinded to the assigned treatment allocation. All sponsor personnel will also be blinded except 
for the sponsor’s quality assurance designee(s), safety designee(s), and clinical supply material 
designee(s).  
If central imaging review determines that a participant has radiographic progressive disease 
(using Response Evaluation Criteria In Solid Tumors [RECIST] v1.1) during the double-blind 
phase of the study, the site will be notified by the central imaging core laboratory. The 
participant will then return for the EOT visit which will unblind the participant and participant 
will have the option to enter OLE phase, if eligible. All EOT assessments and all ongoing 
adverse events (AEs) / serious AEs (SAEs) must (1) be assessed for causality by the investigator 
or qualified designee in a blinded manner and (2) recorded in the electronic case report form 
(eCRF) prior to the unblinding of the study treatment allocation. 
Study participants who discontinue due to clinical progression will NOT be unblinded and will 
NOT be eligible to enroll into the optional OLE phase of the study. These participants should be 
discontinued from the study after completing an EOT and follow-up (FUP) visit as specified in 
applicable SoA table. 
If a participant discontinues study treatment for any reason other than radiographic progressive 
disease as determined via central review, the study treatment allocation will not be unblinded. 
1.2.4. 
Study Procedures 
The schedule of assessments, as outlined in the study protocol, are provided in Table 1 (for 
double-blind phase) and Table 2 (for OLE phase). Please note that references to specific sections 
and table numbers in the schedules (and the associated table footnotes) are referring to sections 
and tables within the study protocol. 


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12 May 2022 Final Version  
 
 
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Table 1. 
Schedule of Assessments (SoA) – Double-Blind Phase 
Double-Blind Phase 
Cycle Number 
Screening1 
Cycle 1 
Cycle 2 
Cycle 4 
Cycle 7 & Every 3 
Cycles26 
EOT27 
Follow-Up28 
Cycle Day 
 
Day 1 
Baseline3 
Day 8 
Day 15 
Day 22 
Day 28 
Day 1 
Day 1 
Visit Week 
 
Week 1 
Week 2 
Week 3 
Week 4 
Week 8 
Week 13 
Week 25 & On 
 
 
See 
footnote 
27 for visit 
window 
 
 
30 days  
after last 
dose 
(+7 days) 
Calendar Day 
 
(up to 28 
days before 
Day 1) 
Day 1 
Day 8 
Day 15 
Day 22 
Day 56 
Day 85 
Day 169 & On 
(Visit Window) 
(up to 48 hours 
prior to 1st dose) 
(± 2 days) 
(± 2 
days) 
(± 2 
days) 
(± 2 
days) 
(± 7 days) 
(± 7 days) 
Informed consent2 
X 
 
 
 
 
 
 
 
 
 
I/E criteria 
X 
X 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
Medical history including 
menstrual history for women 
X 
 
 
 
 
 
 
 
 
 
ECOG performance status4 
X 
X 
 
 
 
X 
X 
X 
X 
X 
Physical examination5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight/height7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG8 
X 
X8a 
(pre-& post 
dose) 
X8b 
(post 
dose) 
 
 
X 
X 
X 
X 
X 
Laboratory 
 
 
 
 
 
 
 
 
 
 
Tumor biopsy9 
X9a 
 
 
 
 
 
 
 
X9b 
(optional) 
 
Blood for serology10 
X 
 
 
 
 
 
 
 
 
 
Blood for serum pregnancy test 
(WOCBP only)11 
X 
 
 
 
 
 
 
 
 
 
Blood for PK sampling12 
 
X12a 
(serial) 
X12b 
(trough) 
X12b 
(trough) 
X12b 
(trough) 
X12b 
(trough) 
X12b 
(trough) 
X12b 
(trough) 
 
 
Blood for pharmacogenomics13 
 
X 
(optional) 
 
 
 
 
 
 
 
 
Blood for genotyping14 
 
X 
 
 
 
 
 
 
 
 
Blood for safety labs15 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Double-Blind Phase 
Cycle Number 
Screening1 
Cycle 1 
Cycle 2 
Cycle 4 
Cycle 7 & Every 3 
Cycles26 
EOT27 
Follow-Up28 
Cycle Day 
 
Day 1 
Baseline3 
Day 8 
Day 15 
Day 22 
Day 28 
Day 1 
Day 1 
Visit Week 
 
Week 1 
Week 2 
Week 3 
Week 4 
Week 8 
Week 13 
Week 25 & On 
 
 
See 
footnote 
27 for visit 
window 
 
 
30 days  
after last 
dose 
(+7 days) 
Calendar Day 
 
(up to 28 
days before 
Day 1) 
Day 1 
Day 8 
Day 15 
Day 22 
Day 56 
Day 85 
Day 169 & On 
(Visit Window) 
(up to 48 hours 
prior to 1st dose) 
(± 2 days) 
(± 2 
days) 
(± 2 
days) 
(± 2 
days) 
(± 7 days) 
(± 7 days) 
Blood for female hormone 
levels15 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
Blood for male hormone levels15 
 
X 
 
 
 
 
X 
X 
X 
X 
Urinalysis16 
X 
X 
 
 
 
X 
X 
X 
X 
X 
Urine pregnancy test 
(WOCBP only)17 
 
X 
 
 
X 
X 
 
(monthly)17a 
X 
X 
Patient-Reported Outcomes (PROs)18 
 
 
 
 
 
 
 
 
 
Home ePRO device training 
X 
 
 
 
 
 
 
 
 
 
GODDESS (symptom scale) 
 
(refer to Protocol Table 8) 
 
 
 
(monthly assessment, refer to 
Protocol Table 8) 
 
 
(refer to 
Protocol  
Table 8) 
BPI short form 
 
PROMIS PF short form 10a plus 
3 additional items from PROMIS 
item banks 
 
 
 
 
GODDESS (impact scale) 
 
 
 
 
EORTC QLQ-C30 
 
 
 
 
PGIS 
 
 
 
 
PGIC 
 
 
 
 
 
 
Imaging and RECIST 
 
 
 
 
 
 
 
 
 
 
Pre-Randomization RECIST v1.1 
Calculation Worksheet19 
X 
 
 
 
 
 
 
 
 
 
CT or MRI scan for tumor 
measurement (using RECIST 
v1.1)20 
X20a 
 
 
 
 
 
X20b 
X20b 
X20c 
 
MRI scan for tumor volume 
assessment20 
X 
 
 
 
 
 
 
X20b 
(every 6 cycles) 
X20c 
 
Local RECIST v1.1 read20  
X20a 
 
 
 
 
 
X 
X20b 
X20c 
 


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Double-Blind Phase 
Cycle Number 
Screening1 
Cycle 1 
Cycle 2 
Cycle 4 
Cycle 7 & Every 3 
Cycles26 
EOT27 
Follow-Up28 
Cycle Day 
 
Day 1 
Baseline3 
Day 8 
Day 15 
Day 22 
Day 28 
Day 1 
Day 1 
Visit Week 
 
Week 1 
Week 2 
Week 3 
Week 4 
Week 8 
Week 13 
Week 25 & On 
 
 
See 
footnote 
27 for visit 
window 
 
 
30 days  
after last 
dose 
(+7 days) 
Calendar Day 
 
(up to 28 
days before 
Day 1) 
Day 1 
Day 8 
Day 15 
Day 22 
Day 56 
Day 85 
Day 169 & On 
(Visit Window) 
(up to 48 hours 
prior to 1st dose) 
(± 2 days) 
(± 2 
days) 
(± 2 
days) 
(± 2 
days) 
(± 7 days) 
(± 7 days) 
Enrollment and Study Treatment 
 
 
 
 
 
 
 
 
 
Randomization21 
 
X 
 
 
 
 
 
 
 
 
Study treatment dispensing22 
 
X 
 
 
 
 
X 
X 
 
 
Study treatment 
administration/diary23 
 
 
 
 
Study treatment accountability 
 
 
 
 
 
 
X 
X 
X 
 
Ongoing Monitoring 
 
 
 
 
 
 
 
 
 
 
Monthly wellness checks24 
 
 
 
ConMed review 
 
AE/SAE review25 
 
AE = adverse event; BID = twice daily; BPI = brief pain inventory; ConMed = concomitant medication; CT = computed tomography; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology 
Group; eCRF = electronic case report form; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30; EOT = end of treatment; ePRO = 
electronic patient-reported outcome; FU = follow-up; GODDESS = GOunder/DTRF DEsmoid Symptom/Impact Scale; ICF = informed consent form; I/E = inclusion/exclusion; IRT = interactive response 
technology; MRI = magnetic resonance imaging;  OLE = open-label extension; PFS = progression free survival; PGIS = patient global impression of severity; PGIC = patient global impression of change; 
PK = pharmacokinetic; PRO = patient-reported outcome; PROMIS PF= Patient-Reported Outcomes Measurement Information System Physical Function; RECIST = Response Evaluation Criteria in Solid 
Tumors; SAE = serious adverse event; SoA = scheduled of activities; v = version; WOCBP = women of child bearing potential.. 
1. Screening visit: Assessments may occur up to 28 days prior to first dose of study treatment with a minimum screening period of 14 days to allow for 
participant completion of the screening and baseline PRO assessments (refer to Protocol Table 8 for PRO administration schedule). An extension to the 
screening period may be permitted on a case-by-case basis following discussion between the investigator and the medical monitor/sponsor. The reason(s) for 
the extension must be clearly documented. 
2. Informed consent process: Includes participant signing the 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 Protocol Section 10.1.3 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 
except for the following assessments: post-dose 12-Lead ECGs and post-dose blood draws for pharmacokinetic (serial PK) sampling. 
4. ECOG performance status: At baseline, assessment must be done prior to first dose of study treatment. Refer to Protocol Section 10.7 for ECOG scale. 


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5. Physical examination: At baseline, assessment must be done prior to first dose of study treatment. Refer to Protocol Section 8.2.2 for detail regarding 
physical examination requirements. 
6. Vital signs: Includes blood pressure, respiratory rate, pulse rate, and body temperature (following at least 5 minutes of rest). At baseline, assessment must be 
done prior to first dose of study treatment. Refer to Protocol Section 8.2.4 for more detail. 
7. Height: Required at screening only. Weight to be collected at all visits. 
8. 12-lead ECGs: Will be administered in triplicate (approximately 2-3 minutes apart and averaged) and read locally at the site. Participants should rest in semi-
recumbent supine position for at least 5 minutes prior to ECG collection. Refer to Protocol Section 8.2.3 for more detail. 
8a. At baseline, triplicate ECGs are required at two timepoints: (1) prior to the first dose of study treatment and (2) approximately 1-hour post-dose. 
8b. At Cycle 1 Day 8, triplicate ECGs are required 1-hour (±10 minutes) post-dose. 
9. Tumor (core needle) biopsy: If tumor biopsy and MRI are performed during the same study visit, the biopsy must be done after MRI. Refer to 
Protocol Section 8.1.3 and central laboratory manual for sample processing details. 
9a. At screening, tumor biopsy is only required if archival tissue is not available for study procedures. Tumor biopsy will be reviewed centrally to 
reconfirm diagnosis, but participant enrollment is not dependent on central review. 
9b. At EOT, tumor biopsy will be optional and additional pharmacogenomic consenting is required (Protocol Section 10.1.3). 
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 Protocol Section 10.2 and central 
laboratory manual for sample processing details. 
11. Serum pregnancy test: Only required at screening for women of childbearing potential (WOCBP). Refer to Protocol Sections 8.3.5 and 10.4, and central 
laboratory manual for sample processing details. 
12. PK sampling: Refer to Protocol Section 8.5 and Protocol Table 11, and central laboratory manual for sample processing details. 
12a. Serial PK: Required on Cycle 1 Day 1 at the following timepoints: pre-dose and 0.25-, 0.5-, 1-, 1.5-, 2- and 3-hours post-dose. All efforts will be 
made to obtain the sample within 10% of the nominal time (e.g., within 6 minutes of a 60-minute sample) from dosing. Out of window PK draws 
will not be captured as deviations if the exact time of the sample collection is noted on the source documents and eCRF. 
12b. Trough PK: The evening before applicable study visits, participants will record the exact time study treatment was taken in the eDiary using the 
home ePRO device. Participants will not take their planned morning dose the day of the study visit. The morning dose will be taken following the 
pre-dose PK blood draw. 
13. Pharmacogenomics: Blood sample will be optional and additional pharmacogenomic consenting is required (Protocol Section 10.1.3). At baseline, blood 
sample must be drawn prior to first dose of study treatment. Refer to Protocol Sections 8.8 and 10.5, and central laboratory manual for sample processing 
details.  


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14. Genotyping: Required blood sample for all participants unless prohibited by local regulations. At baseline, blood sample must be drawn prior to first dose of 
study treatment. Refer to Protocol Section 8.7 and central laboratory manual for sample processing details. 
15. Safety Labs (hematology, serum chemistry, and hormone levels): At baseline, must be done prior to first dose of study treatment. Refer to 
Protocol Section 10.2 for a complete list of analytes and central laboratory manual for sample processing details. The time of hormone level blood draws 
should also be recorded. 
16. Urinalysis: At baseline, must be done prior to first dose of study treatment. Refer to Protocol Section 10.2 for a complete list of analytes and the central 
laboratory manual for sample processing details. Microscopy is to be performed only as needed based on positive dipstick test results and only if blood or 
protein is abnormal. 
17. Urine pregnancy tests: Only required for WOCBP. At baseline, urine pregnancy test must be done prior to first dose of study treatment to reconfirm 
eligibility. Refer to Protocol Sections 8.2.6 and 10.4 for more detail.  
17a. Following the Cycle 4 Day 1 study visit, all WOCBP participants will be required to return to the site for a monthly urine pregnancy test. 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 (refer to the study reference manual for additional details). 
18. PROs: Participants will complete the questionnaires and record study treatment administration in the eDiary using a home ePRO device 
(Protocol Section 8.1.2). Refer to Protocol Table 8 for the PRO administration schedule.  
19. Pre-Randomization RECIST v1.1 Calculation Worksheet (Protocol Section 8.1.1.1): As part of documenting that participants have satisfied inclusion 
criteria 2, sites are required to complete a worksheet (provided by the sponsor). The worksheet must be submitted to the sponsor’s designee during the 
screening period as soon as the data are available to complete the worksheet. All worksheets must be received no later than 7 days prior to C1D1 to allow for 
review prior to randomization (refer to study reference manual for additional details). 
20. Tumor imaging: All scans will be submitted to the central imaging core laboratory and read by Central Imaging Review throughout the study. Refer to 
Protocol Section 8.1.1 and imaging manuals for more detail.  
Tumor measurement using RECIST v1.1 assessment (Protocol Section 8.1.1.2): CT scans (contrast required unless contraindicated) or MRI scans (no 
contrast required) will be acquired to assess tumor changes. The modality (CT or MRI) for tumor assessment is to be determined by the investigator. The 
imaging modality used to assess the tumor at screening must be used at each subsequent visit. All scans will be submitted to the central imaging core 
laboratory and reviewed by Central Imaging Review, but participant enrollment is not dependent on central review. Tumor measurement will also be 
performed locally per RECIST v1.1 using the same target lesion(s) identified on the Pre-Randomization RECIST v.1.1 Calculation Worksheet. 
Tumor volumetric assessment (Protocol Section 8.1.1.3): MRI scans (no contrast required) will be acquired to assess tumor volume. All scans will be 
submitted to the central imaging core laboratory and assessed by Central Imaging Review.  
If applicable, CT and MRI assessments may be conducted on the same day. However, MRI with no contrast must be performed prior to CT with contrast. 
MRI must be done prior to tumor biopsy if assessments occur on the same visit. 
20a. Screening visit scans: 


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• 
MRI and CT scans obtained during the screening visit will serve as the participant’s baseline scan for the study (CT scan only required if it 
is the chosen modality for RECIST v1.1 tumor measurement). Scans should be submitted to central imaging core laboratory as early in the 
screening period as possible to confirm scan quality is acceptable for analysis prior to randomization.  
• 
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 and the quality of the scans are acceptable for analysis (as determined by the central 
imaging core laboratory). These scans will then be collected, stored, and documented as the screening visit scan(s). No other pre-enrollment 
images will be collected for central reading. 
20b. On study treatment scans: Starting at cycle 4, MRI or CT scans for tumor assessment (RECIST v1.1) will be obtained every 3 cycles. Starting at 
cycle 7, MRI for tumor volume assessment will be obtained every 6 cycles. 
20c. EOT visit scans: only required if not performed within the past 3 months. 
21. Randomization: Participants will not be randomized to study treatment using IRT until all I/E criteria (Protocol Sections 5.1 and 5.2) have been confirmed 
and all pre-randomization baseline study assessments have been completed.  
22. Study treatment dispensing: Participants will be dispensed study treatment using the IRT every 3 cycles at applicable study visits. 
23. Study treatment administration/diary: The first dose of study treatment (3 × 50 mg tablets) will be administered orally at the site at Cycle 1 Day 1 followed 
by a 3-hour observation period. Participants will 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 eDiary using the home ePRO device. Refer to Protocol Section 6.1 for more detail. 
24. Monthly wellness checks: Monthly telephone or email contact is required throughout the study (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 Protocol Section 8.2.7 for more detail. 
25. AEs/SAEs: Will be monitored and documented from the time of informed consent up to 30 days after the last dose of study treatment. Refer to 
Protocol Section 8.3 for more detail. Females reporting AEs/AESIs/SAEs of primary ovarian insufficiency (POI) and/or amenorrhea will have hormone levels 
assessed every 3 months until event resolution (or for at least 90 days after discontinuing study treatment). 
26. Every 3 cycles and on: Following Cycle 7 Day 1, participants will return every 3 cycles for study visits until death, progressive disease, discontinuation of 
study treatment for any reason, study is stopped by the sponsor for any reason, or required number of PFS events have been observed and primary PFS 
analysis has been completed. 
27. EOT visit: EOT visit should be conducted prior to study treatment discontinuation to avoid a gap in study treatment for participants entering the OLE phase. 
All EOT assessments must be conducted prior to unblinding (if applicable refer to Protocol Section 6.3.2.1). 
If Central Imaging Review determines that a participant has progressive disease (using RECIST v1.1) the participant will be encouraged to return to the site 
as soon as possible to complete the EOT visit assessments (but no later than 14 days of becoming aware of the progression). 


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If the participant discontinues study treatment for any reason other than progressive disease (as determined by Central Imaging Review using RECIST v1.1), 
they will be encouraged to return to the site as soon as possible to complete the EOT visit assessments prior to study treatment discontinuation or as close as 
possible to the last dose of study treatment. 
28. Follow-up visit: Only required for participants who are not continuing into the optional OLE phase and will occur 30 days (+7 days) after the last dose of 
study treatment. 


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Table 2. 
Schedule of Assessments (SoA) – Open-Label Extension Phase 
OLE Phase 
 
Cycle Number 
Cycle 15 
(Applicable only to participants previously 
randomized to placebo in the double-blind phase) 
Cycle 25 
Cycles 4, 7, 10 
Cycle 13 &  
Every 3 Cycles 
EOT20 
Follow-Up21 
Cycle Day 
Day 1 
Baseline3 
Day 8 
Day 15 
Day 22 
Day 28 
Day 1 
Day 1 
Visit Week 
Week 1 
Week 2 
Week 3 
Week 4 
Week 8 
Weeks 13, 25, 37 
Week 49 & On 
See 
footnote 
20 for 
visit 
window 
30 days after 
last dose 
(+ 7 days) 
Calendar Day 
Day 1 
Day 8 
Day 15 
Day 22 
Day 56 
Days 85, 169, 253 
Day 337 & On 
(Visit Window) 
Same day 
as, or up to 
24 hours 
after, 
double-
blind EOT 
(± 2 days) 
(± 2 days) 
(± 2 days) 
(± 2 
days) 
(± 7 days) 
(± 7 days) 
Informed consent1 
X 
 
 
 
 
 
 
 
 
I/E criteria2 
X 
 
 
 
 
 
 
 
 
ECOG performance status6 
Same as 
double-
blind EOT 
 
 
 
X 
X 
X 
X 
X 
Physical examination7 
Same as 
double-
blind EOT 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs8 
Same as 
double-
blind EOT 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
Same as 
double-
blind EOT 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG9 
X9a 
(post dose) 
X9b 
(post 
dose) 
 
 
X 
X 
X 
X 
X 
Laboratory 
 
 
 
 
 
 
 
 
 
Blood for PK sampling10 
X 
(serial)10a 
X 
(trough)10
b 
X 
(trough)10
b 
X 
(trough)10
b 
X 
(trough)1
0b 
X 
(trough)10b 
X 
(trough)10b 
 
 
Blood for safety labs11 
X11a 
X 
X 
X 
X 
X 
X 
X 
X 
Blood for female hormone levels11 
X11a 
 
 
X 
X 
X 
X 
X 
X 


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OLE Phase 
 
Cycle Number 
Cycle 15 
(Applicable only to participants previously 
randomized to placebo in the double-blind phase) 
Cycle 25 
Cycles 4, 7, 10 
Cycle 13 &  
Every 3 Cycles 
EOT20 
Follow-Up21 
Cycle Day 
Day 1 
Baseline3 
Day 8 
Day 15 
Day 22 
Day 28 
Day 1 
Day 1 
Visit Week 
Week 1 
Week 2 
Week 3 
Week 4 
Week 8 
Weeks 13, 25, 37 
Week 49 & On 
See 
footnote 
20 for 
visit 
window 
30 days after 
last dose 
(+ 7 days) 
Calendar Day 
Day 1 
Day 8 
Day 15 
Day 22 
Day 56 
Days 85, 169, 253 
Day 337 & On 
(Visit Window) 
Same day 
as, or up to 
24 hours 
after, 
double-
blind EOT 
(± 2 days) 
(± 2 days) 
(± 2 days) 
(± 2 
days) 
(± 7 days) 
(± 7 days) 
Blood for male hormone levels11 
X11a 
 
 
 
 
X 
X 
X 
X 
Urinalysis12 
Same as 
double-
blind EOT 
 
 
 
X 
X 
X 
X 
X 
Urine pregnancy test  
(WOCBP only)13 
Same as 
double-
blind EOT 
 
 
X 
X 
 
(Monthly)13a 
X 
X 
Patient-Reported Outcomes (PROs)14 
 
 
 
 
 
 
 
 
GODDESS (symptom scale) 
 
 
 
 
(Monthly assessment, 
refer to Protocol Table 9) 
(Quarterly 
assessment,  
refer to Protocol 
Table 9) 
 
(Refer to 
Protocol  
Table 9) 
BPI short form 
 
 
 
 
 
PROMIS PF short form 10a plus 3 
additional items from PROMIS 
item banks 
 
 
 
 
 
GODDESS (impact scale) 
 
 
 
 
 
EORTC QLQ-C30 
 
 
 
 
 
PGIS 
 
 
 
 
 
PGIC 
 
 
 
 
 
Imaging and RECIST 
 
 
 
 
 
 
 
 
 
CT or MRI scan for tumor 
measurement (using RECIST 
v1.1)15 
Same as 
double-
blind EOT 
 
 
 
 
X 
X15a 
(Cycle 13 and 
then every 6 
cycles) 
X15b 
 


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OLE Phase 
 
Cycle Number 
Cycle 15 
(Applicable only to participants previously 
randomized to placebo in the double-blind phase) 
Cycle 25 
Cycles 4, 7, 10 
Cycle 13 &  
Every 3 Cycles 
EOT20 
Follow-Up21 
Cycle Day 
Day 1 
Baseline3 
Day 8 
Day 15 
Day 22 
Day 28 
Day 1 
Day 1 
Visit Week 
Week 1 
Week 2 
Week 3 
Week 4 
Week 8 
Weeks 13, 25, 37 
Week 49 & On 
See 
footnote 
20 for 
visit 
window 
30 days after 
last dose 
(+ 7 days) 
Calendar Day 
Day 1 
Day 8 
Day 15 
Day 22 
Day 56 
Days 85, 169, 253 
Day 337 & On 
(Visit Window) 
Same day 
as, or up to 
24 hours 
after, 
double-
blind EOT 
(± 2 days) 
(± 2 days) 
(± 2 days) 
(± 2 
days) 
(± 7 days) 
(± 7 days) 
Local RECIST v1.1 read15 
Same as 
double-
blind EOT 
 
 
 
 
X 
X15a 
(Cycle 13 and 
then every 6 
cycles) 
X15b 
 
Enrollment and Study Treatment 
 
 
 
 
 
 
 
 
Enrollment/first dose of open-label 
study treatment4 
X 
 
 
 
 
 
 
 
 
Study treatment dispensing16 
X 
 
 
 
 
X 
X 
 
 
Study treatment 
administration/diary17 
 
 
 
Study treatment accountability 
 
 
 
 
 
X 
X 
X 
 
Ongoing Monitoring 
 
 
 
 
 
 
 
 
 
Monthly wellness checks18 
 
 
 
ConMed review 
 
AE/SAE review19 
 
AE = adverse event; BID = twice daily; BPI = brief pain inventory; ConMed = concomitant medication; CT = computed tomography; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology 
Group; eCRF = electronic case report form; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30; EOT = end of treatment; ePRO = 
electronic patient-reported outcome; FU = follow-up; GODDESS = GOunder/DTRF DEsmoid Symptom/Impact Scale; ICF = informed consent form; I/E = inclusion/exclusion; IRT = interactive response 
technology;  MRI = magnetic resonance imaging;  OLE = open-label extension; PFS = progression free survival; PGIS = patient global impression of severity; PGIC = patient global impression of change; PK 
= pharmacokinetic; PRO = patient-reported outcome; PROMIS PF= Patient-Reported Outcomes Measurement Information System Physical Function; RECIST = Response Evaluation Criteria in Solid Tumors; 
SAE = serious adverse event; SoA = scheduled of activities; v = version; WOCBP = women of child bearing potential. 
1. Informed consent process: Includes participant signing the ICF (exclusive to the OLE study phase) and must be conducted prior to administration of the first 
dose of open-label study treatment. Refer to Protocol Section 10.1.3 for more detail on the process. 


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2. I/E criteria: Exclusive to the OLE phase. Refer to Protocol Sections 6.7.2 and 6.7.3 for participant eligibility criteria specific to the OLE phase. 
3. Baseline visit: The C1D1 visit of the OLE phase should be conducted on the same day as, or within 24 hours after, the double-blind EOT visit. A longer 
window between the double-blind EOT and OLE C1D1 visit may be allowed with prior medical monitor approval; however, repeat assessments may be 
required with medical monitoring guidance depending on the length of time between double-blind EOT and OLE C1D1. All double-blind EOT visit 
assessments, as described in the double-blind SoA (Protocol Section 1.3.1), will be conducted prior to unblinding the participant’s study treatment and prior 
to administration of the first dose of open-label study treatment.  
4. Enrollment and first dose of open-label study treatment: Participants will be enrolled in the OLE phase using the IRT only after (1) all ongoing AEs/SAEs 
from the double-blind phase have been assessed for causality in a blinded manner by the investigator or qualified designee, and (2) all AE/SAE causality 
assessments have been entered into the eCRF. All double-blind EOT visit assessments must be completed prior to unblinding and taking first dose of open-
label study treatment.  
Participants who were randomized to receive placebo in the double-blind phase will receive their first dose of study treatment at the site followed by a 3-hour 
observation period.  
Participants who were randomized to nirogacestat in the double-blind phase may take their first dose of open-label study treatment at home (observation 
period is not required). 
5. Study visits at Cycle 1 (Day 8, 15 and 22) and Cycle 2 (Day 28): Only applicable for participants who were previously randomized to receive placebo in the 
double-blind phase. If a participant was randomized to receive nirogacestat in the double-blind phase, these study visits will not be conducted, and the 
participant will not be required to return to the site until Cycle 4 Day 1 visit.  
6. 
ECOG performance status: Refer to Protocol Section 10.7 for the ECOG scale. 
7. 
Physical examination: Refer to Protocol Section 8.2.2 for more detail regarding physical examination requirements. 
8. 
Vital signs: Includes blood pressure, respiratory rate, pulse rate, and body temperature (following at least 5 minutes of rest). Refer to Protocol Section 8.2.4 
for more detail. 
9. 
12-lead ECGs: Will be administered in triplicate (approximately 2-3 minutes apart and averaged) and read locally at the site. Participants should rest in semi-
recumbent supine position for at least 5 minutes prior to ECG collection. Refer to Protocol Section 8.2.3 for more detail. 
9a. At baseline, triplicate ECGs are required approximately 1-hour post-dose (open-label study treatment). Applicable only to participants who were 
previously randomized to receive placebo in the double-blind study phase. 
9b. At Cycle 1 Day 8 visit, triplicate ECGs are required 1-hour (±10 minutes) post-dose. Applicable to participants who were previously randomized to 
receive placebo in the double-blind study phase only. 
10. PK sampling: Refer to Protocol Section 8.5 and central laboratory manual for sample processing details.  
10a. Serial PK: Only applicable to participants who were previously randomized to receive placebo in the double-blind study phase. PK samples should 
be collected on OLE Cycle 1 Day 1 at the following timepoints: pre-dose and 0.25-, 0.5-, 1-, 1.5-, 2- and 3-hours post-dose. All efforts will be 


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made to obtain within 10% of the nominal time (e.g., within 6 minutes of a 60-minute sample) from dosing. Out of window PK draws will not be 
captured as deviations if the exact time of the sample collection is noted on the source documents and eCRF. 
10b. Trough PK: The evening before applicable study visit, participants will record the exact time study treatment was taken in the eDiary using the 
home ePRO device. Participants will not take their planned morning dose the day of the study visit. The morning dose will be taken following the 
pre-dose PK blood draw. 
11. 
Safety labs (hematology, serum chemistry, and hormone levels): Refer to Protocol Section 10.2 for a complete list of analytes and central laboratory 
manual for sample processing details. The time of hormone level blood draws should also be recorded. 
11a. At baseline, blood draws for hematology, serum chemistry, and hormone levels will be done as part of the double-blind EOT visit (prior to 
unblinding). However, if hematology and serum chemistry safety labs have not been conducted within the 14 days prior to C1D1, an additional 
blood draw will be required for same day local laboratory processing to reconfirm adequate organ and bone marrow function (refer to OLE 
inclusion criteria 2) and must be done prior to first dose of open-label study treatment. 
12. 
Urinalysis: Refer to Protocol Section 10.2 for a complete list of analytes and the central laboratory manual for sample processing details. Microscopy is to 
be performed only as needed based on positive dipstick test results and only if blood or protein is abnormal. 
13. 
Urine pregnancy tests: Only required for WOCBP. Refer to Protocol Sections 8.2.6 and 10.4 for more detail. 
13a. Following Cycle 4 Day 1 study visit, all WOCBP participants will be required to return to the site for a monthly urine pregnancy test. 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 (refer to study reference manual for additional details). 
14. 
PROs: Participants will complete the questionnaires using a home ePRO device (Protocol Section 8.1.2). Refer to Protocol Table 9 for the PRO 
administration schedule. 
15. 
Tumor imaging: CT (contrast required unless contraindicated) or MRI (no contrast required) using RECIST v1.1 (modality to be determined by the 
investigator) is required. Whichever imaging modality is used to measure the tumor by RECIST v1.1 at screening in the double-blind phase must be used at 
each subsequent visit throughout the OLE phase. All scans will be submitted to the central imaging core laboratory and reviewed by Central Imaging 
Review. Tumor measurement will also be performed locally per RECIST v1.1 using the same target lesion(s) identified on the Pre-Randomization RECIST 
v.1.1 Calculation Worksheet. 
15a. Scan is required every 3 cycles until Cycle 13 Day 1, and then every 6 cycles thereafter. 
15b. At EOT, scan is only required if not performed within the past 3 months. 
16. 
Study treatment dispensing: Participants will be dispensed study treatment using the IRT every 3 cycles during study visits. 
17. 
Study treatment administration/diary: Participants will self-administer study treatment at 150 mg (3 × 50 mg tablets) 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 eDiary using the home ePRO device. (Protocol Section 6.1). 


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18. 
Monthly wellness checks: Monthly telephone or email contact is required throughout the study (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 Protocol Section 8.2.7 for more detail. 
19. 
AEs/SAEs: Will be monitored and documented from the time of informed consent and up to 30 days after the last dose of study treatment. Refer to 
Protocol Section 8.3 for more detail. Females reporting AEs/AESIs/SAEs of POI and/or amenorrhea will have hormone levels assessed every three months 
until event resolution (or for at least 90 days after discontinuing study treatment). 
20. 
End of treatment (EOT) visit: Should be conducted prior to study treatment discontinuation or as close as possible to the last dose of open-label study 
treatment.  
21. 
Follow-up visit: Only required for participants who are not transitioning directly to commercial nirogacestat (or sponsor’s Continued Access Plan) at time of 
discontinuation. The follow-up visit will occur 30 days (+7 days) after the last dose of study treatment. 
 
 


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1.2.5. 
Efficacy and Safety Endpoints 
1.2.5.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is PFS, which is defined as the time (in months) from 
randomization until the date of assessment of progression or death by any cause (whichever 
occurs first). Specifically, 
PFS = (Date of progression or death – Date of randomization +1) / 30.4375 
Progression will be determined radiographically using RECIST v1.1 (Eisenhauer, 2009) or 
clinically as assessed by the investigator. Clinical progression is defined as the onset or 
worsening of symptoms resulting in a global deterioration of health status causing the permanent 
discontinuation from study treatment and the initiation of emergent treatment (e.g., radiotherapy, 
surgery, or systemic therapy including chemotherapy or tyrosine kinase inhibitors) for DT/AF. 
Events of clinical progression will be adjudicated by an independent blinded central Endpoint 
Adjudication Committee (EAC) which will qualify events of clinical progression for inclusion in 
the PFS endpoint prior to study unblinding according to an EAC Review Charter. 
Study participants who discontinue the study due to clinical progression and the progression does 
not qualify as determined by EAC will be censored at the time of last response assessment.  
Participants who have not progressed or died will be censored based on the rules outlined in 
Table 5. Participants who do not have any response assessments will be censored at the date of 
randomization. Sensitivity analysis utilizing alternative censoring methods will be described in 
Section 4.3.1.2.  
1.2.5.2. 
Secondary Efficacy Endpoints  
Secondary efficacy endpoints include:  
• Objective Response Rate (ORR), defined in Section 4.3.2.1 
• Duration of responses (in months) as supportive, descriptive analyses of ORR, 
defined in Section 4.3.2.1.1 
• Change in PRO measures from baseline over time, as defined in Section 4.3.2.2 (as well as in 
the PRO Addendum):  
o GOunder/Desmoid Tumor Research Foundation DEsmoid Symptom/Impact Scale  
o Brief Pain Inventory (BPI) short form  
o European Organization for Research and Treatment of Cancer (EORTC) Quality of life 
Questionnaire-Core 30 (QLQ-C30) 


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1.2.5.3. 
Exploratory Endpoints  
Exploratory efficacy endpoints include:  
• Change in tumor volume from baseline as assessed by MRI volumetric 
• Changes using the Patient Global Impression of Severity (PGIS) and the Patient Global 
Impression of Change (PGIC) 
• Frequency and distribution of germline and somatic mutations in APC and CTNNB1 genes 
• Change in expression pre- and post-dose on Notch pathway genes 
• Percent change in MRI T2 intensity 
• PK samples to increase precision of model parameters 
• Exposure-response analysis using a final population PK/PD (PopPK/PD) model to determine 
relationship between exposure and primary, secondary and/or exploratory efficacy and safety 
endpoints 
• The incidence and frequency of clinical events related to disease specific desmoid tumor 
comorbidity which may include hospitalization as a result of small bowel obstruction, 
hospitalization due to desmoid tumor-related pain or surgery for desmoid tumor 
1.2.5.4. 
Safety Parameters 
The safety endpoints are evaluated by means of study treatment-related AE reports, physical 
examinations, and laboratory safety evaluations.  
AEs will be monitored continuously via safety laboratory assessments, ECGs, vital signs, and 
physical examinations. Clinically significant changes in physical examination findings, 
laboratory assessments, and vital signs will be reported as AEs. 


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2. 
SUBJECT POPULATION 
2.1. 
Population Definitions 
The following participant populations will be evaluated and used for presentation and analysis of 
the data: 
• Intent-to-Treat (ITT) Population: The ITT Population will consist of all participants who are 
enrolled and randomized to study treatment (nirogacestat or placebo). Participants will be 
analyzed according to the treatment they were randomized to and the strata to which they 
have been assigned. Participants who were randomized but did not subsequently go on to 
receive study treatment are included in the ITT population. 
• Per-Protocol (PP) Population: The PP Population will consist of those participants who 
received study drug and have no major protocol deviations. Major protocol deviations are 
defined in Section 2.2. and will be determined prior to unblinding. Participants will be 
analyzed according to the study treatment actually received. In addition to major protocol 
deviations, those participants who meet the following criteria may also be excluded from this 
population: 
o Do not have confirmed diagnosis of DT/AF per Inclusion Criterion #2 
o Mis-randomization  
o Permanent discontinuation due to non-compliance with study drug 
• Safety Population: The Safety Population will consist of all participants randomly assigned to 
study treatment and who take at least 1 dose of study treatment. Participants will be analyzed 
according to the treatment they actually received.  
The ITT population is the primary analysis population for the efficacy analyses. The PP 
population will be used for supportive analyses as needed. The Safety population will be the 
primary analysis population for the safety analyses. 
2.2. 
Protocol Deviations 
Protocol deviations are reviewed in accordance with the Protocol Deviation Plan prior to 
unblinding of the study results and the conduct of the primary statistical analyses. A data listing 
of all reportable PDs including a description of the deviation will be generated. Major protocol 
deviations are defined as reportable deviations that may impact the accuracy and or reliability of 
the efficacy data. Major protocol deviations impacting the efficacy analysis will be identified 
prior to conducting the primary statistical analysis.  
The number and percentage of participants with reportable protocol deviations not due to 
COVID-19 and reportable protocol deviations due to COVID-19 will be summarized overall and 
by category of deviation, including inclusion/exclusion criteria, investigational product, 
restricted concomitant medication use, study-required imaging, withdrawal criteria, safety 
reporting, informed consent, study procedures, and study required ePRO assessments.  


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2.3. 
Impacts from COVID-19 
This study was conducted during the global SARS-Cov-2 pandemic. The impact of COVID-19 
was mitigated based on the evolving EMA and FDA COVID-19 guidelines [European Medicines 
Agency 2021; US Food and Drug Administration 2020].  
A summary table and listing of all patients impacted by COVID-19 and how their participation 
in the study was altered, including missed visits, missed assessments and other deviations from 
protocol procedures due to COVID-19 will be provided. 


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3. 
GENERAL STATISTICAL METHODS 
3.1. 
Sample Size Justification 
The study sample size is based on the primary PFS endpoint. A total of 51 events will provide 
90% power and a 1-sided type 1 error rate of 0.025 (1-side hypothesis) to detect a difference 
between nirogacestat and placebo, assuming the median PFS in the nirogacestat group is 
20 months and 8 months in the placebo group (corresponding to a hazard ratio of 0.4 relative to 
placebo). Assuming a 10% dropout rate and a 20% spontaneous regression rate, 118 participants 
will be randomized in a 1:1 ratio to observe the required number of events.  
3.2. 
General Methods 
All data listings that contain an evaluation date will contain a relative study day associated with 
double-blind phase treatment start (Rel Day). Pre-treatment and on-treatment study days in 
double-blind phase represented as Rel Day are numbered relative to the day of the first dose of 
study medication in double-blind phase which is designated as Day 1. The preceding day is 
Day -1, the day before that is Day -2, etc. The last day of study medication is designated with an 
“L” (e.g., Day 14L). Post-treatment study days are numbered relative to the last dose and are 
designated as Day 1P, Day 2P, etc. If applicable, placebo subjects that have entered open-label 
phase will have a second relative study day derived associated with starting active treatment 
within open-label phase (OLE Day). On-treatment study days in open-label phase for placebo 
subjects represented as OLE Day are numbered relative to the day of first dose of open-label 
treatment which is designated as OLE Day 1 and will follow same rules as Rel Day. 
All output will be incorporated into Microsoft Word or Excel files, or Adobe Acrobat PDF files, 
sorted and labeled according to the International Conference on Harmonisation (ICH) 
recommendations, and formatted to the appropriate page size(s). 
Tabulations will be produced for appropriate disposition, demographic, baseline, efficacy, and 
safety parameters. For categorical variables, summary tabulations of the number and percentage 
of participants within each category (with a category for missing data) of the parameter will be 
presented. For continuous variables, the number of participants, mean, median, standard 
deviation, minimum, and maximum values will be presented. Time-to-event data will be 
summarized using Kaplan-Meier methodology using 25th, 50th (median), and 75th percentiles 
with associated 2-sided 95% confidence intervals (CIs), as well as percentage of censored 
observations.  
Formal statistical hypothesis testing on the primary endpoint, for the purpose of New Drug 
Application (NDA), will be conducted at the 1-sided, 0.025 level of significance. Type I errors 
for secondary endpoints will be controlled using a hierarchical testing procedure. Summary 
statistics and modeling results for secondary and exploratory endpoints will be presented, as well 
as confidence intervals on selected parameters, as described in the sections below. 
Data will be presented by participant and summarized by treatment. 
Graphical displays will be provided where useful to aid in the interpretation of results. 


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In addition, the following data conventions will be applied: 
• P-values greater than or equal to 0.001, in general, will be presented to 3 decimal places 
• P-values less than 0.001 will be presented as “<0.001;” P-values greater than 0.999 will 
be presented as “>0.999” 
• CIs will be presented to 1 more decimal place than the raw data 
• Weeks will be calculated as number of days divided by 7 
• Months will be calculated as number of days divided by 30.4375 
• Years will be calculated as number of days divided by 365.25 
• Cycles as used in adverse event summaries are defined as every 28 days 
• Day 1 will be considered as the first day of treatment in double-blind phase 
• All tables, figures, and listings will include footers at the bottom of the page reflecting 
the path of the programs used to generate the tables, figures, and listings, and date and 
time of the generation of the output 
3.3. 
Computing Environment 
All descriptive statistical analyses will be performed using SAS statistical software Version 9.4, 
unless otherwise noted. Medical history and adverse events will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA) Version 24.0 or higher. Concomitant 
medications will be coded using the World Health Organization (WHO) Drug Dictionary 
Version March 2019 or later. 
3.4. 
Baseline Definitions 
For all analyses, baseline for the double-blind phase will be defined as the most recent 
measurement prior to or on the first administration of study drug. For the OLE phase, baseline 
will be defined as the most recent assessment prior to the first administration of nirogacestat. 
Therefore, for participants who are assigned to the placebo arm during the DB phase and who 
enter the OLE phase, this will result in a secondary baseline for OLE which will be defined as 
the most recent measurement prior to the first administration of active treatment.  
3.5. 
Methods of Pooling Data 
Data will be pooled across study sites. 


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3.6. 
Adjustments for Covariates 
The stratified log-rank test and Cox proportional hazards model will include the randomization 
strata as a covariate (strata). In general, the stratification factor will be included in the analysis of 
the primary and secondary endpoints.  
Analyses accounting for baseline demographics or disease characteristics may be conducted as 
part of supportive analyses. This includes each of the subgroup variables listed in Section 3.8 
which will be considered for inclusion as covariates in the multivariable models where noted. 
3.7. 
Multiple Comparisons/Multiplicity 
Multiplicity will be controlled via hierarchical testing method for the primary and secondary 
endpoints in the order as listed in Section 4.3.  
3.8. 
Subgroups 
Select efficacy endpoints (PFS and Objective Response Rate [ORR]) will be examined in (tables 
and forest plots) the following subgroups:  


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Table 3. 
Subgroup for Efficacy Analyses 
Stratification 
 
  
  
Stratification factor as reported in randomization 
  
  
Demographics 
  
  
Sex (Male vs Female) 
Age (by quartile) 
  
Race (White vs Non-White) 
Ethnicity 
  
Geographic region (North America vs the rest of 
world) 
BMI (18.5 kg/m2,18.5 - < 25 kg/m2, 25 - < 30 kg/m2, 
≥ 30 kg/m2) 
  
  
Disease Characteristics 
  
  
Multi-focal disease vs single tumor 
Baseline target lesion size by quartile      
  
Baseline target lesion locations1 
  
  
  
Prior Treatment 
  
  
Any prior therapy (Yes vs No) 
Number of prior lines of therapies (0, 1-3, 4+) 
  
Prior systemic therapy (Yes vs No) 
Prior surgical treatment (Yes vs No) 
  
Prior radiation treatment (Yes vs No) 
Previous exposure with sorafenib (Yes vs No) 
  
Prior chemotherapy exposure (Yes vs No) 
Prior tyrosine kinase inhibitor exposure (Yes vs No) 
  
 
Desmoid tumor treatment status2 
Dose Modification 
  
  
Dosed per protocol vs reduction (Yes vs No) 
 Relative Dose Intensity (≤ 80% vs > 80%) 
  
  
Genetic Mutation 
  
  
History of familial adenomatous polyposis 
(FAP) 
Presence of any CTNNB1 mutation, somatic 
CTNNB1 mutation, or germline CTNNB1 mutation    
 
  
Presence of any APC mutation, somatic APC 
mutation, or germline APC mutation 
  
  
Adverse Event 
  
  
Highest Reported FSH in women of childbearing 
potential (WOCBP) by range indicator 
(Low/Normal, High) 
WOCBP with events of ovarian dysfunction (as 
defined by a narrow list of terms per Section 7.5.1) 
that have resolved versus those that have not resolved 
  
Participants with AEs of Rash or Alopecia (as 
defined by all narrow terms in Section 7.5.2). 
Participants with AEs of Diarrhea within the first 3 
cycles 
1 Baseline target lesion location is based on actual target tumor location from the Electronic Database. Baseline target lesion 
locations: Intra-Abdominal (including mesentery and pelvis) and Extra-Abdominal (including head/neck, para-spinal, extremities, 
abdominal/chest wall, and other locations). If a participant has multiple target tumors that are located in both the intra and extra-
abdominal location, the tumor will be classified as intra-abdominal.  
2 Desmoid tumor treatment status: 1) Treatment naïve, measurably progressing DT/AF, 2) Recurrent, measurably progressing 
DT/AF following at least one line of therapy, and 3) Refractory, measurably progressing DT/AF following at least one line of 
therapy  
 


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TEAE and treatment-related AEs will be examined in the following subgroups: 
Table 4. 
Subgroup Definition for Safety Analyses 
Stratification 
  
  
Stratification factor as reported in randomization 
  
  
Demographics 
  
  
Sex (Male vs Female) 
Age (by quartile) 
  
Race (White vs Non-White) 
Ethnicity 
  
Geographic Region (North America vs the rest of world) BMI (18.5 kg/m2,18.5 - < 25 kg/m2, 25 - < 30 
kg/m2, ≥ 30 kg/m2) 
  
  
Disease Characteristics 
  
  
Multi-focal disease vs single tumor 
Baseline target lesion size by quartile      
  
Baseline target lesion locations1  
  
  
  
Prior Treatment 
  
  
Any prior therapy (Yes vs No) 
Number of prior lines of therapies (0, 1-3, vs 4+)  
  
Prior systemic therapy (Yes vs No) 
Prior surgical treatment (Yes vs No) 
  
Prior radiation treatment (Yes vs No) 
Previous exposure with sorafenib (Yes vs No) 
  
Prior chemotherapy exposure (Yes vs No) 
Prior tyrosine kinase inhibitor exposure (Yes vs 
No) 
 
Desmoid tumor treatment status2 
 
  
  
Dose Modification 
  
  
Dosed per protocol vs reduction (Yes vs No) 
 Relative Dose Intensity (≤ 80% vs > 80%) 
  
 
  
Genetic Mutation 
  
  
History of familial adenomatous polyposis (FAP) 
Presence of any CTNNB1 mutation, somatic 
CTNNB1 mutation, or germline CTNNB1 
mutation    
  
Presence of any APC mutation, somatic APC mutation, 
or germline APC mutation 
  
1 Baseline target lesion location is based on actual target tumor location from the Electronic Database. Baseline target lesion 
locations: Intra-Abdominal (including mesentery and pelvis) and Extra-Abdominal (including head/neck, para-spinal, extremities, 
abdominal/chest wall, and other locations). If a participant has multiple target tumors that are located in both the intra and extra-
abdominal location, the tumor will be classified as intra-abdominal.  
2 Desmoid tumor treatment status: 1) Treatment naïve, measurably progressing DT/AF, 2) Recurrent, measurably progressing 
DT/AF following at least one line of therapy, and 3) Refractory, measurably progressing DT/AF following at least one line of 
therapy.  
3.9. 
Withdrawals, Dropouts, Loss to Follow-up 
Participants who are withdrawn or discontinue from the study will not be replaced. 
3.10. 
Missing, Unused, and Spurious Data 
In general, there will be no substitutions made to accommodate missing data points. All data 
recorded on the eCRF will be included in data listings that will accompany the CSR. Methods for 
handling incomplete PRO instruments will be performed according to their scoring manuals, if 


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available. The imputation of partial/missing dates for AEs, concomitant therapies/medications, 
and disease history/prior therapies are described in Section 7. 
3.11. 
Visit Windows 
It is expected that all visits should occur according to the protocol schedule. All data will be 
tabulated per the evaluation visit as recorded on the eCRF, even if the assessment is outside of 
the visit window. If the evaluation visit is missing in the database but there is data from an 
unscheduled or additional visit that is inside the visit window, the data from the unscheduled or 
additional visit will be used in data summaries. In data listings, the relative day of all dates to 
first study dose will be presented.  


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4. 
STUDY ANALYSES 
4.1. 
Disposition 
The total number of participants who were screened (who have signed the informed consent), the 
number randomized, and the number in each study population will be summarized by treatment 
arm and overall. The number of randomized participants in each primary tumor location stratum 
will also be presented.  
In addition, summaries will be presented for the number and percent of participants who: 
• Discontinued treatment and reasons for treatment discontinuation in the double-blind phase 
• Discontinued the study and reasons for study discontinuation 
• Continued to the open label study 
• Discontinued treatment and reasons for treatment discontinuation in the OLE phase 
• Participants who discontinued double-blind treatment but chose to not enter OLE 
All treatment and study discontinuation data will be listed. A by-participant data listing of 
inclusion and exclusion criteria not met will be presented. 
4.2. 
Demographics, Baseline Characteristics, and Medical History 
Demographics and baseline characteristics will be summarized for the ITT and Safety 
populations by treatment arm and overall. In addition, medical history (including overall medical 
history and any history of infertility) and disease characteristics will also be summarized for the 
safety and ITT populations.  
Demographics will include univariate statistics for age at time of informed consent (years), 
baseline weight, baseline height, baseline body mass index (kg/m2); and categorical summaries 
for sex, women of childbearing potential (yes / no) for females, menstrual history for females, 
infertility history for males and females, age, baseline ECOG, race, ethnicity, BMI group and 
geographic region. Menstrual history for females includes history of amenorrhea (yes / no) and 
menstrual irregularities (yes / no) collected on the eCRF page. 
Disease characteristics to be summarized include time (in month) since date of diagnosis to 
randomization, presence of multi-focal disease versus single tumor, number of target tumors and 
target tumor location(s), desmoid tumor treatment status (treatment-naïve, recurrent or refractory 
disease), baseline target lesion size, family history of FAP, any mutation of APC or CTNNB1, 
somatic mutation status of APC and CTNNB1, germline mutation status of APC and CTNNB1 
and total number of non-target tumors seen by central reviewers and location(s) of non-target 
tumors based on stratification factor and as reported in EDC.  
Demographic and baseline data for each participant will be provided in data listings. 


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4.2.1. 
Prior Therapy 
Prior therapies will be summarized by treatment arm and overall based on the ITT population. 
The variables will include any prior therapy (surgery, radiation, systemic) (yes / no), prior 
therapeutic surgery (yes / no) and resection margins, prior radiation therapy (yes / no), prior 
sorafenib exposure (yes / no), prior TKI exposure (yes/no) [defined as medications in the ATC 
classes of ‘BCR-ABL TYROSINE KINASE INHIBITORS’,’'OTHER PROTEIN KINASE 
INHIBITORS’], prior systemic therapy (yes / no), type of prior systemic therapies, number of 
lines of prior systemic therapies and responses, and months from most recent prior systemic 
therapy to randomization. The total number of prior therapies will also be summarized by 
treatment arm and overall.  
The duration to be summarized is defined as follows.  
• Months from most recent prior systemic therapy to randomization will be calculated as (date 
of randomization – stop date of most recent systemic therapy) / (30.4375).  
The imputation of partial/missing dates is described in Section 7. 
Additionally, prior surgeries and systemic therapies will be presented in separate tables 
summarizing SOC (or ATC) and PT by treatment arm and overall. Prior radiotherapies will also 
be summarized by type by treatment arm and overall. Prior systemic therapies will be 
summarized using modified PT. PTs will be modified to be grouped as outlined in Appendix 7.4 
to consolidate brand and generic medication names for the same active ingredient into a single 
line item to facilitate reporting of the same medication. Both the original and modified PTs will 
be included in the listings. If a participant experiences multiple surgeries or procedures under the 
same PT (or SOC/ATC), then the participant will be counted only once for that PT (or 
SOC/ATC). 
All prior therapy data will be listed in participant data listings.  
4.3. 
Efficacy Evaluations 
The primary and secondary efficacy endpoints will be tested in the following order: PFS, 
objective response rate, disease symptoms, impact, and quality of life evaluations by PRO. If the 
null hypothesis is rejected at the specified significance level, the testing may proceed to the next 
endpoint, but if the null hypothesis is not rejected, all subsequent results will be considered 
descriptive only. All data collected after crossover to nirogacestat in the OLE phase of the study 
will be analyzed and reported separately. 
Efficacy analyses will be conducted using the ITT population.  
4.3.1. 
Primary Efficacy Evaluation 
The primary efficacy endpoint is PFS, where disease progression is determined by either 
independent, blinded central imaging review using RECIST v1.1 as described in Section 8.1.2 of 
the protocol, or clinically as assessed by an investigator whose assessment is qualified via 
independent blinded central clinical review as described in Section 8.1.2 of the protocol. The 
primary efficacy analysis will be performed after approximately 51 events have been observed. 


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PFS will be analyzed using a 1-sided stratified log-rank test to compare the distributions between 
nirogacestat and placebo at alpha level of 0.025. PFS data will be summarized with Kaplan-
Meier methodology. Two sided 95% CIs for the median time-to-event in each study treatment 
arm and the hazard rate ratio will be computed.  
PFS will be calculated from time of randomization to the earlier date of progression or death due 
to any cause. The progression date will be determined based on the date of scan for events that 
are verified by blinded independent central imaging review using RECIST v1.1. For qualified 
events of clinical progression, it will be the earliest date of onset or worsening of symptoms 
resulting in a global deterioration of health status.  
In situations where study participants are discontinued early from the study by investigators for 
clinical progression but cannot be verified as qualified events, they will be considered as 
dropouts and will be censored for the primary analysis. Similarly, participants who do not 
progress or die will be censored at the date of the last valid computed tomography (CT)/MRI 
assessment. 
Censoring rules for the primary analysis are outlined in Table 5.  
Table 5. 
Primary PFS Censoring Methodology 
Situation 
Date of Censoring of Event 
Outcome 
No adequate disease status assessment  
Date of randomization 
Censored 
No documented progression or death  
Date of last adequate disease status assessment  Censored 
Progression that has been verified by the central 
imaging review using RECIST v1.1 with ≤1 
missing consecutive scheduled disease status 
assessment before progression  
Date of the earliest assessment that results in a 
finding of progression  
Event 
Early discontinuation by study investigator due to 
clinical progression that has been verified as 
qualified event by the independent Event 
Adjudication Committee (EAC) for primary 
analysis 
Earliest date of onset or worsening of 
symptoms resulting in a global deterioration of 
health status as documented by the date of 
clinical progression in the case report form 
Event 
Early discontinuation by study investigator due to 
clinical progression that do not meet the definition 
of a qualified event per protocol as judged by the 
EAC. 
Date of last adequate disease status assessment Censored 
Death before progression being documented with 
≤1 missing scheduled disease status assessment 
before death  
Date of death 
Event 
New anticancer therapy or procedure started prior 
to documented radiographic or clinical progression  
Date of last adequate disease status assessment 
before the new therapy 
Censored 
 


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4.3.1.1. 
Analysis of Progression Free Survival 
Kaplan-Meier curves will be presented, and HR and the 95% CI will be estimated using a Cox 
proportional hazards model controlling for stratification factor the participant is assigned to at 
randomization (primary tumor location - intra-abdominal vs extra-abdominal). 
A stratified log-rank test on PFS will be performed using SAS PROC LIFETEST with 
method = PL option (Kaplan-Meier estimates, also known as the product-limit estimates). The 
hazard ratio with 2-sided 95% CI will be estimated from the stratified Cox proportional hazards 
model using SAS PHREG procedure with ties = EXACT option in the model. In this analysis, 
the baseline hazard function will be allowed to vary across strata, i.e., the MODEL statement 
will include treatment arm variable as the only covariate and the STRATA statement will include 
tumor location.  
Number of participants with events, types of events (progression or death before progression), 
number of participants censored, number of participants for each reason of censoring, quartiles 
(i.e., the 25th, 50th (median), 75th percentile estimates), and 95% confidence intervals for PFS will 
be calculated from the product-limit method and presented by treatment arm. Kaplan-Meier plots 
of the survival distribution function will be presented and include the number of participants at 
risk over time by treatment arm. Additionally, a spider plot of percent change from baseline in 
tumor size over time will be presented. Time at which best overall response occurred (for 
participants with CR or PR) will be annotated as will when the participant is off treatment. A 
swimmer plot of duration of treatment will be produced where progression, first response, and 
death are noted. 
4.3.1.2. 
Sensitivity Analyses of PFS 
The following sensitivity analyses will be performed 
a) Calculation of PFS using only events confirmed by central radiographic review per 
RECIST v1.1  
b) Calculation of PFS including all PI-determined clinical progressions to assess the impact 
of the criteria used to determine qualified event adjudicated by EAC on the primary 
endpoint  
c) Analysis using the PP set using the primary endpoint censoring rules 
d) Using the date of the first missing assessment as the date of progression for participants 
who progressed radiographically right after 2 or more consecutively missed radiological 
assessments  
e) Using local RECIST results of PI selected target tumor, instead of results from the central 
review, for the 15 participants whose scans are read prior to the implementation of 
Protocol Amendment 2 (which included the implementation of PI selection of target 
lesions for central review)  
f) Additional sensitivity analyses using only subjects with centrally confirmed diagnosis of 
DT/AF 


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g) A sensitivity analysis using interval-censoring methodology for PFS will be performed. 
When the exact date of progression is not observed due to scheduled assessment, these 
progression events are considered interval censored. The right side of the interval will be 
the date of progression as defined in Table 5, and the left side of the interval will be the 
last adjudicated assessment for disease progression before the right side of the interval. If 
there is no adjudicated assessment before the date of progression, the left side of the 
interval will be the randomization date. Participants without a PFS qualified event will be 
right censored with the same censoring rules as specified in Table 5. 
A generalized stratified log-rank test stratified by the stratification factor will be 
performed for treatment comparison using SAS PROC ICLIFETEST (Guo, et al, 2014). 
This procedure will also be used to estimate the survival function for PFS with the 
EMICM method, which is a combination of the EM algorithm and iterative convex 
minorant algorithm. A multiple imputation method will be used to estimate the standard 
error of the survival function using SEED =138207. 
In addition, to estimate the median PFS follow-up time at the time of analysis, a time-to 
censoring analysis will be performed by reversing the censoring indicator used in the primary 
PFS analysis, i.e., the censored becomes an event and the PFS event becomes censored. 
4.3.1.3. 
Subgroup Analysis 
Subgroup analyses of the primary efficacy will be performed on the ITT population using the 
subgroups specified in Section 3.8. If there are too few events (≤5) in a particular subgroup level, 
only descriptive summaries will be provided. 
For each subgroup, HR and associated CIs will be calculated from a stratified Cox proportional 
hazards model. The stratification factor in the primary analysis will be used in the subgroup 
analyses when applicable. The HRs and 95% CIs will be presented on a forest plot including the 
HR and 95% CI for the overall group. Summaries of the number and percentage of participants 
experiencing a PFS event for each subgroup will be provided along with the median PFS by 
treatment arm. 
4.3.2. 
Secondary Efficacy Evaluations 
Secondary endpoints are described in Section 1.2.5.1. Secondary efficacy analyses will be 
conducted using the ITT population unless otherwise specified. The hierarchy for testing 
secondary endpoints will follow the order of their appearance below.  
4.3.2.1. 
Objective Response Rate (ORR) 
ORR will be calculated for each treatment arm and the proportions will be compared using the 
Cochran-Mantel-Haenszel test stratified by randomization factor. Response used for the 
definition of ORR is defined as having a confirmed Best Overall Response (BOR) of CR or PR 
by RECIST v1.1 during the blinded portion of the study, where BOR is defined in 
Section 4.3.3.1. Summaries of ORR and the 2-sided 95% exact CI will be presented. 


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4.3.2.1.1. Duration of Response 
Duration of Objective Response and duration of stable disease are supportive, descriptive 
analyses for ORR. Duration of Objective Response (DoOR) is defined as the duration in months 
from the time measurement criteria are met for CR or PR (whichever comes first) until the date 
of progression or death (whichever comes first). Duration of Stable Disease (DoSD) is defined as 
the duration in months from the start of treatment until the date of progression or death 
(whichever comes first).  
Pending data availability, DoOR will be analyzed using the Kaplan-Meier method based on 
participants with a documented response (CR or PR) only. Estimates for the 25th percentile, 50th 
percentile (median), and 75th percentile for DoOR (as well as the range) will be presented by 
treatment arms. Similarly, DoSD will be analyzed on participants with CR, PR, or SD only. 
Kaplan-Meier plots for DoOR and DoSD will be provided, respectively. The censoring method 
will be the same as that for the primary endpoint (Section 4.3.1). Since the number of the 
participants available for analysis is random, no formal testing between the two treatment arms 
will be conducted for both DoOR and DoSD. 
By-participant listings will be provided for DoOR and DoSD separately. DoOR listing will 
include number of completed cycles before first response, date of first response, date of 
progression or death if any, and DoOR. DoSD listing will include date of first study treatment, 
date of progression or death if any, and DoSD. Censored or event will be marked. Additionally, 
to evaluate efficacy compared to previous treatment, number of prior therapies will be added to 
the listings. Swimmer plots will be used to present duration of responses over time for each 
participant. 
4.3.2.2. 
Analysis of PRO Assessment data 
Due to the number of instruments used in the study and the complexity of the planned analyses, a 
PRO Addendum was created specifically to detail the PRO data analysis methods to be used. The 
endpoints and testing hierarchy for PRO data analysis can be found in this addendum and are 
repeated below. 
Secondary efficacy endpoints related to the PRO, and their testing order, are as follows: 
• Mean change from baseline at Cycle 10 in BPI-SF Average Pain Intensity (API) score 
• Mean change from baseline at Cycle 10 in Desmoid Tumor Symptom Scale (DTSS) Total 
Symptom Score 
• Mean change from baseline at Cycle 10 in Desmoid Tumor Impact Scale (DTIS) Physical 
Functioning Domain Score 
• Mean change from baseline at Cycle 10 in EORTC QLQ-C30 Global health status/Quality 
of life (GHS/QoL) 
• Mean change from baseline at Cycle 10 during the double-phase period in EORTC QLQ-
C30 Physical Functioning 
• Mean change from baseline at Cycle 10 during the double-phase period in EORTC QLQ-
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The PROMIS questionnaire will not be formally tested in the endpoint hiearchy.  
4.3.3. 
Exploratory and Other Supportive Efficacy Analyses 
4.3.3.1. 
Best Overall Response (BOR) 
Confirmed BOR (as reported from Central Imaging review) is defined as the best response 
obtained across all time points during the DB phase of the study provided after application of the 
following confirmation rules: 
Rule 1:  PR or CR require confirmation by a subsequent scan. To be allowed to confirm a PR or 
a CR, a time point must be at least 4 weeks after the initial PR or CR is observed. 
Rule 2:  To be assigned SD as a BOR, a participant is required to have at least one non-PD/non-
Evaluable (NE) time point response at least 8 weeks after baseline and not meet requirements for 
BOR of PR or CR. 
Rule 3: When one or more NE time points are interleaved between CR or PR time points, these 
NE time points will not impact response confirmation. As an example, a participant with PR-NE-
PR will be assigned a BOR=PR (provided the second PR meets rule 1).  
Table 6. 
BOR Determination Table 
First Time Point 
Response 
Subsequent Time Point Response 
BOR 
CR 
CR* 
 
CR 
CR 
PD 
SD provided rule 2, otherwise PD 
CR 
NE 
SD provided rule 2, otherwise NE 
PR 
PR* or CR* 
CR if CR is confirmed; PR otherwise 
PR 
SD 
SD 
PR 
PD 
SD provided rule 2, otherwise PD 
PR 
NE 
SD provided rule 2, otherwise NE 
SD 
SD 
SD 
SD 
NE 
SD provided rule 2, otherwise NE 
SD 
PD 
SD provided rule 2, otherwise PD 
NE 
CR, PR, SD (and no subsequent response) 
SD provided rule 2, otherwise NE 
NE 
NE 
NE 
Source: MICL Imaging Review Charter 
Note: CR* or PR* indicates that time interval for confirmation must apply, see rule 1. 
Confirmed BOR (as reported by central imaging review) will be summarized with frequency and 
two-sided 95% CI by treatment arm. A comparison between the two treatment arms will be 
performed using Cochran-Mantel-Haenszel test stratified by randomization factor. 


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4.3.3.2. 
Disease Control Rate (DCR) 
DCR (CR+PR+SD) will be calculated for each treatment arm and the proportions will be 
compared using the Cochran-Mantel-Haenszel test stratified by randomization factor. The 
2-sided 95% exact CI will also be presented 
4.3.3.3. 
Time to Tumor Progression (TTP) 
TTP is defined as the time from randomization until objective tumor progression; TTP does not 
include deaths. TTP will be compared between the two arms. Number of participants with 
progression, Kaplan-Meier quartiles (i.e., the 25th, 50th (median), 75th percentile estimates), as 
well as descriptive statistics will be presented by treatment arm. 
4.3.3.4. 
PFS at Month 6 (PFS6), Month 12 (PFS12) and Month 24 (PFS24) of Treatment 
Period  
Proportion of participants with progression free survival at month 6, month 12 and month 24 of 
the treatment period will be compared between the treatment arms. Survival function estimates 
will be presented. 
4.3.3.5. 
DOR at Month 6 (PFS6), Month 12 (PFS12) and Month 24 (PFS24) of 
Treatment Period  
Proportion of participants who have experienced response who are still responders at month 6, 
month 12 and month 24 following the start of response will be compared between the treatment 
arms. Survival function estimates will be presented. 
4.3.3.6. 
Time to Response 
Time to first response and BOR will be calculated as time in months from first dose until date of 
either the first documented response (CR or PR) or BOR. Summary statistics will be provided by 
treatment arms. 
4.3.3.7. 
Change in Tumor Volume Assessed by MRI 
Percent change in tumor volume assessed by MRI will be analyzed using a repeated measures 
model adjusting for baseline tumor volume and randomization strata. The analysis will use 
mixed model with repeated measures (MMRM) and the model will include treatment, baseline 
volume, visit, and randomization strata as covariates. Treatment by visit interaction will be 
included in the model and if significant, treatment differences will be assessed by timepoint. The 
covariance structure will be assumed to be unstructured, although if the matrix fails to converge, 
alternative structures will be used in the following order until convergence is reached: Toeplitz 
with heterogeneity (TOEPH), autoregressive with heterogeneity (ARH[1]), Toeplitz (TOEP), and 
autoregressive (AR[1]). The assessment timepoints will be analyzed as categorical. The model 
will use a Kenward-Rogers approximation for the degrees of freedom. Adjusted mean estimates 
per treatment arm and 95% CIs along with an estimate of treatment difference, 95% CI, and 
p-value will be presented. In addition, unadjusted summary statistics for tumor volume will be 
presented by visit and treatment arm. The main analysis of change in tumor volume will focus 
solely on the largest target lesions per subject while an additional analysis will focus on lesions 
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The same analysis will be repeated on the subset of participants who discontinued the study due 
to PI-determined clinical progression and adjudicated as qualified event for the primary analysis 
by the independent EAC. A listing of tumor volume for all PI-determined clinical progressions 
will also be provided. 
Waterfall plots of the percent change from baseline in target tumor size by tumor volume as 
assessed by MRI will be presented by subject with each subject color-coded based on their best 
overall disease response.  
4.3.3.8. 
Change in Sum of Largest Diameter of Tumor Assessed by RECIST 
Observed value, change from baseline and percent change in sum of largest diameter of tumor 
accessed by RECIST will be summarized over scheduled visits by treatment arm and overall. 
Sum of largest diameter is called as follows:  
• The diameter of each lesion is assessed by two readers.  
• The sum of the lesions is calculated from the tumors identified at baseline for each visit. New 
tumors will not be included in the sum.  
• The average sum of lesions for the two readers is calculated unless the assessments were 
adjudicated. In cases where the assessments are adjudicated, the adjudicated (sum) record 
will be used.  
The readings of tumor diameters accessed by RECIST will be listed in participant data listings.  
Waterfall plots of the percent change from baseline in target tumor size by RECIST v1.1 will be 
presented by subject with each subject color-coded based on their best overall disease response. 
For the RECIST tumor size plot, the percent change from baseline will be computed on the 
averages of sum of target lesion diameters from the two readers for each subject.  
4.3.3.9. 
Tumor Response by Exposure 
The relationship between active treatment exposure (nirogacestat) and disease response (as 
measured by RECIST response categories) will be explored among the actively treated 
participants in the following manner (through modeling when appropriate): 
1. Total exposure by response status will be compared. Total exposure is defined as the total 
number of equivalent cycles treated at per protocol dose during the treatment period. It is 
defined as  
Number of equivalent cycle = total dose administered / (28 * 300mg)   
2. Actual and relative dose intensities (as defined in Sec 4.4.1 below) will be compared by 
response status  
3. Correlation between exposure, as measured by total exposure and exposure intensity, and 
time to first response will be investigated through Cox modeling. HRs will be compared 
between participants with high (> median) or low (<= median) exposure. 


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4. Correlation between change in tumor size/volume and exposure (total and intensity) will 
be explored through linear regression modeling, adjusted for baseline tumor size/volume. 
5. Comparison of time to response between patients who had dose reductions vs those who 
had not using Cox model. 
4.3.3.10. 
Change in Tumor Volume by Tumor Response 
Actual value and change from baseline in tumor volume will be summarized over scheduled 
visits by treatment arm and RECIST tumor response (PD, SD, and CR/PR). 
4.3.3.11. 
Change in Symptoms by Exposure and Change in Tumor Size/Volume  
Analysis has shown that the recently created GODDESS instruments for DT patients, Desmoid 
Tumor Symptom Scale (DTSS) and Desmoid Tumor Impact Scale (DTIS), having good 
psychometric properties. Therefore, the investigation of change in DT symptoms and impact as a 
function of active treatment exposure and change in tumor size/volume will focus on the scores 
of GODDESS and its subdomains, supplemented with scores from BPI and EORTC when 
appropriate. Descriptions of the instruments, item definitions and domain scale construction are 
provided in the PRO Addendum attached to this document. 
a. Change in Symptoms by Change in Tumor Size/Volume 
Correlation between symptom scores of GODDESS, BPI and EORTC and percent change in 
tumor size (per RECIST) / tumor volume (per MRI) will be calculated. 
GODDESS subscales to consider: 
DTSS Weekly Avg Mean Score 
DTIS Physical Functioning Domain Score 
DTSS Pain Domain Score 
DTIS Sleep Domain Score 
DTSS Extra-abdominal Domain Score (among 
participants with extra-abdominal tumor) 
DTIS Emotional Domain Score 
DTSS Intra-abdominal Domain Score (among 
participants with intra-abdominal tumor) 
BPI Subscales to consider: 
BPI #3 (worst pain last 24 hrs) 
BPI Pain Severity Subscale Score 
BPI #5 (avg pain last 24 hrs) 
BPI Pain Interference Subscale Score 
EORTC Subscales to consider: 
QLQ-C30 Physical Functioning 
QLQ-C30 Cognitive Functioning 
QLQ-C30 Role Functioning 
QLQ-C30 Social Functioning 
QLQ-C30 Emotional Functioning 
QLQ-C30 Insomnia 
b. DT Symptoms and Impact by Exposure 


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Difference in exposure levels (total and intensity) between responders and non-responders, as 
defined by clinical meaningful change in GODDESS scores and subscores, will be investigated 
for the overall (exposure during full double-blind period versus responder at any point in 
double-blind period) and within the first six cycles of the study treatment period (exposure 
through six cycles versus early responders through 6 cycles). 
Similar comparisons will be carried out between participants who do or do not experience a 
clinically significant change in pain, as measured by a 2-point or more reduction in BPI #3 
(worst pain in past 24 hrs). 
4.3.3.12. 
PFS by Mutation Status in APC and CTNNB1 Genes 
Besides descriptive statistics (frequency and distribution) and data listings, the relationship 
between germline and somatic mutation status of APC and CTNNB1 and PFS will be explored 
through Cox modeling. 
4.3.3.13. 
Other Prognostic Factors  
Besides genetic mutations in Section 4.3.3.12, stratified Cox proportional hazards model will be 
used to estimate HRs according to stratification factor and additional factors described in 
Section 3.6 and listed under Section 3.7 using a stepwise procedure. Possible interactions among 
those factors will also be explored. 
4.3.3.14. 
Change in Expression of Notch Genes 
Change between pre- and post-dose gene expression values of Notch pathway will be analyzed 
using mixed model. Data listing by participant will be provided. If data is not available by time 
of the primary analysis, this analysis will be carried out as a part of analysis at the end of OLE.  
4.3.3.15. 
Change in MRI T2 intensity 
Actual value and change from baseline in MRI T2 hyperintensity will be summarized over 
scheduled visits by treatment arm and overall. All MRI T2 hyperintensity results will be listed in 
participant data listings. 
4.3.3.16. 
Change in MRI T2 intensity by Tumor Response 
Actual value and change from baseline in MRI T2 hyperintensity will be summarized over 
scheduled visits by treatment arm and RECIST tumor response (PD, SD, and CR/PR). Change in 
MRI T2 intensity by Baseline T2 Intensity Category (90%+ vs <90%) 
Actual value and change from baseline in MRI T2 hyperintensity will be summarized over 
scheduled visits by treatment arm and baseline T2 hyperintensity (<90% and ≥ 90%). 
4.3.3.17. 
DT Specific Comorbidity 
Comparison will be made between the treatment and placebo arms on the incidence and 
frequency of clinical events related to disease specific desmoid tumor comorbidity which may 
include hospitalization as a result of small bowel obstruction, hospitalization due to desmoid 


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tumor-related pain, or surgery for desmoid tumor. The list of terms included in this analysis will 
be identified prior to unblinding for the primary analysis. 
4.3.3.18. 
Local vs Central RECIST v1.1 Readings 
A concordance analysis of RECIST v1.1 results by the local site investigators vs blinded central 
reviewers will be attempted. Cohen’s kappa test will be conducted, whenever data available. If 
sufficient data is not available by time of the primary analysis data cut, this analysis will be 
carried out after last patient, last visit for the double-blind phase of the study.  
4.4. 
Safety Analyses 
Safety analyses will be conducted using the Safety population. All data collected after crossover 
to nirogacestat in the OLE phase of the study will be analyzed and reported separately. 
4.4.1. 
Study Drug Exposure and Compliance 
Extent of exposure will be summarized for each treatment arm based on the Safety population.  
Exposure will be summarized by treatment arm and overall, as follows: 
• Duration of exposure in months (last dose date – first dose date + 1 / 30.4375) summarized as 
a continuous variable  
If a data cut-off date is used at the time of analysis and participants are receiving treatment, 
the last dose date will be the data cut-off date  
• Number and percentage of participants who received treatment with a duration of at least 
1 cycle, 2 cycles, 3 cycles, 6 to < 13 cycles, 13 cycles to <25 cycles and 25 cycles or longer  
• Actual dose intensity (mg/day) – calculated as the cumulative dose received / duration of 
exposure based on dose modification data 
• Relative dose intensity (%) defined as 100 x (total cumulative dose received)/ (planned 
cumulative dose, where planned cumulative dose is 300 mg/day multiplied by duration of 
exposure) and summarized as a continuous variable 
• Number and percentage of participants per relative dose intensity group (< 80% vs ≥ 80%) 
• Number and percentage of participants with a dose modification (dose reduction and/or dose 
interruption as reported on the dose modification eCRF) as well as reasons for dose 
modification 
• Number and percentage of participants with a dose reduction (as reported on the dose 
modification eCRF)  
• Time (in completed cycles) to the first dose reduction and first dose interruption will be 
summarized as continuous variables 
• Number and percentage of participants with a dose interruption including the number of days 
interrupted (cumulative and per interruption) 
• Number and percentage of participants with study drug discontinued  


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A by-participant listing will be presented for exposure to study drug and dosing modifications. 
4.4.2. 
Adverse Events 
All AEs will be coded using the MedDRA coding system version 24.0 or later and displayed in 
tables and data listings using system organ class (SOC) and preferred term (PT).  
Analyses of AEs will be performed for those events that are considered treatment-emergent 
adverse events (TEAEs), where treatment-emergent is defined per protocol as any AE 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 imputation of partial/missing dates is described in Section 7.1.  
Treatment-related TEAEs are defined as a TEAE that was considered by the Investigator to be at 
least possibly related to the study drugs. If the ‘Relationship to study drug’ is missing, then it 
will be imputed as ‘Related to study drug’ in summary tables. AE severity will be classified 
according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) v5.0. 
A summary of AEs by treatment arm and overall will include the number and percentage of 
participants who experience at least one of the following. The total number of events will also be 
reported.  
• TEAEs 
• TEAEs related to study treatment 
• Serious TEAEs  
• Serious TEAEs by Relatedness 
• TEAEs with CTCAE grade ≥ 3  
• TEAEs with CTCAE grade ≥ 3 related to study treatment 
• TEAEs by maximum severity (Grade)  
• TEAEs leading to early discontinuation from study 
• TEAEs leading to death 
• TEAEs by Cycle of Onset * 
• Rash or Alopecia TEAEs+ 
• Ovarian Dysfunction Events (as defined by a narrow list of terms per Section 7.5.1) by 
resolution status (WOCBP only)+ 
• Diarrhea within the first 3 cycles+ 
*A Cycle of Onset is assigned to each TEAE based on 28-day windows starting from treatment start. TEAEs 
in first five cycles are displayed separately while all TEAEs occurring from Cycle 6 to Cycle 12, and Cycle 12 
onward are presented together.  
+indicates these summaries will only be included in the overall summary of AEs and will not be summarized 
by SOC and PT 
In each tabulation of TEAEs, each participant will contribute only once (i.e., the most related 
occurrence, or the most intense occurrence, or the first cycle of onset) to each of the subject 
incidence rates in the descriptive analysis, regardless of the number of episodes. 


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The above categories will also be presented in tables summarizing SOC and PT by treatment arm 
and overall. If a participant experiences multiple AEs under the same PT (or SOC), then the 
participant will be counted only once for that PT (or SOC). The number of events of each type 
will be displayed alongside associated subject incidence percentages. 
A TEAE summary by PT only and sorted by descending frequency of the active treatment arm 
will also be produced.  
All AEs will be listed in participant data listings. 
By-participant listings will also be provided for the following: AEs leading to death, serious 
adverse events, and AEs leading to withdrawal or discontinuation from study.  
4.4.2.1. 
Selected Treatment Emergent Adverse Events 
Additional summary tables are planned for selected adverse events.  
• Ovarian dysfunction (OD) [separately for Narrow terms and both Broad and Narrow 
identified per Section 7.5. –WOCBP only]: 
o Summary of participants and number of events of ovarian dysfunction overall, by 
treatment, and by age category (<35, 35-<40, 40+)  
o Summary statistics for time to onset of first OD event (days), duration of each 
event (days), and time from start of first OD to resolution of all OD (days) 
overall, by treatment and age category (<35, 35-<40, 40+) 
o Summary of OD event outcomes overall, by treatment, and by age category (<35, 
35-<40, 40+). Percentages for this summary will be out of the total number of OD 
events 
o Summary of prior therapy including any prior therapy 
(systemic/radiation/surgical, yes/no), prior radiation therapy (yes/no), prior 
therapeutic surgery (yes/no), or prior systemic therapy (yes/no) in WOCBP with 
and without ovarian dysfunction. Additionally, type of prior systemic therapies, 
number of lines of prior systemic therapies will be summarized.  
o Relative Intensity during Double-Blind Phase in WOCBP with and without 
ovarian dysfunction  
o Summary of dose modifications (reduction, interruptions, withdrawal) in 
participants reporting events of OD overall and by treatment   
o Summary of concomitant medications initiated for the treatment of events of OD 
by ATC classification and PT, grade (Grade 1-2 vs 3+) overall and by treatment 
o Summary of duration of concomitant medication use for treatment of events of 
OD by grade (Grade 1-2 vs 3+) overall and by treatment. If multiple medications 
are received durations will be combined and days in which both medications are 
taken will be counted once. 


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• Diarrhea 
o Summary statistics for time to onset of first Diarrhea event (days), duration of 
each event (days), and time from start of first diarrhea to resolution of all diarrhea 
events (days) overall and by treatment  
o Number and percentage of participants with each event outcome, and number and 
percentage of participants with each grade (Grade 1-2 vs 3+) overall by treatment  
o Summarize concomitant medications initiated for treatment of diarrhea by ATC 
classification and PT by treatment, grade (Grade 1-2 vs 3+) overall and by 
treatment  
o Summarize duration of concomitant medication use for AEs of diarrhea by grade 
(Grade 1-2 vs 3+) overall by treatment. If multiple medications are received 
durations will be combined and days in which both medications are taken will be 
counted once. 
• Hypophosphatemia 
o Summary statistics for time to onset of first hypophosphatemia event (days), 
duration of each event (days), and time from start of first hypophosphatemia to 
resolution of all Hypophosphatemia events (days) overall and by treatment  
o Number and percentage of participants with each event outcome, and number and 
percentage of participants with each grade (Grade 1-2 vs 3+) overall by treatment  
o Summarize concomitant medications initiated for treatment of hypophosphatemia 
by ATC classification and PT, grade (Grade 1, 2, 3+) overall and by treatment  
o Summarize duration of concomitant medication use for AEs of hypophosphatemia 
by grade (Grade 1-2 vs 3+) overall by treatment. If multiple medications are 
received durations will be combined and days in which both medications are 
taken will be counted once. 
• Rash, Hidradenitis, and Hair Follicle AEs (separately for Narrow and both Broad and 
Narrow Terms identified in Section 7.5.2)  
o Summary statistics for time to onset, duration of event, and time to resolution by 
event grade (Grade 1, 2, 3+) and overall 
o Summary statistics for time to onset of first event (days), duration of each event 
(days), and time from start of first event to resolution of all events (days) overall 
and by treatment  
o Number and percentage of participants with each event outcome, and number and 
percentage of participants with each grade (Grade 1-2 vs 3+) overall by treatment  
o Summarize concomitant medications initiated for treatment of events by ATC 
classification and PT, grade (Grade 1, 2, 3+) overall and by treatment  
o Summarize duration of concomitant medication use for AEs by grade (Grade 1-2 
vs 3+) overall by treatment. If multiple medications are received durations will be 
combined and days in which both medications are taken will be counted once. 


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4.4.2.2. 
Adverse Events of Special Interest 
Adverse events of special interest (AESIs) for this study are defined in Protocol Section 8.3.6 
and include the following groups and descriptions:  
• Skin Rash (clinically significant Grade 2 and Grade ≥ 3, per CTCAE v.5) 
1. Maculopapular rash 
2. Pruritic rash 
3. Erythematous rash 
4. Folliculitis  
5. Hidradenitis suppurativa 
• Elevated Liver Enzymes (reported as AESI if Grade ≥ 2, per CTCAE v.5) 
1. Aspartate Aminotransferase  
2. Alanine Aminotransferase 
3. Alkaline Phosphatase 
• Electrolyte Insufficiency (Grade ≥ 3, per CTCAE v.5) 
1. Hypophosphatemia 
2. Hypokalemia 
3. Hypomagnesemia 
• Drug Reactions (All grades) 
1. Allergic reaction 
2. Anaphylaxis 
• Reproductive System Disorders (Grade ≥ 2, per CTCAE v.5) 
1. Amenorrhea 
2. Premature menopause / Primary ovarian insufficiency  
Determination of whether an event is an AESI is based on investigator reported data. The 
incidence of AESI’s will be summarized by AESI group and PT in tables and listed separately in 
participant data listings. 
4.4.2.3. 
DT Specific Comorbidity 
The incidence and frequency of clinical events related to disease specific desmoid tumor 
comorbidity will be summarized by treatment arm. More details are provided in Section 4.3.3.14.  
4.4.3. 
Clinical Safety Laboratory Assessments 
Central results will be the primary results to be analyzed. However, if a subject has local lab 
results collected during a scheduled visit and does not have central laboratory results collected 
for a parameter, the local results will be included for analyses. If a subject has both central and 
local laboratory results collected for a lab parameter during a scheduled visit, only the central 
results will be included for analyses. Central laboratory results from unscheduled visits will be 
used in the baseline and worst post-baseline derivations only. Local unscheduled visits are 
excluded from derivations and summarized results.  


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The actual value and change from baseline will be summarized for each visit for clinical 
laboratory parameters (hematology, chemistry, coagulation, and hormones) by treatment arm and 
overall.  
Laboratory results will also be summarized by maximum CTCAE grade as available. For lab 
tests with NCI – CTCAE classification, the shift from baseline to maximum (worst) post baseline 
grade will be tabulated. Shift tables will summarize the count and frequency of each CTC grade 
to the highest CTC grade on study and where appropriate for the lab test, will include shifts to 
abnormal high values or abnormal low values. Laboratory tests with bi-directional grades will be 
presented separately for each direction (e.g., hyperglycemia and hypoglycemia). For lab tests 
without NCI – CTCAE classifications, the shift from baseline to each post baseline visit as well 
as the shift to the worst value will be summarized using the lab range indicators (normal, high, or 
low).  
Additional shift tables will be produced for ALT, AST, alkaline phosphatase, bilirubin, 
phosphorus, and creatine showing shifts from below normal range, within normal range, >1 to 
2 × upper limit of normal range, >2 to 3 × upper limit of normal range, >3 to 5 × upper limit of 
normal range and > 5 × upper limit of normal range to the worst (highest) post baseline value. 
Analysis related to hormone levels will be presented according to sex and by childbearing 
potential for female participants.  
Box and whiskers plots displaying the values over time by nominal visit will be produced for 
each lab test. Hormone parameters will be displayed separately by sex. Additionally, WOCBP 
and Women who are not of childbearing potentially will be displayed separately. WOCBP will 
also be displayed by OD status and treatment.  
All laboratory results will be listed and laboratory tests with an abnormal result will be listed 
separately. A subset listing will be presented for all grade 3 or higher laboratory values. A listing 
of participants with AST or ALT > 3X ULN that occurred within 2 days of a bilirubin value 
>2 ULN will be presented.  
Serum pregnancy testing data will be presented for each participant in a data listing.  


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4.4.4. 
Physical Examinations and Eastern Cooperative Oncology Group Performance 
Status 
Physical examination abnormalities reported as AEs will be summarized along with other 
TEAEs.  
Shift tables by treatment arm and overall will summarize the count and frequency for each shift 
of baseline ECOG performance status grade to worst post-baseline ECOG grade. Similar tables 
will be provided for shifts to better grades. The ECOG performance status grades are outlined in 
Table 7. 
All physical examination findings and ECOG performance status results will be presented in data 
listings. 
Table 7. 
Eastern Cooperative Oncology Group Performance Status Grades 
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 MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the 
Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982; 5:649-655 
4.4.5. 
Electrocardiogram 
The actual value and change from baseline at each time point will be summarized for 12-lead 
ECG parameters by treatment arm and overall. The triplicated 12-Lead ECG parameters include 
heart rate, PR, RR, QRS, QT and QTcF intervals. The data presented represents the average 
values from the triplicate ECGs. 


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Categorical groups of QTcF will be summarized as follows: 
• 
Maximum post-baseline QTcF 
o ≤ 450 msec 
o > 450 and ≤ 480 msec 
o > 480 and ≤ 500 msec 
o > 500 msec 
• 
Maximum change from baseline for QTcF 
o ≤ 30 msec 
o > 30 and ≤ 60 msec 
o > 60 msec 
All ECG data will be included in a by-participant data listing. Listings will be provided for 
participants with abnormal or outlying values for QTcF and changes in QTcF. 
4.4.6. 
Vital Signs 
The actual value and change from baseline for all parameters (except height) will be summarized 
at each scheduled visit by treatment arm and overall.  
Vital sign measurements will be presented for each participant in a data listing. 
4.4.7. 
Concomitant Medications and Procedures 
Concomitant medications and procedures will be coded using the WHO Drug Dictionary and are 
defined as any medication or procedure that did not end prior to first dose or start after the 
30-day follow-up period. The handling of partial/missing start dates for concomitant 
therapies/medications are described in Appendix 7.2. PTs will be modified to be grouped as 
outlined in Appendix 7.4 to consolidate brand and generic medication names for the same active 
ingredient into a single line item to facilitate reporting of the same medication. Both the original 
and modified PTs will be included in the listings. Concomitant medications will be tabulated by 
anatomic therapeutic class (ATC) and modified PT by treatment arm and overall. In these 
tabulations, each participant will contribute only once to each ATC and modified PT regardless 
of number of uses. 
Medications will be considered prior if they stopped before the first dose of study drug. Prior 
medications will be tabulated separately from concomitant medications.  
All medications and procedures will be included in separate data listings; an identifier will be 
used to show whether a medication/procedure was prior or concomitant. Both original PT and 
modified PT will be presented on the listing. 
4.5. 
Pharmacokinetic and Pharmacodynamic Analyses 
A separate supplementary SAP will describe the PK parameters, PopPK/PD models, and 
analyses. Plasma pharmacokinetic collection dates, times, and concentration results will be 
displayed in a data listing.  


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5. 
CHANGES TO PLANNED ANALYSES 
Notable changes from the protocol-defined statistical analyses compared to this statistical 
analysis plan are described below: 
I. 
An interim analysis is no longer planned 
II. 
“Change in tumor volume from baseline as assessed by MRI volumetric” has been moved 
from secondary to exploratory endpoint, per FDA comment 
III. 
“Patient-Reported Outcomes Measurement Information System Physical Function 
(PROMIS PF) short form 10a plus 3 additional items from PROMIS item banks” has 
been moved from secondary to exploratory endpoint (as described in the PRO 
Addendum), due to duplications to other PROs. 
IV. 
Duration of Response and Duration of Stable disease have been removed from the 
hierarchical testing of secondary endpoints as they are considered supportive of ORR.  
V. 
Proportion of participants with improvement in BPI-SF API score at Cycle 10 has been 
removed from the hierarchical testing of secondary endpoints.  
VI. 
Estimates of duration of response at Months 6, 12 and 24 have been added.  


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6. 
REFERENCES 
Guo C, So Y, and Johnston G. Analyzing Interval-Censored Data with the ICLIFETEST 
Procedure. 2014. https://support.sas.com/resources/papers/proceedings14/SAS279-2014.pdf 
Eisenhaur EA, Therasse P, et al. New response evaluation criteria in solid tumours: Revised 
RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan; 45(2):228-47. 
European Medicines Agency. Guidance on the Management of Clinical Trials During the 
COVID-19 (Coronavirus) Pandemic. 2021 April 02 (Version 4.0). 
O'Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics 1979; 
35:549-556.  
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982; 5:649-655. 
The ICLIFETEST Procedure: 
https://documentation.sas.com/doc/en/statug/15.2/statug_iclifetest_toc.htm 
US Food and Drug Administration. Conduct of Clinical Trials of Medical Products During the 
COVID-19 Public Health Emergency. Guidance for Industry, Investigators, and Institutional 
Review Boards. March 2020 (Updated Jan 2021).  


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7. 
APPENDICES 
7.1. 
Handling of Missing/Partial Dates for AEs 
Adverse events with incomplete onset dates will be handled as follows for the purpose of 
determining treatment emergence.  
If the start date is partially missing, the date will be compared to the start of administration of 
study drug and the end date of administration+30 days. 
1. If the month and day are missing:  
• If the year of the event is the same as the year of the first dosing date, then the day 
and month of the first dosing date will be assigned to the missing fields. 
• If the year is prior to the year of first dosing date, then December 31 will be assigned 
to the missing fields. 
• If the year is after the year of first dosing, then January 1 will be assigned to the 
missing fields. 
2. If the day is missing:  
• If the month and year are the same as the month of treatment, the onset date will be 
assigned to the date of treatment.  
• If the month and year are not the same as the month/year of treatment, then the onset 
day will be set to the first day of the month.  
If the start date is completely missing and end date is not before the first dose of study drug, then 
the adverse event will be considered treatment emergent.  
If the participant has died and the imputed date is later than the date of death, the date of death 
will be used. 
7.2. 
Handling of Missing/Partial Dates for Concomitant 
Therapies/Medications 
Concomitant therapies/medications with start dates that are completely or partially missing will 
be handled as follows for the propose of determining concomitance.  
1. If the start date has the month and year but the day is missing, the therapy will be 
considered concomitant if the month and year are:  
a. On or after the month and year of the date of the first dose of study drug 
b. On or before the month and year of the date of the last dose of study drug plus 
30 days 
2. If the start date has the year, but the day and month are missing, the therapy will be 
considered concomitant if the year is: 
a. On or after the year of the date of the first dose of study drug 


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b. On or before the year of the date of the last dose of study drug plus 30 days. 
3. If the start date of concomitant therapies is completely missing and the stop date of 
concomitant therapies is prior to the date of the first dose of study drug, then this therapy 
will not be considered concomitant.  
4. If the start date of concomitant therapies is completely or partially missing and the stop 
date of concomitant therapies is on or after the date of the first dose of study drug, then 
the therapy will be considered concomitant. 
5. If the start date and stop date of concomitant therapies are completely missing, then the 
therapy will be considered concomitant. 
7.3. 
Handling of Missing Dates for Disease History and Prior Therapies 
For the purpose of calculating time from diagnosis or most recent prior therapy to randomization, 
partial/missing dates for diagnosis and last prior therapy completion will be imputed as follows:  
• If both day and month are missing and the year is prior to the year of screening, the imputed 
day and month will be 01 July. 
• If both day and month are missing and the year is the same as the year of screening, the 
imputed date will be the middle point between 01 Jan of the year and the screening date. If 
the middle point falls between two dates, the first of the two dates will be used. 
• If day is missing and the month and year are prior to the month and year of screening, the 
imputed date will be 15th day of the month. 
• If day is missing and the month and year are the same as the month and year of screening, the 
imputed date will be the middle point between the first date of the month and the screening 
date. If the middle point falls between two dates, the first of the two dates will be used. 
• No imputation will be performed if the year is missing.  
7.4. 
Consolidated Medication Coding 
Consistent with standard conventions for coding concomitant medications using WHO Drug 
preferred terms, the coded term for certain medications varies based on whether the reported 
verbatim term was a brand name or generic name. To facilitate data reporting for the same 
medication, the coded terms for brand and generic named medications will be consolidated in 
summary tables. WHO Drug preferred terms will be combined as outlined below. For all terms 
not listed, the original coded term will be used. Both the original and consolidated terms can be 
found in the datasets. 


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Original Term(s) 
New Term 
Morphine sulfate 
MS Contin 
morphine sulfate 
Loperamide Hydrochloride 
Loperamide 
Ketorolac Tromethamine 
Ketorolac 
Cyclobenzaprine Hydrochloride 
Cyclobenzaprine 
Venlafaxine Hydrochloride 
Venlafaxine 
Ciprofloxacin Hydrochloride 
Ciprofloxacin 
Levothyroxine Sodium 
Levothyroxine 
Prochlorperazine Edisylate 
Maleate 
Prochlorperazine 
Cetirizine hydrochloride 
Cetirizine 
Diphenhydramine Hydrochloride 
Diphenhydramine 
Valaciclovir Hydrochloride 
Valacyclovir 
Oxycodone Hydrochloride 
Oxycodone 
Pantoprazole sodium sesquihydrate 
Pantoprazole 
Macrogol 3350 
Macrogol 
Tramadol HCL 
Tramadol 
Metamizole Sodium 
Metamazole 
Imatinib mesylate 
Imatinib 
Sorafenib Tosilate 
Sorafenib  
Tegavivint 
Tegatrabetan 
Vinblastine Sulfate 
Vinblastine  
Vinorelbine tartrate 
Vinorelbine 
 
 


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7.5. 
Preferred Terms for Adverse Event Analyses 
7.5.1. 
Ovarian Dysfunction (OD) 
The following list of preferred terms will serve to identify which WOCBP who are participating 
in studies of nirogacestat are of interest for additional analyses of the potential for nirogacestat to 
disrupt ovarian follicular cycling. Narrow terms are considered the most specific or "narrow."  
The remaining terms can contribute to a sensitivity analysis and are considered to be "broad." 
Table 8. 
Broad Summary of Preferred Terms to Describe Ovarian Dysfunction in 
WOCBP 
MedDRA Code 
PT 
HLT 
SOC 
10085424 
Abnormal uterine 
bleeding 
Menstruation and uterine bleeding 
NEC 
Reproductive system and 
breast disorders 
10001928 
Amenorrhoea1 
Menstruation with decreased 
bleeding 
Reproductive system and 
breast disorders 
10002659 
Anovulatory cycle 
Female gonadal function disorders 
Endocrine disorders 
10075158 
Anti-Muellerian hormone 
level decreased 
Reproductive hormone analyses 
Investigations 
10075597 
Antral follicle count low 
Fertility analyses 
Investigations 
10003439 
Artificial menopause1 
Menopausal effects NEC 
Reproductive system and 
breast disorders 
10003693 
Atrophic vulvovaginitis 
Menopausal effects on the 
genitourinary tract 
Reproductive system and 
breast disorders 
10005104 
Bleeding anovulatory 
Menstruation and uterine bleeding 
NEC 
Reproductive system and 
breast disorders 
10063241 
Blood gonadotrophin 
releasing hormone 
increased 
Hypothalamic analyses 
Investigations 
10005687 
Blood oestrogen 
decreased 
Reproductive hormone analyses 
Investigations 
10014757 
Endometrial hypoplasia1 
Uterine disorders NEC 
Reproductive system and 
breast disorders 
10065596 
Female sex hormone level 
abnormal 
Reproductive hormone analyses 
Investigations 
10071084 
Follicle stimulating 
hormone deficiency 
Anterior pituitary hypofunction 
Endocrine disorders 
10074538 
Genital atrophy1 
Reproductive tract disorders NEC 
(excl neoplasms) 
Reproductive system and 
breast disorders 
10060800 
Hot flush 
Peripheral vascular disorders NEC 
Vascular disorders 
10021033 
Hypomenorrhoea 
Menstruation with decreased 
bleeding 
Reproductive system and 
breast disorders 
10021928 
Infertility female 
Sexual function and fertility 
disorders NEC 
Reproductive system and 
breast disorders 
10062020 
Infertility tests abnormal 
Fertility analyses 
Investigations 
10071083 
Luteinising hormone 
deficiency 
Anterior pituitary hypofunction 
Endocrine disorders 
10067371 
Menopausal depression1 
Depressive disorders 
Psychiatric disorders 
10058825 
Menopausal disorder1 
Menopausal effects NEC 
Reproductive system and 
breast disorders 


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MedDRA Code 
PT 
HLT 
SOC 
10027304 
Menopausal symptoms1 
Menopausal effects NEC 
Reproductive system and 
breast disorders 
10027327 
Menstrual disorder 
Menstruation and uterine bleeding 
NEC 
Reproductive system and 
breast disorders 
10027336 
Menstruation delayed 
Menstruation with decreased 
bleeding 
Reproductive system and 
breast disorders 
10027339 
Menstruation irregular 
Menstruation and uterine bleeding 
NEC 
Reproductive system and 
breast disorders 
10030229 
Oestradiol decreased 
Reproductive hormone analyses 
Investigations 
10030236 
Oestriol decreased 
Reproductive hormone analyses 
Investigations 
10030247 
Oestrogen deficiency 
Endocrine abnormalities of 
gonadal function NEC 
Endocrine disorders 
10030255 
Oestrogens total urine 
decreased 
Reproductive hormone analyses 
Investigations 
10063268 
Oestrone decreased 
Reproductive hormone analyses 
Investigations 
10030295 
Oligomenorrhoea 
Menstruation with decreased 
bleeding 
Reproductive system and 
breast disorders 
10033122 
Ovarian atrophy1 
Ovarian and fallopian tube 
disorders NEC 
Reproductive system and 
breast disorders 
10033141 
Ovarian disorder1 
Ovarian and fallopian tube 
disorders NEC 
Reproductive system and 
breast disorders 
10033165 
Ovarian failure1 
Ovarian and fallopian tube 
disorders NEC 
Reproductive system and 
breast disorders 
10033310 
Ovulation delayed 
Female gonadal function disorders 
Endocrine disorders 
10067490 
Ovulation disorder 
Ovarian and fallopian tube 
disorders NEC 
Reproductive system and 
breast disorders 
10036601 
Premature menopause1 
Menopausal effects NEC 
Reproductive system and 
breast disorders 
10067168 
Ultrasound ovary 
abnormal 
Reproductive organ and breast 
imaging procedures 
Investigations 
10047791 
Vulvovaginal dryness 
Vulvovaginal signs and symptoms 
Reproductive system and 
breast disorders 
10027308 
Menopause1 
Age related factors 
Social circumstances 
1. Term is both a broad and narrow term  
7.5.2. 
Rash, Hidradenitis, Hair Follicle AEs 
7.5.2.1. 
Rash 
The following list of preferred terms is intended to identify patients participating in studies of 
nirogacestat who experienced adverse generalized rash-like skin events but excluding events due 
to the possible effects of nirogacestat on hair follicles. Narrow terms are considered to be the 
most specific or "narrow."  The remaining terms can contribute to a sensitivity analysis and are 
considered to be "broad."   


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Table 9. 
Broad Summary of Preferred Terms to Describe Rash  
MedDRA Code 
PT 
HLT 
SOC 
10037898 
Rash vesicular 
Rash vesicular 
Rashes, eruptions and 
exanthems NEC 
10037890 
Rash scarlatiniform 
Rash scarlatiniform 
Rashes, eruptions and 
exanthems NEC 
10057984 
Rash rubelliform 
Rash rubelliform 
Rashes, eruptions and 
exanthems NEC 
10037087 
Pruritus 
Pruritus 
Pruritus NEC 
10037884 
Rash pruritic1 
Rash pruritic 
Rashes, eruptions and 
exanthems NEC 
10037876 
Rash papular1 
Rash papular 
Rashes, eruptions and 
exanthems NEC 
10037870 
Rash morbilliform1 
Rash morbilliform 
Rashes, eruptions and 
exanthems NEC 
10050004 
Rash maculovesicular 
Rash maculovesicular 
Rashes, eruptions and 
exanthems NEC 
10037868 
Rash maculo-papular1 
Rash maculo-papular 
Rashes, eruptions and 
exanthems NEC 
10037867 
Rash macular1 
Rash macular 
Rashes, eruptions and 
exanthems NEC 
10015150 
Erythema1 
Erythema 
Erythemas 
10037855 
Rash erythematous1 
Rash erythematous 
Rashes, eruptions and 
exanthems NEC 
10037844 
Rash1 
Rash 
Rashes, eruptions and 
exanthems NEC 
10075807 
Nodular rash1 
Nodular rash 
Rashes, eruptions and 
exanthems NEC 
10056671 
Mucocutaneous rash 
Mucocutaneous rash 
Rashes, eruptions and 
exanthems NEC 
10037879 
Rash papulosquamous1 
Rash papulosquamous 
Papulosquamous conditions 
10037888 
Rash pustular 
Rash pustular 
Skin structures and soft tissue 
infections 
10037578 
Pustule 
Pustule 
Skin structures and soft tissue 
infections 
10064579 
Exfoliative rash 
Exfoliative rash 
Exfoliative conditions 
10040844 
Skin exfoliation 
Skin exfoliation 
Exfoliative conditions 
10012456 
Dermatitis exfoliative 
generalised 
Dermatitis exfoliative generalised 
Exfoliative conditions 
10012455 
Dermatitis exfoliative 
Dermatitis exfoliative 
Exfoliative conditions 
10047111 
Vasculitic rash 
Vasculitic rash 
Skin vasculitides 
10037857 
Rash follicular1 
Rash follicular 
Pustular conditions 
10012431 
Dermatitis1 
Dermatitis 
Dermatitis and eczema 
10082985 
Erythrodermic atopic 
dermatitis 
Erythrodermic atopic dermatitis 
Exfoliative conditions 
10012432 
Dermatitis acneiform 
Dermatitis acneiform 
Acnes 
10000496 
Acne 
Acne 
Acnes 
10000501 
Acne conglobata 
Acne conglobata 
Acnes 
10000503 
Acne cystic 
Acne cystic 
Acnes 
10000513 
Acne pustular 
Acne pustular 
Skin structures and soft tissue 
infections 
10013786 
Dry skin 
Dry skin 
Dermal and epidermal 
conditions NEC 
1. Term is both a broad and narrow term  


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7.5.2.2. 
Hidradenitis 
The following list of preferred terms is intended to identify patients participating in studies of 
nirogacestat who experienced adverse events due to the possible effects of nirogacestat on hair 
follicles and sweat glands, e.g., hidradenitis. Narrow terms are considered to be the most specific 
or "narrow."  The remaining terms can contribute to a sensitivity analysis and are considered to 
be "broad."  
Table 10. 
Broad Summary of Preferred Terms to Describe Rash  
MedDRA 
Code 
PT 
HLT 
SOC 
10020040 
Hidradenitis1 
Hidradenitis 
Apocrine and eccrine gland 
disorders 
10055027 
Sweat gland infection 
Sweat gland infection 
Apocrine and eccrine gland 
disorders 
10000318 
Abscess sweat gland 
Abscess sweat gland 
Skin structures and soft tissue 
infections 
10018736 
Groin sinus excision 
Groin sinus excision 
Abdominal therapeutic 
procedures NEC 
10050269 
Groin abscess 
Groin abscess 
Infections NEC 
1. Term is both a broad and narrow term  
7.5.2.3. 
Hair Follicle AEs 
The following list of preferred terms is intended to identify patients participating in studies of 
nirogacestat who experienced adverse skin events due to the possible effects of nirogacestat on 
hair follicles. Narrow terms are considered to be the most specific or "narrow."  The remaining 
terms can contribute to a sensitivity analysis and are considered to be "broad". 


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Table 11. 
Broad Summary of Preferred Terms to Hair Follicle Adverse Events   
MedDRA Code 
PT 
HLT 
SOC 
10066409 
Staphylococcal skin 
infection 
Staphylococcal skin 
infection 
Staphylococcal infections 
10052891 
Skin bacterial infection 
Skin bacterial infection 
Bacterial infections NEC 
10037637 
Pyoderma streptococcal 
Pyoderma streptococcal 
Streptococcal infections 
10037632 
Pyoderma 
Pyoderma 
Skin structures and soft tissue 
infections 
10017553 
Furuncle1 
Furuncle 
Staphylococcal infections 
10007247 
Carbuncle 
Carbuncle 
Skin structures and soft tissue 
infections 
10042343 
Subcutaneous abscess 
Subcutaneous abscess 
Skin structures and soft tissue 
infections 
10016936 
Folliculitis1 
Folliculitis 
Bacterial infections NEC 
10015988 
Eyelid infection 
Eyelid infection 
Eye and eyelid infections 
10057211 
Eyelid folliculitis 
Eyelid folliculitis 
Skin structures and soft tissue 
infections 
10015980 
Eyelid boil 
Eyelid boil 
Eye and eyelid infections 
10000297 
Abscess of eyelid 
Abscess of eyelid 
Eye and eyelid infections 
10030261 
Oil acne 
Oil acne 
Acnes 
10012432 
Dermatitis acneiform 
Dermatitis acneiform 
Acnes 
10000518 
Acne varioliformis 
Acne varioliformis 
Acnes 
10000511 
Acne occupational 
Acne occupational 
Acnes 
10000507 
Acne infantile 
Acne infantile 
Acnes 
10049141 
Acne fulminans 
Acne fulminans 
Acnes 
10000503 
Acne cystic 
Acne cystic 
Acnes 
10000502 
Acne cosmetica 
Acne cosmetica 
Acnes 
10000501 
Acne conglobata 
Acne conglobata 
Acnes 
10000496 
Acne 
Acne 
Acnes 
10037888 
Rash pustular1 
Rash pustular 
Skin structures and soft tissue 
infections 
10037578 
Pustule1 
Pustule 
Skin structures and soft tissue 
infections 
10020377 
Hordeolum 
Hordeolum 
Eye and eyelid infections 
10001760 
Alopecia 1 
Alopecia 
Alopecias 
10073736 
Diffuse alopecia1 
Diffuse alopecia 
Alopecias 
10001767 
Alopecia universalis1 
Alopecia universalis 
Alopecias 
10001766 
Alopecia totalis1 
Alopecia totalis 
Alopecias 
10001761 
Alopecia areata1 
Alopecia areata 
Alopecias 
1. Term is both a broad and narrow term  


SpringWorks Therapeutics 
Statistical Analysis Plan, Protocol NIR-DT-301 
12 May 2022 Final Version 2.0 
 
CONFIDENTIAL 
66
8. 
CLINICAL STUDY REPORT APPENDICES 
8.1. 
Statistical Tables, Figures and Listings to be Generated 
The Table of Contents for full list of tables, figures and listings can be found in a separate 
document (NIR-DT-301 TFL Table of Contents.pdf).