Conditions: Desmoid Tumors Aggressive Fibromatosis
Keywords: Desmoid Tumor Aggressive Fibromatosis Gamma-secretase Inhibitor Notch Pathway
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 17
Healthy volunteers: no

Brief summary:
Background:

* Desmoid tumors (also known as aggressive fibromatosis), are rare, locally invasive, slow-growing soft-tissue tumors. The disease can be either asymptomatic or be associated with severe loss of organ function and significant morbidity.
* Treatment with the selective small-molecule Gamma-secretase inhibitor PF-03084014 caused significant tumor shrinkage in patients with unresectable desmoid tumors in an early phase clinical trial.
* The Notch pathway is a key regulator of cell differentiation, proliferation and apoptosis; aberrant signaling via the Notch pathway is associated with carcinogenesis.

Objectives:

* Primary: Determine the response rate (Complete Response (CR)+Partial Response (PR)) of PF-03084014 in patients with desmoid tumors/aggressive fibromatosis
* Secondary: Assess symptom measures at baseline and on study; perform genotyping for germline and somatic mutations in adenomatous polyposis coli gene (APC) and catenin-beta 1 (CTNNB1) genes; correlate clinical response to therapy with genotyping data; and assess modulation of the Notch pathway by evaluating notch response genes in tumor biopsies at baseline and after drug administration

Eligibility:

* Age greater than or equal to18; histologically confirmed desmoid tumor not amenable to curative resection or definitive radiation therapy that has progressed after receiving at least one line of standard treatment; adequate organ function
* Willingness to provide blood samples and 10 unstained slides or a tumor block for genetic research studies

Study Design:

* This is an open-label Phase II trial of PF-03084014; study drug will be administered orally at 150 mg twice a day in 21-day cycles
* Optional tumor biopsies for research purposes will be performed at baseline prior to study treatment and at the beginning of cycle 7 (+/- one cycle)
* Restaging scans (magnetic resonance imaging (MRI) with diffusion weighting) will be performed at baseline, at the end of cycles 1 and 6, and then every 6 cycles
* Health-related quality of life (HRQOL)/symptom questionnaires will be administered at baseline and at each Clinical Center visit

Detailed description:
Background:

* Desmoid tumors (also known as aggressive fibromatosis), are rare, locally invasive, slow-growing soft-tissue tumors. The disease can be either asymptomatic or be associated with severe loss of organ function and significant morbidity.
* Treatment with the selective small-molecule Gamma-secretase inhibitor PF-03084014 caused significant tumor shrinkage in patients with unresectable desmoid tumors in an early phase clinical trial.
* The Notch pathway is a key regulator of cell differentiation, proliferation and apoptosis; aberrant signaling via the Notch pathway is associated with carcinogenesis.

Objectives:

* Primary: Determine the response rate (Complete Response (CR)+Partial Response (PR)) of PF-03084014 in patients with desmoid tumors/aggressive fibromatosis
* Exploratory: Assess symptom measures at baseline and on study; perform genotyping for germline and somatic mutations in adenomatous polyposis coli gene (APC) and catenin-beta 1 (CTNNB1) genes; correlate clinical response to therapy with genotyping data; and assess modulation of the Notch pathway by evaluating notch response genes in tumor biopsies at baseline and after drug administration

Eligibility:

* Age greater than or equal to18; histologically confirmed desmoid tumor not amenable to curative resection or definitive radiation therapy that has progressed after receiving at least one line of standard treatment; adequate organ function
* Willingness to provide blood samples and 10 unstained slides or a tumor block for genetic research studies

Study Design:

* This is an open-label Phase II trial of PF-03084014; study drug will be administered orally at 150 mg twice a day in 21-day cycles
* Optional tumor biopsies for research purposes will be performed at baseline prior to study treatment and at the beginning of cycle 7 (+/- one cycle)
* Restaging scans (computed tomography (CT) scan of the known site of disease) will be performed at baseline and then every 6 cycles (+/- one cycle)
* Optional magnetic resonance imaging (MRI) scans may be performed prior to start of study treatment, end of cycle 1, and every 6 cycles (at the same times as the CT scans)
* Health-related quality of life (HRQOL)/symptom questionnaires will be administered at baseline and at restaging

Arms:
arm 1: PF-03084014 will be administered orally at 150 mg twice a day in 21-day cycles

Interventions: intervention 1: PF-03084014
Intervention descriptions: intervention 1: Treatment with the selective small-molecule \>=-secretase inhibitor PF- 3084014 caused significant tumor shrinkage in patients with unresectable desmoid tumors in an early-phase clinical trial.

Protocol document:
ICF_005.pdf: 
IRB NUMBER: 14C0007
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PATIENT IDENTIFICATION
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PRINCIPAL INVESTIGATOR:  Alice P. Chen, MD
STUDY TITLE: Phase II Trial of the γ-secretase Inhibitor Nirogacestat (PF-03084014) in Adults 
with Desmoid Tumors/Aggressive Fibromatosis
STUDY SITE: National Cancer Institute
Cohort: Standard Adult 
Consent Version: 5/18/2023 
WHO DO YOU CONTACT ABOUT THIS STUDY? 
Dr. Alice Chen, Principal Investigator, can be reached by telephone at (240) 781-3320 or by 
email at chenali@mail.nih.gov.
This consent form describes a research study and is designed to help you decide if you would like 
to be a part of the research study.  
You are being asked to take part in a research study at the National Institutes of Health (NIH). This 
section provides the information we believe is most helpful and important to you in making your 
decision about participating in this study. Additional information that may help you decide can be 
found in other sections of the document. Taking part in research at the NIH is your choice.
The remaining document will now describe the research study in more detail.  This information 
should be considered before you make your choice. Members of the study team will talk with you 
about the information in this document. Some people have personal, religious, or ethical beliefs 
that may limit the kinds of medical or research interventions in which they would want to 
participate. Take the time you need to ask any questions and discuss this study with NIH staff, and 
with your family, friends, and personal health care providers.
If the individual being asked to participate in this research study is not able to give consent for 
themselves, you, as the Legally Authorized Representative, will be their decision-maker and you 
are being asked to give permission for this person to be in this study. For the remainder of this 
document, the term “you” refers to you as the decision-maker and/or the individual being asked to 
participate in this research.
IT IS YOUR CHOICE TO TAKE PART IN THE STUDY
You may choose not to take part in this study for any reason. If you join this study, you may change 
your mind and stop participating in the study at any time and for any reason. In either case, you 
will not lose any benefits to which you are otherwise entitled. However, to be seen at the NIH, you 


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must be taking part in a study or are being considered for a study. If you do choose to leave the 
study, please inform your study team to ensure a safe withdrawal from the research.
  
WHY IS THIS STUDY BEING DONE?
The purpose of this study is to find out what effects, good and/or bad, the drug Nirogacestat (which 
used to be called PF-03084014) may have on you and your tumor.  Use of Nirogacestat is 
experimental.  This study will measure whether taking this drug every day makes your tumors 
smaller.  Nirogacestat has been tested in animals and is in the early stages of being tested in patients 
with different types of cancer.  In an earlier clinical trial, some patients with desmoid tumors who 
took Nirogacestat for several months had their tumors become smaller.  
This study may also help us find out whether your tumor has a variation in one of several genes 
that allow your tumor cells to form and grow.  Blood, tissue, and tumor cells contain genes which 
are made up of DNA and which serve as the “instruction book” for each cell in the body.  We 
know that variations in the genes in desmoid tumors are important for their growth.  Identifying 
these tumor variations is one way scientists are trying to study and treat desmoids and other types 
of tumors.  
Why are you being asked to take part in this study?
You are being asked to take part in this research study because you have desmoid tumors that have 
progressed after receiving at least one line of standard treatment.  People with desmoid tumors 
who are not in a study are usually treated with chemotherapy that has already been approved by 
the FDA, or surgery, or radiation therapy.
How many people will take part in this study? 
About 17 people with desmoids will take part in this study.  
Description of Research Study
To take part in this study, you must be willing to provide a tumor block (or slides taken from your 
tumor block) and one blood sample so that we can look for variations in the genes that allow your 
desmoids to form and grow.  Your study doctor will explain these genetic research studies to you 
in more detail.  However, these studies may also reveal information about your hereditary 
risk of developing other diseases or serious illness that, if revealed, might affect your privacy.  
This is very important.  In order to protect your privacy, all samples collected on this study will 
be assigned a special unique code to protect your confidentiality.  If you agree to allow us to save 
certain medical information for our research, your information would be kept in a secure computer 
database and “linked” with the unique code assigned to your samples.  To further help protect your 


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privacy, your medical information would be “unlinked” before we perform detailed genetic 
analysis of your samples so that we cannot connect the results back to you.  The results of the 
research studies would not be reported to you, your family, or your doctor.
The total amount of blood collected at the beginning of the study is about 2 teaspoons.
What will happen if you take part in this research study?  
During the study, you will take Nirogacestat by mouth twice a day every day.  The study team will 
give you a diary to write down what time you take the drug each day as well as any side effects 
you may have.  The team will also give you a chart describing the tests and procedures that will 
be done each day during the study.  
Study tests, and procedures:

CT scans to measure how your tumors are responding to Nirogacestat treatment will be 
done before you begin the study and then every 6 cycles (about every 4 months)

Magnetic resonance imaging (MRI) scans are no longer mandatory and may be performed 
at the PI's discretion prior to start of study treatment, at the end of cycle 1, and then every 
6 cycles (about every 4 months) to measure your tumors
MRI uses a strong magnetic field and radio waves to take pictures of the body.  We will 
obtain pictures of your body for this study. The MRI scanner is a metal cylinder surrounded 
by a strong magnetic field.  During the MRI, you will lie on a table that can slide in and 
out of the cylinder.  We will place soft padding or a coil around your body segment being 
scanned. You will be in the scanner about 60 minutes. You may be asked to lie still for up 
to 60 minutes at a time. While in the scanner you will hear loud knocking noises, and you 
will be fitted with earplugs or earmuffs to muffle the sound. You will be able to 
communicate with the MRI staff at all times during your scan, and you may ask to be 
moved out of the machine at anytime.
During part of the MRI you will receive gadolinium, a contrast agent, through an 
intravenous (IV) catheter. It will be done for research purposes. 

It is not known if MRI with contrast is completely safe for a developing fetus. Therefore, 
all women of childbearing potential will have a pregnancy test performed no more than 24 
hours before each MRI scan with contrast. The scan will not be done if the pregnancy test 
is positive. You will be asked to complete health-related quality of life and symptom 
questionnaires at each Clinical Center visit so that we can learn about symptoms from your 
disease, treatment-related symptoms commonly experienced by patients, and how these 
symptoms affect how you feel and are able to function.  Filling in these questionnaires will 
take about 10 minutes each time.  


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Most of the exams, tests, and procedures you will have are part of your regular care such as a 
complete medical history, blood tests, and scans to measure your tumors.  We would also do a 
pregnancy test in women who are able to become pregnant.
If you choose to take part in this study, then we will also ask you to consider some optional extra 
tests and procedures.  None of these tests are part of the usual approach for desmoid tumors: these 
tests are being done for research to help us learn more about desmoids.  If you choose not to have 
these optional research tests you will still receive study drug and have other tests that are part of 
the study.  

If you agree, we would also like to collect tumor biopsy samples before Nirogacestat is 
given and again after you have been taking the drug for several weeks.  We would also like 
to collect some of your medical information (without personal identifiers), such as what 
type of tumor you have, what drugs you have taken, and whether or not your tumor 
responded to these drugs, but not your name or any other personally identifiable 
information.  
How long will I be in this study?
If you are accepted and you choose to take part in this study, you will begin taking Nirogacestat 
by mouth twice a day.  Nirogacestat is given in cycles; each cycle is 21 days (3 weeks) long.  All 
of the people taking part in this study will initially be given the same dose of drug; this dose may 
be changed by your study doctor based on any side effects that you may experience.  You will stay 
in the study as long as you are tolerating the drug and your tumors are either stable or getting 
better, but you can choose to leave the study at any time. 
Birth Control
If you are a woman who is breast feeding or pregnant, you may not take part in the study because 
we don’t know how this medicine would affect your baby or your unborn child.  If you are a 
woman who can become pregnant, or are the partner of a woman who can become pregnant, you 
will need to practice an effective form of birth control before starting study treatment, during study 
treatment, and for 6 months after you finish study treatment.  If you think that you or your partner 
is pregnant, you should tell your study doctor or nurse at once.  
Effective forms of birth control include: 

abstinence 

intrauterine device (IUD)

hormonal [birth control pills, injections, or implants]

tubal ligation

vasectomy


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Risks or Discomforts of Participation
If you choose to take part in this study, there is a risk that you may:

Lose time at work or home and spend more time in the hospital or doctor’s office than 
usual

Be asked sensitive or private questions which you normally do not discuss
The drug given in this study may affect how different parts of your body work, such as your liver, 
kidneys, heart, and blood.  Your study doctor will be testing your blood and will let you know if 
changes occur that may affect your health.  There is a risk that you could have side effects.
Here are important points about side effects:

Your study doctors do not know who will or will not have side effects.

Some side effects may go away soon, some may last a long time, or some may never go 
away. 

Some side effects may interfere with your ability to have children. 

Some side effects may be serious and may even result in death.
Here are important points about how you and your study doctor can make side effects less of a 
problem:

Tell your study doctor or medical team if you notice or feel anything different so that the 
team can see if you are having a side effect.

Your study doctor may be able to treat some side effects.

Your study doctor may change the dose of the study drug to try to reduce side effects.
The table below shows the most common and the most serious side effects of Nirogacestat that 
researchers know about.  There might be other side effects that researchers do not yet know about.  
If important new side effects are found, the study doctor will discuss these with you.
Risks of Nirogacestat (PF-03084014)
Approximately 169 participants with cancer have received nirogacestat as a single therapy in 
completed clinical studies that include the double-blind phase of NIR-DT-301 for the treatment 
of advanced tumors, of which 95 of these participants had desmoid tumors/aggressive 
fibromatosis. The most commonly reported side effects occurring in approximately 10% or more 
of participants were:


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Common Side Effect (some may be serious)
Nirogacestat (n=169)
Number of participants experiencing the 
side effect out of 169 (%) 
Ovarian dysfunction in women able to have 
children (e.g., hot flashes and missed cycles) 
27 out of 36 women able to have children 
(75%)1
Diarrhea
122 (72%)
Nausea
91 (54%)
Fatigue
81 (48%)
Hypophosphatemia (low level of phosphate in 
the blood that may result in muscle weakness 
and feeling tired) 
72 (43%)
Vomiting
50 (30%)
Headache
42 (25%)
Cough
36 (21%)
Aspartate 
aminotransferase 
increased 
(increased liver enzyme which may be a sign 
of liver damage)
33 (20%)
Decreased appetite
33 (20%)
Rash maculo-papular (flat or raised red 
bumps)
33 (20%)
Rash
32 (19%)
Hypokalemia (Low level of potassium in the 
blood resulting in muscle weakness/cramps, 
and abnormal cardiac rhythm in severe cases) 
31 (18%)
Mouth sores
29 (17%)
Alanine aminotransferase increased (increased 
liver enzyme which may be a sign of liver 
damage)
27 (16%)
Abdominal (stomach) pain
27 (16%)
Fever
27 (16%)
Dry mouth
25 (15%)


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Common Side Effect (some may be serious)
Nirogacestat (n=169)
Number of participants experiencing the 
side effect out of 169 (%) 
Dermatitis acneiform (small, raised, acne-like 
bumps)
25 (15%)
Hot Flush
24 (14%)
Dyspnea (difficulty breathing)
22 (13%)
Anemia (low level of iron in the blood 
resulting in feeling tired)
21 (12%)
Constipation (difficulty passing stool)
19 (11%)
Upper respiratory tract infection (an infection 
of the nose, sinuses, or throat, like a cold or flu)
18 (11%)
Epistaxis (nosebleed)
18 (11%)
Arthralgia (joint pain)
18 (11%)
Dry skin
17 (10%)
Dizziness
17 (10%)
Hypertension (high blood pressure)
17 (10%)
Insomnia (difficulty falling asleep or staying 
asleep)
17 (10%)
Pruritus (itchy skin)
17 (10%)
1 Number and percent of participants reporting ovarian dysfunction from the NIR-DT-301 study 
which included 36 women able to have children.
Other important side effects of nirogacestat included:

The following side effects were reported in < 10% of participants:
o
Folliculitis (red, inflamed, itchy, bumpy, rash involving hair roots)
o
Hidradenitis (Small painful lumps in your groin, arm pits, buttocks, or under your 
breasts)
o
Alopecia (Hair thinning or hair loss)
o
Non-melanoma skin cancer


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
Greater than 20% of participants receiving nirogacestat in the double-blind phase of the 
NIR-DT-301 study had excess protein and glucose (sugar) in their urine, which may be a 
sign of kidney damage. 
Other rare but potentially serious side effects that have been reported in 3 or fewer participants 
include:

Anaphylactic shock (severe and potentially life-threatening allergic reaction)

Atrial fibrillation (irregular and rapid heart rhythm)

Cholecystitis (gallbladder inflammation)

Cyst (abnormal, fluid-filled sacs)

Dehydration

Febrile neutropenia (fever and lower than normal number of cells that fight infections in 
the blood)

Groin abscess (sore between your legs)

Hypersensitivity (an allergic reaction)

Infected cyst (infected abnormal, fluid-filled sacs)

Septic Shock (blood pressure drops very low after infection)
In addition to these risks, taking part in this research may harm you in unknown ways.
Let your study doctor know of any questions you have about possible side effects.  You can ask 
your study doctor and medical team questions about side effects at any time.
What are the risks related to fertility? 
Based on animal studies, nirogacestat may decrease fertility in men and women.  Events of early 
menopause, such as feeling hot and missed monthly cycles, have been reported in women 
receiving nirogacestat.  It is unknown if early menopause is reversible (improves) after stopping 
nirogacestat.  The effects on long term fertility are also unknown.  If you experience any of these 
symptoms, please discuss them with your study doctor.
Potential Risks Related to Blood Samples
Possible side effects from drawing the blood sample include mild pain, bleeding, bruising, and 
infection at the site of the needle insertion.  Fainting or light-headedness can sometimes occur, but 
usually last only a few minutes. 


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Potential Risks Associated With Gene Sequencing 
We will also be performing a full genetic analysis on the tumor samples and blood of patients on 
this study.  This analysis is investigational, and not approved or cleared by the FDA, and is for 
research purposes only.  We will only do this analysis once we have deleted all information that 
identifies the sample as belonging to you before we perform this analysis.  Deleting your 
information is important because by sequencing your tumor and blood cells for gene variations, 
we may find information about your hereditary risk of developing disease, such as an increased 
risk of cancer or other serious illness.  Because you share some genetic information with your 
children, parents, brothers, sisters, and other blood relatives, this information may also tell us about 
your blood relatives’ risk of developing disease.  This information could affect your ability or the 
ability of your family to purchase long term care insurance, disability insurance, and life insurance.  
Your privacy is very important to us.  The best way to protect your privacy is to delete your 
information from your samples before we do these research tests.  This means that we will not be 
able to tell which patients’ tumors have gene variations.  We will not know if a given tumor with 
or without a variation is yours, and therefore will not be able to give you any information we learn.  
If you have any questions about this, please ask your study team.
While neither the public nor the controlled-access databases developed for this project will contain 
information that is traditionally used to identify you, such as your name, address, telephone 
number, or social security number, people may develop ways in the future that would allow 
someone to link your genetic or medical information in our databases back to you.  For example, 
someone could compare information in our databases with information from you (or a blood 
relative) in another database and be able to identify you (or your blood relative).  
There also may be other privacy risks that we have not foreseen.
Will your genomic data be shared outside of this study?
As part of this research study, we will put your genomic data in a large database for broad sharing 
with the research community. These databases are commonly called data repositories. The 
information in this database will include but is not limited to genetic information, race and 
ethnicity, and sex.   If your individual data are placed in one of these repositories, they will be 
labeled with a code and not with your name or other information that could be used to easily 
identify you, and only qualified researchers will be able to access them. These researchers must 
receive prior approval from individuals or committees with authority to determine whether these 
researchers can access the data.
Summary information about all of the participants included in this study (including you) is being 
placed in a database and will be available through open access. That means that researchers and 


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non-researchers will be able to access summary information about all the participants included in 
the study, or summary information combined from multiple studies, without applying for 
permission. The risk of anyone identifying you with this information is very low.
NIH policies require that genomic data be placed in a repository for sharing. Therefore, we cannot 
offer you a choice of whether your data will be shared.  If you do not wish to have your data placed 
in a repository, you should not enroll in this study.  
Risks for CT
During your participation in this research study, you may be exposed to radiation from CT scans.  
The amount of radiation exposure from these procedures is equal to approximately 6 rem per year. 
A rem is a unit of absorbed radiation. 
Every day, people are exposed to low levels of radiation that come from the sun and the 
environment around them.  The average person in the United States receives a radiation exposure 
of 0.3 rem per year from these sources.  This type of radiation is called “background radiation.”  
This study will expose you to more radiation than you get from everyday background radiation. 
No one knows for sure whether exposure to these low amounts of radiation is harmful to your 
body. 
The CT scans that you get in this study will expose you to roughly the same amount of radiation 
as 20 years’ worth of background radiation. Being exposed to too much radiation can cause 
harmful side effects such as an increase in the risk of cancer.  The risk depends on how much 
radiation you are exposed to. Please be aware that about 40 out of 100 people (40%) will get cancer 
during their lifetime, and 20 out of 100 (20%) will die from cancer. The risk of getting cancer from 
the radiation exposure in this study is 0.6 out of 100 (0.6%) and of getting a fatal cancer is 0.3 out 
of 100 (0.3%).
Risks for CT Scans with Contrast Agent
Risks for IV contrast: You may feel discomfort when the contrast is injected. You may feel warm 
or flushed. You may get a metallic taste in your mouth or, rarely, you may vomit or feel sick to 
your stomach.
You could have an allergic reaction to the contrast, which may cause side effects ranging from 
mild itching or a rash, to severe trouble breathing, shock or rarely, death. The contrast may also 
cause kidney problems. The study doctors will do a blood test to make sure it is safe for you to 
get the contrast.


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Risks for oral contrast: You may have vomiting, nausea, cramping, bloating, constipation, or 
diarrhea after drinking the contrast.
Risks for MRI
People are at risk for injury from the MRI magnet if they have some kinds of metal in their body.  
It may be unsafe for you to have an MRI scan if you have pacemakers or other implanted electrical 
devices, brain stimulators, some types of dental implants, aneurysm clips (metal clips on the wall 
of a large artery), metal prostheses (including metal pins and rods, heart valves, and cochlear 
implants), permanent eyeliner, tattoos, an implanted delivery pump, or shrapnel fragments. 
Welders and metal workers may have small metal fragments in the eye. You will be screened for 
these conditions before having any MRI scan.  If you have a question about metal in your body, 
you should inform the staff. You will be asked to complete an MRI screening form before each 
MRI scan you have. 
In addition, all magnetic objects (like watches, coins, jewelry, and credit cards) must be removed 
before entering the MRI scan room.
People with fear of confined spaces may become anxious during an MRI. Those with back 
problems may have back pain or discomfort from lying in the scanner.  The noise from the scanner 
is loud enough to damage hearing, especially in people who already have hearing loss. Everyone 
having a research MRI scan will be fitted with hearing protection. If the hearing protection comes 
loose during the scan, you should let us know right away.
There are no known long-term risks of MRI scans.
Risks for Gadolinium-Enhanced MRI
The risks of an IV catheter include bleeding, infection, or inflammation of the skin and vein with 
pain and swelling.  
Mild symptoms from gadolinium infusion occur in fewer than 1% of those who receive it and 
usually go away quickly.  Mild symptoms may include coldness in the arm during the injection, a 
metallic taste, headache, and nausea.  In an extremely small number, fewer than one in 300,000 
people, more severe symptoms have been reported including shortness of breath, wheezing, hives, 
and lowering of blood pressure. You should not receive gadolinium if you previously had an 
allergic reaction to it.  You will be asked about such allergic reactions before gadolinium is given.   
People with kidney disease are at risk for a serious reaction to gadolinium contrast called 
“nephrogenic systemic fibrosis” which has resulted in a very small number of deaths.  A blood test 
of your kidney function may be done within the month before an MRI scan with gadolinium 
contrast. You will not receive gadolinium for a research MRI scan if your kidney function is not 
normal or if you received gadolinium within the previous month. 


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Most of the gadolinium contrast leaves the body in the urine.  However, the FDA recently issued 
a safety alert that indicates small amounts of gadolinium may remain in the body for months to 
years.  The effects of the retained gadolinium are not clear. At this time, retained gadolinium has 
not been linked to health risks in people whose kidneys work well. Some types of gadolinium 
contrast drugs are less likely to remain than others.  In this study, we will use the gadolinium 
contrast drugs that are less likely to remain. 
Please tell your research team if you have had any MRI scans in the past 12 months. We will 
also give you additional information called a “Medication Guide.”  Upon request, we will give you 
individual information about retained gadolinium we see on your studies. 
Potential Benefits of Participation
Are there benefits to taking part in this study? 
Taking part in this study may or may not make your health better.  We do not know if you will 
receive personal, medical benefit from taking part in this study.  These potential benefits could 
include shrinking of your tumor or lessening of your symptoms, such as pain, that are caused by 
the tumor.  Because there is very little information about the effect of Nirogacestat on your 
tumor, we do not know if you will benefit from taking part in this study, although the knowledge 
gained from this study may help others in the future who have desmoids.
Alternative Approaches or Treatments
What other choices do I have if I do not take part in this study? 
Instead of being in this study, you have these options:

you may choose to have the usual approaches described above

you may choose to take part in a different study, if one is available, such as chemotherapy 
or hormonal therapy or the investigational agents imatinib or sorafenib

or you may choose not to be treated for desmoid, but you may want to receive comfort 
care to relieve symptoms
Please talk to your doctor about these and other options.
Research Subject’s Rights
What are the costs of taking part in this study? 
If you choose to take part in the study, the following will apply, in keeping with the NIH policy:

You will receive study treatment at no charge to you.  This may include surgery, medicines, 
laboratory testing, x-rays or scans done at the Clinical Center, National Institutes of Health 
(NIH), or arranged for you by the research team to be done outside the Clinical Center, 
NIH if the study related treatment is not available at the NIH. 


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
There are limited funds available to cover the cost of some tests and procedures performed 
outside the Clinical Center, NIH.  You may have to pay for these costs if they are not 
covered by your insurance company.

Medicines that are not part of the study treatment will not be provided or paid for by the 
Clinical Center, NIH.

Once you have completed taking part in the study, medical care will no longer be provided 
by the Clinical Center, NIH.
Stopping Therapy 
You can decide to stop at any time.  If you decide to stop for any reason, it is important to let your 
study doctor know as soon as possible so you can stop safely.  If you stop, you can decide whether 
or not to let the study doctor continue to include your medical information in the study.
Your study doctor will tell you about new information or changes in the study that may affect your 
health or your willingness to continue in the study.
Your study doctor may take you out of the study:

If your health changes and the study is no longer in your best interest

If new information becomes available

If you do not follow the study rules

If the study is stopped by the sponsor, IRB, or FDA
Conflict of Interest
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest.  This process is detailed in a Protocol Review Guide.  You may ask your research team 
for a copy of the Protocol Review Guide or for more information.  Members of the research team 
who do not work for NIH are expected to follow these guidelines but they do not need to report 
their personal finances to the NIH.
Members of the research team working on this study may have up to $15,000 of stock in the 
companies that make products used in this study.  This is allowed under federal rules and is not a 
conflict of interest.
Optional Biopsy 
Tumor biopsy:  Only if you have disease that in the opinion of your study doctor can be biopsied 
safely, will we ask you to consider undergoing a procedure to collect tumor biopsy.  If you agree, 
you will undergo imaging-directed biopsy of your tumor (removal of a small bit of tissue for 
research purposes) once before you receive the study drug Nirogacestat and again after you have 


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been taking drug for about 5 months.  After the first biopsy, if you decide not to have the second 
biopsy you will still receive study drug and have other tests that are part of the study.  
You will be asked to sign a separate consent form for each biopsy procedure.
Biopsies will be done using a small bore needle under imaging guidance (CT, MRI, or ultrasound 
as deemed appropriate by the interventional radiologist performing the biopsy).  Imaging helps the 
specialized radiologist know that the needle has been placed into the tumor mass.  You will be 
counseled in more detail about the procedure and its risks at that time.  Your safety is the most 
important thing at all times. 
Even if you sign "yes" to have the biopsy, you can change your mind at any time.  Please read the 
sentence below and think about your choice.  After reading the sentence, circle and initial the 
answer that is right for you.
I agree to have my samples collected and used for research, and have some of my medical 
information (without personal identifiers) stored for research purposes:
Yes              No               Initials_________
 
PAYMENT
Will you receive any type of payment for taking part in this study?
You will not receive any payment for taking part in this study. 
REIMBURSEMENT
Will you receive reimbursement or direct payment by NIH as part of your participation?
On this study, the NCI will cover the cost for some of your expenses.  Some of these costs may be 
paid directly by the NIH and some may be reimbursed after you have paid.  Someone will work 
with you to provide more information.
COSTS
Will taking part in this research study cost you anything? 
NIH does not bill health insurance companies or participants for any research or related clinical 
care that you receive at the NIH Clinical Center. 
CLINICAL TRIAL REGISTRATION and RESULTS REPORTING
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time.


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All participants in MRI research studies will have an MRI scan read by a
credentialed radiologist. Sometimes there are unexpected findings on an MRI scan or on other 
testing that we will perform.  Some findings are of unknown significance or importance to your 
health, which may make you anxious.  We will inform you about any finding that may require 
further evaluation or care. We are not able to provide evaluation or treatment for these conditions 
at NIH. If needed, we will refer you to a health care provider.
CONFIDENTIALITY PROTECTIONS PROVIDED IN THIS STUDY  
Will your medical information be kept private? 
We will do our best to make sure that the personal information in your medical record will be kept 
private.  However, we cannot guarantee total privacy.  Organizations that may look at and/or copy 
your medical records for research, quality assurance, and data analysis include:

The NIH and other government agencies, like the Food and Drug Administration (FDA), 
which are involved in keeping research safe for people.

National Institutes of Health Intramural Institutional Review Board

The study Sponsor (National Cancer Insititute) or their agent(s)

Qualified representatives from SpringWorks, the pharmaceutical company who produces 
Nirogacestat.
The researchers conducting this study and the NIH follow applicable laws and policies to keep 
your identifying information private to the extent possible.  However, there is always a chance 
that, despite our best efforts, your identity and/or information about your participation in this 
research may be inadvertently released or improperly accessed by unauthorized persons.
In most cases, the NIH will not release any identifiable information collected about you without 
your written permission.  However, your information may be shared as described in the section of 
this document on sharing of specimens and data, and as further outlined in the following sections.  
 
Further, the information collected for this study is protected by NIH under a Certificate of 
Confidentiality and the Privacy Act. 
Certificate of Confidentiality
To help us protect your privacy, the NIH Intramural Program has received a Certificate of 
Confidentiality (Certificate). With this certificate, researchers may not release or use data or 
information about you except in certain circumstances.  
NIH researchers must not share information that may identify you in any federal, state, or local 
civil, criminal, administrative, legislative, or other proceedings, for example, if requested by a 
court.  


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The Certificate does not protect your information when it:  
1.
is disclosed to people connected with the research, for example, information may be used for 
auditing or program evaluation internally by the NIH; or 
2.
is required to be disclosed by Federal, State, or local laws, for example, when information 
must be disclosed to meet the legal requirements of the federal Food and Drug Administration 
(FDA); 
3.
is for other research;
4.
is disclosed with your consent. 
The Certificate does not prevent you from voluntarily releasing information about yourself or your 
involvement in this research. 
The Certificate will not be used to prevent disclosure to state or local authorities of harm to self or 
others including, for example, child abuse and neglect, and by signing below you consent to those 
disclosures. Other permissions for release may be made by signing NIH forms, such as the Notice 
and Acknowledgement of Information Practices consent.
Privacy Act
The Federal Privacy Act generally protects the confidentiality of your NIH medical records we 
collect under the authority of the Public Health Service Act.  In some cases, the Privacy Act 
protections differ from the Certificate of Confidentiality.  For example, sometimes the Privacy Act 
allows release of information from your medical record without your permission, for example, if 
it is requested by Congress. Information may also be released for certain research purposes with 
due consideration and protection, to those engaged by the agency for research purposes, to certain 
federal and state agencies, for HIV partner notification, for infectious disease or abuse or neglect 
reporting, to tumor registries, for quality assessment and medical audits, or when the NIH is 
involved in a lawsuit.  However, NIH will only release information from your medical record if it 
is permitted by both the Certificate of Confidentiality and the Privacy Act.
Policy Regarding Research-Related Injuries  
The NIH Clinical Center will provide short-term medical care for any injury resulting from your 
participation in research here. In general, no long-term medical care or financial compensation for 
research-related injuries will be provided by the NIH, the NIH Clinical Center, or the Federal 
Government. However, you have the right to pursue legal remedy if you believe that your injury 
justifies such action.
Problems or Questions
If you have any problems or questions about this study, or about your rights as a research 
participant, or about any research-related injury, contact the Principal Investigator, Alice Chen, 
chenali@mail.nih.gov, (240) 781-3320. You may also call the NIH Clinical Center Patient 
Representative at 301-496-2626, or the NIH Office of IRB Operations at 301-402-3713, if you 
have a research-related complaint or concern.


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Consent Document 
Please keep a copy of this document in case you want to read it again.


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Adult Research Participant: I have read the explanation about this study and have been given the opportunity 
to discuss it and to ask questions. I consent to participate in this study.
Signature of Research Participant
Print Name of Research Participant
Date
Legally Authorized Representative (LAR) for an Adult Unable to Consent: I have read the explanation 
about this study and have been given the opportunity to discuss it and to ask questions. I am legally authorized 
to make research decisions on behalf of the adult participant unable to consent and have the authority to provide 
consent to this study. As applicable, the information in the above consent was described to the adult participant 
unable to consent who agrees to participate in the study.
Signature of LAR
Print Name of LAR
Date
Investigator:
Signature of Investigator
Print Name of Investigator
Date
Witness to the oral short-form consent process only: This section is only required if you are doing the oral 
short-consent process and this English consent form has been approved by the IRB for use as the basis of 
translation.
Witness:
Signature of Witness*
Print Name of Witness
Date
*NIH ADMINISTRATIVE SECTION TO BE COMPLETED REGARDING THE USE OF AN 
INTERPRETER:
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent and served as a witness. The investigator obtaining consent may not 
also serve as the witness.
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated


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the administration of informed consent but did not serve as a witness. The name or ID code of the person 
providing interpretive support is:
.

Prot_SAP_004.pdf: 
1
Abbreviated Title: PhII PF-03084014 Desmoids
Version Date:5-18-2023
Phase II Trial of the γ-secretase Inhibitor Nirogacestat (PF-03084014) in Adults with 
Desmoid Tumors/Aggressive Fibromatosis
Abbreviated Title: PhII PF-03084014 Desmoids
NCI Protocol #: 14-C-0007
Version Date: May 18, 2023
NCT Number: NCT01981551
Clinical Trial Center:
Developmental Therapeutics Clinic (NCIDTC)
National Cancer Institute
10 Center Drive, Bethesda, MD 20892
Principal 
Investigator: 
Alice P. Chen, MDA-E
Bldg 31 Room 3A44
Bethesda, MD 20892
Phone: (240) 781-3320; Fax: (240) 541-4515
E-mail: chenali@mail.nih.gov
Referral Contact:
Murielle Hogu, RN, MSNA,B,E
(240) 858-3335  
murielle.hogu@nih.gov 
Investigational Agent:
IND Number:
Nirogacestat (PF-03084014)
119,796
Sponsor:
Center for Cancer Research, National Cancer Institute
Roles: Aobtains information by intervening or interacting with living individuals for research 
purposes; Bobtains identifiable private information about living individuals; Cobtains the 
voluntary informed consent of individuals to be subjects; Dmakes decisions about subject 
eligibility; Estudies, interprets, or analyzes identifiable private information or data/specimens for 
research purposes


2
Abbreviated Title: PhII PF-03084014 Desmoids
Version Date:5-18-2023
PRÉCIS
Background: 

Desmoid tumors (also known as aggressive fibromatosis), are rare, locally invasive, slow-
growing soft-tissue tumors.  The disease can be either asymptomatic or be associated with severe 
loss of organ function and significant morbidity.  

Treatment with the selective small-molecule γ-secretase inhibitor PF-03084014 caused significant 
tumor shrinkage in patients with unresectable desmoid tumors in an early-phase clinical trial 


The Notch pathway is a key regulator of cell differentiation, proliferation and apoptosis; aberrant 
signaling via the Notch pathway is associated with carcinogenesis. 
Objectives: 

Primary: Determine the response rate (CR+PR) of Nirogacestat in patients with desmoid 
tumors/aggressive fibromatosis

Exploratory: Assess symptom measures at baseline and on study; perform genotyping for 
germline and somatic mutations in APC and CTNNB1 genes; correlate clinical response to 
therapy with genotyping data; and assess modulation of the Notch pathway by evaluating notch 
response genes in tumor biopsies at baseline and after drug administration
Eligibility: 

Age >18; histologically confirmed desmoid tumor not amenable to curative resection or definitive 
radiation therapy that has progressed after receiving at least one line of standard treatment; 
adequate organ function

Willingness to provide blood samples and 10 unstained slides or a tumor block for genetic 
research studies
Study Design:  

This is an open-label Phase II trial of Nirogacestat; study drug will be administered orally at 150 
mg twice a day in 21-day cycles

Optional tumor biopsies for research purposes will be performed at baseline prior to study 
treatment and at the beginning of cycle 7 (+/- one cycle)

Restaging scans (CT scan of the known site of disease) will be performed at baseline and then 
every 6 cycles (+/- one cycle).  

Optional MRI scans may be performed prior to start of study treatment, end of cycle 1, and every 
6 cycles (at the same times as the CT scans)

Health-related quality of life (HRQOL)/symptom questionnaires will be administered at baseline 
and at restaging


3
Abbreviated Title: PhII PF-03084014 Desmoids
Version Date:5-18-2023
SCHEMA
Cycle 1
Cycle 2
Nirogacestat will be administered at 150 mg, orally, BID, in 21-day cycles
Tumor biopsies (optional) will be performed at baseline (pre-treatment) and at the beginning of 
cycle 7 (+/- one cycle)  
Blood sample for germline analysis will be collected at baseline
 
    
PF-03084014 
D1
D14
D21
D7
PF-03084014 
D1
D14
D21
D7
Tumor 
Biopsy
Blood 
Sample


4
Abbreviated Title: PhII PF-03084014 Desmoids
Version Date:5-18-2023
Table of Contents
Précis.............................................................................................................................................................2
Schema ..........................................................................................................................................................3
1.
INTRODUCTION.................................................................................................................................6
1.1
Study Objectives............................................................................................................................6
1.2
Background and Rationale:............................................................................................................6
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT.....................................................................14
2.1
Eligibility Criteria........................................................................................................................14
2.2
Screening Evaluation ...................................................................................................................16
2.3
Registration Procedures ...............................................................................................................16
2.4
Randomization Procedures ..........................................................................................................17
3
STUDY IMPLEMENTATION...........................................................................................................17
3.1
Study Design................................................................................................................................17
3.2
Drug Administration....................................................................................................................18
3.3
Dose Modifications......................................................................................................................18
3.4
Patient Reported Outcome Questionnaire....................................................................................19
3.5
Study Calendar.............................................................................................................................19
3.6
Criteria for Removal from Protocol Therapy and Off Study Criteria..........................................21
4
CONCOMITANT MEDICATIONS...................................................................................................21
5
BIOSPECIMEN COLLECTION........................................................................................................23
5.1
Correlative Studies for Research .................................................................................................23
5.2
Pharmacodynamics ......................................................................................................................23
5.3
Sample Storage, Tracking and Disposition..................................................................................26
5.4
Samples for Genetic/Genomic Analysis......................................................................................27
5.5
Magnetic Resonance Imaging (MRI) – Optional only ................................................................28
5.6
Human Data Sharing Plan............................................................................................................29
6
DATA COLLECTION AND EVALUATION...................................................................................30
6.1
Data Collection ............................................................................................................................30
6.2
Response Criteria.........................................................................................................................30
6.3
Toxicity Criteria...........................................................................................................................36
7
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN ..................36
7.1
Definitions....................................................................................................................................36
7.2
OHSRP Office of Compliance and Training / IRB Reporting ....................................................36
7.3
NCI Clinical Director Reporting..................................................................................................36
7.4
Expedited Adverse Event Reporting Criteria to the IND Manufacturer......................................37
7.5
NIH Office of Biotechnology Activities (OBA)/Institutional Biosafety Committee (IBC) 
Reporting Criteria....................................................................................................................................37
7.6
NIH Required Data and Safety Monitoring Plan.........................................................................37
8
Sponsor Protocol/safety reporting.......................................................................................................37
8.1
Definitions....................................................................................................................................37
8.2
Assessment of Safety Events .......................................................................................................39
8.3
Reporting of Serious Adverse Events..........................................................................................39
8.4
Safety Reporting Criteria to the Pharmaceutical Collaborators...................................................39


5
Abbreviated Title: PhII PF-03084014 Desmoids
Version Date:5-18-2023
8.5
Reporting Pregnancy....................................................................................................................40
8.6
Regulatory Reporting for Studies Conducted Under CCR-Sponsored IND................................40
9
CLINICAL MONITORING ...............................................................................................................40
10
STATISTICAL SECTION..................................................................................................................41
10.1
Statistical Considerations for Exploratory Correlative Studies ...................................................41
11
COLLABORATIVE AGREEMENTS ...............................................................................................41
11.1
Agreement Type...........................................................................................................................41
12
HUMAN SUBJECTS PROTECTIONS .............................................................................................41
12.1
Rationale For Subject Selection...................................................................................................41
12.2
Participation of Children..............................................................................................................42
12.3
Evaluation of Benefits and Risks/Discomforts............................................................................42
12.4
Risks/Benefits Analysis ...............................................................................................................42
12.5
Consent and Assent Process and Documentation........................................................................43
13
PHARMACEUTICAL AND DEVICE INFORMATION..................................................................43
13.1
Nirogacestat (PF-03084014) (IND #119,769).............................................................................43
13.2
Magnetic Resonance Imaging Scanner........................................................................................45
REFERENCES ............................................................................................................................................46
APPENDIX A: Performance Status Criteria ...............................................................................................49
APPENDIX B: Patient’s Medication Diary.................................................................................................50
APPENDIX C: Potential Drug Interactions.................................................................................................54
APPENDIX D: Quality-of-Life Questionnaire............................................................................................60
APPENDIX E: QTC Prolongation...............................................................................................................63


6
Abbreviated Title: PhII PF-03084014 Desmoids
Version Date:5-18-2023
1. INTRODUCTION
1.1
STUDY OBJECTIVES
1.1.1
Primary Objective:

Determine the response rate (CR+PR) of Nirogacestat in patients with desmoid tumors/ 
aggressive fibromatosis
1.1.2
Exploratory Objectives:

Assess symptoms at baseline and at intervals on study

Perform genotyping for germline and somatic mutations in APC and CTNNB1 genes

Correlate clinical response to therapy with genotyping data

Assess modulation of the Notch pathway by evaluating notch response genes in tumor 
biopsies at baseline and post-drug administration
1.2
BACKGROUND AND RATIONALE:
1.2.1
Desmoid Tumors 
Desmoid tumors (also known as aggressive fibromatosis), are rare, locally invasive, slow-
growing soft-tissue tumors.  These tumors are considered benign; however, they are highly 
heterogeneous.  The disease can be either asymptomatic requiring no intervention or be 
associated with severe loss of organ function and significant morbidity.  Treatment options 
include wide surgical resection and radiotherapy, but not all tumors are amenable to resection 
and the post-surgical recurrence rate is high.  Systemic chemotherapy may be indicated for 
inoperable or unresectable tumors, but watchful waiting may also be recommended as prolonged 
disease stabilization can occur [1-3].  
Desmoid tumors frequently carry mutations in CTNNB1, the gene that encodes β-catenin, 
resulting in stabilization and nuclear accumulation of the protein [4-7].  β-catenin is an integral 
component of the Wnt/ β-catenin/Tcf signaling pathway, which is frequently dysregulated in 
cancer [8-10].  Patients with desmoid tumors carrying β-catenin mutations have a worse 5-year 
recurrence-free survival rate than patients with wild-type tumors [11, 12].  At least three different 
point mutations have been identified in exon 3 of CTNNB1 (T41A, S45F, and S45P), one of 
which (S45F) may be a predictor of tumor recurrence after resection.  All three oncogenic 
mutations limit phosphorylation and consequently degradation of β-catenin, resulting in the 
protein being translocated to the nucleus to activate Wnt pathway target genes [11].  
Patients with familial adenomatous polyposis (FAP) can also develop desmoid tumors as a result 
of somatic and germline mutations in the adenomatous polyposis coli (APC) tumor suppressor 
gene; these patients have an 800-fold increased risk of developing desmoids [1, 13-15].  APC 
protein is critical for preventing constitutive activation of Wnt signaling by regulating levels of 
β-catenin.  In normal cells a multiprotein complex of APC, axin, casein kinase 1α (CK1α) and 
glycogen synthase kinase (GSK3β) regulates the phosphorylation of β-catenin, resulting in its 


7
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degradation [14, 16].  Mutations in the APC gene can generate altered or truncated protein which 
is unable to phosphorylate β-catenin.  This results in increased in β-catenin that is subsequently 
translocated to the nucleus, resulting in activation of T cell transcription factor 4 (Tcf-4) and 
aberrant gene expression [9, 17] (Figure 1).  
Figure 1: Model of the Wnt/APC/beta-catenin pathway.  Wnt protein binds to its receptor on the 
cell surface to increase accumulation of β-catenin, which is translocated to the nucleus, resulting 
in activation of Wnt pathway transcription factors (left panel).  If an active APC complex forms, 
the complex can bind and phosphorylate β-catenin, leading to its subsequent ubiquitin-mediated 
degradation (right panel).  If an active APC complex cannot form due to mutations in either APC 
or β-catenin itself, β-catenin is not degraded and remains constitutively active (Figure from [15]). 
A limited number of clinical studies have been done due in part to the rarity of desmoid tumors; 
clinical activity has been reported in trials of targeted agents.  Penel et al. reported one complete 
response and three partial confirmed responses (3% and 9%) in 40 patients with recurrent or 
established desmoid tumors in a Phase II clinical trial of the tyrosine kinase inhibitor imatinib 
[18].  Partial responses (6/13) and stable disease (8/13) were also reported in patients treated on 
an expanded access study with the multikinase inhibitor sorafenib [19].
1.2.2
PF-03084014 (Nirogacestat)
Significant tumor shrinkage in patients with unresectable desmoid tumors was recently reported 
in a Phase I clinical trial of the small-molecule γ-secretase inhibitor PF-03084014 in patients 
with advanced solid tumors; four of nine evaluable patients with desmoid tumors experienced 
partial responses and the remaining five patients had some evidence of tumor shrinkage with 
prolonged disease stabilization [20, 21]. Gamma-secretase is required to activate intracellular 


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Notch signaling [22].  Notch pathway γ-secretase inhibitors have been postulated as a treatment 
for desmoid tumors as desmoid tumor-derived mesenchymal stromal cells express stem cell 
markers including BMI-1, a transcriptional repressor downstream of the Notch pathway [23].   A 
diagram outlining the complex potential interaction between components of the Notch and Wnt 
signaling pathways is presented in Figure 2 below: 
Figure 2:  Some of the embryonic signalling pathways that may interact to initiate and promote 
carcinogenesis: transforming growth factor (TGF)-β, Hedgehog (Hh), Notch, Wnt, and ErbB. 
From Takebe et al 2011 [24].   
Preclinical Pharmacokinetics 
Single dose pharmacokinetics of PF-03084014 following intravenous (IV) and oral 
administration was assessed in the toxicology species (rat and dog).  PF-03084014 demonstrates 
moderate systemic clearance in rat and dog, with T1/2 values of 11.7 and 12.4 hour, respectively.  
Systemic exposure increased with increasing dose in rats (2 to 50 mg/kg/day) and dogs (2, 10, 
and 50→20 mg/kg/day) from 3-month toxicological studies.  Although the increase was greater 
than dose proportionality in the rats on both Day 1 and 90 and in the dogs on Day 1, the exposure 
increase was dose proportional in the dog on Day 91.
Volume of distribution at steady state values of PF-03084014 were greater than total body water 
in rats and dogs, suggesting that this compound readily distributes to tissues in these species.  
PF-03084014 showed high plasma protein binding with average unbound fraction (%) of 0.64, 
1.95, 4.22, and 2.61 for mice, rats, dogs, and humans, respectively, at nominal concentrations of 
490 ng/mL for mouse and 1,000 ng/mL for rat, dog and human determinations.


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In vitro metabolism of PF-03084014 is consistent across nonclinical species and humans.  All 
circulating-metabolites observed in humans were present in one or more of the evaluated 
nonclinical species.  PF-03084014 appears to be metabolized to several oxidative metabolites.  In 
vitro, CYP 3A4 has been shown to catalyze the metabolism of PF-03084014.  In rats, <1% of the 
administered dose is eliminated unchanged via biliary excretion or eliminated unchanged in urine 
or feces.
Preclinical Toxicology
PF-03084014 was administered to rats and dogs in oral studies up to 1 month in duration.  The 
no-observed-adverse-effect level (NOAEL) in rats was 5 mg/kg, and the mean Cmax and area 
under the plasma concentration-time curve from 0 to 24 hours (AUC0-24) were 19.3/42.7 ng/mL 
(male/female [M/F]) and 50.7/137 ng•h/mL (M/F), respectively.  In dogs, the NOAEL was 
10 mg/kg, and the mean Cmax and AUC0-24 were 448 ng/mL and 1920 ng•h/mL, respectively.  
The target systems identified were the hematopoietic/immune, gastrointestinal (GI), 
musculoskeletal, reproductive, and hepatic systems.
Hematopoietic/immune effects were seen in both species and included decreases in B and T 
cells, natural killer lymphocytes (NK) cells, Immunoglobulin M (IgM) and Immunoglobulin D 
(IgD) expression on B cells (rat only), and lymphoid depletion in spleen, thymus (thymic cortical 
atrophy in dog), lymph nodes, and/or gut-associated lymphoid tissue (GALT).  Treatment-related 
intestinal tract changes consisted of epithelial hyperplasia and, with higher exposures, epithelial 
degeneration and necrosis.  In general, both the hematopoietic/immune and GI changes showed 
recoverability in rats when treatment was discontinued, except for decreases in T cells and IgD 
and IgM expression on B cells.  These changes were considered mechanism-related due to the 
effects of PF-03084014 on Notch.
Increased retention of the hypertrophic zone of the growth plate and articular cartilage (sternum 
and joint), and ovarian atrophy, increased number of corpora lutea, and asynchrony of the estrus 
cycle were seen in rats only; partial recovery of these effects was evident after discontinuation of 
PF-03084014.  These responses were similar to those observed with vascular endothelial growth 
factor (VEGF) inhibitors in nonclinical toxicologic studies.  Whether the anti-angiogenic like 
effects of PF-03084014 are mechanism-related (i.e., a result of Notch inhibition or effects on 
other γ-secretase substrates) or are downstream effects on angiogenic growth factor signaling 
(i.e., VEGF), cannot be determined at this time.  The fact the bone and ovary effects were seen in 
the rat and not the dog may be attributed to the fact the rat has an open growth plate, is actively 
developing, and the estrus cycle is more frequent in the rat compared with the dog.  In addition, 
these nonclinical findings were not replicated observed in clinical studies with VEGF inhibitors 
(Investigators Brochure).  
Hepatic vacuolation was observed in rats without changes in clinical chemical or hematologic 
effects, and no primary liver toxic effects were apparent.  Inflammation of the liver in dogs was 
considered secondary to intestinal hyperplasia and a disruption of the intestinal mucosal barrier.  
Additional organs affected by treatment with PF-03084014 were the lung (increased number of 
foam cell foci in rats suggestive of phospholipidosis), kidney (protein casts in lumen in rat; 
hypertrophy of tubular epithelial cells and increased pigment in dog), and salivary gland 
(necrosis of glandular epithelial cells in rat).  These latter changes were seen predominantly in 


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rats at high doses and exposures that exceed the estimated clinically efficacious concentration. 
There was no indication of adverse effects on the function of these organs and these changes 
were not evident in recovery animals.
PF-03084014 was also administered to rats and dogs in oral studies up to 3 months in duration 
followed by a 1-month recovery.  In the rat study, based on ovarian atrophy, alterations in the 
estrous cycle and decreased cellularity in GALT in females and mesenteric lymph nodes in males 
and females at 5 mg/kg/day, a NOAEL was not identified.  Adverse treatment-related effects 
were observed at all dose levels evaluated and included increased incidence and severity of 
chronic progressive nephropathy, pulmonary phospholipidosis, and salivary gland necrosis at 
≥ 5 mg/kg/day, and morbidity/mortality and fibrinoid necrosis of the pulmonary arteries in both 
males and females at 50 mg/kg/day.  
In the dog study, treatment-related effects of variable incidence and severity were noted in the 
dosing phase within the intestines, spleen, gall bladder, liver, kidney, testes, and ovary at doses
≥ 10 mg/kg/day (except oocyte mineralization which was noted at 2 mg/kg/day).  The intestinal 
and liver findings were associated with generalized inflammation and associated clinical 
pathology changes in most of these animals.  Based on oocyte mineralization noted at the lowest 
of 2 mg/kg/day, a NOAEL was not identified.
PF-03084014 was negative in genetic toxicology assays (bacterial mutagenicity and human
lymphocyte cytogenetic assays) and safety pharmacology assessments.  PF-03084014-01 was 
also evaluated for its effect in the human ether-a-go-go related gene (HeRG) potassium channel 
assay and determined to present minimal risk of electrocardiogram (QT) prolongation.  No 
reproductive and developmental toxicity studies have been conducted with PF-03084014. 
Current Human Experience
PF-03084014 (Nirogacestat) has been evaluated in three Phase I clinical studies in healthy adults 
and one ongoing Phase I study in patients with advanced solid tumors and refractory ALL.  In 
healthy volunteer studies, single oral doses of PF-03084014 up to 120 mg (Studies A8641001 
and A8641008) and multiple doses up to 95 mg (Study A8641002) once daily for up to 14-days 
administered were deemed safe and well tolerated.  No maximum tolerated single or repeat dose 
was identified.  Adverse events across the three studies were generally mild and transient: the 
most frequently observed adverse events were headache, dizziness, and fatigue.  In studies with a 
lumbar puncture (Studies A8641002 and A8641008), back pain was also frequently observed.  
There were no clinically relevant treatment-related changes in vital signs or electrocardiograph 
endpoints.  No clinically important changes were observed in clinical safety laboratory 
endpoints, including serum chemistry evaluations, hematological profiles (including T- and B- 
cell biomarkers), and urinalysis.  There were dose-related trends for increases in eosinophils and 
immature B cell subsets observed after administration of PF-03084014 95 mg daily in Study 
A8641002, which returned to pretreatment values about 4 days after the final dose of study drug 
was administered.  
Evaluation of pharmacokinetic characteristics indicated that PF-03084014 was rapidly absorbed, 
with median time of occurrence of Cmax (Tmax) values of 0.5 to 1 hour generally observed 
across the three Phase I studies.  Exposure increased with escalating single and repeat doses, 


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with some evidence for greater than dose proportional increases observed across the dose range 
studied in trials A8641001 and A8641002.  The terminal elimination half-life of PF-03084014 
was approximately 19 hours after single doses and 26 hours after multiple doses (Investigators 
Brochure).
There is currently one ongoing clinical study with PF-03084014 (Study A8641014), an open-
label, non-randomized, Phase I dose finding study in patients with advanced solid tumor 
malignancies and patients with relapsed/refractory acute T-ALL.  In the dose-finding portion of 
the study, the maximum tolerated dose (MTD) of PF-03084014 administered twice daily 
continually for 21 days was established at 220 mg BID in patients with advanced solid tumors.  
Additional patients were subsequently enrolled in the expansion cohort at 150 mg or 220 mg 
BID.  The Recommended Phase II Dose (RP2D) in patients with advanced solid tumors has been 
determined to be 150 mg BID by comparing the tolerability, pharmacokinetic and 
pharmacodynamic profile of PF-03084014 at these two doses.  The MTD in patients with 
refractory or relapsed T-ALL/LBL leukemia has not been established.  
Safety
As of the March 1, 2013 cut-off date, 64 adult patients with advanced solid tumor malignancies 
have data in the safety database, and six patients were still on treatment.  The most common AEs 
independent of causality seen in patients with advanced solid tumors were diarrhea, nausea, 
fatigue, vomiting, hypophosphatemia, decreased appetite, cough and rash; all of these events 
were considered to be treatment related in some patients (Table 1).  The majority of AEs were 
considered mild to moderate but treatment related Grade 3 hypophosphatemia, diarrhea, and rash 
have been frequently reported.  The only treatment-related Grade 4 AE was anaphylactic shock 
reported in one patient, an event thought to be related to co-administration of intravenous 
morphine.  No clinically relevant changes in vital signs or electrocardiograph endpoints have 
been reported.  The severe hematology laboratory test abnormalities reported were low 
lymphocyte count and platelets.  The most frequently reported severe serum chemistry 
abnormalities were hypophosphatemia, hypokalemia and hyperglycemia.
Patients, n (%)
Adverse event*
Grade 1/2
Grade 3
Diarrhea 
29 (45)
6 (9)
Nausea 
23 (36)
1 (2)
Fatigue 
19 (30)
0
Hypophosphatemia 
2 (3)
15 (23)
Vomiting 
14 (22)
1 (2)
Rash (cumulative terms) 
11 (17)
3 (5)
Decreased appetite 
11 (17)
0
Table 1: Treatment-related AEs in patients with advanced solid tumors (N = 64; ≥ 10%) 
* Gr 4 anaphylactic shock (n=1) likely related to morphine administration.


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In the Phase I study, five first cycle dose-limiting toxicities (DLTs) were observed among the 
patients with advanced solid malignancies Grade 4 anaphylactic shock for one patient, thought to 
be related to intravenous morphine (100 mg BID); Grade 3 diarrhea for two patients (150 mg and 
220 mg BID); Grade 3 rash; and inability to administer 80% of planned dose during Cycle 1 for 
one patient (330 mg BID).  
Although efficacy is not the primary objective of the dose-finding study, patients with advanced 
solid tumors were evaluated for best response according to Response Criteria in Solid Tumors 
(RECIST) version 1.0.  As of March 1, 2013, 46 patients were evaluable for response: a 
complete response was observed in one patient with papillary thyroid cancer; five patients (out of 
seven evaluable, overall response rate 71%) with desmoid tumors achieved a partial response 
(Figure 3).  Stable disease was reported for 14 patients with a variety of tumor types, and 26 
patients had objective progression as best overall response on study.  
Figure 3: Waterfall plot for response in evaluable patients receiving PF-03084014 on the Phase I 
trial (data from Pfizer).  Responses were measured after 6 to 9 months on study.  
Clinical Pharmacokinetics
Evaluation of the pharmacokinetic characteristics of PF-03084014 indicated that it was rapidly 
absorbed, with median time of occurrence of Cmax (Tmax) values of 0.5 to 1 hour generally 
observed across the three clinical studies.  PF-03084104 exposure increased with escalating 
single and repeat doses, with some evidence for greater than dose proportional increases 
observed across the dose range studied in trials A8641001 and A8641002.  The terminal 
elimination half-life of PF-03084014 was approximately 19 hours after single doses and 26 hours 
after multiple doses.  
Potential Drug Interactions


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PF-03084014 induced CYP 3A4 in human hepatocytes in vitro.  Nirogacestat does not inhibit 
CYP 1A2 at concentrations <30 μM, but weakly inhibits CYP 2C9, CYP 2C19 and CYP 2D6 in 
human liver microsomes with 50% inhibitory concentration (IC50) values of 18.5 +/- 1.6 μM, 
20.3 +/- 2.0 μM and 13.5 +/- 1.2 μM.  PF-03084014 inhibits CYP 3A with an IC50 value of 
4.6 +/- 0.3 μM.  Additionally, preliminary assessment suggests that Nirogacestat is a weak time- 
dependent inhibitor of CYP 3A4 with an inhibition constant (Ki) value of 2.2 μM and a kinact 
rate of 0.059/min.  In a healthy volunteer clinical drug-drug interaction study, Nirogacestat 
increased the area under the plasma concentration-time curve from zero to infinity (AUC0-∞) 
58.9% and maximum observed plasma concentration (Cmax) 30.7% of Midazolam following 
9 days of dosing at 95 mg daily.  In nonclinical studies conducted in mdr1a/1b (-/-) knockout and 
wild-type mice, PF-03084014 readily penetrates the blood-brain barrier and shows interaction 
with the efflux transporter P-glycoprotein (P-gp) at the blood-brain barrier.
Correlative Studies Background
Pre- and post-dose (cycle 1) blood and hair follicle samples were collected for pharmacodynamic 
analysis on the Phase I clinical trial in patients with advanced solid tumors.  Changes in gene 
expression in these samples were measured by TaqManR qRT-PCR.  Notch pathway modulation 
was demonstrated in all evaluable patients, with transcriptional repressor Hes4 showing the most 
consistent regulation, with a greater than 2-fold down-regulation in an initial cohort of nine 
patients (Figure 4) [20].  Hes4 is also one of several Notch pathway target genes down-regulated 
following Nirogacestat treatment in breast cancer xenograft models [25] (Figure 2).
Figure 4: Changes in Hes4 gene expression following treatment with Nirogacestat in samples 
from 9 patients on the Phase I trial [20].  
In this current study, optional tumor biopsies will be collected at baseline and during cycle 7 to 
look at changes in the expression of Notch response genes in the Clinical Tumor Profiling 
Laboratory of Dr. Paul Meltzer, CCR.  A blood sample will also be collected at baseline; blood 
and tumor biopsy samples will undergo genotyping for germline and somatic mutations in APC 
and CTNNB1 genes.  
Because prior studies have indicated that desmoid tumors may be aneuploid, copy number 
analysis will be performed on tumor biopsy DNA for correlative studies.  Blood and tumor 
biopsy tissue will also be subject to whole exome sequencing for somatic mutations in genes 


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which may contribute to tumor formation.  Samples will be delinked prior to performing any 
genotyping studies.  Details of the correlative studies to be performed are provided in Section 
5.1; none of the genetic information obtained will be used to inform clinical decision making or 
be shared with the patient.  The potential risks associated with obtaining genetic information are 
discussed in Section 5.4.  If sufficient biopsy material is available, the following assays will be 
performed to obtain comprehensive genomic profiling of these tumors: transcriptome sequencing 
and DNA methylation analysis.
 
Rationale
Based on the promising activity in desmoid tumors observed in patients on the Phase I trial, we 
propose a Phase II trial of Nirogacestat in patients with unresectable desmoid tumors to further 
evaluate the activity of this agent in this rare disease.  
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT 
Nirogacestat will be administered at the recommended Phase II dose of 150 mg BID orally, 
continually, in 21-day cycles.  Optional tumor biopsies for research purposes will be performed 
at baseline prior to study treatment and at the beginning of cycle 7 (+/- one cycle).  
2.1
ELIGIBILITY CRITERIA
2.1.1
Inclusion Criteria
2.1.1.1
Patients must have histologically confirmed desmoid tumor confirmed by the 
Laboratory of Pathology, NCI, that has progressed after receiving at least one line of 
standard treatment and that is not amenable to surgical resection or definitive radiation 
therapy.
2.1.1.2
Willingness to provide blood samples and 10 unstained slides or a tumor block for 
genetic research studies. 
2.1.1.3
Any line of therapy with prior desmoid therapy, including radiotherapy, should have 
been completed at least 2 weeks before study entry and all toxicities must have resolved 
at least to eligibility levels.  
2.1.1.4
Age >18 years; because no dosing or adverse event data are currently available on the 
use of Nirogacestat in patients <18 years of age, children are excluded from this study, 
but may be eligible for future pediatric trials.
2.1.1.5
ECOG performance status <2 (see Appendix A).
2.1.1.6
Life expectancy > 3 months.
2.1.1.7
Patients must have normal organ and marrow function as defined below: 
absolute neutrophil count
> 1,500/mcL
platelets
> 100,000/mcL
total bilirubin
< 1.5 X institutional upper limit of normal
AST(SGOT)/ALT(SGPT)
< 5 X institutional upper limit of normal


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creatinine
< 1.5 X institutional upper limit of normal
OR
creatinine clearance
> 60 mL/min/1.73 m2 for patients with 
creatinine levels >1.5 mg/dL
hemoglobin
> 9 g/dL 
2.1.1.8
Patients must be able to swallow whole tablets or capsules with no GI condition 
affecting absorption; nasogastric or G-tube administration is not allowed.
2.1.1.9
The effects of Nirogacestat on the developing human fetus are unknown.  For this 
reason and because γ-secretase inhibitors are known to be teratogenic, women of child-
bearing potential and men must agree to use adequate contraception (hormonal or 
barrier method of birth control; abstinence) for the duration of study participation and 
for at least 6 months after dosing with study drugs ceases.  Should a woman become 
pregnant or suspect she is pregnant while she or her partner is participating in this study, 
she should inform her treating physician immediately.  Men treated or enrolled on this 
protocol must also agree to use adequate contraception for the duration of study 
participation, and 6 months after completion of study drug administration.
2.1.1.10 Ability to understand and the willingness to sign a written informed consent document.
2.1.1.11  Evidence of measurable disease by CT scan.  Measurable lesions are defined as those 
that can be accurately measured in at least one dimension (longest diameter to be 
recorded) as >20 mm by chest x-ray, as >10 mm with CT scan, or >10 mm with 
calipers by clinical exam.  
2.1.2
Exclusion Criteria
2.1.2.1
Patients who are receiving any other investigational agents.  Concurrent mediations that 
the patient is taking will be reviewed by the PI to assess safety and eligibility.  
2.1.2.2
Prior treatment with γ-secretase inhibitors or anti-notch antibody therapy.
2.1.2.3
Uncontrolled intercurrent illness including, but not limited to, serious infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study 
requirements.
2.1.2.4
QTc interval of >470 msec at study entry; congenital long QT syndrome.
2.1.2.5
Pregnant women are excluded from this study because Nirogacestat is a γ-secretase 
inhibitor with the potential for teratogenic or abortifacient effects.  Because there is an 
unknown but potential risk for adverse events in nursing infants secondary to treatment 
of the mother with Nirogacestat, breastfeeding should be discontinued if the mother is 
treated with Nirogacestat. 
2.1.2.6
Patients with gastrointestinal conditions that might predispose for drug intolerability or 
poor drug absorption (e.g., inability to take oral medication or a requirement for IV 
alimentation, prior surgical procedures affecting absorption, malabsorption syndrome, 
and active peptic ulcer disease) are excluded.  Subjects with ulcerative colitis, 


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inflammatory bowel disease, or a partial or complete small bowel obstruction are also 
excluded, as are any patients who cannot swallow the tablet whole.  Tablets must not be 
crushed or chewed; nasogastric or G-tube administration is not allowed.
2.1.2.7
HIV-positive patients on combination antiretroviral therapy are ineligible because of the 
potential for pharmacokinetic interactions with Nirogacestat. 
2.1.3
Recruitment Strategies
We have had multiple discussions with the Desmoid Tumor Research Foundation, Inc., 
who have various outreach efforts including patient meetings and webcasts.  Senior 
executives of the Foundation have indicated strong interest in this trial and willingness 
to inform their members.  We also have a network of referring physicians nationally 
that refers patients with solid tumors to our clinical program.  Given our interest and 
trials for sarcomas, we have formed connections with centers that treat patients with 
mesenchymal malignancies.  We will be informing all of these of the availability of this 
trial once it is open.  
2.2
SCREENING EVALUATION
2.2.1.1
Histologic confirmation: A block or stained slides of tumor tissue from each participant 
to confirm diagnosis.  All patients will be required to submit a tumor block or 10 
unstained slides for genetic research purposes. 
2.2.1.2
History and physical examination: Complete history and physical examination 
(including height, weight, vital signs, performance score, EKG) will be conducted 
within 72 hours prior to enrollment. 
2.2.1.3
Imaging Studies (Baseline): Every participant should have an evaluation of known sites 
of disease as part of the baseline evaluation.  All patients will be required to undergo a 
CT scan of the area of known disease; an MRI with diffusion weighting may be 
performed prior to start of study treatment, at the end of cycle 1, and at the time of 
restaging, per PI’s discretion. 
2.2.1.4
Laboratory Evaluation: Baseline laboratory data are to be obtained within 72 hours prior 
to enrollment:
•
Hematological Profile: CBC with differential.
•
Biochemical Profile: albumin, alkaline phosphatase, total bilirubin, BUN, 
calcium, creatinine, phosphorus, SGOT[AST], SGPT[ALT], magnesium, 
potassium, and sodium.
•
Coagulation Profile: PT, PTT, INR 
•
Urine and/or serum pregnancy test for female participants of childbearing 
potential.
2.3
REGISTRATION PROCEDURES
Authorized staff must register an eligible candidate with NCI Central Registration Office (CRO) 
within 24 hours of signing consent.  A registration Eligibility Checklist from the Web site 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) must be completed and sent via 
encrypted email to: NCI Central Registration Office ncicentralregistration-l@mail.nih.gov.  


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After confirmation of eligibility at Central Registration Office, CRO staff will call pharmacy to 
advise them of the acceptance of the patient on the protocol prior to the release of investigational 
agent.  Verification of Registration will be forwarded electronically via e-mail to the research 
team.  A recorder is available during non-working hours.  . 
Off Protocol Therapy and Off-Study Procedure: Authorized staff must notify the Central 
Registration Office (CRO) when a patient is taken off protocol therapy and when a patient is 
taken off-study.  The Participant Status Updates Form from the Web site 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be completed and 
sent via encrypted email to the NCI Central Registration Office (HOIS; ncicentralregistration-
l@mail.nih.gov). 
 
2.4
RANDOMIZATION PROCEDURES
N/A
3
STUDY IMPLEMENTATION
3.1
STUDY DESIGN
This is an open-label Phase II trial of Nirogacestat.  Study drug will be administered at 150 mg, 
orally, BID, continually, in 21-day cycles.  
Labs (CBC with differential and serum chemistries, including electrolytes) will be monitored 
each week during cycle 1, and then every other cycle.  History and physical examination will be 
performed before the start of every other cycle.  For patients having a history and physical 
examination performed by their local physician, study drug will be held until receipt of results; 
this may result in an interruption of therapy.  For patients on study for more than a year, history 
and physical examination and labs can be performed every 3 cycles (up to 2 weeks before the 
start of the cycle).  EKG monitoring will be performed at baseline and then post-drug 
administration on study day 1.  Additional EKG monitoring may be performed during cycle 1 as 
clinically indicated.  
Response assessment will be performed using RECIST 1.1.  Restaging scans (CT scans of the 
known site of disease) will be performed at baseline prior to starting study treatment and then 
every 6 cycles (+/- 1 cycle) as described in Section 5.5.  An MRI with diffusion weighting may 
be performed prior to start of study treatment, end of cycle 1, and at the time of restaging, per 
PI’s discretion.   
Health-related quality of life (HRQOL)/symptom questionnaires will be administered at baseline 
and at restaging (response assessment) as described in Section 3.4.      
Archival unstained slides or tumor block will be sent for genetic research studies as described in 
Section 5.4.
 


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Blood for research (whole exome sequencing) will be collected at baseline as described in 
Section 5.2.
Optional tumor biopsies for research purposes will be performed at baseline prior to study 
treatment and at the beginning of cycle 7 (+/- one cycle) as described in Section 5.2.
3.2
DRUG ADMINISTRATION
Reported adverse events and potential risks are described in Section 11.1.   Appropriate dose 
modifications are described in Section 3.3.  No investigational or commercial agents or therapies 
other than those described below may be administered with the intent to treat the patient's tumor. 
Patients will be asked to maintain a Study Medication Diary (Appendix B) and record each dose 
of medication.  Patients will be given instructions for completing the medication diary and will 
be asked to return it to the clinic staff at their follow up visits.  There is no restriction on taking 
the study drug with food; patients who miss a dose or vomit the drug will be instructed to not 
take an additional dose.  A cycle will be considered completed if 90% of the planned dose is 
administered.  Occasionally patients may miss a dose for non-medical reasons, but this should 
not have an impact in the overall conduct of the trial or be a risk to their safety.
3.3
DOSE MODIFICATIONS

Grade 3 non-hematologic toxicities (other than alopecia; easily correctable electrolyte 
abnormalities) would require holding study drug until recovery to grade ≤ 2 or baseline, 
with reinstituting study drug at the next lower dose level (see below).  

Grade 2 or higher nausea, vomiting, or diarrhea would result in dose reduction only if not 
controlled by supportive measures.  

Any grade of allergic reaction would result in discontinuing study drug and taking patient 
off study. 

Grade 3 hematologic toxicities (except any grade lymphopenia, leucopenia in the absence 
of neutropenia) would result in dose being held till recovery to grade 2 or less with 
reinstitution of study drug at the next lower dose level.  Anemia would require dose 
reduction if there is a drop in hemoglobin of ≥ 2 g/dL from baseline without other causes 
such as nutritional deficiency.  
A maximum of 2 dose reductions will be allowed on study.  Study drug can be held for a 
maximum of 3 weeks to allow recovery from toxicities.  If toxicities do not resolve to 
retreatment criteria by the end of 3 weeks, the patient will only resume treatment at the discretion 
of the PI (i.e., if the patient is benefiting from therapy). 
Dose Level
Dose (orally BID q 21-day cycles)
-1
100 mg


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-2
80 mg
3.4
PATIENT REPORTED OUTCOME QUESTIONNAIRE
Participants on this study will be asked to complete health-related quality-of-life 
(HRQOL)/symptom questionnaires to assess the severity and associated interference caused by 
disease and treatment-related symptoms and track their severity and interference over the course 
of treatment.  These patient-reported outcome (PRO) measures will capture the emergence or 
worsening of selected symptoms from baseline to study completion, thus improving the 
identification of treatment-emergent symptomatic toxicity and better capturing improvements in 
disease-related symptoms which may inform decisions about therapeutic response and clinical 
benefit   Such patient-reported outcomes (PRO) allow participants to rate their own HRQOL, 
thereby providing a direct measure of each patient’s experience of treatment over the course of 
the study [26, 27].  
This protocol will use the psychometrically-validated M.D. Anderson Symptom Inventory 
(MDASI) to assess PRO disease and treatment-related symptoms [28].  MDASI uses a 0-10 
numerical scale to assess, over the previous 24 hours, 13 symptoms commonly experienced by 
patients with cancer and 6 additional items that assess the extent to which these symptoms 
interfered with how patients felt and were able to function:

13 treatment symptoms assessed: pain, fatigue, nausea, disturbed sleep, distress 
(emotional), shortness of breath, lack of appetite, drowsiness, dry mouth, sadness, 
vomiting, difficulty remembering, and numbness or tingling 

6 symptom interference items assessed: general activity, mood, walking ability, normal 
work, relations with other people, and enjoyment of life 
A copy of MDASI is provided in Appendix D.  The questionnaires will be administered at 
baseline and at restaging.  Completing the MDASI takes approximately 2-5 minutes and the 
symptom scale will take an additional 5 minutes to complete.  All patients will complete these 
questionnaires under the supervision of a member of the clinic staff.   
A component score representing symptom severity is obtained by taking the average of the 13 
symptom items together.  A component score representing symptom distress is obtaining by 
averaging the 6 symptom interference items.  Questionnaires will be maintained in the research 
chart of each patient.  The NCI has received permission to use MDASI by the copyright holder, 
The University of Texas MD Anderson Cancer Center. 
3.5
STUDY CALENDAR
Baseline history and physical exam are to be conducted within 1 week prior to start of protocol 
therapy; laboratory evaluations must be done within 72 hours prior to start of protocol therapy.  
Scans and x-rays must be done ≤ 28 days prior to the start of therapy.  The duration of a cycle 
will be 21 days (± 1 day for scheduling).  The start of the next cycle may be delayed for up to 
1 week to accommodate scheduling conflicts.  History and physical examination and laboratory 


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evaluations can be performed before the start of a cycle.  For patients having their history and 
physical examination performed by their local physician, study drug will be held until receipt of 
results.  For patients on study for more than a year, history, physical examination, and labs can 
be performed every 3 cycles (up to 2 weeks before the start of the cycle).  


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Pre-
Study
C1 W1
(D1-7)
C1 W2
(D8-14) 
C1 W3 
D15-21)
C2 W1 
(D1-7)
C2 W2 
(D8-14)
C2 W3 
(D15-21)
C3 
W1 on
Off 
Treat-
ment
Nirogacestat (PF-
03084014) a
X
X
X
X
X
X
X
Informed consent
X
Demographics
X
Medical history
X
Concurrent meds
X
     X--------------------------------------------------------------------X
Physical exam b
X
X
X
Vital signs b
X
X
X
Height
X
Weight b
X
X
X
Performance status b
X
X
X
CBC w/diff, plts c
X
X
X
X
X
Serum chemistry c
X
X
X
X
X
Coagulation profile
X
Adverse event 
evaluation
X------------------------------------------------------------------X
X
Tumor measurements d
X
X
B-HCG e
X
EKG f
X
Tumor biopsies g
X
Archival tissue h
PG blood sampling h
X
Questionnaire i
X
a. PF-03084014 twice daily in 21-day cycles.
b. Should be performed on day 1 at the Clinical Center, and then at the start of every other cycle at the 
Clinical Center or by patient’s local physician.  For patients on study more than a year, history and 
physical examination can be performed every 3 cycles (up to 2 weeks before the start of the cycle).  
c. Serum chemistry (albumin, alkaline phosphatase, total bilirubin, BUN, calcium, creatinine, glucose, 
phosphorus, magnesium, potassium, SGOT [AST], SGPT [ALT], sodium) and CBC w/diff, platelets 
should be performed within 72 hours before enrollment (pre-study) and weekly during cycle 1, at the 
start of every other cycle and as clinically indicated.  For patients on study more than a year, labs can 
be performed every 3 cycles (up to 2 weeks before the start of the cycle).  
d. Tumor measurements are repeated every 6 cycles (±1 cycle).  Documentation (radiologic) must be 
provided for patients removed from study for progressive disease.  Optional MRI scans may be 
performed prior to start of study treatment, end of cycle 1, and every 6 cycles.
e. Serum or urine pregnancy test (women of childbearing potential) within 1 week prior to enrollment


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f. EKG at baseline and then post-drug administration on day 1.  Additional monitoring may be 
performed during cycle 1 as clinically indicated. 
g. Tumor biopsies are optional at baseline and at the beginning of cycle 7
h. Archival tumor biopsy tissue and blood sample for pharmacogenomic analysis collected at baseline
i. Quality-of-life questionnaire to be administered at baseline and at restaging
3.6
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
3.6.1
Criteria for removal from protocol therapy
In the absence of treatment delays due to adverse event(s), treatment may continue until one of 
the following criteria applies:

Disease progression,

Intercurrent illness that prevents further administration of treatment

Significant toxicity occurs despite 2 dose reductions as described in Section 3.3 or no 
lower dose level exists

Pregnancy

Patient decides to withdraw from the study

General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator.
Patients will be followed for 30 days after the last dose is administered or until one of the 
following occurs: patient enrolls on another protocol, patient receives standard of care, or death, 
whichever comes first.  The follow-up will consist of a phone call between Days 27-30 after the 
last dose to evaluate adverse events that were ongoing and any new events that might be deemed 
related to the therapy.  Toxicities felt to be possibly, probably, or definitely related to the study 
drugs that have not resolved or stabilized by Day 30 post-treatment will be followed until 
stabilization or resolution via phone calls as clinically indicated.
3.6.2
Off-Study Criteria
Patients will be removed from this study for one of the following reasons: completed 30-day 
follow-up period, toxicities are unresolved but stabilized, patient enrolls on another protocol, or 
patient receives standard of care.  The reason for study removal and the date the patient was 
removed must be documented in the medical record.
3.6.3
Off Protocol Therapy and Off-Study Procedure
Authorized staff must notify Central Registration Office (CRO) when a subject is taken off 
protocol therapy and when a subject is taken off-study.  A Participant Status Updates Form from 
the web site (http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be 
completed and sent via encrypted email to:  NCI Central Registration Office (HOIS) 
ncicentralregistration-l@mail.nih.gov.


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4
CONCOMITANT MEDICATIONS
All patients will be provided with the best available supportive care.  All concurrent medications 
should be documented prior to initiation of treatment, and be periodically reviewed with the 
patient.  Particular attention must be paid to medications which may cause hemolytic anemia.
No other approved or investigational treatment for desmoid tumors will be permitted during the 
study period, including chemotherapy, biologic response modifiers, hormone therapy, 
immunotherapy, or radiotherapy.  
Nausea/Vomiting
Anti-emetics will not be administered routinely prior to Nirogacestat.  However, if a 
patient develops nausea/vomiting, anti-emetics such as but not limited to 
prochlorperazine, metoclopramide, 5-HT3 antagonists, or aprepitant may be given.  In 
addition, if a patient develops nausea and/or vomiting that is Grade 2 or greater, anti-
emetics may be instituted prophylactically at the discretion of the investigator.  Nausea 
and vomiting will be considered refractory if it does not resolve to ≤ Grade 1 with 
treatment with a combination of at least 2 of the antiemetics within 24 hours.
Diarrhea
If diarrhea develops and does not have an identifiable cause other than study drug 
administration, anti-diarrheals such as Lomotil (diphenoxylate HCl 2.5 mg + atropine 
sulfate 0.025 mg/tablet) dosed according to package insert or loperamide 4 mg po after 
the first unformed stool with 2 mg po every 2 hours as long as unformed stools continue 
(4 mg every 4 hours while asleep).  No more than 16 mg of loperamide should be taken 
during a 24-hour period.  This regimen can be repeated for each diarrheal episode.  
Diarrhea will be considered refractory if it does not resolve within 24 hours to Grade ≤ 2 
with the above regimen ((loperamide ≤16 mg in a 24-hour period if there is resolution of 
the symptoms).
Neutropenia
Febrile neutropenia is a life-threatening complication requiring hospitalization and urgent 
broad-spectrum antibiotics, as well as an aggressive search for the source and microbial 
cause of the episode.  Growth factors to prevent neutropenia will not be administered 
prophylactically.  If necessary, they may be administered according to accepted 
American Society of Clinical Oncology (ASCO) guidelines to allow re-treatment.
Anemia
Symptomatic anemia should be treated with red blood cell transfusion and is 
recommended if the hemoglobin falls below 8 g/dL.  Use of erythropoietin will follow 
ASCO guidelines.
Thrombocytopenia
Thrombocytopenia will be treated conservatively.  In the absence of bleeding, or a 
necessary invasive procedure, platelet transfusions should be given for a platelet count 
≤10,000/mm3.  If invasive procedure(s) is (are) planned, or the patient develops bleeding, 


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platelet transfusions should be administered in accordance with the standard of practice, 
usually maintaining a platelet count above 50,000/mm3.
Hypophosphatemia
Institutional normal value for serum phosphate: 2.5-4.8 mg/dL.  Mild to moderate 
hypophosphatemia (1.0–2.4 mg/dL) will be managed with oral replacement therapy; 
PHOS-NaK packet (280 mg K+/160 mg Na+/250 mg Phos) up to 1000 mg/day.  In 
instances where patients are intolerant or refractory to oral replacement, intravenous 
replacement therapy with sodium phosphate infusion may be administered at a rate of 
0.08-0.16 mmol/kg over 2-6 hours.  For severe hypophosphatemia (< 1.0 mg/dL) or in 
patients with clinical sequelae of hypophosphatemia (e.g., hemolysis) will be managed 
with intravenous replacement therapy (0.08–0.16 mmol/kg) over 2-6 hours. 
Hypokalemia
Institutional normal value for serum potassium: 3.3-5.1 mmol/L.  Mild to moderate 
hypokalemia (2.5–3.2 mmol/L) will be managed with oral replacement therapy; 
potassium chloride 20 mEq orally up to a maximum of 100 mEq/day.  For severe 
hypokalemia (< 2.5 mmol/L) or in patients with mild to moderate hypokalemia with 
evidence of cardiac arrhythmia, intravenous potassium will be administered intravenously 
at 10 mEq/hour through a peripheral IV or up to 40m Eq/hour through a central catheter 
and with cardiac monitoring.
5
BIOSPECIMEN COLLECTION
5.1
CORRELATIVE STUDIES FOR RESEARCH
In normal cells, the APC complex of APC, axin, Ck1α, and GSK3β regulates β-catenin levels, 
resulting in degradation of the protein [14].  More than 1000 mutations that lead to missense or 
frame shift mutations or premature stop codons and consequently synthesis of truncated APC 
protein have been described [17, 29] (listed in the Sanger Center COSMIC database at 
http://cancer.sanger.ac.uk/cancergenome/projects/cosmic/).  These mutations result in non-
functional APC protein that cannot phosphorylate β-catenin for subsequent degradation; 
dysregulation of β-catenin levels results in protein accumulation in the nucleus and activation of 
Tcf-4.  Prior studies of desmoid tumors indicate that aneuploidy does occur in some of these 
tumors [30].  There is no information available regarding cooperating mutations which may 
contribute to tumor progression.
5.2
PHARMACODYNAMICS 
5.2.1
Laboratory Contact
At least 24 hours prior to biopsy or blood sample collection, the research nurse will 
contact the NCI Phase I/II PK/PD Support Group in NIH Building 10: 
E-mail (preferred): NCIPK-PDsupportgroup@mail.nih.gov 


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Abbreviated Title: PhII PF-03084014 Desmoids
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Pager (preferred): 102-12798 
Phone: 240-858-3963 
Fax: 301-480-5871.  
For biopsies, tubes pre-labeled with the participant ID, biopsy date, protocol number, and 
site of tissue biopsy will be provided.  Initial processing and shipping of the samples will 
be completed as described below. 
5.2.2
Tumor Biopsies
5.2.2.1
Timing of tumor biopsies
Optional biopsies will be collected:  

before drug administration on study (baseline), 

at the beginning of cycle 7 (+/- one cycle)
5.2.2.2
Biopsy Procedure
Serial tumor biopsies will be obtained through Interventional Radiology by a 
percutaneous approach.  A maximum of 3 core biopsies 18-gauge in diameter and at 
least 1 cm in length will be obtained at each time point.  Only percutaneous biopsies 
will be performed.  
It is estimated that there will be between 2-5 million cells from each biopsy.  If a site is 
deemed appropriate for biopsy with minimal risk to the participant by agreement 
between the investigators and Interventional Radiology, an attempt at biopsy will be 
made.  Determination of a disease site amenable to biopsy will be determined on an 
individual case basis after discussion with an interventional radiologist.  The biopsy 
procedure to be used in this protocol is described below; local anesthesia will be 
administered.  Such biopsies can be safely performed as evidenced by literature reports 
[31] as well as our experience at the Clinical Center.  Risks of the procedure include, 
but are not limited to, bleeding, infection, pain, and scarring.  We will follow Clinical 
Center Interventional Radiology SOPs for coagulant panel and platelets.

All biopsies will be by percutaneous approach 

No biopsy by an invasive (endoscopic, laparoscopic, or surgical) procedure will 
be performed
The use of imaging to facilitate biopsies will be decided by members of the 
Interventional Radiology team and may include ultrasound, CT scan, or MRI.  Should 
CT scan be needed for biopsy, the number of scans for each procedure will be limited 
to the minimum number needed to safely obtain a biopsy.  All cases will be carefully 
reviewed with the interventional radiologists at NIH who have extensive experience in 
performing such procedures.  Only if the procedure is considered to be low risk will we 
proceed with tumor biopsy in a given participant.  
Tumor biopsies are optional.  Baseline biopsies will be performed following patient 
enrolling on study.  If the baseline biopsy is unsuccessful or the patient refuses to 
undergo subsequent biopsies, no further biopsies will be performed but the patient will 


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remain on study, receive study medication, and other correlative studies will be 
performed.  
5.2.2.3
Solid Tumor Biopsy Processing
A maximum of three tissue cores will be collected.  Biopsies will be fixed in formalin 
then sent to the Laboratory of Pathology, NCI.  One 4-micron H&E-stained section and 
either a matching FFPE tissue block or 10 unstained slides will be sent to the Clinical 
Tumor Profiling Laboratory where an examination of tumor content will be performed 
by a designated pathologist:
Contact: Marbin Pineda
37/6138 
301-496-5266
pinedama@mail.nih.gov;  cc Paul Meltzer (pmeltzer@mail.nih.gov) and Keith 
Killian (killianj@mail.nih.gov).
Tumor content must exceed 40% and estimated tumor content will be recorded.  The 
H&E section will serve to confirm original diagnosis and also estimate tumor nuclei 
content.  The remaining biopsy will be extracted for nucleic acids using the Qiagen 
FFPET All-Prep procedure.  DNA will be assessed for quantity and quality by 
spectroscopy (OD 260/280) and a PCR-based amplification quality assessment 
test.  RNA will be assessed for quality by analysis on the Agilent Bioanalyzer.
10-20 ng of RNA will be analyzed from pre-treatment and cycle 7 biopsies to 
determine the level of Notch target gene HES4 using a Taqman assay.  
If sufficient samples are available, whole-exome sequencing will be performed on the 
DNA and transcriptome sequencing will be performed on the RNA, both done 
retrospectively for research purposes on samples unlinked from patient identifiers.
5.2.3
Blood Samples
A blood sample will be obtained at baseline for germline sequencing of APC and 
CTNNB1.
A minimum of 2 mL of whole blood is required for genetic sequencing.  For this, 5 mL of 
blood will be collected in a purple top (EDTA) tube at baseline prior to starting treatment.  
The blood can be collected using a standard protocol.  After blood draw, the sample 
should be aliquoted and frozen in 2-mL screw-top cryovials at -20°C.  These samples 
need to be sent on dry ice to the following address.  The samples should be labeled with 
only the unique patient ID.  Do NOT include patient identifiers (e.g., medical record 
number, patient name or initials) with the samples.   
Please e-mail contact person 24 hours prior to shipment.  
Upon receipt at the Clinical Tumor Profiling Laboratory, genomic DNA will be extracted 
for clinical targeted sequencing.


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5.3
SAMPLE STORAGE, TRACKING AND DISPOSITION
5.3.1
Sample Collection and Processing
Biospecimens will be collected and processed using validated SOPs that will ensure both 
specimen quality and patient confidentiality pursuant to informed consent provisions.  
Information about each specimen will be recorded on a PK/PD collection worksheet.
Using a computerized inventory system and a backup hardcopy process, all specimen 
collection and processing steps will be documented and the specific location of each 
specimen will be tracked.  Each new specimen collected will be assigned a unique 
barcode identifier that can be linked to the original specimen collected and other relevant 
information within the inventory system.  To ensure patient confidentiality, only 
containers used for the initial specimen collections will be labeled with patient identifiers.  
Only the barcode identifier will be applied to all subsequent specimen containers.  When 
specimens are processed and aliquoted, no patient information will be included on the 
new containers.  Original specimen containers will be discarded.  Only barcode-labeled 
specimens without patient identifiers will be shipped for analysis and/or storage.  
Specimen labels will indicate: protocol number, unique patient accession number, 3-digit 
sample number (see list below), collection time, and total volume collected, as 
appropriate.  Samples from sets of at least three patients will be grouped for scientific 
analysis.  
Standardized 3-digit sample collection numbers:
500 series: tumor biopsies
800 series: blood for pharmacogenomic analysis
The inventory process contains other security provisions sufficient to safeguard patient 
privacy and confidentiality.  Access to the inventory system and associated documents 
will be restricted to appropriate individuals.  Requests to use specimens stored in the 
repository must be approved.  The only patient information available in the inventory 
system will be the patient sex, diagnosis, and level of informed consent given.  SOPs 
ensure that any changes in informed consent made by a patient and relayed to the PI will 
be reflected in the inventory system to ensure that specimens are destroyed as 
appropriate.  All laboratory personnel will be trained to adhere to SOPs and will be 
monitored for high-quality performance.
Any new use of these samples will require prospective IRB review and approval.  Access 
to these samples will only be granted following IRB approval of an additional protocol, 
granting the rights to use the material.
If at any time, a patient withdraws from the study and does not wish for their existing 
samples to be utilized, the individual must provide a written request.  Following receipt of 
this request, the samples will be destroyed (or returned to the patient, if so requested), and 
reported as such to the IRB.  Any samples lost (in transit or by a researcher) or destroyed 
due to unknown sample integrity (i.e., broken freezer or lack of dry ice in a shipping 


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container allows for extensive sample thawing, etc.) will be reported as such to the IRB, 
the NCI Clinical Director, and the office of the CCR, NCI.
All specimens obtained in the protocol are used as defined in the protocol, and any new 
use of these samples will require prospective IRB review and approval.  Any specimens 
that are remaining at the completion of the protocol will be stored in the conditions 
described below; the study will remain open so long as sample or data analysis continues.  
5.4
SAMPLES FOR GENETIC/GENOMIC ANALYSIS
5.4.1
Description of the scope of genetic/genomic analysis
Optional biopsy samples will be collected at baseline and during cycle 7, but delinking 
will occur once a patient has come off study for one of the reasons listed in Section 3.6 or 
has had a response.  At this point, patient identifiers will be de-linked and the Clinical 
Tumor Profiling Laboratory will perform whole exome sequencing on the de-identified 
samples; this lab is CLIA-certified for sample handling but not for the correlative studies 
that will be performed on this study.  No genetic data will be shared with the patient.  The 
process for de-identifying the samples is described further below.  
A section of each biopsy will be stained for H&E and the stained slide scanned into an 
Aperio Image Database.  For a tumor biopsy sample to be considered adequate, a 
minimum of 40% of the biopsy should have tumor content; biopsy samples with a lower 
tumor content will not undergo macrodissection or laser capture microdissection to 
enrich for tumor cells.  In cases where sufficient tumor DNA is not obtained for analysis, 
the patient will be given the option to undergo a repeat tumor biopsy to obtain more 
tissue.  
The remaining specimen will be extracted using Qiagen’s AllPrep FFPET nucleic acid 
extraction methodology.  Resultant DNA and RNA will be quantified by NanoDrop 
spectroscopy.  500 ng DNA will be analyzed for copy number variation on an Illumina 
CytoSNP array following standard protocols.  If sufficient DNA is obtained, 500 ng will 
be used for sequencing library preparation using standard Illumina methods.  The 
identical procedure will be applied to the blood sample.  Both libraries will be sequenced 
on an Illumina HiSeq 2000 sequencer.  If sample is sufficient, 1 µg of RNA from the 
ALLPrep extraction will be converted to cDNA and sequenced on the HiSeq2000. If 
available, 250-750 ng of tumor DNA will be analyzed using Illumina 450K methylation 
arrays.
5.4.2
Description of how privacy and confidentiality of medical information/biological 
specimens will be maximized
Archival tumor, blood, and optional tumor biopsy samples will be collected from 
participants on this study, but genetic analysis will only be performed on de-identified 
samples.  Whole-exome sequencing (performed for research purposes) of tumor and 
blood can detect nonambiguous germline variants, which may raise health and privacy 
implications for the patient and his or her family.  Whole exome sequencing on this study 


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will not be validated for clinical use and no clinical decisions can be made based on its 
results.  No genetic data will be shared with the patient or his/her family.  Given the 
uncertain clinical significance of some of these variants and the ethical implications, we 
will perform such research analysis on de-identified samples only.  
Clinical information linked to the unique patient IDs will be stored in a bioinformatics 
database.  Once the patient has been taken off study or at a defined time point determined 
by the study PI, the unique patient ID will be deleted and a new random ID generated 
(arbitrary or random alphanumeric code) in the database by the bioinformatics team, 
thereby un-linking the patient identifier from the information in the database.  The 
Bioinformatics team will inform the Clinical Tumor Profiling Lab of the new random ID, 
all samples from a given patient will be transferred to the new ID, and the Clinical Tumor 
Profiling Lab will also break the link to the unique patient ID.  The unique patient IDs 
will be discarded so there is no possibility of linking the samples to the sources.  The 
Clinical Tumor Profiling Lab will proceed with whole exome sequencing on de-identified 
samples for research purposes only.  Data reports sent to the clinical site will be summary 
reports with no identifiable patient IDs whatsoever.
This study affords a unique opportunity to collect information about mutations in genes 
associated with desmoids tumors, a rare and poorly characterized cancer, as well as how 
patients’ tumors respond to this targeted therapy.  The NIH IRB will be consulted and 
kept informed of progress of this study and other trials conducted with the study agent 
that may affect study design and conduct.  
5.4.3
Management of Results
Given the uncertain clinical significance of some of the variants in genes of interest to 
this study and the ethical implications of these potential findings, we will perform genetic 
research analysis on de-identified samples only.  No genetic data will be shared with the 
patient or his/her family.  A Certificate of Confidentiality will not be obtained for this 
study. 
5.4.4
Genetic counseling
N/A; all samples will be unlinked before analysis.
5.5
MAGNETIC RESONANCE IMAGING (MRI) – OPTIONAL ONLY
According to the National Comprehensive Cancer Network’s guidelines on soft tissue 
sarcomas[32], MRI is a recommended imaging modality for patients with desmoids tumors and 
will be offered in cases where it is deemed appropriate. MR imaging will consist of 3 
components:  T2 weighted (T2W), diffusion weighted (DW) and Dynamic Contrast Enhanced 
MRI (DCE).  Imaging will be performed at 3 Tesla in the Molecular Imaging Clinic.  Each 
sequence contributes a different functional parameter to the study.  It is estimated the scan time 
will be approximately 30 minutes.  There are well known contraindications to MRI that will be 
observed (e.g., shrapnel, a pacemaker, etc.).  For the gadolinium injection, the patient must have 
an eGFR > 30cc/min.   
Here we describe the value of each imaging parameter:


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T2W provides anatomic imaging of the lesion at high spatial resolution.  T2W signal is also 
dependent on the amount of free water in the lesion.  It is predicted that with increasing fibrosis, 
water content will decrease, thus shortening the T2 of the lesion, resulting in a darker lesion.  
The T2 value can be calculated and additionally, ratios of the tumor to an unaffected tissue (e.g., 
muscle) can provide a quantitative index of changes consistent with fibrosis over time.
DW depends on the Brownian motion of water within tissue.  By using varying “b values”, one 
can calculate the Apparent Diffusion Coefficient (ADC) which is an index of water diffusion in 
tissue (higher values indicate more water diffusion) Loose connective tissue is associated with 
free water migration resulting in high ADC values, whereas dense connective tissue associated 
with fibrosis would be predicted to restrict diffusion resulting in progressively lower ADC 
values.  For this protocol, we will obtain serial ADC values at each time point.
DCE MRI consists of the rapid acquisition of T1 weighted images before, during and after the 
bolus administration of a gadolinium-containing MR contrast agent.  Serial regions of interest are 
then placed over the tumor and time-signal curves are generated.  By calculating the T1 of the 
tissue prior to injection, one can convert the signal intensity into the actual gadolinium 
concentration within the tissue over time.  These gadolinium concentration-time curves can then 
be fit to a 2-compartment exponential model that generates parameters associated with the initial 
uptake of contrast (Ktrans) and with the washout of the contrast (kep), both of which are related 
to vascular permeability.  In addition, heuristic measurements of the curve such as area under the 
curve (AUC) and time to peak (TTP) can be measured to add further data.  Angiogenic inhibitors 
are predicted to decrease Ktrans, kep, AUC, and TTP and are especially useful when compared 
in the same patient over time.  Gamma-secretase inhibitors have been shown to affect the 
leakiness of blood vessels; therefore, serial DCE-MRI measurements will be obtained in patients 
over time.
Optional MRI scans may be performed at baseline prior to study drug administration, at the end 
of cycle 1 and at the time of restaging, per PI’s discretion.  Although optional, every attempt to 
will be made to obtain MRI scans on patients when possible.  To accommodate scheduling 
issues, scans can be performed +/- one week from the scheduled date. 
5.6
HUMAN DATA SHARING PLAN
What data will be shared?
We will share human data generated in this research for future research as 
follows:
X De-identified data in an NIH-funded or approved public repository
X Identified data in BTRIS (automatic for activities in the Clinical Center)
X De-identified or identified data with approved outside collaborators under
appropriate agreements
How and where will the data be shared?
Data will be shared through:
X An NIH-funded or approved public repository: clinicaltrials.gov
X BTRIS (automatic for activities in the Clinical Center)


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X Approved outside collaborators under appropriate individual agreements
X Publication and/or public presentations
When will the data be shared?
X At the time of publication or shortly thereafter
6
DATA COLLECTION AND EVALUATION 
6.1
DATA COLLECTION
All data will be kept secure.  Personal identifiers will not be used when collecting and storing 
data.  An enrollment log will be maintained in the regulatory binder/file which is the only 
location of personal identifiers with unique subject identification number.
All AEs must be recorded on the AE case report form.
All AEs, including clinically significant abnormal findings on laboratory evaluations, regardless 
of severity, will be followed until satisfactory resolution.  AEs should be reported up to 30 days 
following the last dose of study drug.  
An abnormal laboratory value will be considered an AE if the laboratory abnormality is 
characterized by any of the following:

Results in discontinuation from the study

Is associated with clinical signs or symptoms 

Requires treatment or any other therapeutic intervention

Is associated with death or another serious adverse event, including hospitalization. 

Is judged by the Investigator to be of significant clinical impact

If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the patient’s 
outcome.
6.2
RESPONSE CRITERIA
CT restaging scans will be performed at baseline prior to study drug administration and then 
every 6 cycles (+/- one cycle).  An MRI scan with diffusion weighting may be performed prior to 
start of study treatment, end of cycle 1, and at the time of restaging, per PI’s discretion.  In 
addition to a baseline scan, confirmatory CT scans should also be obtained at least 4 weeks 
following initial documentation of objective response.
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [33].  Changes in the largest diameter (unidimensional measurement) of the tumor 


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lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST 
criteria.
6.2.1
Definitions
Evaluable for toxicity:  All patients will be evaluable for toxicity from the time of their first 
treatment with Nirogacestat.
Evaluable for objective response: Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will 
be considered evaluable for response.  These patients will have their response classified 
according to the definitions stated below.  (Note:  Patients who exhibit objective disease 
progression prior to the end of cycle 1 will also be considered evaluable.)
Evaluable Non-Target Disease Response:  Patients who have lesions present at baseline that are 
evaluable but do not meet the definitions of measurable disease, have received at least one cycle 
of therapy, and have had their disease re-evaluated will be considered evaluable for non-target 
disease.  The response assessment is based on the presence, absence, or unequivocal progression 
of the lesions. 
6.2.2
Disease Parameters
Measurable disease:  Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded) as >20 mm by chest x-ray, as >10 mm 
with CT scan, or >10 mm with calipers by clinical exam.  All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters).
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a lymph 
node must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  At baseline and in follow-up, only the short axis will 
be measured and followed.
Non-measurable disease.  All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered 
non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses 
(not followed by CT or MRI), are considered as non-measurable.
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts.
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above.  However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions.
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline.  Target lesions should be selected on the basis of their size (lesions 


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with the longest diameter), be representative of all involved organs, but in addition should be 
those that lend themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be selected.  A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum.  The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease.
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline.  Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted throughout follow-up. 
6.2.3
Methods for Evaluation of Measurable Disease
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment.
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up.  Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam.
Clinical lesions:  Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as assessed using calipers 
(e.g., skin nodules).  In the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended. 
Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung.  However, CT is preferable. 
Conventional CT and MRI:  This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less.  If CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness.  
MRI is also acceptable in certain situations (e.g. for body scans).  
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement.  Furthermore, the availability of 
MRI is variable globally.  As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and site of disease.  
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence.  It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 


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scanners, body parts, and diseases.  Ideally, the same type of scanner should be used and the 
image acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible.
PET-CT:  At present, the low dose or attenuation correction CT portion of a combined PET-CT 
is not always of optimal diagnostic CT quality for use with RECIST measurements.  However, if 
the site can document that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be 
used for RECIST measurements and can be used interchangeably with conventional CT in 
accurately measuring cancer lesions over time.  Note, however, that the PET portion of the CT 
introduces additional data which may bias an investigator if it is not routinely or serially 
performed.  
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement.  Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next.  If new lesions are identified by ultrasound in the course of the study, confirmation by CT 
or MRI is advised.  If there is concern about radiation exposure at CT, MRI may be used instead 
of CT in selected instances.
Endoscopy, Laparoscopy:  The utilization of these techniques for objective tumor evaluation is 
not advised.  However, such techniques may be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence following 
complete response (CR) or surgical resection is an endpoint.
Cytology, Histology:  These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain).
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease.
FDG-PET:  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis of 
FDG-PET imaging can be identified according to the following algorithm: 
a.
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion.
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If the 
positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT  scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-
PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, this is not PD.
c.
FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in 


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cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively described in 
the protocol and supported by disease-specific medical literature for the indication.  
However, it must be acknowledged that both approaches may lead to false positive CR 
due to limitations of FDG-PET and biopsy resolution/sensitivity.
 Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image.
6.2.4
Response Criteria
6.2.4.1
Evaluation of Target Lesions
Complete Response (CR): Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm.
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters.
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm.  (Note:  the appearance of one or more new lesions is also 
considered progressions).
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study.
6.2.4.2
Evaluation of Non-Target Lesions
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size (<10 mm short axis).
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response.
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits.
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not normally trump 
target lesion status.  It must be representative of overall disease status change, not a single lesion 
increase.    
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal Investigator).


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6.2.4.3
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria.
For Patients with Measurable Disease (i.e., Target Disease)
Target 
Lesions
Non-Target 
Lesions
New 
Lesions
Overall 
Response
Best Overall Response when Confirmation 
is Required*
CR
CR
No
CR
>4 wks. Confirmation**
CR
Non-CR/Non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-CR/Non-
PD/not evaluated
No
PR
>4 wks. Confirmation**
SD
Non-CR/Non-
PD/not evaluated
No
SD
Documented at least once >4 wks. from 
baseline**
PD
Any
Yes or 
No
PD
Any
PD***
Yes or 
No
PD
Any
Any
Yes
PD
no prior SD, PR or CR
*
See RECIST 1.1 manuscript [33] for further details on what is evidence of a new lesion.
**
Only for non-randomized trials with response as primary endpoint.
***
In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease 
progression.
Note:
Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as “symptomatic 
deterioration.”  Every effort should be made to document the objective progression even after 
discontinuation of treatment.
For Patients with Non-Measurable Disease (i.e., Non-Target Disease)
6.2.5
Duration of Response
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD*
Not all evaluated
No
not evaluated
Unequivocal PD
Yes or No
PD
Any
Yes
PD
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used as an 
endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be measured is 
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recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started).
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented.
Duration of stable disease:  Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements. 
6.3
TOXICITY CRITERIA
The following adverse event management guidelines are intended to ensure the safety of each 
patient while on the study.  The descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE 
reporting.  All appropriate treatment areas should have access to a copy of the CTCAE version 
4.0.   A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40). 
7
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN
7.1
DEFINITIONS
Please refer to definitions provided in Policy 801: Reporting Research Events 
https://irbo.nih.gov/confluence/display/IRBO/Policies+and+SOPs).  There will be no adverse 
event reporting on the extended follow-up portion of this trial.   
7.2
OHSRP OFFICE OF COMPLIANCE AND TRAINING / IRB REPORTING
7.2.1
Expedited Reporting 
Please refer to the reporting requirements in Policy 801: Reporting Research Events, and Policy 
802: Non-Compliance in Human Subjects Research (found in 
https://irbo.nih.gov/confluence/display/IRBO/Policies+and+SOPs). Note: Only IND Safety 
Reports that meet the definition of an unanticipated problem will need to be reported per these 
policies.
7.2.2
IRB Requirements for PI Reporting at Continuing Review
Please refer to the reporting requirements in Policy 801: Reporting Research Events found here: 
https://irbo.nih.gov/confluence/display/IRBO/Policies+and+SOPs
7.3
NCI CLINICAL DIRECTOR REPORTING
Problems expeditiously reviewed by the OHSRP/IRB in the NIH eIRB system will also be 
reported to the NCI Clinical Director/designee; therefore, a separate submission for these reports 
is not necessary. 


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In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email unless they are due to progressive disease. 
To report these deaths, please send an email describing the circumstances of the death to the 
Clinical Director/designee at NCICCRQA@mail.nih.gov within one business day of learning of 
the death.
7.4
EXPEDITED ADVERSE EVENT REPORTING CRITERIA TO THE IND MANUFACTURER
All serious adverse events must be reported in the defined timelines to 
CCRsafety@mail.nih.gov.  The CCR Office of Regulatory Affairs will send all reports to 
the manufacturer as described below: 
Reporting of Serious Adverse Events.  Within 24 hours of sponsor awareness of the 
event, the sponsor will report to SpringWorks by facsimile any Serious Adverse Event 
(“SAE,” as defined in Section 7.1.4) that occurs during the SAE reporting period (as 
defined in Section 7.1) in a study subject assigned to receive Nirogacestat.  The PI will 
report such SAEs using an FDA MEDWATCH form or equivalent.  The Reportable 
Event Fax Cover Sheet provided by should also be provided.  SAEs should be reported as 
soon as they are determined to meet the definition, even if complete information is not 
yet available.  
7.5
NIH OFFICE OF BIOTECHNOLOGY ACTIVITIES (OBA)/INSTITUTIONAL BIOSAFETY 
COMMITTEE (IBC) REPORTING CRITERIA
N/A.
7.6
NIH REQUIRED DATA AND SAFETY MONITORING PLAN
7.6.1
Principal Investigator/Research Team 
The clinical research team will meet on a weekly basis when patients are being actively treated 
on the trial to discuss each patient.  Decisions about dose level enrollment and dose modification 
if applicable will be made based on the toxicity data from prior patients. 
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator.  Events meeting requirements for expedited reporting as described in 
Section 7.2.1 will be submitted within the appropriate timelines.
The principal investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy.  The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff. 


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8
SPONSOR PROTOCOL/SAFETY REPORTING  
8.1
DEFINITIONS
8.1.1
Adverse Event 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment.  An adverse event (AE) can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product (ICH E6 (R2))
8.1.2
Serious Adverse Event (SAE)
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following:

Death,

A life-threatening adverse event (see section 8.1.3)

Inpatient hospitalization or prolongation of existing hospitalization 
o
A hospitalization/admission that is pre-planned (i.e., elective or scheduled surgery 
arranged prior to the start of the study), a planned hospitalization for pre-existing 
condition, or a procedure required by the protocol, without a serious deterioration in 
health, is not considered a serious adverse event.
o
A hospitalization/admission that is solely driven by non-medical reasons (e.g., 
hospitalization for patient convenience) is not considered a serious adverse event. 
o
Emergency room visits or stays in observation units that do not result in admission to 
the hospital would not be considered a serious adverse event. The reason for seeking 
medical care should be evaluated for meeting one of the other serious criteria.

Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions

A congenital anomaly/birth defect

Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition.
8.1.3
Life-threatening 
An adverse event or suspected adverse reaction is considered "life-threatening" if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a 
more severe form, might have caused death. (21CFR312.32)


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8.1.4
Severity
The severity of each Adverse Event will be assessed utilizing the CTCAE version 4.
8.1.5
Relationship to Study Product
All AEs will have their relationship to study product assessed using the terms:  related or not 
related.  

Related – There is a reasonable possibility that the study product caused the adverse 
event. Reasonable possibility means that there is evidence to suggest a causal relationship 
between the study product and the adverse event.

Not Related – There is not a reasonable possibility that the administration of the study 
product caused the event.
8.2
ASSESSMENT OF SAFETY EVENTS
AE information collected will include event description, date of onset, assessment of severity 
and relationship to study product and alternate etiology (if not related to study product), date of 
resolution of the event, seriousness and outcome. The assessment of severity and relationship to 
the study product will be done only by those with the training and authority to make a diagnosis 
and listed on the Form FDA 1572 as the site principal investigator or sub-investigator.  AEs 
occurring during the collection and reporting period will be documented appropriately regardless 
of relationship.  AEs will be followed through resolution.
SAEs will be:

Assessed for severity and relationship to study product and alternate etiology (if not 
related to study product) by a licensed study physician listed on the Form FDA 1572 as 
the site principal investigator or sub-investigator.

Recorded on the appropriate SAE report form, the medical record and captured in the 
clinical database.

Followed through resolution by a licensed study physician listed on the Form FDA 1572 
as the site principal investigator or sub-investigator.
For timeframe of recording adverse events, please refer to Section Error! Reference source not 
found..  All serious adverse events recorded from the time of first investigational product 
administration must be reported to the sponsor. 
8.3
REPORTING OF SERIOUS ADVERSE EVENTS
Any AE that meets protocol-defined serious criteria must be submitted immediately (within 24 
hours of awareness) to OSRO Safety using the CCR SAE report form.  
All SAE reporting must include the elements described in section 8.2.
SAE reports will be submitted to the Center for Cancer Research (CCR) at: 
OSROSafety@mail.nih.gov and to the CCR PI and study coordinator.  CCR SAE report form 


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and instructions can be found at: 
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=157942842
Following the assessment of the SAE by OSRO, other supporting documentation of the event 
may be requested by the OSRO Safety and should be provided as soon as possible.
8.4
SAFETY REPORTING CRITERIA TO THE PHARMACEUTICAL COLLABORATORS
Reporting will be per the collaborative agreement. 
8.5
REPORTING PREGNANCY 
8.5.1
Maternal exposure
If a patient becomes pregnant during the course of the study, the study treatment should be 
discontinued immediately, and the pregnancy reported to the Sponsor no later than 24 hours of 
when the Investigator becomes aware of it. The Investigator should notify the Sponsor no later 
than 24 hours of when the outcome of the Pregnancy becomes known,
Pregnancy itself is not regarded as an SAE.  However, congenital abnormalities or birth defects 
and spontaneous miscarriages that meet serious criteria (section 8.1.2) should be reported as 
SAEs. The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic 
pregnancy, normal birth, or congenital abnormality) should be followed up and documented.
8.5.2
Paternal exposure
Male patients should refrain from fathering a child or donating sperm during the study and for 
180 days after the last dose of Nirogacestat.
Pregnancy of the patient’s partner is not considered to be an AE.  However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or 
congenital abnormality) occurring from the date of the first dose until 30 days after the last dose 
should, if possible, be followed up and documented.
8.6
REGULATORY REPORTING FOR STUDIES CONDUCTED UNDER CCR-SPONSORED IND
Following notification from the investigator, CCR, the IND sponsor, will report any suspected 
adverse reaction that is both serious and unexpected.  CCR will report an AE as a suspected 
adverse reaction only if there is evidence to suggest a causal relationship between the study 
product and the adverse event.  CCR will notify FDA and all participating investigators (i.e., all 
investigators to whom the sponsor is providing drug under its INDs or under any investigator’s 
IND) in an IND safety report of potential serious risks from clinical trials or any other source, as 
soon as possible, in accordance to 21 CFR Part 312.32. 
All serious events will be reported to the FDA at least annually in a summary format.


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9
CLINICAL MONITORING 
As a sponsor for clinical trials, FDA regulations require the CCR to maintain a monitoring 
program. The CCR’s program allows for confirmation of: study data, specifically data that could 
affect the interpretation of primary and secondary study endpoints; adherence to the protocol, 
regulations, ICH E6, and SOPs; and human subjects protection. This is done through 
independent verification of study data with source documentation focusing on:

Informed consent process

Eligibility confirmation

Drug administration and accountability

Adverse events monitoring

Response assessment.
This trial will be monitored by personnel employed by a CCR contractor. Monitors are qualified 
by training and experience to monitor the progress of clinical trials.  Personnel monitoring this 
study will not be affiliated in any way with the trial conduct.
10 STATISTICAL SECTION  
This study will be conducted as a single stage Phase II trial to rule out an unacceptably low 10% 
clinical response rate (PR+CR; p0=0.10) in favor of a modestly high response rate of 35% 
(p1=0.35).  If we assume a type I error rate (alpha, probability of accepting a poor treatment) of 
0.10 when the response rate is 0.10 and a statistical power of 0.90 (beta=0.10, probability of 
rejecting a good treatment) when the true response rate is 0.35, then we plan to accrue a total of 
17 patients.  The null hypothesis will be rejected if 4 or more responses are observed in the 17 
patients.  It is anticipated that 1 patient per month may be enrolled onto this study.  Thus, it will 
take approximately 17 months to complete enrollment. 
10.1 STATISTICAL CONSIDERATIONS FOR EXPLORATORY CORRELATIVE STUDIES
Symptom measurements will be summarized by mean and standard deviation for continuous 
measurements and by frequency distributions for categorical measurements.  Mutations in APC 
and CTNNB1 will be summarized with frequency distributions, respectively.  The clinical 
response rate will be compared between the mutated and non-mutated subgroups.  Modulation of 
the Notch pathway will be assessed by a paired t-test for a change in expression from baseline to 
post-drug administration. 
11 COLLABORATIVE AGREEMENTS 
11.1 AGREEMENT TYPE
Springworks is providing the agent used in this study to the PI under a Collaborative Agreement 
(CTA); providing this agent constitutes the research support for this investigator-initiated 
study.    


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12 HUMAN SUBJECTS PROTECTIONS 
12.1 RATIONALE FOR SUBJECT SELECTION
Men and women of all races and ethnic groups are eligible for this trial.
12.2 PARTICIPATION OF CHILDREN
Because no dosing or adverse event data are currently available on the use of Nirogacestat in 
patients <18 years of age, children are excluded from this study, but may be eligible for future 
pediatric trials.
12.3 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS
This study will be open to all individuals regardless of gender, ethnicity, or race, provided that 
the aforementioned inclusion and exclusion criteria are met.  Patients for this study will be 
recruited through internal referral, our physician referral base, and through various cancer 
information hotlines (i.e., Clinical Studies Support Center, 1-800-4Cancer).  To date, there is no 
information that suggests that differences in drug metabolism or effect on tumor would be 
expected in one ethnic group compared to another.  Efforts will be made to extend accrual to 
each representative population, but a balance must be struck between participant safety 
considerations and limitations on the number of individuals exposed to potentially ineffective 
treatments on the one hand and the need to explore racial/ethnic aspects of clinical research on 
the other hand.  If differences in outcome that correlate to ethnic identity are noted, a follow-up 
study may be written to investigate those differences more fully.
12.3.1 Patient Advocate
The patients’ rights representative is available to patients receiving treatment on this protocol at 
the NIH Clinical Center at (301) 496-2626 in Building 10 of the Clinical Research Center, Room 
1-3521, on the Bethesda NIH campus.  Patients will be informed that they can contact the study 
PI or RN at any time with questions about their medical care, and that the patients’ rights 
representative is also available to answer non-medical questions about the study. 
12.4 RISKS/BENEFITS ANALYSIS
There may or may not be any clinical benefit to a patient from participation in this trial.  Their 
participation will benefit future cancer patients.  Potential risks include the possible occurrence 
of any of a range of nirogacestat side effects (listed in Section 13.1.1), gene sequencing risks 
(Section 5.4.2), MRI imaging risks (Section 13.2), and phlebotomy and CT radiation and contrast 
agent risks (details below).  The procedure for protecting against or minimizing risks will be to 
medically evaluate patients as described in Section 3.   Although no compensation is available, 
any injury will be fully evaluated and treated in keeping with the benefits or care to which 
participants are entitled under applicable regulations. 
All care will be taken to minimize side effects, but they can be unpredictable in nature and 
severity.  This study may involve risks to patients, which are currently unforeseeable.  All 
patients will be monitored for side effects from taking study medication.  This research 


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represents a greater than minimal risk to participants, but presents the prospect of direct benefit 
to individual subjects.
Risks Related to CT Radiation: This study includes 2 optional CT-guided tumor biopsies and 
up to 3 CT restaging scans per year. These procedures confer radiation exposure at an effective 
dose of up to approximately 6 rem per year.  This dose is above NIH RSC guidelines of less than 
5.0 rem per year in adults. 
Risks Related to Contrast Agents: 
Risks for IV Contrast: Symptoms from the contrast infusion are usually mild and may include 
discomfort from the injection, feeling hot, a metallic taste, nausea or vomiting, and allergic 
reaction (ranging from mild itching or rash to severe trouble breathing, shock or, rarely, death). 
The contrast may also cause kidney problems.
Risks for Oral Contrast: Symptoms from oral contrast are usually mild and may include 
vomiting, nausea, cramping, bloating, constipation, or diarrhea.
Risks Related to Phlebotomy: There are no major risks involved with blood draws. Minor 
complications include bleeding, pain, bruising at the site of phlebotomy, vasovagal reactions or 
infections may rarely occur.
12.5 CONSENT AND ASSENT PROCESS AND DOCUMENTATION
An associate or principal investigator on the trial will inform patients of the purpose, alternatives, 
drug administration plan, research objectives, and follow-up of this trial.  The patient will be 
provided an IRB-approved consent for review and signature and his/her questions will be 
answered.  After a decision is made to enroll into the study, a signature will be obtained from the 
patient.  The original signed consent goes to Medical Records; a copy will be placed in the 
research record.  Patients will not be consented by telephone
All patients must have a signed informed consent form and an on-study (confirmation of 
eligibility) form filled out and signed by a participating investigator before entering on study.
When a hand signature on an electronic document is used for the documentation of consent, this 
study will use the iMedConsent platform (which is 21 CFR Part 11 compliant) to obtain the 
required signatures.  Both the investigator and the participant will sign the electronic document 
using a finger, stylus, or mouse.  Electronic signatures (i.e., “signatures” that are digitally 
generated) will not be used.
12.5.1 Participation of subjects unable to give consent
Adults unable to give consent are excluded from enrolling in the protocol.  However, re-consent 
may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired.  For this reason and because there is a prospect of direct benefit from 
research participation (i.e., long-term stabilization and/or improvement in the pain and physical 
impairment caused by desmoid tumors), all subjects ≥ age 18 at the NCI only will be offered the 


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opportunity to fill in their wishes for research and care, and assign a substitute decision maker on 
the “NIH Advance Directive for Health Care and Medical Research Participation” form so that 
another person can make decisions about their medical care in the event that they become 
incapacitated or cognitively impaired during the course of the study. Note: The PI or AI will 
contact the NIH Ability to Consent Assessment Team (ACAT) for evaluation as needed for the 
following: an independent assessment of whether an individual has the capacity to provide 
consent; assistance in identifying and assessing an appropriate surrogate when indicated; and/or 
an assessment of the capacity to appoint a surrogate.  For those subjects that become 
incapacitated and do not have pre-determined substitute decision maker, the procedures 
described in MAS Policy 19-1 and NIH OHSRP Policy 403 for appointing a surrogate decision 
maker for adult subjects who are (a) decisionally impaired, and (b) who do not have a legal 
guardian or durable power of attorney, will be followed.
13 PHARMACEUTICAL AND DEVICE INFORMATION  
13.1 NIROGACESTAT (PF-03084014) (IND #119,769)
PF-03084014 is an investigational agent supplied by SpringWorks; the dihydrobromide salt form 
will be used in the clinical studies. 
Molecular Weight: 651.47 (dihydrobromide salt)
Molecular Formula: C27H43Br2F2N5O 
Physical Description: white to off-white powder
Route: oral 
Mechanism of Action: selective noncompetitive inhibitor of γ-secretase 
Contraindications: none identified 
Other Names: PF-4014
13.1.1 Nirogacestat Toxicity 
Preclinical—The target systems reported in chronic oral dosing studies in dogs were the GI, 
hematopoietic/ immune, musculoskeletal, reproductive, and hepatic systems.  
Hematopoietic/immune effects were seen in both rat and dog, and included decreases in B and T 
cells, NK cells, IgM and IgD expression on B cells (rat only), and lymphoid depletion in spleen, 
thymus (thymic cortical atrophy in dog), lymph nodes, and/or gut-associated lymphoid tissue.  
Treatment-related intestinal tract changes consisted of epithelial hyperplasia and, with higher 
exposures, epithelial degeneration and necrosis (more detailed information is provided in Section 
1.2.2). 
Clinical—The most common AEs independent of causality seen in patients with advanced solid 
tumors were diarrhea, nausea, fatigue, vomiting, hypophosphatemia, decreased appetite, cough 
and rash; all of these events were considered to be treatment related in some patients.  The 
majority of AEs were considered mild to moderate but treatment related Grade 3 
hypophosphatemia, diarrhea, and rash have been frequently reported.  The only treatment-related 


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Grade 4 AE was anaphylactic shock reported in one patient, an event thought to be related to co-
administration of intravenous morphine.   
No clinically relevant changes in vital signs or electrocardiograph endpoints have been reported.  
The severe hematology laboratory test abnormalities reported were low lymphocyte count and 
platelets.  The most frequently reported severe serum chemistry abnormalities were 
hypophosphatemia, hypokalemia and hyperglycemia (more detailed information is provided in 
Section 1.2.2).  
An IND/CIOMS safety report was issued to study sites on 18 December 2019 for a 
serious adverse event of "premature menopause" in a 25-year-old female participant on the 
randomized phase 3 study.  Since this event was reported, 3 additional SAE reports for potential 
primary ovarian insufficiency have been reported to SpringWorks Therapeutics.  SpringWorks 
has conducted a comprehensive review of adverse events entered into the electronic data capture 
(EDC) system and are actively following 2 additional cases of hot flashes/ facial flushing to 
determine if these are symptoms of primary ovarian insufficiency or due to other unrelated 
causes.  SpringWorks, site investigators, and site staff remain blinded to study treatment and it is 
unknown if these participants were receiving nirogacestat or placebo, but "primary 
ovarian insufficiency" as a risk for women of childbearing potential has been added to the 
informed consent form with Amendment L. 
As of June 21, 2021, the SpringWorks Global Safety Committee additionally designated 
hidradenitis suppurativa, folliculitis, and alopecia as “identified risks” in patients treated with 
nirogacestat.  Of note, none of these risks met the criteria for being designated as “important” 
identified risks.  These risks have been added to the informed consent form with Amendment N. 
The basis for the decision for each event is as follows:

Recognized hidradenitis suppurativa as an identified risk based on
–
the validated signal process, analysis, and final Signal Assessment Report
–
Gamma secretase inhibition mechanism involving hair follicles described in the 
literature

Recognized folliculitis as a validated signal and an identified risk
–
Observation during hidradenitis Safety Assessment Report analysis
–
Gamma secretase inhibition mechanism involving hair follicles shared with 
hidradenitis as described in the literature

Recognized alopecia as a validated signal and an identified risk
–
Observation identified as part of the hidradenitis and folliculitis investigations
–
Gamma secretase inhibition mechanism involving hair follicles shared with 
hidradenitis as described in the literature 
–
Decrease in estrogen due to ovarian insufficiency could lead to release of follicle from
–
telogen and loss of hair [34]
–
Estrogen depletion during menopause can lead to female pattern hair loss [35]
As of April 25, 2023, Springworks identified non-melanoma skin cancer (defined as the 
MedDRA Preferred terms of Basal cell carcinoma, Squamous cell carcinoma, and Squamous cell 
carcinoma of the skin) as an important potential risk for nirogacestat, based on occurrence in six 
nirogacestat trial participants.  All participants have continued treatment with nirogacestat after 


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the report of their non-melanoma skin cancer [with three patients on extended treatment, up to 
1448 days after onset of their non-melanoma skin cancer] with no reported occurrence of another 
non-melanoma skin cancer. No reports of malignant melanoma have been reported from 
participants in the nirogacestat development program. SpringWorks recommended that an 
association between treatment with nirogacestat and the appearance and diagnosis of non-
melanoma skin cancer be recognized as an important potential risk for nirogacestat, and this risk 
has been added to the informed consent form with Amendment R (version date 5/18/2023).
13.1.2 Formulation and Preparation 
Nirogacestat is available as 10 mg and 50 mg tablets.  All tablets contain common compendial 
excipients. 
13.1.3 Stability and Storage 
Tablets should be stored at 15-25° C (59-77°F).
13.1.4 Incompatibilities/Drug Interactions  
In vitro studies indicate that Nirogacestat is metabolized primarily by the drug-metabolizing 
enzyme, CYP3A4.  Nirogacestat does not inhibit CYP1A2, weakly inhibits CYP2C9, CYP2C19 
and CYP2D6, and causes induction of CYP3A4.  Nirogacestat may however increase exposure 
to sensitive substrates of CYP2C9, CYP2C19, and CYP2D6, or CYP2C9, CYP2C19, and 
CYP2D6 substrates with a narrow therapeutic range.
Cytochrome P450 Inhibitors: Co-administration of Nirogacestat with potent inhibitors 
of CYP3A4 may increase plasma Nirogacestat concentrations.  Caution should be 
exercised in patients receiving Nirogacestat in combination with these and other potent 
CYP3A4 inhibitors (see Appendix C).
Cytochrome P450 Inducers: Nirogacestat metabolism may be induced when taking 
potent CYP3A4 inducers resulting in reduced Nirogacestat plasma concentrations.  
Caution should be exercised in patients receiving Nirogacestat in combination with these 
and other potent CYP3A4 inducers (see Appendix C).
Cytochrome P450 Substrates: Patients treated with Nirogacestat should avoid the use of 
CYP3A4 substrates with narrow therapeutic indices (see Appendix C).
13.2 MAGNETIC RESONANCE IMAGING SCANNER
The use of Magnetic Resonance Imaging scanners on this study for assessment of disease burden 
meets the requirements for an IDE exemption under Category 1. The devices in the Clinical 
Center are commercially obtained and FDA approved. The device is being used in accordance 
with FDA labeling and was not regulated as a device before the enactment of the Medical Device 
Amendments
13.2.1 Source 
MRI scans will be performed using the devices available in the NIH Clinical Center.


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13.2.2 MRI and Contrast Agent Toxicity
Risks associated with MRIs include the following: participants may be at risk for injury from the 
MRI magnet if they have some kinds of metal in their body.  It may be unsafe for participants to 
have an MRI scan if they have a pacemaker or other implanted electrical device, brain 
stimulator; some types of dental implants, aneurysm clips, and metallic prostheses (including 
metal pins and rods, heart valves, and cochlear implants); permanent eyeliner; implanted delivery 
pump; or shrapnel fragments. Welders and metal workers may have small metal fragments in the 
eye. Participants will be screened for such metal before having any scan. If they have any, you 
will not receive an MRI scan.  If they have a question about metal in their body, they should 
inform the study investigators.  Participants will be asked to complete an MRI screening form 
before each MRI scan they have.
All magnetic objects must be removed before entering the MRI scan room. This includes items 
like watches, coins, jewelry, and credit cards.
People with fear of confined spaces may become anxious during an MRI. Those with back 
problems may have back pain or discomfort from lying in the scanner.  The noise from the 
scanner is loud enough to damage hearing, especially in people who already have hearing loss. 
Everyone having a research MRI scan will be fitted with hearing protection. If the hearing 
protection comes loose during the scan, participants should let us know right away.   
Symptoms from the contrast infusion are usually mild and may include feeling hot, burning, or 
coldness in the arm during the injection, a metallic taste, headache, allergic reactions and nausea. 
In an extremely small number of individuals, more severe symptoms have been reported 
including shortness of breath, wheezing, hives, and lowering of blood pressure. Unless 
specifically allowed by the protocol, participants will not receive gadolinium-based contrast 
agents for research purposes if they have previously had an allergic reaction to them. Individuals 
with a history of anaphylaxis to other agents or chronic asthma requiring treatment will not 
receive gadolinium under this protocol unless they have previously received gadolinium and 
tolerated it well. Participants will be asked about such allergic reactions and history of asthma 
before a contrast agent is administered.
People with kidney disease are at risk for a serious reaction to gadolinium contrast called 
“nephrogenic systemic fibrosis,” which has resulted in a very small number of deaths. If subjects 
are 60 years old or greater or have diabetes, kidney disease or liver disease, blood work to assess 
kidney function will be performed within 4 weeks before any MRI scan with gadolinium 
contrast. Participants may not receive gadolinium for a research MRI scan if kidney function is 
not normal. There is no evidence for the potential of gadolinium-related toxicity in people with 
normal kidney function. This protocol follows NIH Clinical Center guidelines for kidney-
function screening related to gadolinium administration.
Most of the gadolinium contrast is eliminated in the urine. However, recent studies have found 
very small amounts of residual gadolinium in the body, including the brain, by imaging and at 
autopsy. Macrocyclic gadolinium-containing contrast agents are substantially less likely to leave 
gadolinium behind than linear agents. The use of macrocyclic vs. linear agents in this study is 
delineated in the procedures section above. There is presently no evidence that the retained 
gadolinium is associated with any adverse effects.   


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Anastas, J.N. and R.T. Moon, WNT signalling pathways as therapeutic targets in cancer. 
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11.
Lazar, A.J.F., et al., Specific Mutations in the β-Catenin Gene (CTNNB1) Correlate with 
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12.
Domont, J., et al., High frequency of [beta]-catenin heterozygous mutations in extra-
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Kasper, B., P. Ströbel, and P. Hohenberger, Desmoid Tumors: Clinical Features and 
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Escobar, C., et al., Update on desmoid tumors. Annals of Oncology, 2012. 23(3): p. 562-
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15.
Calvert, G.T., et al., Extra-Abdominal Desmoid Tumors Associated with Familial 
Adenomatous Polyposis. Sarcoma, 2012. 2012: p. 11.
16.
Meneghello, C., et al., Nuclear GSK-3β segregation in desmoid-type fibromatosis. 
Histopathology, 2013: p. n/a-n/a.


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Penel, N., et al., Imatinib for progressive and recurrent aggressive fibromatosis (desmoid 
tumors): an FNCLCC/French Sarcoma Group phase II trial with a long-term follow-up. Annals 
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19.
Gounder, M., et al., Activity of sorafenib against desmoid tumor/deep fibromatosis 
(DT/DF). JCO, 2010. 28(15 (supplement)): p. 10013.
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Messersmith, W., et al. A First-in-Patient Phase I Study of the Novel Gamma Secretase 
Inhibitor PF-03084014 in Patients With Advanced Solid Tumor Malignancies. in EORTC. 2012. 
Dublin, Ireland.
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Messersmith, W.A., et al., A Phase I, Dose-Finding Study in Patients with Advanced 
Solid Malignancies of the Oral gamma-Secretase Inhibitor PF-03084014. Clin Cancer Res, 
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Kopan, R. and M.X.G. Ilagan, The Canonical Notch Signaling Pathway: Unfolding the 
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Carothers, A.M., et al., Mesenchymal Stromal Cell Mutations and Wound Healing 
Contribute to the Etiology of Desmoid Tumors. Cancer Research, 2012. 72(1): p. 346-355.
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Takebe, N. and S. Ivy, Controversies in cancer stem cells: targeting embryonic signaling 
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Zhang, C.C., et al., Biomarker and Pharmacologic Evaluation of the γ-Secretase 
Inhibitor PF-03084014 in Breast Cancer Models. Clinical Cancer Research, 2012. 18(18): p. 
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Tavernier, S., et al., Validity of the Patient Generated Index as a Quality-of-Life Measure 
in Radiation Oncology. Oncology Nursing Forum, 2011. 38(3): p. 319-329.
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Basch, E., et al., Recommendations for Incorporating Patient-Reported Outcomes Into 
Clinical Comparative Effectiveness Research in Adult Oncology. Journal of Clinical Oncology, 
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Laurent-Puig, P., C. Béroud, and T. Soussi, APC gene: Database of germline and somatic 
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30.
Salas, S., et al., Molecular characterization by array comparative genomic hybridization 
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Dowlati, A., et al., Sequential tumor biopsies in early phase clinical trials of anticancer 
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33.
Eisenhauer, E.A., et al., New response evaluation criteria in solid tumours: Revised 
RECIST guideline (version 1.1). European Journal of Cancer, 2009. 45(2): p. 228-247.
34.
Hu, H.M., et al., Estrogen leads to reversible hair cycle retardation through inducing 
premature catagen and maintaining telogen. PLoS One, 2012. 7(7): p. e40124.
35.
Grymowicz, M., et al., Hormonal Effects on Hair Follicles. Int J Mol Sci, 2020. 21(15).


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APPENDIX A: PERFORMANCE STATUS CRITERIA
ECOG Performance Status Scale
Grade
Descriptions
Percent
100
0
Normal activity.  Fully active, able to 
carry on all pre-disease performance 
without restriction.
90
80
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).
70
60
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.
50
40
3
In bed >50% of the time.  Capable of only 
limited self-care, confined to bed or chair 
more than 50% of waking hours.
30
20
4
100% bedridden.  Completely disabled.  
Cannot carry on any self-care.  Totally 
confined to bed or chair.
10
5
Dead.
0


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APPENDIX B: PATIENT’S MEDICATION DIARY
INSTRUCTIONS
1. Complete one form for each cycle of treatment.
2. Swallow study drugs whole with a full glass of water.  There is no restriction on taking the 
study drug with food.  Do not chew the tablets.  
3. Record the date and time you took the drugs. 
4. If you have any comments or notice any side effects, please record them in the Comments 
column.
5. Please bring this form and your bottle of drugs when you return for your appointment.  
6. In case you make a mistake when filling in his form, please place a single slash mark through 
the error (error) and initial it.  Please do not white out any errors or scribble them out with 
ink.  Please do not write the correct information directly over the error, but on a separate line 
next to the error.


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Today’s Date _____________________Cycle #______ Nirogacestat Dose _______mg 
Patient Name_____________________(initials are acceptable)  Patient Study ID_______________
Day
Date
Time of dose
AM               PM
Number of 
Tablets Taken
Comments
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Patient’s signature: ___________________________________________________________________


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Patient Study Calendar
Nirogacestat treatment is given over periods called cycles.  All cycles are 3 weeks (21 days) 
long.  Treatment cycles will be repeated as long as you are tolerating the drug and your cancer is 
either stable or getting better.  Each cycle is numbered in consecutive order.  
The chart below shows what will happen during Cycle 1 and future cycles.  The left-hand 
column shows the day in the cycle, and the right-hand column tells you what will happen on that 
day.  This schedule shows what will happen to you after you sign the consent and start the study.  
Day
What to do and what will happen to you
Before 
starting 
study drug
Check in at the Outpatient Clinic
Have a history taken of how you feel and undergo a physical examination 
including vital signs by a Health Care Provider
Get routine blood and urine tests
Have a research blood sample taken 
Pregnancy test for women who are able to become pregnant 
Take a health questionnaire
CT scan of the known site of disease will be done
o Research tumor biopsy may be taken (optional)
Cycle 1, 
Day 1
Admitted to Clinical Center
Begin taking Nirogacestat by mouth twice a day each day 
EKG will be done
Cycle 1, 
Days 2-20
Continue taking Nirogacestat by mouth twice a day each day 
Get routine blood tests each week during cycle 1
Cycle 1, 
Day 21
Continue taking Nirogacestat by mouth twice a day each day
An optional MRI scan to measure how your tumors are responding to 
Nirogacestat treatment may be performed per PI’s discretion 
Cycle 2,
Week 1
Check in at the Outpatient Clinic
Get routine blood tests at the start of each new cycle
Continue taking Nirogacestat by mouth twice a day each day 
Cycle 3 and 
onwards
Have a history taken of how you feel and undergo a physical examination 
including vital signs by a Health Care Provider at the start of every other 
cycle (if you have been on the study for more than a year, this will be done 
every 3 cycles, up to 2 weeks before the start of the cycle)
Get routine blood tests every other cycle (if you have been on the study 
for more than a year, this will be done every 3 cycles, up to 2 weeks before 
the start of the cycle)
Continue taking Nirogacestat by mouth twice a day each day


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Day
What to do and what will happen to you
Cycle 6 
Day 21
Continue taking Nirogacestat by mouth twice a day each day
CT scan to measure how your tumors are responding to Nirogacestat 
treatment will be done every 6 cycles (+/- 1 cycle) (about 4 months)
An optional MRI scan to measure how your tumors are responding to 
Nirogacestat treatment may be done every 6 cycles (about 4 months) per 
PI’s discretion
Take a health questionnaire when we measure how your tumors are 
responding to Nirogacestat treatment (every 6 cycles, about 4 months)
Cycle 7
Day 1
Continue taking Nirogacestat by mouth twice a day each day 
Only for patients who undergo research tumor biopsies (optional)
Check in at the Outpatient Clinic
Have a history taken of how you feel and undergo a physical examination 
including vital signs by a Health Care Provider 
o Research tumor biopsy may be taken (optional)


57
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Version Date:5-18-2023
APPENDIX C: POTENTIAL DRUG INTERACTIONS
Co-administration of Nirogacestat with potent inhibitors of CYP3A4 may increase plasma 
concentrations.  Nirogacestat metabolism may be induced when taking potent CYP3A4 
inducers, resulting in reduced plasma concentrations.  Patients treated with Nirogacestat should 
also avoid the use of CYP3A4 substrates with narrow therapeutic indices.
CYP2C19 Inhibitors
Amiodarone
Amitriptyline
Amprenavir
Aprepitant
Azelastine
Bortezomib
Buprenorphine
Cholecalciferol/Vitamin D3
Cimetidine
Citalopram
Clotrimazole
Clozapine
Delavirdine
Diazepam
Dimethyl sulfoxide
Drospirenone
Efavirenz
Entacapone
Ethinyl estradiol
Ethotoin
Felbamate
Fenofibrate
Fluconazole
Fluoxetine
Fluvoxamine
Fosamprenavir
Gefitinib
Gemfibrozil
Imipramine
Indinavir
Indomethacin
Isoniazid
Ketoconazole
Lansoprazole
Letrozole
Loratadine
Losartan
Mephobarbital
Mestranol
Methimazole
Methoxsalen
Methsuximide
Miconazole
Moclobemide
Modafinil
Nelfinavir
Nicardipine
Nilutamide
Olanzapine
Omeprazole
Orphenadrine
Oxcarbazepine
Paroxetine
Pentamidine
Pimozide
Pioglitazone
Probenecid
Progesterone
Propofol
Rabeprazole
Ritonavir
Rosiglitazone
Saquinavir
Selegiline
Sertraline
Sildenafil
Sulconazole
Telmisartan
Ticlopidine
Tioconazole
Topiramate
Torsemide
Tranylcypromine
Valdecoxib
Valproic acid
Voriconazole
Warfarin
Zafirlukast
CYP2C19 Inducers
Aminoglutethimide
Carbamazepine
Fosphenytoin
Phenytoin
Rifampin
St. John’s wort
CYP2C19 Substrates
Carisoprodol
Cilostazol
Citalopram
Clobazam
Clomipramine
Desogestrel
Diazepam
Escitalopram 
Esomeprazole 
Fosphenytoin
Imipramine
Lansoprazole
Mephenytoin
Mephobarbital
Methsuximide
Moclobemide 
Nelfinavir 
Nilutamide
Omeprazole
Pantoprazole
Pentamidine
Phenobarbital
Phenytoin
Progesterone 
Rabeprazole
Sertraline
Trimipramine
Voriconazole
Only major substrates and effective inducers are listed.  Additional information for drug interactions with 
cytochrome P450 isoenzymes can be found at http://medicine.iupui.edu/flockhart/.


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Abbreviated Title: PhII PF-03084014 Desmoids
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Adapted from Cytochrome P450 Enzymes: Substrates, Inhibitors, and Inducers.  In: Lacy CF, Armstrong 
LL, Goldman MP, Lance LL eds. Drug Information Handbook 15TH ed. Hudson, OH; LexiComp Inc. 
2007: 1899-1912.  


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CYP3A4 Inhibitors
Acetazolamide
Amiodarone
Amlodipine
Amprenavir
Anastrozole
Aprepitant
Atazanavir
Atorvastatin
Azelastine
Azithromycin
Betamethasone
Bortezomib
Bromocriptine
Caffeine
Cerivastatin
Chloramphenicol
Chlorzoxazone
Cimetidine
Ciprofloxacin
Cisapride
Clarithromycin
Clemastine
Clofazimine
Clotrimazole
Clozapine
Cocaine
Conivaptan
Cyclophosphamide 
Cyclosporine
Danazol
Dasatinib 
Delavirdine
Desipramine
Dexmedetomidine 
Diazepam 
Diclofenac 
Dihydroergotamine 
Diltiazem
Disulfiram
Docetaxel
Doxorubicin
Doxycycline
Drospirenone
Efavirenz
Enoxacin
Entacapone
Ergotamine
Erythromycin
Ethinyl estradiol
Etoposide
Felodipine
Fentanyl
Fluconazole
Fluoxetine
Fluvastatin
Fluvoxamine
Fosamprenavir 
Glyburide
Grapefruit juice 
Haloperidol
Hydralazine
Ifosfamide
Imatinib
Indinavir
Irbesartan
Isoniazid
Isradipine
Itraconazole 
Ketoconazole
Lansoprazole
Lidocaine 
Lomustine
Losartan 
Lovastatin
Mefloquine
Mestranol
Methadone
Methimazole
Methoxsalen
Methylprednisolone
Metronidazole
Miconazole
Midazolam
Mifepristone
Mirtazapine
Mitoxantrone
Modafinil
Nefazodone
Nelfinavir
Nevirapine
Nicardipine
Nifedipine
Nisoldipine
Nizatidine
Norfloxacin
Olanzapine
Omeprazole
Orphenadrine
Oxybutynin
Paroxetine
Pentamidine
Pergolide
Phencyclidine
Pilocarpine
Pimozide
Pravastatin
Prednisolone 
Primaquine
Progesterone
Propofol 
Propoxyphene
Quinidine
Quinine
Quinupristin
Rabeprazole 
Ranolazine
Risperidone
Ritonavir
Saquinavir
Selegiline
Sertraline
Sildenafil
Sirolimus
Sulconazole
Tacrolimus
Tamoxifen
Telithromycin
Teniposide
Testosterone
Tetracycline
Ticlopidine
Tranylcypromine
Trazodone
Troleandomycin
Valproic acid
Venlafaxine
Verapamil
Vinblastine
Vincristine
Vinorelbine
Voriconazole
Zafirlukast
Ziprasidone
CYP3A4 Inducers
Aminoglutethimide
Carbamazepine
Fosphenytoin
Nafcillin 
Nevirapine
Oxcarbazepine
Pentobarbital
Phenobarbital 
Phenytoin
Primidone
Rifabutin
Rifampin 
Rifapentine
St. John’s wort 


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CYP3A4 Substrates
Albuterol
Alfentanil
Alprazolam
Amlodipine
Amprenavir
Aprepitant
Aripiprazole
Atazanavir
Atorvastatin
Benzphetamine
Bisoprolol
Bortezomib
Bosentan
Bromazepam
Bromocriptine
Buprenorphine
Buspirone
Busulfan
Carbamazepine
Cerivastatin
Chlordiazepoxide
Chloroquine
Chlorpheniramine
Cisapride
Citalopram
Clarithromycin
Clobazam
Clonazepam
Clorazepate
Cocaine
Colchicine
Cyclophosphamide
Cyclosporine
Dantrolene
Dapsone
Delavirdine
Diazepam
Digitoxin
Dihydroergotamine
Diltiazem
Disopyramide
Docetaxel
Doxepin
Doxorubicin
Doxycycline
Efavirenz
Eletriptan
Enalapril
Eplerenone
Ergoloid mesylates
Ergonovine
Ergotamine
Erythromycin
Escitalopram
Estradiol
Estrogens, conj., 
synthetic
Estrogens, conj., equine
Estrogens, conj., 
esterified
Estrone
Estropipate
Ethinyl estradiol
Ethosuximide
Etoposide
Felbamate
Felodipine
Fentanyl
Flurazepam
Flutamide
Fosamprenavir
Fulvestrant
Gefitinib
Halofantrine
Haloperidol
Ifosfamide
Imatinib
Indinavir
Irinotecan
Isosorbide dinitrate
Isosorbide mononitrate
Isradipine
Itraconazole
Ketamine 
Ketoconazole
Lansoprazole
Letrozole
Levomethadyl acetate
    hydrochloride
Levonorgestrel
Lidocaine
Losartan
Lovastatin
Medroxyprogesterone 
Mefloquine
Mestranol
Methadone
Methylergonovine
Methysergide
Miconazole
Midazolam
Miglustat
Mirtazapine
Modafinil
Montelukast
Moricizine
Nateglinide
Nefazodone
Nelfinavir
Nevirapine
Nicardipine
Nifedipine
Nimodipine
Nisoldipine
Nitrendipine
Norethindrone
Norgestrel
Ondansetron
Paclitaxel
Pergolide
Phencyclidine
Pimozide
Pioglitazone
Primaquine
Progesterone 
Quetiapine
Quinidine
Rabeprazole
Repaglinide
Rifabutin
Rifampin
Ritonavir
Saquinavir
Sertraline
Sibutramine
Sildenafil
Simvastatin
Sirolimus
Sufentanil
Tacrolimus
Tamoxifen
Tamsulosin
Telithromycin
Teniposide
Terbinafine
Tetracycline
Theophylline
Tiagabine
Ticlopidine
Tolterodine
Toremifene
Trazodone
Triazolam
Trimethoprim
Trimipramine
Troleandomycin
Vardenafil
Venlafaxine
Verapamil
Vinblastine
Vincristine
Vinorelbine
Zolpidem
Zonisamide
Zopiclone


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CYP2C8/9 Inhibitors
Amiodarone
Amitriptyline
Amlodipine
Anastrozole
Aprepitant
Atazanavir
Azelastine
Bortezomib
Candesartan
Chloramphenicol
Cholecalciferol (Vitamin D3)
Cimetidine
Clopidogrel
Clotrimazole
Clozapine
Cyclosporine
Delavirdine
Dexmedetomidine
Diclofenac
Diltiazem
Dimethyl sulfoxide
Disulfiram
Drospirenone
Efavirenz
Entacapone
Eprosartan
Etoposide
Felodipine
Fluconazole
Fluoxetine
Fluphenazine
Flurbiprofen
Fluvastatin
Fluvoxamine
Gemfibrozil
Ibuprofen
Imatinib
Indinavir
Indomethacin
Irbesartan
Isoniazid
Ketoconazole
Ketoprofen
Lansoprazole
Leflunomide
Losartan
Lovastatin
Mefenamic acid
Meloxicam
Methimazole
Methoxsalen
Metronidazole
Miconazole
Midazolam
Modafinil
Montelukast
Nateglinide
Nelfinavir
Nicardipine
Nifedipine
Olanzapine
Omeprazole
Ondansetron
Orphenadrine
Pantoprazole
Paroxetine
Pentamidine
Pioglitazone
Piroxicam
Pravastatin
Progesterone
Propafenone
Propofol
Propoxyphene
Pyrimethamine
Quinidine
Quinine
Ritonavir
Rosiglitazone
Saquinavir
Selegiline
Sertraline
Sildenafil
Simvastatin
Sulconazole
Sulfadiazine
Sulfamethoxazole
Sulfinpyrazone
Sulfisoxazole
Tamoxifen
Teniposide
Thioridazine
Ticlopidine
Tioconazole
Tolbutamide
Tolcapone
Tranylcypromine
Tretinoin
Triazolam
Trimethoprim
Valdecoxib
Valproic acid
Valsartan
Verapamil
Voriconazole
Warfarin
Zafirlukast
CYP2C8/9 Inducers
Carbamazepine
Fosphenytoin
Phenobarbital
Phenytoin
Primidone
Rifampin
Rifapentine
Secobarbital
CYP2C8/9 Substrates
Alosetron
Amiodarone
Bosentan
Carvedilol
Fluoxetine
Fosphenytoin
Glimepiride
Glipizide
Ketamine
Losartan
Mephenytoin
Mestranol
Montelukast
Nateglinide
Paclitaxel
Phenytoin
Pioglitazone
Propofol
Rifampin
Rosiglitazone
Selegiline
Sertraline
Sulfadiazine
Sulfamethoxazole
Sulfinpyrazone
Sulfisoxazole
Tamoxifen
Tolbutamide
Torsemide
Trimethoprim
Voriconazole
Warfarin
Zafirlukast
Zopiclone


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Abbreviated Title: PhII PF-03084014 Desmoids
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CYP2D6 Substrates
Amitriptyline
Atomoxetine
Carvedilol
Chlorpheniramine
Chlorpromazine
Clomipramine
Codeine
Desipramine
Dextromethorphan
Dihydrocodeine
Diphenhydramine
Dolasetron
Doxepin
Duloxetine
Flecainide 
Fluoxetine
Fluvoxamine
Haloperidol
Hydrocodone
Imipramine
Maprotiline
Metoclopramide
Metoprolol
Mexiletine
Nortriptyline
Palonosetron
Paroxetine
Perhexiline
Promethazine
Propafenone
Propranolol
Protriptyline
Risperidone
Tamoxifen
Thioridazine
Timolol
Tolterodine
Tramadol
Trazodone
Venlafaxine


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APPENDIX D: QUALITY-OF-LIFE QUESTIONNAIRE
Date: 
Subject Initials: 
Study Subject #
Continued next page


64
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Continued next page


65
Abbreviated Title: PhII PF-03084014 Desmoids
Version Date:5-18-2023
OTHER SYMPTOMS
Do you have any other symptoms that you wish to report?  
        Yes
      No
Please list these other symptoms in the chart below and rate the severity each symptom by 
filling in a circle from 0 (symptom not present) to 10 (symptom was as bad as you can 
imagine) 
What was the severity of this symptom at its 
WORST?
not 
present
as bad as 
you can 
imagine
List any other symptoms
0
1
2
3
4
5
6
7
8
9
10
1.
2.
3.
4.
5.
6


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Version Date:5-18-2023
APPENDIX E: QTC PROLONGATION
The following table presents a list of drugs that prolong, may prolong, or are unlikely to prolong the 
QTc.  Please note that this list is frequently updated.  For the most current list of medications, users 
should be directed to the following website: 
http://www.azcert.org/medical-pros/drug-lists/drug-lists.cfm.
Drugs that are generally 
accepted to have a risk of 
causing Torsades de Pointes
Drugs that in some reports have been 
associated with Torsades de Pointes 
and/or QTc prolongation but at this 
time lack substantial evidence for 
causing Torsades de Pointes
Drugs that, in some reports, have been 
weakly associated with Torsades de 
Pointes and/or QTc prolongation but that 
are unlikely to be a risk for Torsades de 
Pointes when used in usual recommended 
dosages and in subjects without other risk 
factors (e.g., concomitant QTc prolonging 
drugs, bradycardia, electrolyte 
disturbances, congenital long QTc 
syndrome, concomitant drugs that inhibit 
metabolism)
Generic/Brand Name
Generic/Brand Name
Generic/Brand Name
Amiodarone /Cordarone®
Alfuzosin /Uroxatral®
Amitriptyline /Elavil®
Amiodarone /Pacerone®
Amantadine /Symmetrel®
Ciprofloxacin /Cipro®
Arsenic trioxide /Trisenox®
Atazanavir /Reyataz®
Citalopram /Celexa®
Astemizole /Hismanal®
Azithromycin /Zithromax®
Clomipramine /Anafranil®
Bepridil /Vascor®
Chloral hydrate /Noctec®
Desipramine /Pertofrane®
Chloroquine /Aralen®
Clozapine /Clozaril®
Diphenhydramine /Benadryl®
Chlorpromazine /Thorazine®
Dolasetron /Anzemet®
Diphenhydramine /Nytol®
Cisapride /Propulsid®
Dronedarone /Multaq®
Doxepin /Sinequan®
Clarithromycin /Biaxin®
Felbamate /Felbatrol®
Fluconazole /Diflucan®
Disopyramide /Norpace®
Flecainide /Tambocor®
Fluoxetine /Sarafem®
Dofetilide /Tikosyn®
Foscarnet /Foscavir®
Fluoxetine /Prozac®
Domperidone /Motilium®
Fosphenytoin /Cerebyx®
Galantamine /Reminyl®
Droperidol /Inapsine®
Gatifloxacin /Tequin®
Imipramine /Norfranil®
Erythromycin /Erythrocin®
Gemifloxacin /Factive®
Itraconazole /Sporanox®
Erythromycin /E.E.S.®
Granisetron /Kytril®
Ketoconazole /Nizoral®
Halofantrine /Halfan®
Indapamide /Lozol®
Mexiletine /Mexitil®
Haloperidol /Haldol®
Isradipine /Dynacirc®
Nortriptyline /Pamelor®
Ibutilide /Corvert®
Lapatinib /Tykerb®
Paroxetine /Paxil®
Levomethadyl /Orlaam®
Lapatinib /Tyverb®
Protriptyline /Vivactil®
Mesoridazine /Serentil®
Levofloxacin /Levaquin®
Sertraline /Zoloft®


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Drugs that are generally 
accepted to have a risk of 
causing Torsades de Pointes
Drugs that in some reports have been 
associated with Torsades de Pointes 
and/or QTc prolongation but at this 
time lack substantial evidence for 
causing Torsades de Pointes
Drugs that, in some reports, have been 
weakly associated with Torsades de 
Pointes and/or QTc prolongation but that 
are unlikely to be a risk for Torsades de 
Pointes when used in usual recommended 
dosages and in subjects without other risk 
factors (e.g., concomitant QTc prolonging 
drugs, bradycardia, electrolyte 
disturbances, congenital long QTc 
syndrome, concomitant drugs that inhibit 
metabolism)
Generic/Brand Name
Generic/Brand Name
Generic/Brand Name
Methadone /Dolophine®
Lithium /Lithobid®
Solifenacin /VESIcare®
Methadone /Methadose®
Lithium /Eskalith®
Trimethoprim-Sulfa /Sulfa®
Pentamidine /Pentam®
Moexipril/HCTZ /Uniretic®
Trimethoprim-Sulfa /Bactrim®
Pentamidine /NebuPent®
Moxifloxacin /Avelox®
Trimipramine /Surmontil®
Pimozide /Orap®
Nicardipine /Cardene®
 
Probucol /Lorelco®
Nilotinib /Tasigna®
 
Procainamide /Pronestyl®
Octreotide /Sandostatin®
 
Procainamide /Procan®
Ofloxacin /Floxin®
 
Quinidine /Cardioquin®
Ondansetron /Zofran®
 
Quinidine /Quinaglute®
Oxytocin /Pitocin®
 
Sotalol /Betapace®
Paliperidone /Invega®
 
Sparfloxacin /Zagam®
Perflutren lipid microspheres 
/Definity
 
Terfenadine /Seldane®
Quetiapine /Seroquel®
 
Thioridazine /Mellaril®
Ranolazine /Ranexa®
 
 
Risperidone /Risperdal®
 
 
Roxithromycin* /Rulide®
 
 
Sertindole /Serlect®
 
 
Sertindole /Serdolect®
 
 
Sunitinib /Sutent®
 
 
Tacrolimus /Prograf®
 
 
Tamoxifen /Nolvadex®
 
 
Telithromycin /Ketek®
 
 
Tizanidine /Zanaflex®
 
 
Vardenafil /Levitra®
 
 
Venlafaxine /Effexor®
 
 
Voriconazole /VFend®
 
 
Ziprasidone /Geodon®
 
References:
1.
Physician’s Desk Reference 2002
2.
Facts and Comparisons (update to June 2005)
3.
The Pharmacological Basis of Therapeutics 9th Edition, 1996