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| Reporting Pregnancy                                                                                                                                             |                                                                                                                                                      |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------|
| 8.5                                                                                                                                                             | Regulatory Reporting for Studies Conducted Under CCR-Sponsored IND...................................40                                              |
| 8.6                                                                                                                                                             |                                                                                                                                                      |
| 9                                                                                                                                                               | CLINICAL MONITORING .........................................................................................................................40      |
| 10                                                                                                                                                              | STATISTICAL SECTION                                                                                                                                  |
| Statistical Considerations for Exploratory Correlative Studies .......................................................41                                        |                                                                                                                                                      |
| 10.1                                                                                                                                                            |                                                                                                                                                      |
| l l                                                                                                                                                             | COLLABORATIVE AGREEMENTS .........................................................................................................41                 |
| 11.1                                                                                                                                                            | Agreement Type..................................................................................................................................41   |
| 12                                                                                                                                                              | HUMAN SUBJECTS PROTECTIONS ....................................................................................................41                    |
| 12.1                                                                                                                                                            | RATIONALE FOR SUBJECT Selection                                                                                                                      |
| 12.2                                                                                                                                                            | Participation of Children                                                                                                                            |
| Evaluation of Benefits and Risks/Discomforts ...................................................................................42                              |                                                                                                                                                      |
| 12.3                                                                                                                                                            | Risks/Benefits Analysis ..........................................................................................................................42 |
| 12.4                                                                                                                                                            | Consent and Assent Process and Documentation .................................................................................43                     |
| 12.5                                                                                                                                                            |                                                                                                                                                      |
| PHARMACEUTICAL AND DEVICE INFORMATION ........................................................................43                                                |                                                                                                                                                      |
| 13                                                                                                                                                              | Nirogacestat (PF-03084014) (IND #119,769) .....................................................................................43                    |
| 13.1                                                                                                                                                            |                                                                                                                                                      |
| 13.2                                                                                                                                                            | Magnetic Resonance Imaging Scanner                                                                                                                   |
| REFERENCES .                                                                                                                                                    |                                                                                                                                                      |
| APPENDIX A: Performance Status Criteria ..............................................................................................49                        |                                                                                                                                                      |
| APPENDIX B: Patient's Medication Diary.......................................................................................................................50 |                                                                                                                                                      |
| APPENDIX C: Potential Drug Interactions                                                                                                                         |                                                                                                                                                      |
| APPENDIX D: Quality-of-Life Questionnaire................................................................................................60                     |                                                                                                                                                      |
| APPENDIX E: QTC Prolongation...........................................................................................................................63       |                                                                                                                                                      |
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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:
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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 T 1/2 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. 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.
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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 C max and area under the plasma concentration-time curve from 0 to 24 hours (AUC 0 -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 C max and AUC 0.24 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 cle 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
(.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 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.
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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,  
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 openlabel, 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.
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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 (%)         |         |         |
|-------------------------|---------|---------|
| Grade 1/2               |         |         |
| Adverse event*          | 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) | 1 (17)  | 3 (5)   |
| Decreased appetite      | 1 (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.  
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 20 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.
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clinical pharmacokinetics

Evaluation of the pharmacokinetic characteristics of PF-03084014 indicated that it was rapidly absorbed, with median time of occurrence of C max (T max ) 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.
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potential drug interactions

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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.
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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.
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eligibility assessment and enrollment 2

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).
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eligibility criteria 2.1 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.  
Patients must have normal organ and marrow function as defined below:
2.1.1.7 absolute neutrophil count
≥ 1,500/mcL  
| platelets          | ≥ 100,000/mcL                               |
|--------------------|---------------------------------------------|
| total bilirubin    | < 1.5 X institutional upper limit of normal |
| AT(SGOT)/ALT(SGPT) | < 5 X institutional upper limit of normal   |  
| creatinine   |
|--------------|  
| creatinine clearance   |
|------------------------|  
| hemoglobin   |
|--------------|  
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
< 1.5 X institutional upper limit of normal
> 60 mL/min/1.73 m2 for patients with creatinine levels >1.5 mg/dL  
| OR   |
|------|
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>= 9 g/dl

The effects of Nirogacestat on the developing human fetus are unknown.  For this reason and because y-secretase inhibitors are known to be teratogenic, women of childbearing 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.
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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 -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, 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 HV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with Nirogacestat.
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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.
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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.
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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.  
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; ncicentralregistrationl@mail.nih.gov ).  
2.4
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study implementation 3 3.1 study

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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cdc fpnakpflblcjolpmn

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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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platelet transfusions should be administered in accordance with the standard of practice, usually maintaining a platelet count above 50,000/mm 3 .  
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 In stitutional 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.
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biospecimen collection s 5.1 correlative

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 nonfunctional 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.
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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 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.
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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)
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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 remain on study, receive study medication, and other correlative studies will be performed.
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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.
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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 ned to be sent on dry ice to the following address.  The samples should be labeled with oly the unique patient ID.  Do NOT include patient identifiers (e.g., medical record nmber, 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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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.
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5.4 samples for 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.
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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 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.
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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.
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5.4.4 genetic counseling n/a all

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: 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.
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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)
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
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data collection and evaluation 6

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.
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response criteria 6.2

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 lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST
criteria.
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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.
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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 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.
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6.2.3 methods for evaluation of

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 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 nxt.  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:
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD
a.  
based on a new lesion.  
No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
b.  
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.  
FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in C.  
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.
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6.2.4 response criteria 6.2.4.1 evaluation

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.
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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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| ,/y(*%+8&'lm               | q/0+2h+     | lm             |
| o,p           | q/0 | l              |
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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.
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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).
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7 nih reporting requirements/data and

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.
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7.2 ohsrp office of compliance

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.
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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
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7.3 nci clinical director reporting

Problems expeditiously reported to the OHSRP/IRB in iRIS will also be reported to the NCI
Clinical Director.  A separate submission is not necessary as reports in iRIS will be available to the Clinical Director.  
Version Date: 12-3-2021 In addition to those reports, all deaths that occur within 30 days after receiving a research intervention should be reported via email to the Clinical Director unless they are due to progressive disease. To report these deaths, please send an email describing the circumstances of the death to Dr.  
Dahut at dahutw@mail.nih.gov and to NCICCRQA@mail.nih.gov within one business day of learning of the death.
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7.4 expedited adverse event reporting

All serious adverse events must be reported in the defined timelines to CRsafety@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.
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7.5 nih office of biotechnology

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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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
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8.5 reporting pregnancy 8.5.1 maternal

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.
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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.
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8.6 regulatory reporting for studies

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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The research component of this study required to obtain 2 optional CT-guided tumor biopsies confers radiation exposure at an effective dose of 1.6 rem.  This dose is below NIH RSC guidelines of less than 5.0 rem per year in adults, and represents a slightly greater than minimal risk to patients.
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12.5 consent and assent process

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.
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12.5.1 participation of subjects unable

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 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.
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13 pharmaceutical and device information

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)
-  
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| IJ6J                                            | 0F5K*2"H          |   |
| !$K.*)'!$L*7                                            | ,"55*7)' |   |
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untitled h1
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|---|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---|
| (Q"R(ST&Uqrst[\ H6782>KM:@:B7675@ 14;D464]@C78@   | d29CB@8J:278 FB@8J:278                                                                                                                                                                                                             | k7<46C78                                                                                                                                                                                                                             | l:Lu2B8v9A2;:   |
| (Q"R(ST0rX\Y[wYt\ 14;792C;252K 17K29:4]2K 17:4K2C;46 1K2D4]46 1K267C;4678@ a@92>@9:;@K a74]@C46   | c9?7:4K2C;46 c926@C;4]2K@ d29CB@8J:278 f67C;4678@ h4892C;4]2K@ i@CB@8J:278 CB2D4;D7:4K                                                                                                                                                                                                                                    | i@:B9Mb7675@ i2?K2D@675@ =@K<784P7; =7KM:4675@ j6@C;4]2K@ F48:2C;4]2K@ F@8:467578@                                                                                                                                                                                                                                      | FB@82D4;D7:4K FB@8J:278 F;2>@9:@;28@ k4D@C;4]2K@ l@;:;4K78@ n;767C;4678@ `2;7?284]2K@   |  
j8KJ64x2;9MD9:;4:@9485@<<@?:7P@785M?@;94;@K79:@5LH557:7284K78<2;64:728<2;5;M>78:@;4?:7289A7:B ?J:2?B;26@FIy792@8]J6@9?48D@<2M854:B::Cz__6@57?78@L7MCM7L@5M_<K2?NB4;:_L  
Adapted from Cytochrome P450 Enzymes: Substrates, Inhibitors, and Inducers.  In: Lacy CF, Armstrong L, Goldman MP, Lance LL eds. Drug Information Handbook 15™ ed. Hudson, OH; LexiComp Inc.  
2007: 1899-1912.  
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untitled h1
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|---------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------|  
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|---|---|---------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------|  
Abbreviated Title: PhII PF-03084014 Desmoids Version Date: 12-3-2021
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m. d. anderson symptom inventory

Part I. How severe are your symptoms?  
People with cancer frequently have symptoms that are caused by their disease or by their treatment. We ask you to rate how severe the following symptoms have been in the last 24 hours. Please fill in the circle below from 0
(symptom has not beeh present) to 10 (the symptom was as bad as you can imagine it could be) for each item.  
| As Bad As You                      |                                    |     |    |    |    |    |    |         |     |    |     |    |    |
|------------------------------------|------------------------------------|-----|----|----|----|----|----|---------|-----|----|-----|----|----|
| Not                                |                                    |     |    |    |    |    |    |         |     |    |     |    |    |
| Present                            | Can Imagine                        |     |    |    |    |    |    |         |     |    |     |    |    |
| 9                                  | 110                                |     |    |    |    |    |    |         |     |    |     |    |    |
| o                                  | 5                                  | 8   |    |    |    |    |    |         |     |    |     |    |    |
| 1.                                 | Your pain at its WORST?            | o   | o  | o  | o  | o  |    |         |     |    |     |    |    |
| 2.                                 | Your fatigue (tiredness) at        | o   | o  | o  | o  |    |    |         |     |    |     |    |    |
| its WORST?                         |                                    |     |    |    |    |    |    |         |     |    |     |    |    |
| 3.                                 | Your nausea at its WORST?          | o   | o  | o  | o  | o  | C  | CONTROL | . O | o  | o   |    |    |
| Your disturbed sleep at its        |                                    |     |    |    |    |    |    |         |     |    |     |    |    |
| 4.                                 | o                                  | o   | o  | o  | o  | o  |    |         |     |    |     |    |    |
| o                                  | o                                  | o   |    |    |    |    |    |         |     |    |     |    |    |
| WORST?                             |                                    |     |    |    |    |    |    |         |     |    |     |    |    |
| 5.                                 | Your feelings of being             | o   | o  | o  | o  | o  | O  | o       | o   | .  | o   |    |    |
| distressed (upset) at its WORST?   |                                    |     |    |    |    |    |    |         |     |    |     |    |    |
| 6.                                 | Your shortness of breath at its    | o   | o  | o  | o  | o  | o  | o       | o   |    |     |    |    |
| WORST?                             |                                    |     |    |    |    |    |    |         |     |    |     |    |    |
| Your problem with remembering      |                                    |     |    |    |    |    |    |         |     |    |     |    |    |
| 7.                                 | o                                  | o   | o  | o  | O  | o  | .  | o       | o   | o  |     |    |    |
| things at its WORST?               |                                    |     |    |    |    |    |    |         |     |    |     |    |    |
| 8.                                 | Your problem with lack of appetite | o   | o  | o  |    |    |    |         |     |    |     |    |    |
| o                                  | o                                  |     |    |    |    |    |    |         |     |    |     |    |    |
| at its WORST?                      |                                    |     |    |    |    |    |    |         |     |    |     |    |    |
| 9.                                 | Your feeling drowsy (sleepy) at    | i O |    |    |    |    |    |         |     |    |     |    |    |
| o                                  | i                                  | o   | i  | o  | o  | i  | O  | o       | :   | O  | l O | o  | o  |
| its WORST?                         |                                    |     |    |    |    |    |    |         |     |    |     |    |    |
| 10. Your having a dry mouth at its | O                                  | o   | .  |    |    |    |    |         |     |    |     |    |    |
| WORST?                             |                                    |     |    |    |    |    |    |         |     |    |     |    |    |  
| Not                               | As Bad As You   |    |    |    |    |    |    |    |    |    |    |    |    |    |
|-----------------------------------|-----------------|----|----|----|----|----|----|----|----|----|----|----|----|----|
| Present                           | Can Imagine     |    |    |    |    |    |    |    |    |    |    |    |    |    |
| 7                                 | .               | 10 |    |    |    |    |    |    |    |    |    |    |    |    |
| 0                                 | 3               | 5  | 6  | 8  | 9  |    |    |    |    |    |    |    |    |    |
| 1. Your feeling sad at its WORST? | o               | i  | o  | O  | .  | o  | O  | O  | O  | o  | o  | o  | i  | o  |
| 12. Your vomiting at its WORST?   | o               | o  | o  | o  | o  | o  | o  |    |    |    |    |    |    |    |
| :                                 | o               | o  | o  | -  | o  |    |    |    |    |    |    |    |    |    |
| 13. Your numbness or tingling at  | O               | o  | o  | o  | o  | o  | o  | o  | o  | O  | o  |    |    |    |
| its WORST?                        |                 |    |    |    |    |    |    |    |    |    |    |    |    |    |  
Part II. How have your symptoms interfered with your life?  
Symptoms frequently interfere with how we feel and function. How much have your symptoms interfered with the following items in the last 24 hours:  
| Did Not                          |    |    |    |     |    |    |    |    |
|----------------------------------|----|----|----|-----|----|----|----|----|
| Interfere                        |    |    |    |     |    |    |    |    |
| 0                                | 1  | -  | 2  | 3 : | 4  | 5  | 6  |    |
| 14. General activity?            | o  | o  | '  | o   | o  | o  | O  | o  |
| .                                |    |    |    |     |    |    |    |    |
| 15. Mood?                        | O  | o  | o  | o   | o  | o  | o  |    |
| 16.  Work (including work around | O  | O  | O  | o   | o  | o  | o  |    |
| .                                |    |    |    |     |    |    |    |    |
| the house)?                      |    |    |    |     |    |    |    |    |
| 17. Relations with other people? | o  | o  | o  | o   | o  | o  | o  |    |
| -                                |    |    |    |     |    |    |    |    |
| 18. Walking?                     | o  | O  | o  | o   | o  | o  | o  |    |
| 19.  Enjoyment of life?          | o  | o  | o  | o   | o  | o  | o  |    |
| .                                |    |    |    |     |    |    |    |    |  
| Interefered
Completely   |    |    |    |    |    |    |
|---|----|----|----|----|----|----|
| 7 | 8  | .  | 9  | 10 |    |    |
| . |    |    |    |    |    |    |
| . | o  | o  | .  | o  | i  | o  |
| o | o  | o  | o  |    |    |    |
| o | o  | o  | o  |    |    |    |
| i | i  | .  | i  |    |    |    |
| o | o  | o  | o  |    |    |    |
| . | o  | .  | o  | o  | i  | o  |
| o | o  | o  | o  |    |    |    |  
Continued next page  
| OTHER SYMPTOMS                                                                            |                                              |    |    |    |    |    |    |    |    |    |    |
|-------------------------------------------------------------------------------------------|----------------------------------------------|----|----|----|----|----|----|----|----|----|----|
| Do you have any other symptoms that you wish to report?                                   |                                              |    |    |    |    |    |    |    |    |    |    |
| o                                                                                         | 10 No                                        |    |    |    |    |    |    |    |    |    |    |
| Yes                                                                                       |                                              |    |    |    |    |    |    |    |    |    |    |
| 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                                                                                       | as bad as                                    |    |    |    |    |    |    |    |    |    |    |
| present                                                                                   | you can                                      |    |    |    |    |    |    |    |    |    |    |
| imagine                                                                                   |                                              |    |    |    |    |    |    |    |    |    |    |
| List any other symptoms                                                                   | 0                                            | l  | 2  | 3  | 4  | S  | 6  | 7  | 8  | 9  | 10 |
| l.                                                                                        | o                                            | o  | o  | O  | o  | o  | o  | o  | o  | o  | o  |
| 2.                                                                                        | o                                            | o  | o  | o  | o  | o  | O  | o  | o  | O  | O  |
| 3.                                                                                        | o                                            | o  | o  | o  | o  | O  | O  | o  | O  | O  | o  |
| 4.                                                                                        | o                                            | o  | o  | o  | O  | O  | o  | O  | o  | O  | o  |
| s.                                                                                        | o                                            | o  | o  | o  | o  | o  | O  | o  | o  | o  | o  |
| 6                                                                                         | o                                            | O  | o  | o  | o  | o  | O  | o  | o  | o  | O  |
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