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

Sponsor

SpringWorks Therapeutics, Inc. (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT03785964

Collaborator

(none)

142

Enrollment

Locations

Arms

55.6

Anticipated Duration (Months)

2.7

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Desmoid Tumor Aggressive Fibromatosis	Drug: Nirogacestat oral tablet Drug: Placebo Oral Tablet	Phase 3

Detailed Description

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

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

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

Study Design

Study Type:

Interventional

Actual Enrollment :

142 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description:

For the double-blind phase, the participant, investigator, and all other clinical site personnel will be blinded to the assigned treatment allocation. All sponsor personnel will also be blinded except for the sponsor's quality assurance designee(s), safety designee(s), and clinical supply material designee(s). Once participants are eligible, they will roll into the open-label phase where they will receive nirogacestat. In the open-label phase, the participant, investigator, all other clinical site personnel, and the sponsor are not blinded.

Primary Purpose:

Treatment

Official Title:

A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial of Nirogacestat Versus Placebo in Adult Patients With Progressing Desmoid Tumors/Aggressive Fibromatosis (DT/AF)

Actual Study Start Date :

May 15, 2019

Actual Primary Completion Date :

Apr 7, 2022

Anticipated Study Completion Date :

Dec 31, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Double-Blind Phase - Nirogacestat Nirogacestat 150 mg by mouth, twice daily	Drug: Nirogacestat oral tablet Nirogacestat tablet Other Names: PF-03084014
Placebo Comparator: Double-Blind Phase - Placebo Placebo 150 mg by mouth, twice daily	Drug: Placebo Oral Tablet Sugar pill manufactured to mimic nirogacestat 50 mg tablet
Experimental: Open-Label Phase - Nirogacestat Nirogacestat 150 mg by mouth, twice daily	Drug: Nirogacestat oral tablet Nirogacestat tablet Other Names: PF-03084014

Arm

Intervention/Treatment

Experimental: Double-Blind Phase - Nirogacestat

Nirogacestat 150 mg by mouth, twice daily

Drug: Nirogacestat oral tablet

Nirogacestat tablet

Other Names:

PF-03084014

Placebo Comparator: Double-Blind Phase - Placebo

Placebo 150 mg by mouth, twice daily

Drug: Placebo Oral Tablet

Sugar pill manufactured to mimic nirogacestat 50 mg tablet

Experimental: Open-Label Phase - Nirogacestat

Nirogacestat 150 mg by mouth, twice daily

Drug: Nirogacestat oral tablet

Nirogacestat tablet

Other Names:

PF-03084014

Outcome Measures

Primary Outcome Measures

Number of progression free survival (PFS) events as defined as the time from randomization until date of assessment of progression or death by any cause. [On the first day of every 3 cycles (each cycle is 28 days) until disease progression is observed or death, whichever comes first, assessed up to approximately 2 years]
Progression will be determined radiographically using RECIST v1.1 criteria by an independent, blinded, central radiologic review, or clinically as assessed by the Investigator.

Secondary Outcome Measures

The incidence of adverse events (AEs) according to toxicities graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. [Weekly for cycle 1, last day of cycle 2, first day of cycle 4 and then the first day of every 3 cycles (each cycle is 28 days) through study completion, an average of 2 years]
Overall response rate using RECIST Version 1.1 criteria. [On the first day of every 3 cycles (each cycle is 28 days) through study completion, an average of 2 years]
Overall response rate is defined as the proportion of participants with complete response (CR) + partial response (PR) assessed by central reader using RECIST v1.1 criteria.
Duration of response for participants whose best response is CR or PR. [On the first day of every 3 cycles (each cycle is 28 days) through study completion, an average of 2 years]
Tumor volume changes from baseline as measured by MRI volumetric. [On the first day of every 6 cycles (each cycle is 28 days) through study completion, an average of 2 years]
Change from baseline in patient reported outcome (PRO) scores using the GOunder/Desmoid Tumor Research Tumor Foundation (DTRF) DEsmoid Symptom Scale (GODDESS);. [Daily for the last 7 days of every cycle (each cycle is 28 days) through study completion, an average of 2 years]
This PRO will measure desmoid tumor symptoms by evaluating change from baseline. The items are evaluated on an 11-point numeric rating scale (NRS) form 0-10 measure severity from "none" to "as bad as you can imagine," with a 24-hour recall period.
Change from baseline in PRO scores using the Brief Pain Inventory (BPI) short form. [Daily for the last 7 days of every cycle (each cycle is 28 days) through study completion, an average of 2 years]
This PRO will measure clinical pain by evaluating change from baseline. It consists of 9 questions and will utilize an 11-point NRS from 0-10 measure severity from "no pain" to "pain as bad as you can imagine," with a 24-hour recall period.
Change in baseline in PRO scores using the Patient-Reported Outcomes Measurement Information System Physical Function (PROMIS PF) short form 10a plus 3 additional items from PROMIS item banks. [On the last day of every cycle (each cycle is 28 days) through study completion, an average of 2 years]
This PRO will measure self-reported capability of physical activities by evaluating change from baseline. This includes the functioning of one's upper extremities (dexterity), lower extremities (walking or mobility), and central regions (neck, back), as well as instrumental activities of daily living, such as running errands. The PROMIS PF short form 10a plus (consisting) of 10 questions plus 3 additional questions from the PROMIS item bank will be used with a 7-day recall period.
Change from baseline in PRO scores using the GOunder/Desmoid Tumor Research Tumor Foundation (DTRF) DEsmoid Impact Scale (GODDESS); [On the last day of every cycle (each cycle is 28 days) through study completion, an average of 2 years]
This PRO will measure desmoid tumor impacts by evaluating change from baseline. The items are evaluated either on an 11-point NRS to measure severity, or a 5-point Likert Scale ranging from "none of the time" to "all of the time" to measure frequency, with a 7-day recall period.
Change from baseline in PRO scores using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC) QLQ-C30. [Last day of every cycle (each cycle is 28 days) through study completion, an average of 2 years]
This PRO will measure the health-related quality of life of cancer patients by evaluated change from baseline. It consists of 30 questions overall with a 4-point scale and incorporates 5 functional scales (physical, role, cognitive, emotional and social), 3 symptom scales (fatigue, pain, and nausea and vomiting), a global health status/quality of life scale, and a number of single items assessing additional symptoms commonly reported by cancer patients (dyspnea, loss of appetite, insomnia, constipation and diarrhea) and perceived financial impact of disease.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Double-Blind Key Inclusion Criteria:

Participant has histologically confirmed DT/AF (by local pathologist prior to informed consent) that has progressed by ≥ 20% as measured by RECIST v1.1 within 12 months of the screening visit scan.
Participant has:

Treatment naïve, measurably progressing DT/AF that is deemed not amenable to surgery without the risk of significant morbidity; OR
Recurrent, measurably progressing DT/AF following at least one line of therapy; OR
Refractory, measurably progressing DT/AF following at least one line of therapy.

Participant has a DT/AF tumor where continued progressive disease will not result in immediate significant risk to the participant.
Participant agrees to provide archival or new tumor tissue for re-confirmation of disease.
If participant is currently being treated with any therapy for the treatment of DT/AF, this must be completed at least 28 days (or 5 half-lives, whichever is longer) prior to first dose of study treatment. All toxicities from prior therapy must be resolved to ≤ Grade 1 or clinical baseline.
Participants who are receiving chronic nonsteroidal anti-inflammatory drugs (NSAIDs) as treatment for conditions other than DT/AF must be receiving them prior to the documented DT/AF progressive disease (inclusion criteria 2) and on a stable dose for at least 28 days prior to first dose of study treatment.
Participant has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 at screening.
Participant has adequate organ and bone marrow function.

Double-Blind Key Exclusion Criteria:

Participant has known malabsorption syndrome or preexisting gastrointestinal conditions that may impair absorption of nirogacestat.
Participant has experienced any of the following within 6 months of signing informed consent: clinically significant cardiac disease (New York Heart Association Class III or IV), myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident, transient ischemic attack, or symptomatic pulmonary embolism.
Participant has an abnormal QT interval at screening.
Participant is using concomitant medications that are known to prolong the QT/QTcF interval including Class Ia and Class III antiarrhythmics at the time of informed consent. Non-antiarrhythmic medications which may prolong the QT/QTcF interval are allowed provided the participant does not have additional risk factors for Torsades de Pointes (TdP)
Participant has congenital long QT syndrome.
Participant has a history of additional risk factors for Torsades de Pointes (TdP) (e.g., heart failure, hypokalemia, family history of Long QT Syndrome).
Participant has had lymphoma, leukemia, or any malignancy within the past 5 years at the time of informed consent, except for any locally recurring cancer that has been treated curatively (e.g., resected basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix or breast), with no evidence of metastatic disease for 3 years at the time of informed consent.
Participant has current or chronic history of liver disease or known hepatic or biliary abnormalities (except for Gilbert's syndrome or asymptomatic gallstones).
Participant previously received or is currently receiving therapy with GS inhibitors or anti-Notch antibody therapy.
Participant is currently using any treatment for DT/AF including tyrosine kinase inhibitors (TKIs), NSAIDs (chronic daily use) or any investigational treatment 28 days (or 5 half-lives, whichever is longer) prior to the first dose of study treatment.

Participant has started any treatment for DT/AF after the documented DT/AF progressive disease.

Participant is currently using or anticipates using food or drugs that are known strong/moderate cytochrome P450 3A4 (CYP3A4) inhibitors, or strong CYP3A inducers within 14 days prior to the first dose of study treatment.
Participant has a positive human immunodeficiency virus antibody test.
Participant has presence of Hepatitis B surface antigen at screening.
Participant has a positive Hepatitis C antibody or Hepatitis C ribonucleic acid (RNA) test result at screening or within 3 months prior to starting study treatment.
Participant is unable to tolerate MRI or for whom MRI is contraindicated.
Participant with active or chronic infection at the time of informed consent and during the screening period.
Participant has experienced other severe acute or chronic medical or psychiatric conditions within 1 year of signing informed consent.
Participant is unable to comply with study related procedures (including, but not limited to, the completion of electronic patient report outcomes (ePROs), or the ePRO questionnaires are not available in the participant's preferred language).

Open-Label Key Inclusion

Participant is enrolled in the double-blind phase when the estimated number of PFS events have been observed and the primary PFS analysis has been completed; OR
Participant is randomized to receive placebo in the double-blind phase and Central Imaging Review determines that the participant has radiographic progressive disease; OR
Participant is randomized to receive nirogacestat in the double-blind phase and Central Imaging Review determines that the participant has radiographic progressive disease but the participant is deriving clinical benefit without significant toxicity (as determined by the investigator).
Participant has adequate organ and bone marrow function

Open-Label Key Exclusion

Participant requires surgery to prevent organ dysfunction.
Participant has prematurely discontinued from the double-blind phase for any reason other than radiographic progressive disease (as determined by Central Imaging Review).
Participant developed a concurrent illness/condition that, in the opinion of the investigator, would represent a risk to overall health if they enroll in this study.
Participant has initiated a new treatment for DT/AF after the Central Imaging Review determines that a participant has radiographic progressive disease.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Arkansas Children's Hospital	Little Rock	Arkansas	United States	72202
2	USC/Norris Comprehensive Cancer Center	Los Angeles	California	United States	90033
3	Ronald Regan UCLA Medical Center	Los Angeles	California	United States	90095
4	Stanford Cancer Center	Palo Alto	California	United States	94304
5	UCSF Mission Bay	San Francisco	California	United States	94158
6	Sarcoma Oncology Research Center	Santa Monica	California	United States	90403
7	University of Colorado Hospital-Anschutz Cancer Pavillion (ACP)	Aurora	Colorado	United States	80045
8	Smilow Cancer Hospital at Yale-New Haven	New Haven	Connecticut	United States	06510
9	Washington Cancer Institute at MedStar Washington Hospital Center	Washington	District of Columbia	United States	20010
10	Mayo Clinic Florida	Jacksonville	Florida	United States	32224
11	Sylvester Comprehensive Cancer Center	Miami	Florida	United States	33136
12	Northwestern Memorial Hospital	Chicago	Illinois	United States	60611
13	Johns Hopkins Hospital	Baltimore	Maryland	United States	21287
14	Massachusetts General Hosptial (MGH)	Boston	Massachusetts	United States	02114
15	Dana-Farber Cancer Institute (DFCI)	Boston	Massachusetts	United States	02215
16	University of Michigan	Ann Arbor	Michigan	United States	48109
17	Mayo Clinic Rochester	Rochester	Minnesota	United States	55905
18	Washington Univerisity School of Medicine	Saint Louis	Missouri	United States	63110
19	Northwell Health	Lake Success	New York	United States	11042
20	Columbia University Medical Center	New York	New York	United States	10032
21	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
22	DUMC/Duke Cancer Center	Durham	North Carolina	United States	27710
23	Cincinnati Childrens's Hospital Medical Center	Cincinnati	Ohio	United States	45229
24	James Cancer Hospital and Solove Research Institute at The Ohio State University Comprehensive Cancer Center	Columbus	Ohio	United States	43210
25	Oregon Health & Science Univeristy-Center for Health & Healing	Portland	Oregon	United States	97201
26	Abramson Cancer Center at Pennsylvania Hospital	Philadelphia	Pennsylvania	United States	19106
27	Fox Chase Cancer Center	Philadelphia	Pennsylvania	United States	19111
28	UPMC Hillman Cancer Ceter	Pittsburgh	Pennsylvania	United States	15232
29	Henry-Joyce Cancer Clinic	Nashville	Tennessee	United States	37232
30	UT Southwestern Medical Center	Dallas	Texas	United States	75390
31	The University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030
32	Seattle Cancer Care Alliance	Seattle	Washington	United States	98109
33	University of Wisconsin Clinical Science Center	Madison	Wisconsin	United States	53792
34	Froedtert Hospital & the Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226
35	Institut Jules Bordet-Medical Onocology	Brussels		Belgium	1000
36	Cliniques Universitaires Saint-Luc, Institut Roi Albert II	Brussels		Belgium	1200
37	UZ Gent	Gent		Belgium	9000
38	UZ Leuven	Leuven		Belgium	3000
39	Princess Margaret Cancer Centre	Toronto	Ontario	Canada	M5G2M9
40	McGill University Health Centre	Montréal	Quebec	Canada	H4A3JI
41	Helios Klinikum Berlin-Buch	Berlin		Germany	13125
42	Universitaetsklinikum Hamburg-Eppendorf	Hamburg		Germany	20246
43	Universitätsmedizin Mannheim	Mannheim		Germany	D-68167
44	IRCCS Istituto Ortopedico Rizzoli	Bologna		Italy	40136
45	Istituto di Candiolo IRCCS Oncologia Medica	Candiolo		Italy	10060
46	Fondazione IRCCS Instituto Nazionale dei Tumori di Milano	Milano		Italy	20133
47	Policlinico Unvrsitario Campus Bio-Medico	Roma		Italy	00128
48	Radboud University Medical Centre	Nijmegen	Gelderland	Netherlands	6525GA
49	The Netherlands Cancer Institute	Amsterdam		Netherlands	1066
50	Leiden University Medical Center (LUMC)	Leiden		Netherlands	23333
51	Department of Oncology, University College of London Hospital	London		United Kingdom	NW12PG
52	The Royal Marsden NHS Foundation Trust	London		United Kingdom	SW36JJ