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

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

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.

Study Overview

• Status: Completed
• Conditions: Desmoid Tumor; Aggressive Fibromatosis
• Intervention / Treatment: Drug: Nirogacestat oral tablet; Drug: Placebo Oral Tablet

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 Type: Interventional
• Enrollment (Actual): 142
• Phase: Phase 3

Expanded Access

Available outside the clinical trial. See expanded access record.

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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:

  1. Treatment naïve, measurably progressing DT/AF that is deemed not amenable to surgery without the risk of significant morbidity; OR
  2. Recurrent, measurably progressing DT/AF following at least one line of therapy; OR
  3. 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.

OR

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / 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
Experimental: Open-Label 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 by mouth, twice daily	Drug: Placebo Oral Tablet; Sugar pill manufactured to mimic nirogacestat 50 mg tablet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS) Defined as the Time From Randomization Until Date of Assessment of Progression or Death by Any Cause.	Progression will be determined radiographically using RECIST v1.1 (Eisenhauer, 2009) or clinically as assessed by the investigator. Clinical progression is defined as the onset or worsening of symptoms resulting in a global deterioration of health status causing the permanent discontinuation from study treatment and the initiation of emergent treatment (e.g., radiotherapy, surgery, or systemic therapy including chemotherapy or tyrosine kinase inhibitors) for DT/AF. Events of clinical progression will be adjudicated by an independent blinded central Endpoint Adjudication Committee (EAC) which will qualify events of clinical progression for inclusion in the PFS endpoint prior to study unblinding according to an EAC Review Charter.	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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate Using RECIST Version 1.1 Criteria.	Objective response rate (ORR) is defined as the proportion of participants having a confirmed Best Overall Response (BOR) of CR or PR by central reader using RECIST v1.1 criteria. Responses obtained up until progression, or last evaluable assessment in the absence of progression, will be included in the assessment of ORR. However, any responses, which occurred after a new anticancer therapy was received, will not be included. ORR is presented by percentages of responders.	On the first day of every 3 cycles (each cycle is 28 days) through study completion, an average of 2 years
Change From Baseline at Cycle 10 in the Brief Pain Inventory (BPI) Average Pain Intensity (API) Score.	The Brief Pain Inventory consists of 9 questions and utilizes a 11-point Numerical pain Rating Scale from 0-10 measuring severity from "no pain" to "pain as bad as you can imagine," with a 24-hour recall period. Average Pain Intensity is calculated as the 7-day average (when results on at least 4 days for a VISIT are available) of Brief Pain Inventory Question #3 - Worst Pain in last 24 hours. A lower score indicates greater pain relief. The minimum and maximum of the actual score are (0, 8) for Nirogacestat and (0,9) for Placebo, respectively. A positive change from Baseline value indicates worsening of Average Pain Intensity and a negative change from Baseline value indicates improvement of Average Pain Intensity. The minimum and maximum of change from baseline score are (-7, 3) for Nirogacestat and (-5, 5) for Placebo, respectively.	Daily for the last 7 days of every cycle (each cycle is 28 days) through study completion, an average of 2 years
Change From Baseline at Cycle 10 in the GOunder/Desmoid Tumor Research Tumor Foundation (DTRF) DEsmoid Tumor Symptom Scale (DTSS) - Total Score	The DEsmoid Tumor Symptom Scale is an 11-point, numeric rating scale from 0 to 10 to measure severity from "none" to "as bad as you can imagine," with a 24-hour recall period. The Total Symptom Score is calculated as the mean of Pain items (Items 1-3) as a single score, then a mean of this with items 4-7). Weekly summary scores will be created by averaging the daily scores over the 7 days period prior to each visit. A weekly score will be derived only if 4 or more out of 7 days period have non-missing scores. The weekly summary score will be used in analyses. If no weekly summary score is calculable, the participant will have data considered as missing at that visit. Higher scores represent worse symptom severity. The minimum and maximum of the actual score are (0,7) for Nirogacestat and (0,10) for Placebo. A positive change from Baseline value indicated worsening of symptoms. The minimum and maximum of change from baseline are (-6,1) for Nirogacestat and (-4,5) for Placebo.	Daily for the last 7 days of every cycle (each cycle is 28 days) through study completion, an average of 2 years
Change From Baseline in the GOunder/Desmoid Tumor Research Foundation (DTRF) DEsmoid Tumor Impact Scale (DTIS) - Physical Functioning Domain Score	The items are evaluated on a 5-point Likert Scale ranging from "none of the time" to "all of the time" to measure frequency, with a 7-day recall period. The Physical Function Domain Score are calculated as the average Item 01 Moving, Item 02 Reaching (Freq), Item 06 Vigorous Activity, Item 7 Moderate Activity, and Item 08 Accomplished Less. Higher scores represent worst impact severity. The minimum and maximum of the actual score are (1, 5) for Nirogacestat and (1,5) for Placebo, respectively. A positive change from baseline value indicates worsening impact and a negative change from baseline value indicates improvement in impact. The minimum and maximum of change from baseline score are (-3, 0) for Nirogacestat and (-1, 2) for Placebo, respectively.	On the last day of every cycle (each cycle is 28 days) through study completion, average of 2 years.
Change From Baseline at Cycle10 in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status/Quality of Life (GHS/QoL) Scale.	The EORTC Quality of Life Questionnaire-Core 30 version 3.0 was used with a 7-day recall period. It consists of 30 questions with all items scored 1 ("not at all") to 4 ("very much") except for the 2 items contributing to the global health status/QoL, which are scored 1 ("very poor") to 7 ("excellent"). The instrument yields the following scales:5 functional scales, 3 symptom scales, and a global health status/quality of life scale. A high score for the global health status/QoL represents a high QoL. The minimum and maximum of the actual score are (33, 100) for Nirogacestat and (8,92) for Placebo, respectively. A positive change from baseline indicated improvement of global health status and a negative change from baseline value indicated worsening of global health status. The minimum and maximum of change from baseline score are (-58, 67) for Nirogacestat and (-67, 42) for Placebo, respectively.	Last day of every cycle (each cycle is 28 days) through study completion, an average of 2 years
Change From Baseline at Cycle 10 in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Physical Functioning	The EORTC Quality of Life Questionnaire-Core 30 version 3.0 was used with a 7-day recall period. It consists of 30 questions with all items scored 1 ("not at all") to 4 ("very much") except for the 2 items contributing to the global health status/QoL, which are scored 1 ("very poor") to 7 ("excellent"). The instrument yields the following scales:5 functional scales, 3 symptom scales, and a global health status/quality of life scale. A high score for a Physical functional scale represents a high/healthy level of functioning. The minimum and maximum of the actual score are (27, 100) for Nirogacestat and (7,100) for Placebo, respectively. A positive change from baseline indicated improvement of global health status and a negative change from baseline value indicated worsening of physical functioning scores. The minimum and maximum of change from baseline score are (-7, 40) for Nirogacestat and (-40, 27) for Placebo, respectively.	Last day of every cycle (each cycle is 28 days) through study completion, an average of 2 years
Change From Baseline at Cycle 10 in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Role Functioning.	The EORTC Quality of Life Questionnaire-Core 30 version 3.0 was used with a 7-day recall period. It consists of 30 questions with all items scored 1 ("not at all") to 4 ("very much") except for the 2 items contributing to the global health status/QoL, which are scored 1 ("very poor") to 7 ("excellent"). The instrument yields the following scales:5 functional scales, 3 symptom scales, and a global health status/quality of life scale. A positive change from baseline indicated improvement of global health status and a negative change from baseline value indicated worsening of global health status and functioning scores. The minimum and maximum of change from baseline score are (-17, 83) for Nirogacestat and (-100, 50) for Placebo, respectively.	Last day of every cycle (each cycle is 28 days) through study completion, an average of 2 years

Collaborators and Investigators

• Sponsor: SpringWorks Therapeutics, Inc.
• Investigators: Principal Investigator: Bernd Kasper, MD, Mannheim university medical center

Study record dates

Study Major Dates

• Study Start (Actual): April 17, 2019
• Primary Completion (Actual): April 7, 2022
• Study Completion (Actual): October 17, 2024

Study Registration Dates

• First Submitted: December 17, 2018
• First Submitted That Met QC Criteria: December 20, 2018
• First Posted (Actual): December 24, 2018

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 17, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: GSI; PF-03084014; gamma secretase inhibitor; notch pathway
• Additional Relevant MeSH Terms: Aberrant Motor Behavior in Dementia; Neoplasms; Behavioral Symptoms; Neoplasms by Histologic Type; Neoplasms, Connective and Soft Tissue; Neoplasms, Connective Tissue; Neoplasms, Fibrous Tissue; Aggression; Fibromatosis, Aggressive; Fibroma; Gamma Secretase Inhibitors and Modulators; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Nirogacestat
• Other Study ID Numbers: NIR-DT-301

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: SpringWorks Therapeutics is committed to data transparency and sharing data to further research while maintaining the privacy and confidentiality of research participants. Pertinent patient-level data from completed registrational clinical trials will be made available by SpringWorks to qualified researchers upon approval of reasonable requests following de-identification/anonymization pursuant to applicable law.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No