Desmoid TumorPhase 3DeFiNCT03785964
Nirogacestat for Adults With Desmoid Tumor/Aggressive Fibromatosis (DT/AF)
A Phase 3 study testing Nirogacestat oral tablet in people with Desmoid Tumor and Aggressive Fibromatosis, run by SpringWorks Therapeutics, Inc., a healthcare company of Merck KGaA, Darmstadt, Germany at 52 sites in 7 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Desmoid Tumor, Aggressive Fibromatosis
- What is being tested?
- Nirogacestat oral tablet
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 142 participants
- Where
- 52 sitesin 7 countries
- Study dates
- 17 Apr 2019to 17 Oct 2024
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
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.
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.
Trial locations and contacts
52 sites in 7 countries.
52 sites in 7 countries
United States34 sites
University of Michigan
Ann Arbor, Michigan, 48109
University of Colorado Hospital-Anschutz Cancer Pavilion (ACP)
Aurora, Colorado, 80045
Johns Hopkins Hospital
Baltimore, Maryland, 21287
Massachusetts General Hosptial (MGH)
Boston, Massachusetts, 02114
Dana-Farber Cancer Institute (DFCI)
Boston, Massachusetts, 02215
Northwestern Memorial Hospital
Chicago, Illinois, 60611
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, 45229
James Cancer Hospital and Solove Research Institute at The Ohio State University Comprehensive Cancer Center
Columbus, Ohio, 43210
UT Southwestern Medical Center
Dallas, Texas, 75390
DUMC/Duke Cancer Center
Durham, North Carolina, 27710
The University of Texas MD Anderson Cancer Center
Houston, Texas, 77030
Mayo Clinic Florida
Jacksonville, Florida, 32224
Northwell Health
Lake Success, New York, 11042
Arkansas Children's Hospital
Little Rock, Arkansas, 72202
USC/Norris Comprehensive Cancer Center
Los Angeles, California, 90033
Ronald Regan UCLA Medical Center
Los Angeles, California, 90095
University of Wisconsin Clinical Science Center
Madison, Wisconsin, 53792
Sylvester Comprehensive Cancer Center
Miami, Florida, 33136
Froedtert Hospital & the Medical College of Wisconsin
Milwaukee, Wisconsin, 53226
Henry-Joyce Cancer Clinic
Nashville, Tennessee, 37232
Smilow Cancer Hospital at Yale-New Haven
New Haven, Connecticut, 06510
Columbia University Medical Center
New York, New York, 10032
Memorial Sloan Kettering Cancer Center
New York, New York, 10065
Stanford Cancer Center
Palo Alto, California, 94304
Abramson Cancer Center at Pennsylvania Hospital
Philadelphia, Pennsylvania, 19106
Fox Chase Cancer Center
Philadelphia, Pennsylvania, 19111
UPMC Hillman Cancer Center
Pittsburgh, Pennsylvania, 15232
Oregon Health & Science University-Center for Health & Healing
Portland, Oregon, 97201
Mayo Clinic Rochester
Rochester, Minnesota, 55905
UCSF Mission Bay
San Francisco, California, 94158
Sarcoma Oncology Research Center
Santa Monica, California, 90403
Seattle Cancer Care Alliance
Seattle, Washington, 98109
Washington University School of Medicine
St Louis, Missouri, 63110
Washington Cancer Institute at MedStar Washington Hospital Center
Washington D.C., District of Columbia, 20010
Belgium4 sites
Institut Jules Bordet-Medical Oncology
Brussels, 1000
Cliniques Universitaires Saint-Luc, Institut Roi Albert II
Brussels, 1200
UZ Gent
Ghent, 9000
UZ Leuven
Leuven, 3000
Italy4 sites
IRCCS Istituto Ortopedico Rizzoli
Bologna, 40136
Istituto di Candiolo IRCCS Oncologia Medica
Candiolo, 10060
Fondazione IRCCS Instituto Nazionale dei Tumori di Milano
Milan, 20133
Policlinico Unvrsitario Campus Bio-Medico
Roma, 00128
Germany3 sites
Helios Klinikum Berlin-Buch
Berlin, 13125
Universitaetsklinikum Hamburg-Eppendorf
Hamburg, 20246
Universitätsmedizin Mannheim
Mannheim, D-68167
Netherlands3 sites
The Netherlands Cancer Institute
Amsterdam, 1066
Leiden University Medical Center (LUMC)
Leiden, 23333
Radboud University Medical Centre
Nijmegen, Gelderland, 6525GA
Canada2 sites
McGill University Health Centre
Montreal, Quebec, H4A3JI
Princess Margaret Cancer Centre
Toronto, Ontario, M5G2M9
United Kingdom2 sites
Department of Oncology, University College of London Hospital
London, NW12PG
The Royal Marsden NHS Foundation Trust
London, SW36JJ
About this study
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)
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.
Read the 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.
- Conditions
- Desmoid Tumor, Aggressive Fibromatosis
- Being tested
- Nirogacestat oral tablet, Placebo Oral Tablet
- Keywords
- PF-03084014, GSI, gamma secretase inhibitor, notch pathway
- Medical subject headings
- Desmoid Tumors
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Nirogacestat oral tabletDrug
Also called PF-03084014
Nirogacestat tablet
Placebo Oral TabletDrug
Sugar pill manufactured to mimic nirogacestat 50 mg tablet
| Study group | Role | What they receive |
|---|---|---|
| Double-Blind Phase - Nirogacestat | Experimental | Nirogacestat 150 mg by mouth, twice daily Receives: Drug: Nirogacestat oral tablet |
| Double-Blind Phase - Placebo | Placebo comparator | Placebo by mouth, twice daily Receives: Drug: Placebo Oral Tablet |
| Open-Label Phase - Nirogacestat | Experimental | Nirogacestat 150 mg by mouth, twice daily Receives: Drug: Nirogacestat oral tablet |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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 outcomes (7)
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Last day of every cycle (each cycle is 28 days) through study completion, an average of 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Dec 2018
- Study start17 Apr 2019
- Primary completion7 Apr 2022
- Study completion17 Oct 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Desmoid TumorStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 142 participants (actual)
Sponsor and investigators
- Lead sponsor
- SpringWorks Therapeutics, Inc., a healthcare company of Merck KGaA, Darmstadt, Germany
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Bernd Kasper, MD, Principal investigator, Mannheim University Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03785964
- Sponsor's protocol ID
- NIR-DT-301
- Acronym
- DeFi
- Status last verified
- Jan 2025
- First submitted
- 17 Dec 2018
- Last updated
- 20 Aug 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: IPD supporting publicly available results will be evaluated for sharing.
- Expanded access
- Available
Publications
Ratan R, Kasper B, Alcindor T, Schoffski P, van der Graaf WTA, Federman N, Bui NQ, D'Amato G, Riedel RF, Attia S, Chawla S, Lim A, Tumminello B, Oton AB, Chu Y, Zhou S, Gounder M. Efficacy and Safety of Long-Term Continuous Nirogacestat Treatment in Adults With Desmoid Tumors: Results From the DeFi Trial. J Clin Oncol. 2025 Dec;43(34):3646-3651. doi: 10.1200/JCO-25-00582. Epub 2025 Oct 20.
PubMed 41115259Gounder MM, Atkinson TM, Bell T, Daskalopoulou C, Griffiths P, Martindale M, Smith LM, Lim A. GOunder/Desmoid Tumor Research Foundation DEsmoid Symptom/Impact Scale (GODDESS(c)): psychometric properties and clinically meaningful thresholds as assessed in the Phase 3 DeFi randomized controlled clinical trial. Qual Life Res. 2023 Oct;32(10):2861-2873. doi: 10.1007/s11136-023-03445-7. Epub 2023 Jun 22.
PubMed 37347393Gounder M, Ratan R, Alcindor T, Schoffski P, van der Graaf WT, Wilky BA, Riedel RF, Lim A, Smith LM, Moody S, Attia S, Chawla S, D'Amato G, Federman N, Merriam P, Van Tine BA, Vincenzi B, Benson C, Bui NQ, Chugh R, Tinoco G, Charlson J, Dileo P, Hartner L, Lapeire L, Mazzeo F, Palmerini E, Reichardt P, Stacchiotti S, Bailey HH, Burgess MA, Cote GM, Davis LE, Deshpande H, Gelderblom H, Grignani G, Loggers E, Philip T, Pressey JG, Kummar S, Kasper B. Nirogacestat, a gamma-Secretase Inhibitor for Desmoid Tumors. N Engl J Med. 2023 Mar 9;388(10):898-912. doi: 10.1056/NEJMoa2210140.
PubMed 36884323
Study at a glance
From the registry record, last updated by the sponsor on 20 Aug 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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)
- ClinicalTrials.gov ID
- NCT03785964
- Acronym / sponsor ID
- DeFi / NIR-DT-301
- Conditions
- Desmoid Tumor, Aggressive Fibromatosis
- Keywords
- PF-03084014, GSI, gamma secretase inhibitor, notch pathway
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 142 participants (actual)
- Lead sponsor
- SpringWorks Therapeutics, Inc., a healthcare company of Merck KGaA, Darmstadt, GermanyIndustry (pharma, biotech, devices)
- Study start
- 17 Apr 2019 (actual)
- Primary completion
- 7 Apr 2022 (actual)
- Study completion
- 17 Oct 2024 (actual)
- First posted
- 24 Dec 2018 (actual)
- Results
- Posted 12 Jun 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This study evaluates nirogacestat (PF-03084014) in the treatment of desmoid tumor/aggressive fibromatosis (DT/AF). In the double-blind phase, half of the participants will receive nirogacestat while the other half will receive placebo. Once participants are eligible to roll into the open-label phase, they will receive nirogacestat.
Detailed description
Desmoid tumors, also referred to as aggressive fibromatosis, are rare, locally invasive, slow growing soft tissue tumors. Although considered benign because of their inability to metastasize, desmoid tumors can cause significant morbidity and occasionally mortality in patients.
Nirogacestat (PF-03084014) is a potent, small molecule, selective, reversible, noncompetitive inhibitor of γ-secretase (GS) with a potential antitumor activity.
Nirogacestat is being investigated for the treatment of desmoid tumors due to its ability to bind to GS, blocking proteolytic activation of Notch receptors. Previous clinical study data have shown that Notch signaling plays an important role in cancer development. Hence, inhibition of Notch signaling is an important strategy for therapeutic treatment.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Double-Blind Phase - Nirogacestat | Experimental | Drug: Nirogacestat oral tabletNirogacestat 150 mg by mouth, twice daily |
| Double-Blind Phase - Placebo | Placebo comparator | Drug: Placebo Oral TabletPlacebo by mouth, twice daily |
| Open-Label Phase - Nirogacestat | Experimental | Drug: Nirogacestat oral tabletNirogacestat 150 mg by mouth, twice daily |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Nirogacestat oral tabletAlso: PF-03084014Nirogacestat tablet | Drug | Double-Blind Phase - Nirogacestat, Open-Label Phase - Nirogacestat |
| Placebo Oral TabletSugar pill manufactured to mimic nirogacestat 50 mg tablet | Drug | Double-Blind Phase - Placebo |
Primary outcome
Progression Free Survival (PFS) Defined as the Time From Randomization Until Date of Assessment of Progression or Death by Any Cause.
Time frame: 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 (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.
7 secondary outcomes
Objective Response Rate Using RECIST Version 1.1 Criteria.
Time frame: 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.
Time frame: 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
Time frame: 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
Time frame: 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.
Time frame: 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
Time frame: 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.
Time frame: Last day of every cycle (each cycle is 28 days) through study completion, an average of 2 years
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Aug 2026.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 41115259Ratan R, Kasper B, Alcindor T, Schoffski P, van der Graaf WTA, Federman N, Bui NQ, D'Amato G, Riedel RF, Attia S, Chawla S, Lim A, Tumminello B, Oton AB, Chu Y, Zhou S, Gounder M. Efficacy and Safety of Long-Term Continuous Nirogacestat Treatment in Adults With Desmoid Tumors: Results From the DeFi Trial. J Clin Oncol. 2025 Dec;43(34):3646-3651. doi: 10.1200/JCO-25-00582. Epub 2025 Oct 20.
- Derived from this study: PubMed 37347393Gounder MM, Atkinson TM, Bell T, Daskalopoulou C, Griffiths P, Martindale M, Smith LM, Lim A. GOunder/Desmoid Tumor Research Foundation DEsmoid Symptom/Impact Scale (GODDESS(c)): psychometric properties and clinically meaningful thresholds as assessed in the Phase 3 DeFi randomized controlled clinical trial. Qual Life Res. 2023 Oct;32(10):2861-2873. doi: 10.1007/s11136-023-03445-7. Epub 2023 Jun 22.
- Derived from this study: PubMed 36884323Gounder M, Ratan R, Alcindor T, Schoffski P, van der Graaf WT, Wilky BA, Riedel RF, Lim A, Smith LM, Moody S, Attia S, Chawla S, D'Amato G, Federman N, Merriam P, Van Tine BA, Vincenzi B, Benson C, Bui NQ, Chugh R, Tinoco G, Charlson J, Dileo P, Hartner L, Lapeire L, Mazzeo F, Palmerini E, Reichardt P, Stacchiotti S, Bailey HH, Burgess MA, Cote GM, Davis LE, Deshpande H, Gelderblom H, Grignani G, Loggers E, Philip T, Pressey JG, Kummar S, Kasper B. Nirogacestat, a gamma-Secretase Inhibitor for Desmoid Tumors. N Engl J Med. 2023 Mar 9;388(10):898-912. doi: 10.1056/NEJMoa2210140.
- Individual participant dataSharing planned: Yes. IPD supporting publicly available results will be evaluated for sharing.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Bernd Kasper, MD principal investigator
Mannheim University Medical Center
52 sites in 7 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Nirogacestat oral tablet in people with Desmoid Tumor and Aggressive Fibromatosis, run by SpringWorks Therapeutics, Inc., a healthcare company of Merck KGaA, Darmstadt, Germany at 52 sites in 7 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 20 Aug 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 52 sites in United States, Belgium, Italy, Germany, Netherlands and 2 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 12 Jun 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Progression Free Survival (PFS) Defined as the Time From Randomization Until Date of Assessment of Progression or Death by Any Cause. (time frame: 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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03785964, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Aug 2026.