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

NCT03785964 | Completed Phase 3 Results DMC FDA Drug

• 1 other identifier: NIR-DT-301
• Study Type: interventional
• Target: 142
• Locations: 7 countries
• Sites: 52

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.

Conditions

Desmoid Tumor; Aggressive Fibromatosis

Keywords

PF-03084014; GSI; gamma secretase inhibitor; notch pathway

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (7)

• Objective 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

• Change From Baseline at Cycle 10 in the Brief Pain Inventory (BPI) Average Pain Intensity (API) Score.

  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

  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

  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.

  Last day of every cycle (each cycle is 28 days) through study completion, an average of 2 years

Study Arms (3)

Double-Blind Phase - Nirogacestat

EXPERIMENTAL

Nirogacestat 150 mg by mouth, twice daily

Drug: Nirogacestat oral tablet

Double-Blind Phase - Placebo

PLACEBO COMPARATOR

Placebo by mouth, twice daily

Drug: Placebo Oral Tablet

Open-Label Phase - Nirogacestat

EXPERIMENTAL

Nirogacestat 150 mg by mouth, twice daily

Drug: Nirogacestat oral tablet

Interventions

Nirogacestat oral tablet DRUG

Nirogacestat tablet

Also known as: PF-03084014

Double-Blind Phase - Nirogacestat; Open-Label Phase - Nirogacestat

Placebo Oral Tablet DRUG

Sugar pill manufactured to mimic nirogacestat 50 mg tablet

Double-Blind Phase - Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• Participant has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 at screening.
• Participant has adequate organ and bone marrow function.

You may not qualify if:

• 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.

Sponsors & Collaborators

• SpringWorks Therapeutics, Inc.: lead

Study Sites (52)

Arkansas Children's Hospital

Little Rock, Arkansas, 72202, United States

Location

USC/Norris Comprehensive Cancer Center

Los Angeles, California, 90033, United States

Location

Ronald Regan UCLA Medical Center

Los Angeles, California, 90095, United States

Location

Stanford Cancer Center

Palo Alto, California, 94304, United States

Location

UCSF Mission Bay

San Francisco, California, 94158, United States

Location

Sarcoma Oncology Research Center

Santa Monica, California, 90403, United States

Location

University of Colorado Hospital-Anschutz Cancer Pavilion (ACP)

Aurora, Colorado, 80045, United States

Location

Smilow Cancer Hospital at Yale-New Haven

New Haven, Connecticut, 06510, United States

Location

Washington Cancer Institute at MedStar Washington Hospital Center

Washington D.C., District of Columbia, 20010, United States

Location

Mayo Clinic Florida

Jacksonville, Florida, 32224, United States

Location

Sylvester Comprehensive Cancer Center

Miami, Florida, 33136, United States

Location

Northwestern Memorial Hospital

Chicago, Illinois, 60611, United States

Location

Johns Hopkins Hospital

Baltimore, Maryland, 21287, United States

Location

Massachusetts General Hosptial (MGH)

Boston, Massachusetts, 02114, United States

Location

Dana-Farber Cancer Institute (DFCI)

Boston, Massachusetts, 02215, United States

Location

University of Michigan

Ann Arbor, Michigan, 48109, United States

Location

Mayo Clinic Rochester

Rochester, Minnesota, 55905, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Northwell Health

Lake Success, New York, 11042, United States

Location

Columbia University Medical Center

New York, New York, 10032, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

DUMC/Duke Cancer Center

Durham, North Carolina, 27710, United States

Location

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229, United States

Location

James Cancer Hospital and Solove Research Institute at The Ohio State University Comprehensive Cancer Center

Columbus, Ohio, 43210, United States

Location

Oregon Health & Science University-Center for Health & Healing

Portland, Oregon, 97201, United States

Location

Abramson Cancer Center at Pennsylvania Hospital

Philadelphia, Pennsylvania, 19106, United States

Location

Fox Chase Cancer Center

Philadelphia, Pennsylvania, 19111, United States

Location

UPMC Hillman Cancer Center

Pittsburgh, Pennsylvania, 15232, United States

Location

Henry-Joyce Cancer Clinic

Nashville, Tennessee, 37232, United States

Location

UT Southwestern Medical Center

Dallas, Texas, 75390, United States

Location

The University of Texas MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Seattle Cancer Care Alliance

Seattle, Washington, 98109, United States

Location

University of Wisconsin Clinical Science Center

Madison, Wisconsin, 53792, United States

Location

Froedtert Hospital & the Medical College of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

Institut Jules Bordet-Medical Oncology

Brussels, 1000, Belgium

Location

Cliniques Universitaires Saint-Luc, Institut Roi Albert II

Brussels, 1200, Belgium

Location

UZ Gent

Ghent, 9000, Belgium

Location

UZ Leuven

Leuven, 3000, Belgium

Location

Princess Margaret Cancer Centre

Toronto, Ontario, M5G2M9, Canada

Location

McGill University Health Centre

Montreal, Quebec, H4A3JI, Canada

Location

Helios Klinikum Berlin-Buch

Berlin, 13125, Germany

Location

Universitaetsklinikum Hamburg-Eppendorf

Hamburg, 20246, Germany

Location

Universitätsmedizin Mannheim

Mannheim, D-68167, Germany

Location

IRCCS Istituto Ortopedico Rizzoli

Bologna, 40136, Italy

Location

Istituto di Candiolo IRCCS Oncologia Medica

Candiolo, 10060, Italy

Location

Fondazione IRCCS Instituto Nazionale dei Tumori di Milano

Milan, 20133, Italy

Location

Policlinico Unvrsitario Campus Bio-Medico

Roma, 00128, Italy

Location

Radboud University Medical Centre

Nijmegen, Gelderland, 6525GA, Netherlands

Location

The Netherlands Cancer Institute

Amsterdam, 1066, Netherlands

Location

Leiden University Medical Center (LUMC)

Leiden, 23333, Netherlands

Location

Department of Oncology, University College of London Hospital

London, NW12PG, United Kingdom

Location

The Royal Marsden NHS Foundation Trust

London, SW36JJ, United Kingdom

Location

Related Publications (3)

• 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.

  PMID: 41115259 DERIVED

• Gounder 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.

  PMID: 37347393 DERIVED

• Gounder 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.

  PMID: 36884323 DERIVED

MeSH Terms

Conditions

Desmoid Tumors

Interventions

nirogacestat

Condition Hierarchy (Ancestors)

Fibroma; Neoplasms, Fibrous Tissue; Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms

Results Point of Contact

• Title: Head of Clinical Operations
• Organization: SpringWorks Therapeutics

clinical@springworkstx.com

877-279-4870

Study Officials

• Bernd Kasper, MD

  Mannheim University Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR
• Expanded Access: Yes

Study Record Dates

• First Submitted: December 17, 2018
• First Posted: December 24, 2018
• Study Start: April 17, 2019
• Primary Completion: April 7, 2022
• Study Completion: October 17, 2024
• Last Updated: January 31, 2025
• Results First Posted: June 12, 2024

Record last verified: 2025-01

Data Sharing

• IPD Sharing: Will share

Locations

BE (4); CA (2); IT (4); US (34); DE (3); NL (3); GB (2)