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: Active, not recruiting
• 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, 1000
    • Institut Jules Bordet-Medical Onocology
  • Brussels, Belgium, 1200
    • Cliniques Universitaires Saint-Luc, Institut Roi Albert II
  • 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 Pavillion (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 Univerisity 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 Childrens'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 Univeristy-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 Ceter
  • 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
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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Progression will be determined radiographically using RECIST v1.1 criteria by an independent, blinded, central radiologic review, or clinically as assessed by the Investigator.	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
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.	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.	On the first day of every 3 cycles (each cycle is 28 days) through study completion, an average of 2 years
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);.	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.	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 PRO scores using the Brief Pain Inventory (BPI) short form.	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.	Daily for the last 7 days of every cycle (each cycle is 28 days) through study completion, an average of 2 years
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.	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.	On the last day of every cycle (each cycle is 28 days) through study completion, an average of 2 years
Change from baseline in PRO scores using the GOunder/Desmoid Tumor Research Tumor Foundation (DTRF) DEsmoid Impact Scale (GODDESS);	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.	On the last day of every cycle (each cycle is 28 days) through study completion, an average of 2 years
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.	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.	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 (Estimated): December 31, 2023

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): June 28, 2023
• Last Update Submitted That Met QC Criteria: June 26, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: GSI; PF-03084014; gamma secretase inhibitor; notch pathway
• Additional Relevant MeSH Terms: Behavioral Symptoms; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Connective Tissue; Neoplasms, Fibrous Tissue; Aggression; Fibromatosis, Aggressive; Fibroma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Gamma Secretase Inhibitors and Modulators; 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