Clinical trial NCT03785964: Nirogacestat for Adults With Desmoid Tumor/Aggressive Fibromatosis (DT/AF)
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Desmoid Tumor
Aggressive Fibromatosis
Keywords: PF-03084014
GSI
gamma secretase inhibitor
notch pathway
Lead sponsor: SpringWorks Therapeutics, Inc.
Sponsor class: INDUSTRY
First posted: 2018-12-24
Enrollment: 142
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Progression Free Survival (PFS) Defined as the Time From Randomization Until Date of Assessment of Progression or Death by Any Cause.
timeFrame: 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:
measure: Objective Response Rate Using RECIST Version 1.1 Criteria.
timeFrame: On the first day of every 3 cycles (each cycle is 28 days) through study completion, an average of 2 years
measure: Change From Baseline at Cycle 10 in the Brief Pain Inventory (BPI) Average Pain Intensity (API) Score.
timeFrame: Daily for the last 7 days of every cycle (each cycle is 28 days) through study completion, an average of 2 years
measure: Change From Baseline at Cycle 10 in the GOunder/Desmoid Tumor Research Tumor Foundation (DTRF) DEsmoid Tumor Symptom Scale (DTSS) - Total Score
timeFrame: Daily for the last 7 days of every cycle (each cycle is 28 days) through study completion, an average of 2 years
measure: Change From Baseline in the GOunder/Desmoid Tumor Research Foundation (DTRF) DEsmoid Tumor Impact Scale (DTIS) - Physical Functioning Domain Score
timeFrame: On the last day of every cycle (each cycle is 28 days) through study completion, average of 2 years.
measure: 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.
timeFrame: Last day of every cycle (each cycle is 28 days) through study completion, an average of 2 years
measure: 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
timeFrame: Last day of every cycle (each cycle is 28 days) through study completion, an average of 2 years
measure: 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.
timeFrame: Last day of every cycle (each cycle is 28 days) through study completion, an average of 2 years
Other outcomes:
Locations:
city: Little Rock
country: United States
facility: Arkansas Children's Hospital
state: Arkansas
city: Los Angeles
country: United States
facility: USC/Norris Comprehensive Cancer Center
state: California
city: Los Angeles
country: United States
facility: Ronald Regan UCLA Medical Center
state: California
city: Palo Alto
country: United States
facility: Stanford Cancer Center
state: California
city: San Francisco
country: United States
facility: UCSF Mission Bay
state: California
city: Santa Monica
country: United States
facility: Sarcoma Oncology Research Center
state: California
city: Aurora
country: United States
facility: University of Colorado Hospital-Anschutz Cancer Pavilion (ACP)
state: Colorado
city: New Haven
country: United States
facility: Smilow Cancer Hospital at Yale-New Haven
state: Connecticut
city: Washington
country: United States
facility: Washington Cancer Institute at MedStar Washington Hospital Center
state: District of Columbia
city: Jacksonville
country: United States
facility: Mayo Clinic Florida
state: Florida
city: Miami
country: United States
facility: Sylvester Comprehensive Cancer Center
state: Florida
city: Chicago
country: United States
facility: Northwestern Memorial Hospital
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins Hospital
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hosptial (MGH)
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute (DFCI)
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic Rochester
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Lake Success
country: United States
facility: Northwell Health
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Durham
country: United States
facility: DUMC/Duke Cancer Center
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Columbus
country: United States
facility: James Cancer Hospital and Solove Research Institute at The Ohio State University Comprehensive Cancer Center
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Science University-Center for Health & Healing
state: Oregon
city: Philadelphia
country: United States
facility: Abramson Cancer Center at Pennsylvania Hospital
state: Pennsylvania
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC Hillman Cancer Center
state: Pennsylvania
city: Nashville
country: United States
facility: Henry-Joyce Cancer Clinic
state: Tennessee
city: Dallas
country: United States
facility: UT Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance
state: Washington
city: Madison
country: United States
facility: University of Wisconsin Clinical Science Center
state: Wisconsin
city: Milwaukee
country: United States
facility: Froedtert Hospital & the Medical College of Wisconsin
state: Wisconsin
city: Brussels
country: Belgium
facility: Institut Jules Bordet-Medical Oncology
city: Brussels
country: Belgium
facility: Cliniques Universitaires Saint-Luc, Institut Roi Albert II
city: Gent
country: Belgium
facility: UZ Gent
city: Leuven
country: Belgium
facility: UZ Leuven
city: Toronto
country: Canada
facility: Princess Margaret Cancer Centre
state: Ontario
city: Montréal
country: Canada
facility: McGill University Health Centre
state: Quebec
city: Berlin
country: Germany
facility: Helios Klinikum Berlin-Buch
city: Hamburg
country: Germany
facility: Universitaetsklinikum Hamburg-Eppendorf
city: Mannheim
country: Germany
facility: Universitätsmedizin Mannheim
city: Bologna
country: Italy
facility: IRCCS Istituto Ortopedico Rizzoli
city: Candiolo
country: Italy
facility: Istituto di Candiolo IRCCS Oncologia Medica
city: Milano
country: Italy
facility: Fondazione IRCCS Instituto Nazionale dei Tumori di Milano
city: Roma
country: Italy
facility: Policlinico Unvrsitario Campus Bio-Medico
city: Nijmegen
country: Netherlands
facility: Radboud University Medical Centre
state: Gelderland
city: Amsterdam
country: Netherlands
facility: The Netherlands Cancer Institute
city: Leiden
country: Netherlands
facility: Leiden University Medical Center (LUMC)
city: London
country: United Kingdom
facility: Department of Oncology, University College of London Hospital
city: London
country: United Kingdom
facility: The Royal Marsden NHS Foundation Trust
Study officials:
affiliation: Mannheim University Medical Center
name: Bernd Kasper, MD
role: PRINCIPAL_INVESTIGATOR
References: