Principal Investigator
Enrollment Status
Clinical Trial ID
Clinical 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. Once participants are eligible to
roll into the open-label phase, they will receive nirogacestat.
Phase
Phase 3
Funding Agency/Sponsor
Industrial
Disease
Bone and Soft Tissue Cancers
Enrollment Eligibility
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.