A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial of Nirogacestat Versus Placebo in Adult Patients with Progressing Desmoid Tumors/Aggressive Fibromatosis (DT/AF).

Phase 3

Recruiting

Conditions: Desmoid Tumor/Aggressive Fibromatosis
Aggressive Fibromatosis
Desmoid Tumor
10027656

Registration Number: NL-OMON55814

Lead Sponsor: SpringWorks Therapeutics

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Recruiting

Sex: Not specified

Target Recruitment: 8

Inclusion Criteria

1. Participant must be at least 18 years of age at the time of signing the
informed consent.
2. 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.
3. 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 at least one line of therapy; OR
Refactory, measurably progressing DT/AF following at least one line of therapy.
4. Participant has a DT/AF tumor where continued progressive disease will not
result in
immediate significant risk to the participant.
5. Participant agrees to provide archival or new tumor tissue for
re-confirmation of disease.
6. If participant is currently being treated with any therapy for the
treatment of
DT/AF, this must have be completed at least 28 days (or 5 half-lives,
whichever is longer) prior first dose of study treatment. All toxicities from
prior therapy must be resolved to <=Grade 1 or clinical baseline (as measured
by NCI Common Terminology Criteria for Adverse Events v5.0).
7. 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) for and on a stable
dose for at least 28 days prior to first dose of study treatment.
8. Participant has an Eastern Cooperative Oncology Group (ECOG) performance
status <=2
at screening (refer to Section 10.7 for ECOG performance status scale).
9. Participant has adequate organ and bone marrow function as defined by the
following
screening laboratory values:
a. Absolute neutrophil count =>1500 cells/µL;
b. Platelets =>100,000µL;
c. Hemoglobin =>9 g/dL;
d. Total bilirubin =<1.5 x upper limit of normal (ULN) (isolated bilirubin >1.5
x ULN
is acceptable if bilirubin is fractionated and direct bilirubin <35%);
e. Aspartate aminotransferase (AST) (serum glutamic oxaloacetic
transaminase)/alanine aminotransferase (ALT) (serum glutamic pyruvate
transaminase) =<2 x ULN; and
f. Serum creatinine =<1.5 x ULN or if creatinine >1.5 x ULN then calculated
creatinine clearance must be =>60 mL/min (using the Cockcroft-Gault
formula);
10. Participant can swallow tablets and has no gastrointestinal conditions
affecting
absorption.
11. Male or Female:
Contraceptive use by men or women should be consistent with local regulations
regarding the methods of contraception for those participating in clinical
studies.
a. Male participants are eligible to participate if they agree to the following
during the treatment period and for at least 90 days after the last dose of
study treatment:
- Refrain from donating or preserving sperm;
PLUS either:
- Be abstinent from sexual intercourse as their preferred and usual lifestyle
(abstinent on a long term and persistent basis) and agree to remain abstinent;
OR
- Must agree male condom when having sexual intercourse with women of
childbearing potential (WOCBP). An additional form of contraception as
described in Section 10.4 should also be used by the female partner, if she is
of childbearing potential. Refer to Secti

Exclusion Criteria

1. Participant has known malabsorption syndrome or preexisting gastrointestinal
conditions
that may impair absorption of nirogacestat (e.g., gastric bypass, lap band, or
other gastric
procedures that would alter absorption); delivery of nirogacestat via
nasogastric tube or gastrostomy tube is not
allowed.
2. 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.
3. Participant has abnormal QT interval corrected by Fridericia*s formula (>450
msec for
male participants, >470 msec for female participants, or >480 msec for
participants with
bundle branch block) after electrolytes have been corrected (triplicate ECG
readings,
done approximately 2-3 minutes apart and averaged) at screening.
4. Participant is using concomitant medications that are known to prolong the
QT/QTcF interval, including Class Ia (e.g. quinidine, procainamide,
disopromide) and class III (e.g. dofetilide, ibutilide, sotalol)
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).
5. Participant has congenital long QT syndrome.
6. Participant has a history of additional risk factors for Torsades de Pointes
(TdP) (e.g.,
heart failure, hypokalemia, family history of Long QT Syndrome).
7. 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.
8. Participant has current or chronic history of liver disease or known hepatic
or biliary abnormalities
(except for Gilbert's syndrome or asymptomatic gallstones).
9. Participant previously received or is currently receiving therapy with GS
inhibitors or
anti-Notch antibody therapy.
10. 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 (inclusion criteria 2).
11. 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.
12. Participant is currently enrolled or was enrolled within 28 days of first
dose of
study treatment in another clinical study with any investigational drug or
device.
Participation in observational studies may be permitted with prior approval
from the medical monitor/sponsor.
13. Pa

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p>PFS defined as the time from randomization until the date of assessment of<br /><br>progression or death by any cause will be determined using Response Evaluation<br /><br>Criteria In Solid Tumors (RECIST) version (v)1.1. The documented date of<br /><br>progression will be determined by an independent, blinded, central radiologic<br /><br>review.</p><br>

Secondary Outcome Measures