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Protocol Details

Phase II Trial of the Gamma-Secretase Inhibitor Nirogacestat (PF-03084014) in Adults with Desmoid Tumors/Aggressive Fibromatosis

This study is NOT currently recruiting participants.

Summary | Eligibility | Citations | Contacts




Sponsoring Institute

National Cancer Institute (NCI)

Recruitment Detail

Type: No longer recruiting/follow-up only
Gender: Male & Female
Min Age: 18 Years
Max Age: N/A

Referral Letter Required


Population Exclusion(s)



Desmoid Tumor;
Aggressive Fibromatosis;
Gamma-secretase Inhibitor;
Notch Pathway

Recruitment Keyword(s)



Desmoid Tumors;
Aggressive Fibromatosis

Investigational Drug(s)

Nirogacestat (PF-03084014)

Investigational Device(s)



Drug: PF-03084014

Supporting Site

National Cancer Institute


-Desmoid tumors (also known as aggressive fibromatosis), are rare, locally invasive, slow-growing soft-tissue tumors. The disease can be either asymptomatic or be associated with severe loss of organ function and significant morbidity.

-Treatment with the selective small-molecule Gamma-secretase inhibitor Nirogacestat caused significant tumor shrinkage in patients with unresectable desmoid tumors in an early phase clinical trial.

-The Notch pathway is a key regulator of cell differentiation, proliferation and apoptosis; aberrant signaling via the Notch pathway is associated with carcinogenesis.


-Primary: Determine the response rate (Complete Response (CR)+Partial Response (PR)) of PF-03084014 in patients with desmoid tumors/aggressive fibromatosis

-Secondary: Assess symptom measures at baseline and on study; perform genotyping for germline and somatic mutations in adenomatous polyposis coli gene (APC) and catenin-beta 1 (CTNNB1) genes; correlate clinical response to therapy with genotyping data; and assess modulation of the Notch pathway by evaluating notch response genes in tumor biopsies at baseline and after drug administration


-Age greater than or equal to18; histologically confirmed desmoid tumor not amenable to curative resection or definitive radiation therapy that has progressed after receiving at least one line of standard treatment; adequate organ function

-Willingness to provide blood samples and 10 unstained slides or a tumor block for genetic research studies

Study Design:

-This is an open-label Phase II trial of Nirogacestat; study drug will be administered orally at 150 mg twice a day in 21-day cycles

-Optional tumor biopsies for research purposes will be performed at baseline prior to study treatment and at the beginning of cycle 7 (+/- one cycle)

-Restaging scans (MRI with diffusion weighting) will be performed at baseline, at the end of cycles 1 and 6, and then every 6 cycles

-Health-related quality of life (HRQOL)/symptom questionnaires will be administered at baseline and at each Clinical Center visit

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INCLUSION CRITERIA: Patients must have histologically confirmed desmoid tumor confirmed by the Laboratory of Pathology, NCI, that has progressed after receiving at least one line of standard treatment and that is not amenable to surgical resection or definitive radiation therapy. Willingness to provide blood samples and 10 unstained slides or a tumor block for genetic research studies. Any line of therapy with prior desmoid therapy, including radiotherapy, should have been completed at least 2 weeks before study entry and all toxicities must have resolved at least to eligibility levels. Age greater than or equal 18 years; because no dosing or adverse event data are currently available on the use of PF-03084014 in patients <18 years of age, children are excluded from this study, but may be eligible for future pediatric trials. ECOG performance status less than or equal 2. Life expectancy > 3 months. Patients must have normal organ and marrow function as defined below:

- -absolute neutrophil count greater than or equal 1,500/mcL

- -platelets greater than or equal 100,000/mcL

- -total bilirubin less than or equal 1.5 times institutional upper limit of normal

- -AST(SGOT)/ALT(SGPT) less than or equal 5 times institutional upper limit of normal

- -creatinine < 1.5 times institutional upper limit of normal


- -creatinine clearance greater than or equal 60 mL/min/1.73 m(2) for patients with creatinine levels >1.5 mg/dL

- -hemoglobin greater than or equal 9 g/dL Patients must be able to swallow whole tablets or capsules with no GI condition affecting absorption; nasogastric or G-tube administration is not allowed. The effects of Nirogacestat on the developing human fetus are unknown. For this reason and because >=-secretase inhibitors are known to be teratogenic, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) for the duration of study participation and for at least 6 months after dosing with study drugs ceases. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception for the duration of study participation, and 6 months after completion of study drug administration. Ability to understand and the willingness to sign a written informed consent document. Evidence of measurable disease by CT scan. Measurable lesions are defined as those that can be accurately measured in at least one dimension (longest diameter to be recorded) as greater than or equal 20 mm by chest x-ray, as greater than or equal 10 mm with CT scan, or greater than or equal 10 mm with calipers by clinical exam.

EXCLUSION CRITERIA: Patients who are receiving any other investigational agents. Concurrent mediations that the patient is taking will be reviewed by the PI to assess safety and eligibility. Prior treatment with Gamma-secretase inhibitors or anti-notch antibody therapy. Uncontrolled intercurrent illness including, but not limited to, serious infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. QTc interval of >470 msec at study entry; congenital long QT syndrome. Pregnant women are excluded from this study because Nirogacestat is a Gamma-secretase inhibitor with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with Nirogacestat, breastfeeding should be discontinued if the mother is treated with Nirogacestat. Patients with gastrointestinal conditions that might predispose for drug intolerability or poor drug absorption (e.g., inability to take oral medication or a requirement for IV alimentation, prior surgical procedures affecting absorption, malabsorption syndrome, and active peptic ulcer disease) are excluded. Subjects with ulcerative colitis, inflammatory bowel disease, or a partial or complete small bowel obstruction are also excluded, as are any patients who cannot swallow the tablet whole. Tablets must not be crushed or chewed; nasogastric or G-tube administration is not allowed. HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with Nirogacestat.

2.1.3 Recruitment Strategies

We have had multiple discussions with the Desmoid Tumor Research Foundation, Inc., who have various outreach efforts including patient meetings and webcasts. Senior executives of the Foundation have indicated strong interest in this trial and willingness to inform their members. We also have a network of referring physicians nationally that refers patients with solid tumors to our clinical program. Given our interest and trials for sarcomas, we have formed connections with centers that treat patients with mesenchymal malignancies. We will be informing all of these of the availability of this trial once it is open.

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O'Sullivan Coyne G, Woodring TS, Lee CR, Chen AP, Kong HH. Hidradenitis Suppurativa-Like Lesions Associated with Pharmacologic Inhibition of (Cross)Gamma-Secretase. J Invest Dermatol. 2018 Apr;138(4):979-981. doi: 10.1016/j.jid.2017.09.051. Epub 2017 Nov 11.

Kummar S, O'Sullivan Coyne G, Do KT, Turkbey B, Meltzer PS, Polley E, Choyke PL, Meehan R, Vilimas R, Horneffer Y, Juwara L, Lih A, Choudhary A, Mitchell SA, Helman LJ, Doroshow JH, Chen AP. Clinical Activity of the >=-Secretase Inhibitor PF-03084014 in Adults With Desmoid Tumors (Aggressive Fibromatosis). J Clin Oncol. 2017 May 10;35(14):1561-1569. doi: 10.1200/JCO.2016.71.1994. Epub 2017 Mar 28.

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Principal Investigator

Referral Contact

For more information:

Alice P. Chen, M.D.
National Cancer Institute (NCI)
(240) 781-3320

Murielle Hogu
National Cancer Institute (NCI)

(240) 858-3335

NCI Referral Office
National Institute of Health Clinical Center (CC), 9000 Rockville Pike, Bethesda, Maryland 20892, United States: NCI Clinical Trials Referral Office

Clinical Trials Number:


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