Nirogacestat for Aggressive Fibromatosis

(DeFi Trial)

Recruiting at 57 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: SpringWorks Therapeutics, Inc.

Must not be taking: Antiarrhythmics, CYP3A4 inhibitors

Disqualifiers: Cardiac disease, Malabsorption, Liver disease, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 28

142 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

If you are currently taking any treatment specifically for DT/AF, you must stop at least 28 days (or 5 half-lives, whichever is longer) before starting the study treatment. If you are on chronic NSAIDs for other conditions, you can continue them if they were started before your DT/AF progressed and have been stable for at least 28 days before the study.

How is the drug Nirogacestat different from other treatments for aggressive fibromatosis?

Nirogacestat is unique because it is a gamma-secretase inhibitor, which targets a specific pathway involved in tumor growth, and has shown promising results in both adults and young patients with desmoid tumors, a type of aggressive fibromatosis. Unlike traditional treatments like surgery or chemotherapy, Nirogacestat offers a non-surgical option with potential for durable responses and fewer severe side effects. ^{1 2 3 4 5}

What is the purpose of this trial?

This trial tests nirogacestat, a medication that blocks a protein involved in tumor growth, on patients with desmoid tumors. These tumors are rare and can cause serious health issues. The drug aims to stop a chain reaction that helps these tumors grow. Nirogacestat has shown antitumor activity in several tumor types.

Research Team

Bernd Kasper, MD

Principal Investigator

Mannheim University Medical Center

Eligibility Criteria

This trial is for adults with a type of tumor called desmoid tumor/aggressive fibromatosis (DT/AF) that has grown by at least 20% in the past year. Candidates must have finished any previous treatments for DT/AF at least 28 days before starting the study and resolved all treatment side effects to mild levels. They should be able to perform daily activities with slight limitations or better, as assessed by their ECOG performance status.

Inclusion Criteria

Participant has a DT/AF tumor where continued progressive disease will not result in immediate significant risk to the participant.

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 following at least one line of therapy; OR Refractory, measurably progressing DT/AF following at least one line of therapy.

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.

Exclusion Criteria

Participant previously received or is currently receiving therapy with GS inhibitors or anti-Notch antibody therapy.

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 presence of Hepatitis B surface antigen at screening.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Double-Blind Treatment

Participants receive either nirogacestat or placebo by mouth, twice daily

Average of 2 years

Visits every 28 days

Open-Label Extension

Participants receive nirogacestat by mouth, twice daily

Long-term

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Nirogacestat

Trial Overview The trial is testing nirogacestat, an oral tablet, against a placebo (a pill without active medication). Participants are randomly assigned to one of these two groups in a double-blind phase where neither they nor the researchers know who's receiving which treatment. After this phase, all participants will receive nirogacestat during an open-label phase.

Participant Groups

Group I: Open-Label Phase - Nirogacestat Experimental Treatment 1 Intervention

Nirogacestat 150 mg by mouth, twice daily

Group II: Double-Blind Phase - Nirogacestat Experimental Treatment 1 Intervention

Nirogacestat 150 mg by mouth, twice daily

Group III: Double-Blind Phase - Placebo Placebo Group 1 Intervention

Placebo by mouth, twice daily

Who Is Running the Clinical Trial?

SpringWorks Therapeutics, Inc.

Lead Sponsor

Trials

14

Recruited

900+

Findings from Research

Wider surgical resection in patients with aggressive fibromatosis led to a lower recurrence rate, highlighting the importance of surgical intervention in managing this condition.

Two-thirds of the tumors exhibited estrogen or progesterone receptors, and all tumors showed inappropriate expression of c-sis and PDGF, suggesting these factors may play a significant role in the growth and behavior of aggressive fibromatosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aggressive fibromatosis. Alman, BA., Goldberg, MJ., Naber, SP., et al.[2004]

A three-year-old patient successfully underwent conservative surgery for aggressive fibromatosis of the mandible, remaining free of recurrence for nine years post-surgery.

The case suggests that conservative surgical approaches may be more beneficial than radical surgeries in children, as they minimize the impact on facial growth while effectively managing the tumor.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Mandibular aggressive fibromatosis]. Jeblaoui, Y., Bouguila, J., Haddad, S., et al.[2007]

In a compassionate use study involving four pediatric and young adult patients with desmoid tumors, three patients showed durable benefits from the gamma-secretase inhibitor nirogacestat after a median treatment duration of 13.5 months, including one complete response and one partial response.

Importantly, nirogacestat was well-tolerated, with no patients experiencing severe adverse events (grade 3 or 4), suggesting a favorable safety profile for this treatment in young patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of gamma-secretase inhibitor nirogacestat (PF-03084014) in desmoid tumor: Report of four pediatric/young adult cases. Takahashi, T., Prensner, JR., Robson, CD., et al.[2021]

In a study of 90 children and adolescents with aggressive fibromatosis, systemic therapy (ST) was found to be effective, particularly when primary resection was not possible, leading to a 5-year overall survival rate of 100%.

The most common initial response to ST was stable disease at 3 months and partial response at 6 months, indicating that while ST can be beneficial, the 5-year event-free survival rate was only 44%, highlighting the need for ongoing treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systemic therapy of aggressive fibromatosis in children and adolescents: Report of the Cooperative Weichteilsarkom Studiengruppe (CWS). Sparber-Sauer, M., Seitz, G., von Kalle, T., et al.[2019]

In a study of 25 cases of aggressive fibromatosis in Iran, most patients were female and the tumors were primarily located in the abdominal area, lower extremities, and head and neck.

Surgical excision was performed in 23 cases, but 15 patients experienced at least one recurrence, highlighting the tumor's aggressive nature, although no deaths or metastasis were reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aggressive Fibromatosis, Clinicopathologic Findings of 25 Cases; A Single-Center Experience and Review of the Literature. Geramizadeh, B., Jalali, F.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Aggressive fibromatosis. [2004]

2. France pubmed.ncbi.nlm.nih.gov

[Mandibular aggressive fibromatosis]. [2007]

3. United States pubmed.ncbi.nlm.nih.gov

Safety and efficacy of gamma-secretase inhibitor nirogacestat (PF-03084014) in desmoid tumor: Report of four pediatric/young adult cases. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

Systemic therapy of aggressive fibromatosis in children and adolescents: Report of the Cooperative Weichteilsarkom Studiengruppe (CWS). [2019]

5. Iran pubmed.ncbi.nlm.nih.gov

Aggressive Fibromatosis, Clinicopathologic Findings of 25 Cases; A Single-Center Experience and Review of the Literature. [2022]