Nirogacestat for Aggressive Fibromatosis

(DeFi Trial)

No longer recruiting at 62 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a drug called nirogacestat to determine its effectiveness in treating desmoid tumors, also known as aggressive fibromatosis. These non-cancerous tumors can grow in the body and cause problems. In the first part of the trial, some participants will receive nirogacestat, while others will receive a placebo (a pill with no active medicine). Later, all eligible participants will have the opportunity to receive the actual drug. Those considering joining should have a growing desmoid tumor that cannot be easily removed by surgery. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment.

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.

Is there any evidence suggesting that nirogacestat is likely to be safe for humans?

Studies have shown that nirogacestat is generally safe for humans. Research indicates that after an average use of over 33 months, patients experienced tumor shrinkage and reduced pain. Some patients encountered side effects while taking nirogacestat, but these were manageable. Most continued their treatment without major issues. This safety record supports the use of nirogacestat for treating aggressive fibromatosis. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for aggressive fibromatosis?

Nirogacestat is unique because it targets a specific pathway involved in the growth of aggressive fibromatosis, also known as desmoid tumors. While traditional treatments often involve surgery, radiation, or systemic therapies like non-steroidal anti-inflammatory drugs (NSAIDs) and hormonal therapies, Nirogacestat works as a gamma-secretase inhibitor. This means it blocks signals that promote tumor growth, potentially offering a more targeted and effective approach. Researchers are particularly excited because this mechanism could lead to fewer side effects and improved outcomes compared to existing options.

What evidence suggests that nirogacestat might be an effective treatment for aggressive fibromatosis?

Research has shown that nirogacestat effectively treats desmoid tumors, also known as aggressive fibromatosis. Studies have found that it prolongs the period patients remain without disease progression. Nirogacestat also reduces tumor size and alleviates symptoms, such as pain and impaired physical abilities. Patients using this treatment have experienced long-lasting benefits. Overall, nirogacestat has consistently proven effective and safe for these patients over time. During the double-blind phase of this trial, participants may receive either nirogacestat or a placebo, with an option for nirogacestat in the open-label phase. ^{1 2 3 4 6}

Who Is on the Research Team?

Bernd Kasper, MD

Principal Investigator

Mannheim University Medical Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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 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]

Citations

1. nejm.org nejm.org/doi/full/10.1056/NEJMoa2210140

Nirogacestat, a γ-Secretase Inhibitor for Desmoid Tumors Nirogacestat was associated with significant benefits with respect to progression-free survival, objective response, pain, symptom burden, physical functioning ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03785964

Nirogacestat for Adults With Desmoid Tumor/Aggressive ... This study evaluates nirogacestat (PF-03084014) in the treatment of desmoid tumor/aggressive fibromatosis (DT/AF).

3. ascopubs.org ascopubs.org/doi/10.1200/JCO-25-00582

Efficacy and Safety of Long-Term Continuous Nirogacestat ... In conclusion, long-term continuous nirogacestat treatment was associated with further tumor size reductions, durable objective responses, ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11815814/

Nirogacestat—the pathway to approval of the first treatment ... Beyond reductions in tumor size, this trial noted that every patient had “dramatic, sustained symptomatic relief (decreased tumor pain and/or ...

5. onclive.com onclive.com/view/long-term-defi-data-confirm-durable-efficacy-and-consistent-safety-of-nirogacestat-in-desmoid-tumors

Long-Term DeFi Data Confirm Durable Efficacy and ... Nirogacestat demonstrated sustained efficacy and safety in treating progressing desmoid tumors, with improved objective response rates over time ...

6. springworkstx.com springworkstx.com/wp-content/uploads/2024/11/Ratan-CTOS-2024-DeFi-Landmark-Oral_FINAL.pdf

Long-Term Efficacy and Safety From the Phase 3 DeFi Trial ▫ These results show the longer-term efficacy and safety of continuous use of nirogacestat with median exposure of 33.6 months, extended from 20.6 months ...