Nirogacestat for Aggressive Fibromatosis

Overseen By Keila Torres, MD,PHD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Antiretrovirals

Disqualifiers: Pregnancy, Breastfeeding, Cognitive impairment, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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: Unknown

Duration: 12 months

40 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety and effectiveness of a new drug, nirogacestat, for individuals with aggressive fibromatosis, also known as desmoid tumors. These rare, non-cancerous growths can cause issues as they expand. The study examines the drug's impact on the tumor when taken daily. Suitable candidates for this trial have been diagnosed with aggressive fibromatosis and have experienced recent tumor growth. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial requires that participants stop their prior therapy for at least 28 days or 5 half-lives of the drug, whichever is longer, before starting the study treatment. However, the protocol does not specify if you need to stop all current medications, so it's best to discuss your specific situation with the study team.

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

Research has shown that nirogacestat has been tested for safety in treating desmoid tumors, also known as aggressive fibromatosis. In earlier studies, patients taking nirogacestat experienced some side effects, but many were manageable. Common side effects included diarrhea, nausea, and fatigue, typically mild to moderate.

One study found that patients tolerated nirogacestat well over a long period, meaning they generally did not experience severe problems even with extended use. Another study demonstrated that the drug helped reduce tumor size, indicating effectiveness while maintaining reasonable safety.

Overall, the safety data suggests that nirogacestat is generally well-tolerated, with side effects that are usually manageable. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Nirogacestat is unique because it specifically targets the abnormal growth of fibromatosis cells by inhibiting a protein called gamma-secretase. Unlike standard treatments, which often involve surgery or radiation, nirogacestat offers a non-invasive, oral option that can be taken daily. Researchers are excited because this targeted approach could potentially shrink tumors more effectively and with fewer side effects compared to traditional therapies.

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

Research has shown that nirogacestat, the treatment under study in this trial, may help treat aggressive fibromatosis, also known as desmoid tumors. One study found that it significantly improved progression-free survival, preventing the tumor from worsening. Patients experienced noticeable reductions in tumor size and had lasting positive responses to the treatment. Additionally, many patients reported less pain and fewer symptoms, indicating an overall improvement in well-being. These findings suggest that nirogacestat could effectively manage desmoid tumors. ^{1 2 3 4 6}

Who Is on the Research Team?

Keila Torres, MD, PHD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with desmoid tumors/aggressive fibromatosis who have either not been treated or whose tumors grew after treatment. They must be able to swallow tablets, sign consent, and have a tumor that can be measured. Participants need proper liver, kidney, and bone marrow function and agree to use contraception. Excluded are pregnant/breastfeeding women, those with certain health conditions or treatments that could interfere with the study.

Inclusion Criteria

My organs and bone marrow are working well.

I have a known heart condition or symptoms.

I can understand and am willing to sign the consent form.

Exclusion Criteria

Known hypersensitivity to nirogacestat or any of its excipients

Patients with psychiatric illness/social situations limiting compliance with study requirements

I cannot have repeated tissue samples taken.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive nirogacestat by mouth every day of each 28-day study cycle

12 months

Monthly visits for assessment

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's safety and effects on patients with desmoid tumors. About 40 participants will receive this investigational drug to see how well it works against their tumors which have shown growth despite previous treatments or in those untreated.

How Is the Trial Designed?

Group I: nirogacestat Experimental Treatment 1 Intervention

Participants will take nirogacestat by mouth every day of each 28-day study cycle. Based on when you enroll in this study, you will take nirogacestat either 1 time a day at about the same time each day OR 2 times a day, about 12 hours apart.

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

SpringWorks Therapeutics, Inc.

Industry Sponsor

Trials

14

Recruited

900+

Published Research Related to This Trial

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]

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 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]

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. 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, ...

3. 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).

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/41115259/

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, ...

5. 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 ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT07170644

A Study of Nirogacestat in Japanese Adults With Desmoid ... This is an open-label study to characterize the efficacy and safety of nirogacestat in Japanese adults with progressing desmoid tumors/ ...