Cryoablation + Nirogacestat for Desmoid Tumors

Overseen By Amir Emami

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Nam Bui

Must not be taking: GS inhibitors, Anti-Notch antibodies, TKIs, others

Disqualifiers: Infections, Cardiac disease, Liver disease, 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: 24 months

28 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination treatment for people with desmoid tumors. The goal is to determine if taking nirogacestat, an oral medication, followed by a cryoablation procedure (which uses extreme cold to destroy tissue), can help manage these tumors. It seeks participants diagnosed with a desmoid tumor that is growing or causing symptoms, such as pain or difficulty with daily activities. Participants should also have a tumor that can be partially treated with cryoablation. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Do I need to stop my current medications to join the trial?

Yes, if you are currently taking any treatment for desmoid tumors, you must stop at least 28 days before starting the study treatment. If you are on chronic NSAIDs for other conditions, you need to be on a stable dose for at least 28 days before starting the study treatment.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that nirogacestat is generally safe for people with desmoid tumors. In studies lasting up to four years, many patients responded positively, with nearly half experiencing a significant reduction in tumor size.

Although nirogacestat appears promising, it can have side effects like any medication. However, most side effects are mild and manageable. For those considering joining a trial, this information suggests that nirogacestat has maintained a good safety record in previous studies. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard care for desmoid tumors, which often involves surgery, radiation, or other systemic therapies, nirogacestat offers a novel approach. It works by inhibiting gamma-secretase, an enzyme involved in the growth of desmoid tumors. This targeted mechanism is promising because it directly interferes with the tumor's growth pathways, potentially leading to more effective control of the tumor with fewer side effects. Researchers are excited about nirogacestat as it represents a shift towards more precise, targeted therapy for desmoid tumors, which could improve patient outcomes and quality of life.

What evidence suggests that cryoablation and nirogacestat might be effective for desmoid tumors?

Research has shown that nirogacestat, a type of medication, effectively treats desmoid tumors. Studies have found that patients taking nirogacestat experienced a decrease in tumor size over time. Long-term use led to lasting improvements, with benefits continuing. Patients also reported significant relief from symptoms like tumor pain. The treatment increased the number of patients experiencing positive changes. Overall, nirogacestat appears promising in providing both tumor control and symptom relief for those with desmoid tumors. ^{1 3 4 5 6}

Who Is on the Research Team?

Nam Bui, M.D.

Principal Investigator

Stanford University

Are You a Good Fit for This Trial?

Adults with a confirmed diagnosis of desmoid tumor that is either growing or causing symptoms, and who can swallow tablets. The tumor must be partially treatable by cryoablation without harming nearby critical structures. Participants need proper organ function, no severe cardiac issues or recent heart attacks, and cannot be on certain medications. Women must not be pregnant or breastfeeding and use contraception; men agree to use condoms.

Inclusion Criteria

I can swallow pills.

My desmoid tumor can be mostly treated with freezing.

Women of childbearing potential must have a negative serum pregnancy test at screening

Exclusion Criteria

I haven't taken strong or moderate CYP3A4 inhibitors or inducers in the last 14 days.

Current enrollment or recent enrollment in another clinical study with any investigational drug or device

Known hypersensitivity to nirogacestat

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Systemic therapy with oral study agent, nirogacestat, for 3 cycles (1 cycle = 28 days) followed by a single cryoablation procedure, then continued nirogacestat for Cycles 4 through 26

24 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year

What Are the Treatments Tested in This Trial?

Interventions

• Cryoablation
• Nirogacestat

Trial Overview The trial tests the effectiveness of nirogacestat taken orally followed by a single cryoablation procedure for treating desmoid tumors. Nirogacestat is given first to potentially shrink the tumor before freezing it with cryoablation to destroy remaining cancer cells.

How Is the Trial Designed?

Group I: Nirogacestat 150 mg Experimental Treatment 2 Interventions

Patients will receive 3-cycle lead-in with systemic therapy with nirogacestat 150 mg po BID, given continuously.

Who Is Running the Clinical Trial?

Nam Bui

Lead Sponsor

Stanford University

Lead Sponsor

Trials

2,527

Recruited

17,430,000+

SpringWorks Therapeutics, Inc.

Industry Sponsor

Trials

14

Recruited

900+

Published Research Related to This Trial

Cryoablation has been successfully performed on 10 patients with desmoid fibromatosis, showing a reproducible technique with low toxicity and significant symptomatic improvement in 8 out of 10 patients after a median follow-up of 353 days.

Larger tumors required more resources and had a higher chance of leaving residual tumor tissue, but complete ablation led to no recurrences or need for further treatment, indicating the importance of fully covering the tumor during the procedure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Percutaneous cryoablation for desmoid fibromatosis: initial experience at a UK centre. Johnston, EW., Alves, A., Messiou, C., et al.[2022]

Cryoablation was found to be an effective treatment for desmoid tumors, with a significant reduction in viable tumor volume (43.7%) after the procedure, and 96.9% of patients experienced symptomatic relief.

The procedure was safe, with a technical success rate of 100% and only one major complication reported among 44 cryoablation procedures performed on 25 patients over a 10-year period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Single-Center 10-Year Retrospective Analysis of Cryoablation for the Management of Desmoid Tumors. Yan, YY., Walsh, JP., Munk, PL., et al.[2021]

Percutaneous image-guided cryoablation is a safe and effective treatment for inoperable extra-abdominal desmoid tumors, with a major complication rate of only 5.8% and a disease-free survival rate of 82.3% over 24 months.

Although 47% of patients had residual tumors after treatment, there was no local tumor progression observed at 6, 12, or 24 months, indicating good local control of the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Percutaneous image-guided cryoablation in inoperable extra-abdominal desmoid tumors: a study of tolerability and efficacy. Havez, M., Lippa, N., Al-Ammari, S., et al.[2020]

In a study of 21 patients with metastatic medullary thyroid cancer (MTC) treated with 90Y-DOTATOC, 10% achieved a complete response and 57% had stable disease, indicating some efficacy in this challenging condition.

Patients with lower tumor burden and lower calcitonin levels at treatment showed better responses, suggesting that earlier intervention with 90Y-DOTATOC may improve outcomes and that future studies should explore its use in earlier disease stages.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Receptor radionuclide therapy with 90Y-DOTATOC in patients with medullary thyroid carcinomas. Bodei, L., Handkiewicz-Junak, D., Grana, C., et al.[2013]

In a study of 128 patients with high-grade gliomas, the combination of radiotherapy and temozolomide showed favorable outcomes, with only 9% experiencing grade 3 hematological toxicity and no grade 4 toxicity reported, indicating a manageable safety profile.

Statistical analysis revealed that factors such as age, tumor histology, and the use of temozolomide were linked to improved 2-year overall survival, supporting the efficacy of this treatment regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide and radiotherapy as first-line treatment of high-grade gliomas. Corsa, P., Parisi, S., Raguso, A., et al.[2022]

In a pilot study involving 16 patients with high-grade gliomas (HGGs) that were inoperable or resistant to standard treatments, 177Lu-DOTATATE showed potential therapeutic effects, with 12.5% achieving complete remission and 31.25% showing partial remission.

Despite some positive treatment responses, overall quality of life scores did not significantly improve, indicating that while 177Lu-DOTATATE may be beneficial, further research is needed in a more targeted patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Feasibility and Therapeutic Potential of Peptide Receptor Radionuclide Therapy for High-Grade Gliomas. Nemati, R., Shooli, H., Rekabpour, SJ., et al.[2023]

Percutaneous cryoablation (CA) demonstrated high efficacy in treating advanced and refractory extra-abdominal desmoid tumors, with an 85.1% progression-free survival rate at 1 year and an 80% objective response rate among 30 patients studied over a median follow-up of 18.5 months.

The treatment resulted in significant pain reduction for 96.7% of patients and a median tumor volume reduction of 66.6% at 1 year, although there was a 36.6% rate of adverse events, including some major complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Percutaneous cryoablation for advanced and refractory extra-abdominal desmoid tumors. Auloge, P., Garnon, J., Robinson, JM., et al.[2021]

In a study of 84 patients treated with cryoablation for nonabdominopelvic desmoid tumors, local recurrence occurred in 22.62% of cases, with 36-month progression-free survival rates at 68%.

Key risk factors for local recurrence included the tumor's location (non-abdominal wall), previous treatments like surgery or radiation, and the method of cryoablation used, highlighting the importance of these factors in treatment planning.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prognostic Factors for Local Recurrence after Cryoablation of Desmoid Tumors. Bouhamama, A., Wdowik, Q., Grillet, F., et al.[2023]

Cryoablation effectively reduces pain and tumor size in patients with inoperable or recurring desmoid tumors, with a significant decrease in pain scores from 5.7 to 2.4 on the visual analog scale after 6 months.

In a study of 34 patients treated over 4 years, 42.2% achieved disease-free survival at 3 years, indicating that cryoablation can provide both local control and pain relief for these tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Local Control and Analgesic Efficacy of Percutaneous Cryoablation for Desmoid Tumors. Bouhamama, A., Lame, F., Mastier, C., et al.[2020]

In a pilot study involving 11 glioma patients, the peptide DOTATOC was successfully used to target somatostatin receptor type 2 in low-grade and anaplastic gliomas, leading to six cases of disease stabilization and reduction in tumor size.

The treatment showed a favorable safety profile, with only minor toxicity observed as perifocal edema, indicating that DOTATOC could be a promising option for targeting receptor-positive gliomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Locoregional regulatory peptide receptor targeting with the diffusible somatostatin analogue 90Y-labeled DOTA0-D-Phe1-Tyr3-octreotide (DOTATOC): a pilot study in human gliomas. Merlo, A., Hausmann, O., Wasner, M., et al.[2018]

Temozolomide is effective in treating aggressive pituitary adenomas and carcinomas, with 10 out of 13 adenomas and all 6 carcinomas responding positively to the treatment in a review of 19 cases.

Low levels of the DNA repair enzyme MGMT are associated with better treatment responses to temozolomide, suggesting that MGMT expression could be a useful biomarker for predicting efficacy in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of pituitary neoplasms with temozolomide: a review. Syro, LV., Ortiz, LD., Scheithauer, BW., et al.[2018]

Citations

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

Nirogacestat, a γ-Secretase Inhibitor for Desmoid Tumors Results · Efficacy. As of the data-cutoff date (April 7, 2022), the overall median follow-up for progression-free survival was 15.9 months.

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. ir.springworkstx.com ir.springworkstx.com/news-releases/news-release-details/springworks-therapeutics-announces-long-term-efficacy-and-safety/

Press Release Details Long-term follow-up data highlight further reductions in tumor size, increase in ORR with additional CRs, sustained improvement in desmoid ...

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

Efficacy and Safety of Long-Term Continuous Nirogacestat ... Median PFS was not reached. The ORR with up to 4 years of nirogacestat treatment was 45.7% (32 of 70), with three additional partial and three ...