Tazemetostat for Nerve Sheath Cancer

Overseen By Priya Gurjar

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Florida

Must not be taking: Anti-cancer agents, CYP3A4 agents

Disqualifiers: Active infection, Cardiac issues, 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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 2 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the use of tazemetostat, a new drug, for treating malignant peripheral nerve sheath tumors. The goal is to assess the effectiveness of tazemetostat in patients whose cancer has recurred or spread. The trial seeks participants with a confirmed diagnosis of this cancer. Those who have tried other treatments but still have measurable disease may be suitable candidates. Participants must not have previously used tazemetostat and should be able to take oral medication without issues. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to important findings.

Will I have to stop taking my current medications?

The trial requires that you stop taking any other anti-cancer agents and drugs that strongly affect CYP3A4 enzymes at least 14 days before starting the study. If you are on dexamethasone for brain tumors or metastases, you can continue it if the dose is stable.

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

Research has shown that tazemetostat is generally well-tolerated by patients. In studies on various tumor types, this drug demonstrated a manageable safety profile. It is already approved for treating advanced epithelioid sarcomas, indicating some level of safety in humans. Although no treatment is without risks, data so far show that most side effects are mild to moderate, with serious side effects being less common.

The trial is at a stage where researchers are learning more about how people handle the drug and its effects on nerve sheath tumors. While some safety information is available, researchers are collecting more detailed results to ensure its safety for wider use. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Tazemetostat is unique because it targets a specific enzyme called EZH2, which plays a role in cancer cell growth. Unlike traditional treatments for nerve sheath cancer, such as surgery and radiation, which physically remove or destroy cancer cells, tazemetostat works at the molecular level to inhibit this enzyme, potentially slowing down or stopping tumor growth. Researchers are excited about tazemetostat because it represents a targeted therapy approach, which may offer a more effective treatment with fewer side effects compared to conventional methods.

What evidence suggests that tazemetostat might be an effective treatment for nerve sheath cancer?

Research shows that tazemetostat, the treatment under study in this trial, is a promising option for solid tumors. It is already approved for advanced epithelioid sarcomas, a type of cancer, suggesting it might work well for similar conditions. Patients with malignant peripheral nerve sheath tumors (MPNSTs) typically face a poor outlook, with only 34% to 44% surviving five years. However, tazemetostat targets cancer cells at the genetic level, offering hope for better outcomes in these challenging cases. Early studies in other cancers also support its potential to stop tumor growth. ^{1 2 4 6 7}

Who Is on the Research Team?

Joanne Lagmay, M.D.

Principal Investigator

University of Florida

Are You a Good Fit for This Trial?

This trial is for individuals aged 12 and older with a specific type of cancer called malignant peripheral nerve sheath tumors that have come back or spread. Participants need to have recovered from previous cancer treatments, be able to take oral medication, not be pregnant or breastfeeding, and must use contraception. They should only have this one active cancer and be in stable condition.

Inclusion Criteria

I have recovered from the side effects of my previous cancer treatments.

Use of contraception as specified for women of childbearing potential and males with female partners of child-bearing potential

I am 12 years old or older.

Exclusion Criteria

Known hypersensitivity to tazmetostat or any component of the formulation

Incarcerated or compulsorily detained subjects

I have serious heart problems.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive tazemetostat for the treatment of recurrent/refractory and/or metastatic malignant peripheral nerve sheath tumors

2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year

What Are the Treatments Tested in This Trial?

Interventions

• Tazemetostat

Trial Overview The study is testing Tazemetostat's effectiveness on patients with recurrent or metastatic malignant peripheral nerve sheath tumors. It's an open-label phase 2 trial, meaning everyone gets the drug and both the patient and doctor know what’s being given.

How Is the Trial Designed?

Group I: tazemetostat Experimental Treatment 1 Intervention

Tazemetostat is already approved in United States, European Union for the following indications:

Approved in United States as Tazverik for:

• Epithelioid sarcoma
• Follicular lymphoma

Approved in European Union as Tazverik for:

• Epithelioid sarcoma

Who Is Running the Clinical Trial?

University of Florida

Lead Sponsor

Trials

1,428

Recruited

987,000+

Epizyme, Inc.

Industry Sponsor

Trials

34

Recruited

2,800+

Published Research Related to This Trial

The study successfully developed the first potent inhibitor of NTMT1, named NAM-TZ-SPKRIA, which has a low inhibition constant (Ki = 0.20 μM) and shows selectivity against other methyltransferases, indicating its potential as an anticancer therapeutic.

NAM-TZ-SPKRIA works by competitively inhibiting NTMT1's activity, significantly reducing protein methylation, and demonstrates a novel approach to designing selective inhibitors for protein methyltransferases, paving the way for future cancer research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Design, synthesis, and kinetic analysis of potent protein N-terminal methyltransferase 1 inhibitors. Zhang, G., Richardson, SL., Mao, Y., et al.[2023]

Tazemetostat has been introduced as a treatment for advanced epithelioid sarcoma (ES), a rare cancer where the INI1 protein is lost in over 90% of cases, and has shown efficacy and manageable toxicity.

In a real-world case, a patient with relapsed, metastatic ES experienced a partial response to tazemetostat and tolerated the treatment well without serious side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early clinical and metabolic response to tazemetostat in advanced relapsed INI1 negative epithelioid sarcoma. Tansir, G., Rastogi, S., Shamim, SA., et al.[2021]

Tazemetostat (Tazverik™) is the first approved treatment specifically for adults and adolescents aged 16 years and older with locally advanced or metastatic epithelioid sarcoma, receiving accelerated approval in January 2020 in the USA.

The recommended dosage is 800 mg taken orally twice daily, and Tazemetostat is also being studied for other cancers, including diffuse large B-cell lymphoma and follicular lymphoma, indicating its potential broader therapeutic applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tazemetostat: First Approval. Hoy, SM.[2021]

In a phase II study involving 20 Japanese patients with relapsed or refractory B-cell non-Hodgkin lymphoma and EZH2 mutations, tazemetostat showed a high objective response rate of 76.5% in follicular lymphoma, with 35.3% achieving complete response.

The safety profile of tazemetostat was manageable, with the most common serious side effect being lymphopenia, and only four patients discontinuing treatment due to adverse events, indicating it could be a viable treatment option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of tazemetostat for relapsed or refractory B-cell non-Hodgkin lymphoma with EZH2 mutation in Japan. Izutsu, K., Ando, K., Nishikori, M., et al.[2021]

Gabapentin is the preferred treatment for most neuropathic pain disorders due to its ease of use, broad therapeutic range, and proven efficacy in clinical trials.

Lamotrigine is effective and well-tolerated when introduced gradually, helping to prevent side effects like rash, while pregabalin shows promise for treating post-herpetic neuralgia and is pending approval.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neuromodulating drugs for the symptomatic treatment of neuropathic pain. Backonja, M.[2019]

A novel PRMT5 inhibitor, compound 43g, demonstrated significant antitumor activity across various cancer cell lines and effectively reduced symmetric arginine dimethylation levels, which is linked to cancer progression.

Compound 43g selectively inhibited PRMT5 without affecting other protein arginine methyltransferase isoforms, suggesting a targeted approach that could minimize side effects in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Discovery of novel PRMT5 inhibitors bearing a methylpiperazinyl moiety. Bai, X., Zhai, Z., Zhao, X., et al.[2022]

Tazemetostat is the first targeted treatment approved by the FDA for epithelioid sarcoma, marking a significant advancement in therapy for this rare cancer.

In a phase II trial, tazemetostat showed a response rate of 15% in patients, with 67% of those responses lasting at least 6 months, indicating its potential efficacy in managing the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First EZH2 Inhibitor Approved-for Rare Sarcoma. [2020]

Tazemetostat is an effective oral treatment for patients aged 16 and older with metastatic or advanced epithelioid sarcoma (ES) that cannot be completely removed, as shown in a Phase II study.

This drug works by inhibiting EZH2, a protein that promotes cancer cell growth in ES due to SMARCB1/INI1 deficiency, and is being explored in combination with other therapies like doxorubicin and immunotherapy for potentially improved outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tazemetostat for advanced epithelioid sarcoma: current status and future perspectives. Simeone, N., Frezza, AM., Zaffaroni, N., et al.[2021]

Nasal sumatriptan may be an effective adjunctive therapy for patients with idiopathic trigeminal neuralgia who do not respond well to carbamazepine, especially when increasing the carbamazepine dose is not an option.

This therapy could be particularly beneficial for patients experiencing poor pain control and who are not suitable candidates for nerve blocks or surgical interventions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nasal sumatriptan as adjunctive therapy for idiopathic trigeminal neuralgia: report of three cases. Shimohata, K., Shimohata, T., Motegi, R., et al.[2018]

The study introduces BM30, the first potent peptidomimetic inhibitor of protein N-terminal methyltransferases (NTMT1/2), which shows a strong inhibitory effect with a half-maximal inhibitory concentration of 0.89 μM and over 100-fold selectivity against other methyltransferases.

The cell-permeable analogue DC432 of BM30 effectively reduces N-terminal methylation in specific proteins within HCT116 cells, demonstrating its potential for further research into the roles of NTMTs in cell mitosis and DNA damage repair.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selective Peptidomimetic Inhibitors of NTMT1/2: Rational Design, Synthesis, Characterization, and Crystallographic Studies. Mackie, BD., Chen, D., Dong, G., et al.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04917042

Tazemetostat in Malignant Peripheral Nerve Sheath Tumors The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04917042?cond=tazemetostat&viewType=Table&rank=3

Tazemetostat in Malignant Peripheral Nerve Sheath Tumors An unfavorable change in the health of a participant, including abnormal laboratory findings, that happens during a clinical study or within a certain amount of ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11392982/

Malignant Peripheral Nerve Sheath Tumor, a Heterogeneous ... The 10-year OS rate for localized MPNST was also significantly reduced in those with NF1-associated tumors (45% ± 11% versus 60% ± 8%; p = 0.046) ...

4. sciencedirect.com sciencedirect.com/topics/medicine-and-dentistry/tazemetostat

Tazemetostat - an overview | ScienceDirect Topics Tazemetostat represents the first epigenetic therapy approved for solid tumors, being the first drug approved for advanced epithelioid sarcomas treatment.

5. academic.oup.com academic.oup.com/noa/article/6/Supplement_3/iii83/7715919

Current state of spinal nerve sheath tumor management and ... Prognosis of MPNSTs overall is poor, with 5-year survival ranging from 34% to 44% despite aggressive treatment.

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/nda/2020/211723Orig1s000MultidisciplineR.pdf

Multi-Discipline Review - accessdata.fda.gov EZH-202, an ongoing, non-randomized trial of tazemetostat in patients with various tumor types. ... In summary, the available safety data and ...

7. mdpi.com mdpi.com/2072-6694/16/19/3266

The Multimodality Management of Malignant Peripheral ... However, up to 50% of all MPNSTs occur in individuals with NF1, where the reported lifetime risk of developing these tumours is 8–13% [1,2].