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

10 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase 2, open label, single arm study will investigate the use of tazemetostat in patients with recurrent/refractory and/or metastatic malignant peripheral nerve sheath tumors.

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 Tazemetostat safe for humans?

Tazemetostat has been shown to have a manageable safety profile in clinical trials for various conditions, including epithelioid sarcoma and B-cell non-Hodgkin lymphoma. Common side effects include lymphopenia (low white blood cell count), but serious side effects were rare and not directly related to the drug. Overall, the safety profile is considered acceptable for use in humans. ^{1 2 3 4 5}

What makes the drug Tazemetostat unique for treating nerve sheath cancer?

Tazemetostat is unique because it targets specific enzymes involved in cancer cell growth, such as protein methyltransferases, which are not typically targeted by other treatments for nerve sheath cancer. This approach may offer a novel way to slow down or stop the progression of the cancer. ^{6 7 8 9 10}

Research Team

Joanne Lagmay, M.D.

Principal Investigator

University of Florida

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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]

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]

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]

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]

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]

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]

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]

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]

References

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

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

2. England pubmed.ncbi.nlm.nih.gov

Early clinical and metabolic response to tazemetostat in advanced relapsed INI1 negative epithelioid sarcoma. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Phase II study of tazemetostat for relapsed or refractory B-cell non-Hodgkin lymphoma with EZH2 mutation in Japan. [2021]

4. New Zealand pubmed.ncbi.nlm.nih.gov

Tazemetostat: First Approval. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Tazemetostat for advanced epithelioid sarcoma: current status and future perspectives. [2021]

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

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

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

Selective Peptidomimetic Inhibitors of NTMT1/2: Rational Design, Synthesis, Characterization, and Crystallographic Studies. [2021]

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

Nasal sumatriptan as adjunctive therapy for idiopathic trigeminal neuralgia: report of three cases. [2018]

9. England pubmed.ncbi.nlm.nih.gov

Discovery of novel PRMT5 inhibitors bearing a methylpiperazinyl moiety. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Design, synthesis, and kinetic analysis of potent protein N-terminal methyltransferase 1 inhibitors. [2023]