Tazemetostat for Advanced Cancer with Liver Impairment

Recruiting at 8 trial locations

Overseen By Ipsen Recruitment Enquiries

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Epizyme, Inc.

Must not be taking: CYP3A4 inducers/inhibitors

Disqualifiers: Brain metastases, Hepatitis B/C, others

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

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

Compensation: Varies

Number of Visits: Unknown

24 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests tazemetostat, an oral medication, in patients with advanced solid tumors and different liver functions. It aims to understand how the drug behaves in the body and its safety. Researchers will measure drug levels in the blood and monitor for side effects. Tazemetostat is approved by the FDA for certain types of cancer.

Will I have to stop taking my current medications?

The trial requires that you stop taking any chemotherapy, targeted therapy, or major surgery treatments at least 28 days before joining. If you're on daily or weekly chemotherapy without delayed toxicity, a 14-day break might be okay. Also, you can't take medications that are known potent CYP3A4 inducers or inhibitors.

Is tazemetostat generally safe for humans?

Tazemetostat has been studied in various clinical trials, including for B-cell non-Hodgkin lymphoma, and has shown a manageable safety profile. Common side effects include lymphopenia (low white blood cell count), and some serious side effects like hypertriglyceridemia (high levels of triglycerides in the blood) and pneumonia aspiration were reported but were not related to the drug. Overall, the safety profile is considered acceptable. ^{1 2 3 4 5}

What makes the drug Tazemetostat unique for treating advanced cancer with liver impairment?

Tazemetostat is unique because it targets a specific enzyme called EZH2, which is involved in cancer cell growth, making it different from traditional chemotherapy drugs that target rapidly dividing cells in general. This targeted approach may offer a novel treatment option for patients with advanced cancer and liver impairment, where standard treatments may not be effective or safe. ^{6 7 8 9 10}

What data supports the effectiveness of the drug Tazemetostat for advanced cancer with liver impairment?

Tazemetostat has shown effectiveness in treating epithelioid sarcoma, with 15% of patients responding to the drug and 67% of those responses lasting at least 6 months. It is also being studied for other cancers like B-cell lymphoma, indicating its potential in treating various tumor types. ^{1 2 3 4 11}

Research Team

Ipsen Medical Director

Principal Investigator

Ipsen

Eligibility Criteria

Adults with advanced cancer and liver impairment or normal liver function can join this trial. They should be able to understand the study, have a life expectancy over 3 months, and not have had recent treatments that could affect results. Participants must use effective contraception if of childbearing potential and cannot have certain blood disorders or severe allergies to tazemetostat components.

Inclusion Criteria

Must have evaluable or measurable disease

I can take pills and don't have major stomach or bowel issues affecting drug absorption.

I understand the study details and have signed the consent form.

Exclusion Criteria

I am not taking strong CYP3A4 drugs or St. John's Wort.

Known hypersensitivity to any of the components of tazemetostat

I have severe blood cell count issues or a history of blood cancer.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Part 1 Treatment

Participants receive a single oral 800 mg dose of tazemetostat on Day 1 and Day 15, and twice daily from Day 5 to Day 14. Blood samples for PK analysis are obtained.

18 days

Multiple visits for PK sampling

Part 2 Treatment

Participants continuing treatment receive tazemetostat (oral 800 mg dose) tablets twice daily in repeated 28-day cycles until clinical progression or unacceptable toxicity.

28-day cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment. An end of study visit for safety assessment occurs 30 days after the last dose.

30 days

Treatment Details

Interventions

• Tazemetostat

Trial Overview The trial is testing how different levels of liver function affect the blood levels and safety of Tazemetostat in patients with advanced solid tumors. It compares those with moderate/severe liver problems to those with normal liver function, focusing on how well they tolerate the drug.

Participant Groups

Group I: Open label Tazemetostat Experimental Treatment 1 Intervention

Part 1: Participants will receive a single oral 800 mg dose on day 1, and twice daily from day 5 to day 14. Participants will return to the clinical study unit on an out-patient basis from day 15 to day 18. A single oral 800 mg dose of tazemetostat will be administered on day 15. Part 2: Will begin on day 19 and participants continuing treatment in Part 2 will receive tazemetostat (oral 800 mg dose) tablets to be taken twice daily in repeated 28-day cycles.

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?

Epizyme, Inc.

Lead Sponsor

Trials

34

Recruited

2,800+

Sponsor GmbH

Collaborator

Trials

36

Recruited

11,000+

Findings from Research

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 I study involving seven Japanese patients with relapsed or refractory B-cell non-Hodgkin lymphoma, tazemetostat demonstrated a promising objective response rate of 57%, indicating its potential effectiveness in treating this type of cancer.

The treatment was well-tolerated, with no dose-limiting toxicities observed and only mild adverse events such as thrombocytopenia and dysgeusia reported, suggesting a favorable safety profile for tazemetostat.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 study of tazemetostat in Japanese patients with relapsed or refractory B-cell lymphoma. Munakata, W., Shirasugi, Y., Tobinai, K., et al.[2021]

Tazemetostat is the first FDA-approved epigenetic therapy for solid tumors, specifically targeting the EZH2 enzyme involved in gene silencing.

This therapy is particularly effective for tumors with mutations in the SWI/SNF chromatin remodeling complex, such as most epithelioid sarcomas, highlighting its potential in treating these specific cancer types.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Epigenetic Therapy for Epithelioid Sarcoma. Rothbart, SB., Baylin, SB.[2021]

Tazemetostat, a selective EZH2 inhibitor, showed significant antitumor activity specifically in rhabdoid tumor xenografts, with 71% of these models demonstrating improved event-free survival compared to controls.

The treatment effectively reduced H3K27me3 levels in most tumors, indicating its mechanism of action, but it did not show consistent efficacy against other tumor types, suggesting a need for further research, especially in combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Initial testing (stage 1) of tazemetostat (EPZ-6438), a novel EZH2 inhibitor, by the Pediatric Preclinical Testing Program. Kurmasheva, RT., Sammons, M., Favours, E., 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]

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]

The newly synthesized compound, 9-methyl-10-deazaminopterin (13a), was found to be 21 times more potent than methotrexate (MTX) in inhibiting cell growth in L1210 leukemia cells, indicating a significant enhancement in cytotoxicity.

Despite the increased potency in L1210 cells, the mechanism behind this enhanced effect remains unclear, as both enzyme inhibition and transport parameters were similar to those of MTX, and the compound showed only modest growth inhibition in human Manca leukemia cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synthesis and antifolate properties of 9-alkyl-10-deazaminopterins. DeGraw, JI., Christie, PH., Kisliuk, RL., et al.[2019]

Pemetrexed is a novel antifolate that effectively inhibits multiple folate-dependent enzymes, showing broad activity against solid tumors like non-small cell lung, colorectal, and pancreatic cancers, which are often resistant to other treatments.

The risk of life-threatening toxicity associated with pemetrexed has been mitigated by using low-dose folic acid and vitamin B12 supplements, making it a safer option for patients undergoing treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Future directions in the development of pemetrexed. Calvert, H., Bunn, PA.[2019]

Pemetrexed is a multitargeted antifolate drug that has shown promise in treating solid tumors, including nonsmall cell lung cancer and mesothelioma, and is currently being investigated for its efficacy in ovarian cancer through various Phase I and II clinical trials.

While pemetrexed has demonstrated activity in patients with ovarian cancer, particularly those resistant to platinum-based treatments, there is a need for randomized studies to compare its effectiveness against standard therapies and to focus on biomarker-driven patient selection for future trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The current state of pemetrexed in ovarian cancer. Miller, RE., Banerjee, S.[2015]

Pemetrexed (PEM) shows promise in treating recurrent ovarian cancer, particularly when combined with carboplatin, with response rates comparable to other combination therapies, based on eight trials reviewed.

However, due to a lack of randomized trials directly comparing PEM with existing treatments, its definitive efficacy remains uncertain, especially in platinum-resistant cases where PEM may perform similarly to other single-agent therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pemetrexed disodium in ovarian cancer treatment. Morotti, M., Valenzano Menada, M., Venturini, PL., et al.[2015]

In a study involving human tumor xenografts in nude mice, the new folate analog 10-ethyl, 10-deaza-aminopterin showed significant antitumor activity, particularly against MX-1 mammary carcinoma and LX-1 lung carcinoma, leading to tumor regressions at doses of 2-4.5 mg/kg.

In contrast, the original 10-deaza-aminopterin and methotrexate demonstrated minimal or no activity against the tumors, highlighting the potential of the new analog as a more effective treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New folate analogs of the 10-deaza-aminopterin series: markedly increased antitumor activity of the 10-ethyl analog compared to the parent compound and methotrexate against some human tumor xenografts in nude mice. Schmid, FA., Sirotnak, FM., Otter, GM., et al.[2015]

References

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

Tazemetostat: First Approval. [2021]

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

Phase 1 study of tazemetostat in Japanese patients with relapsed or refractory B-cell lymphoma. [2021]

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

Epigenetic Therapy for Epithelioid Sarcoma. [2021]

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

Initial testing (stage 1) of tazemetostat (EPZ-6438), a novel EZH2 inhibitor, by the Pediatric Preclinical Testing Program. [2022]

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

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

6. 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]

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

Synthesis and antifolate properties of 9-alkyl-10-deazaminopterins. [2019]

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

Future directions in the development of pemetrexed. [2019]

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

The current state of pemetrexed in ovarian cancer. [2015]

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

Pemetrexed disodium in ovarian cancer treatment. [2015]

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

New folate analogs of the 10-deaza-aminopterin series: markedly increased antitumor activity of the 10-ethyl analog compared to the parent compound and methotrexate against some human tumor xenografts in nude mice. [2015]