Tazemetostat for Advanced Cancer with Liver Impairment

Recruiting at 1 trial location

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests tazemetostat, a potential new treatment for advanced cancer in patients with liver problems. Researchers aim to understand how the body processes this drug in individuals with serious liver issues compared to those with normal liver function. They also seek to determine the drug's safety and tolerability. The trial seeks participants with advanced cancers unresponsive to other treatments and with moderate or severe liver impairment. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new drug.

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

Research has shown that tazemetostat is generally well-tolerated by patients with certain advanced cancers. In studies, many participants continued treatment without needing to stop or adjust their dose due to side effects. Common side effects include fatigue and upset stomach, but these are often manageable.

The FDA has also approved tazemetostat for other cancers, such as epithelioid sarcoma, which further supports its safety in humans. However, since this trial involves participants with liver problems, studying how their bodies process the drug is crucial. This ensures safety for everyone involved.

Overall, tazemetostat has a history of being quite safe, but discussing any concerns with a doctor is always advisable. ^{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 is often overactive in some cancers. Unlike traditional chemotherapy that attacks all rapidly dividing cells, tazemetostat is more selective, potentially leading to fewer side effects and a better quality of life for patients. Researchers are excited about its potential to provide a more targeted therapy for advanced cancer patients with liver impairment, offering a new option where current treatments might not be as effective or safe.

What evidence suggests that tazemetostat might be an effective treatment for advanced cancer with liver impairment?

Research shows that tazemetostat, which participants in this trial will receive, may help treat certain advanced cancers. In earlier studies, up to 27% of patients taking tazemetostat experienced tumor shrinkage or halted growth, indicating positive changes in their cancer. The drug blocks a specific enzyme, slowing or stopping cancer cell multiplication. Additionally, research indicates that even with liver or kidney problems, the drug's levels in the body remain stable, suggesting it could be safe to use without adjusting the dose. These findings support tazemetostat as a potentially effective treatment for advanced cancers. ^{3 4 6 7 8}

Who Is on the Research Team?

Ipsen Medical Director

Principal Investigator

Ipsen

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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 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 (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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04241835?term=tazverik&aggFilters=status:rec&viewType=Table&rank=8

A Study to Compare the Blood Levels and Safety of ... Members are chosen based on the scientific skills and knowledge needed to monitor the particular trial. Also called a data safety and monitoring ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11559081/

Pharmacology and pharmacokinetics of tazemetostat - PMC Tazemetostat exposure and clearance did not significatively change in patients with hepatic or renal impairments, therefore no dosage modifications were ...

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

Multi-Discipline Review - accessdata.fda.gov The clinical pharmacology data are supportive of the efficacy results. The primary evidence of effectiveness at the proposed 800 mg BID ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT04241835

NCT04241835 | A Study to Compare the Blood Levels and ... A Study to Compare the Blood Levels and Safety of Tazemetostat in Participants With Advanced Cancer and Moderate/​Severe Liver Impairment to Participants With ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8247010/

Real‐world outcomes of patients with locally advanced or ... A retrospective study of 115 patients with advanced ES reported an overall response rate (ORR) of 22% and 27% for anthracycline‐based and ...

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2020/213400s000lbl.pdf

TAZVERIK (tazemetostat) - accessdata.fda.gov The safety and effectiveness of TAZVERIK have been established in pediatric patients aged 16 years and older. (adolescents) with metastatic or locally advanced ...

7. tazverik.com tazverik.com/hcp/epithelioid-sarcoma/safety-and-tolerability

Safety & Tolerability in Advanced Epithelioid Sarcoma TAZVERIK® (tazemetostat) safety data, including discontinuations, dose reductions and interruptions, adverse reactions, and lab abnormalities in advanced ...

8. eocco.com eocco.com/-/media/EOCCO/PDFs/Formulary/tazemetostat-_Tazverik.pdf

tazemetostat (Tazverik™) There is a lack of high-quality data from randomized controlled trials to indicate the safety and efficacy of tazemetostat (Tazverik) in the following ...