Tazemetostat for Advanced Cancer with Liver Impairment
Recruiting in Palo Alto (17 mi)
+9 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Epizyme, Inc.
Must not be taking: CYP3A4 inducers/inhibitors
Disqualifiers: Brain metastases, Hepatitis B/C, others
No Placebo Group
Approved in 2 jurisdictions
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.
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.
12345Is 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.
12346What 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.
7891011Eligibility 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.
+14 more
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.
+16 more
Trial 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
Participant Groups
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.
1Treatment groups
Experimental Treatment
Group I: Open label TazemetostatExperimental Treatment1 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Florida Cancer Specialists & Research InstituteLake Mary, FL
Rutgers Cancer InstituteNew Brunswick, NJ
Hematology Oncology ConsultantsRoyal Oak, MI
Virginia Cancer SpecialistsFairfax, VA
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Who Is Running the Clinical Trial?
Epizyme, Inc.Lead Sponsor
Sponsor GmbHCollaborator
References
Tazemetostat: First Approval. [2021]Tazemetostat (Tazverik™), a first-in-class, small molecule enhancer of zeste homolog 2 (EZH2) inhibitor, received accelerated approval in January 2020 in the USA for the treatment of adults and adolescents aged ≥ 16 years with locally advanced or metastatic epithelioid sarcoma not eligible for complete resection. Developed by Epizyme, in collaboration with Eisai, it is the first therapy to be approved specifically for the treatment of epithelioid sarcoma in the USA. The recommended dosage regimen is 800 mg twice daily, administered orally with or without food, until disease progression or unacceptable toxicity. Tazemetostat is also undergoing clinical development in various countries worldwide for use in several other tumour types, including diffuse large B-cell lymphoma and mesothelioma, with the US FDA accepting a New Drug Application and granting priority review for its use in the treatment of follicular lymphoma. This article summarizes the milestones in the development of tazemetostat leading to this first approval for the treatment of adults and adolescents aged ≥ 16 years with locally advanced or metastatic epithelioid sarcoma not eligible for complete resection.
Phase 1 study of tazemetostat in Japanese patients with relapsed or refractory B-cell lymphoma. [2021]Tazemetostat is a selective and orally available inhibitor of enhancer of zeste homolog 2 (EZH2), a histone methyltransferase and epigenetic regulator of cellular differentiation programs. We carried out a phase I study of tazemetostat in Japanese patients with relapsed or refractory B-cell non-Hodgkin-type lymphoma (B-NHL) to evaluate its tolerability, safety, pharmacokinetics, and preliminary antitumor activity.
Initial testing (stage 1) of tazemetostat (EPZ-6438), a novel EZH2 inhibitor, by the Pediatric Preclinical Testing Program. [2022]Tazemetostat (EPZ-6438) is a selective inhibitor of the histone methyltransferase EZH2 and currently in clinical development for non-Hodgkin lymphoma and genetically defined tumors.
Epigenetic Therapy for Epithelioid Sarcoma. [2021]Tazemetostat is the first epigenetic therapy to gain FDA approval in a solid tumor. This lysine methyltransferase inhibitor targets EZH2, the enzymatic subunit of the PRC2 transcriptional silencing complex. Tumors with mutations in subunits of the SWI/SNF chromatin remodeling complex, inclusive of most epithelioid sarcomas, are sensitive to EZH2 inhibition.
First EZH2 Inhibitor Approved-for Rare Sarcoma. [2020]The FDA has approved tazemetostat for treating epithelioid sarcoma. The drug produced responses in 15% of patients with the disease in a phase II trial, and 67% of the responses lasted at least 6 months. The drug is the first targeted treatment for epithelioid sarcoma.
Phase II study of tazemetostat for relapsed or refractory B-cell non-Hodgkin lymphoma with EZH2 mutation in Japan. [2021]Tazemetostat is a selective, reversible, small-molecule inhibitor of the histone methyltransferase enzyme, enhancer of zest homolog 2 (EZH2). In this multicenter, open-label, phase II study, we assessed the efficacy and safety of tazemetostat in Japanese patients with relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma harboring the EZH2 mutation. Tazemetostat (800 mg twice daily) was given orally (28-day cycle) until disease progression or unacceptable toxicity. Among the 20 eligible patients, 17 were enrolled in cohort 1 (follicular lymphoma [FL]), and three were enrolled in cohort 2 (diffuse large B-cell lymphoma). At data cut-off, the objective response rate in cohort 1 was 76.5%, including six patients (35.3%) with complete response and seven patients (41.2%) with partial response (PR). All three patients in cohort 2 achieved PR. In cohort 1, median progression-free survival (PFS) was not reached at the median follow-up of 12.9 months. The estimated PFS rate at 12 and 15 months was 94.1% and 73.2%, respectively. The most common grade 3 treatment-emergent adverse event (TEAE) was lymphopenia (n = 2). Grade 4 TEAEs included hypertriglyceridemia and pneumonia aspiration (n = 1 each), which were not related to tazemetostat. Treatment-emergent adverse events leading to study drug discontinuation were reported in four of the 20 patients, indicating that the safety profile of tazemetostat was acceptable and manageable. Tazemetostat 800 mg twice daily showed encouraging efficacy in patients with R/R EZH2 mutation-positive FL with a manageable safety profile in the overall population. Thus, tazemetostat could be a potential treatment for R/R EZH2 mutation-positive FL.
Synthesis and antifolate properties of 9-alkyl-10-deazaminopterins. [2019]Reformatski condensation of benzyl 2-bromopropionate with 4-carbomethoxybenzaldehyde, followed by dehydration afforded benzyl 2-methyl-p-carbomethoxycinnamate (4a). Hydrogenation over a Pd catalyst gave the hydrocinnamic acid 5a. Conversion to the chloromethyl (6a) and azidomethyl ketone (7a) was followed by hydrogenation to the aminomethyl ketone (8a). Direct N-alkylation by 2,4-diamino-5-nitro-6-chloropyrimidine followed by reductive ring closure in Zn-HOAc and subsequent saponification of the benzoate ester yielded 4-amino-4-deoxy-9-methyl-10-deazapteroic acid (11a). Coupling with diethyl L-glutamate and saponification afforded 9-methyl-10-deazaminopterin (13a). The 9-ethyl analogue (13b) was similarly prepared from benzyl 2-bromobutyrate. The 9-methyl analogue (13a) was 21 times more potent than MTX as an inhibitor of cell growth in L1210 cells. The reason for this enhanced cytotoxicity in L1210 is unclear, since enzyme inhibition and transport parameters were similar to those of MTX. In human Manca leukemia cells growth inhibition was not dramatic and paralleled MTX.
Future directions in the development of pemetrexed. [2019]Pemetrexed is a novel antifolate that inhibits several folate-dependent enzymes in addition to thymidylate synthase. Such a drug may have theoretical advantages over fluoropyrimidines and specifically acting antifolates. Phase I studies identified a preferred schedule of an intravenous dose once every 3 weeks. Phase II studies showed a broad spectrum of activity in solid tumors (ie, non-small cell lung, colorectal, and pancreatic cancers) usually considered refractory to most antimetabolites. Binary combinations with cisplatin, carboplatin, and gemcitabine have proven feasible and show encouraging activity in lung cancer and mesothelioma. Problems of sporadic life-threatening toxicity identified in early studies of this and other antifolates have been resolved by the discovery that they were caused by functional folate deficiency and may be avoided by a low-dose nutritional supplement of folic acid and vitamin B(12). Pemetrexed is a promising new drug that should make a contribution to solid tumor oncology.
The current state of pemetrexed in ovarian cancer. [2015]Pemetrexed is a multitargeted antifolate drug that has shown benefit in several clinical trials in solid tumors. It is currently approved for the treatment of nonsmall cell lung cancer (NSCLC) and mesothelioma, and is being explored in epithelial ovarian cancer.
Pemetrexed disodium in ovarian cancer treatment. [2015]Current therapies for recurrent ovarian cancer (OC) yield relatively modest improvements in survival. Many drugs are available but recently a renewed interest is addressed on antimetabolite drugs. Pemetrexed (PEM) is a multitargeted antifolate cytotoxic agent mainly used in lung cancer.
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]In an extension of our prior studies in murine tumor models, we examined two new folate analogs in the 10-deaza-aminopterin series for antitumor activity against a group of human tumor xenografts in nude mice. In all three xenograft models studied, MX-1 mammary carcinoma, LX-1 lung carcinoma, and CX-1 colon carcinoma, 10-deaza-aminopterin was minimally active, while methotrexate was inactive. In contrast, against the MX-1 and LX-1 tumors, 10-ethyl, 10-deaza-aminopterin at or near the LD10 dose (2-4.5 mg/kg) given once per day X 5 produced frank regressions. Activity of this analog against the CX-1 tumor was less, but retardation of tumor growth was observed with some minor regressions.