Tazemetostat for Solid Cancers

Overseen By Julie C Martin, DNP

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Prisma Health-Upstate

Must not be taking: CYP3A4 inducers/inhibitors

Disqualifiers: Epithelioid sarcoma, CNS metastases, 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: 12 months

40 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests tazemetostat, a drug targeting a specific protein involved in cancer growth, to determine its effectiveness for people with certain solid tumors. It focuses on tumors with a specific genetic mutation called ARID1A in patients who have not responded to other treatments. The trial suits those with advanced or spreading tumors who have not found success with standard therapies and are ready to explore new options. As a Phase 2 trial, the research measures the treatment's effectiveness in an initial, smaller group of participants.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot take medications that are known potent CYP3A4 inducers/inhibitors, like St. John's wort. There are also specific time requirements between prior anticancer therapies and starting the trial drug.

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

Research has shown that tazemetostat is generally well-tolerated. In studies, tazemetostat, which blocks a protein called EZH2 that can promote tumor growth, has shown promising results. The FDA has already approved it for certain cancers, such as epithelioid sarcoma and B-cell non-Hodgkin's lymphoma, indicating it is safe for these conditions.

In studies, some patients experienced side effects, but most were mild to moderate. Common side effects included fatigue, nausea, and loss of appetite. Serious side effects were less common. Since tazemetostat is already in a phase 2 trial for other conditions, it has passed earlier safety tests. This suggests it is generally safe, but ongoing studies will help confirm this for new uses, such as cancers with ARID1A mutations. ^{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 the growth of certain solid cancers. Unlike standard treatments such as chemotherapy, which attack both healthy and cancerous cells, Tazemetostat offers a more targeted approach, potentially reducing side effects. Researchers are excited about this treatment because it opens up new possibilities for patients with cancers that have limited effective treatment options.

What evidence suggests that tazemetostat might be an effective treatment for ARID1A mutated malignancies?

Research has shown that tazemetostat, a cancer drug under investigation in this trial, holds potential for treating certain solid tumors. It blocks a protein called EZH2, which can promote cancer growth. Tazemetostat proved effective in patients with B-cell non-Hodgkin's lymphoma and epithelioid sarcomas. Positive outcomes also appeared in patients with tumors lacking INI1 or SMARCA4. Specifically, those with EZH2 mutations had a response rate of 69%, compared to 35% in those without the mutation. This suggests tazemetostat may be particularly effective for cancers with specific genetic changes. ^{3 4 6 7 8}

Who Is on the Research Team?

Ki Chung, MD

Principal Investigator

Prisma Health

Are You a Good Fit for This Trial?

This trial is for adults with advanced or metastatic solid tumors that have an ARID1A mutation, excluding those with epithelioid sarcoma. Participants must have tried other treatments without success and should not be pregnant, breastfeeding, or have had major surgery recently. They need to be able to take oral medication and not have a history of certain cancers or severe heart conditions.

Inclusion Criteria

I can take care of myself and am up and about more than half of my waking hours.

My condition worsened after treatment or no standard treatment is available for me.

My kidney function is good, with creatinine below 2.0 or clearance above 35 mL/min.

Exclusion Criteria

I do not have epithelioid sarcoma.

I need steroids for my uncontrolled brain metastases.

Are unwilling to exclude Seville oranges, grapefruit juice, AND grapefruit from their diet

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive tazemetostat 800 mg orally twice daily in continuous 28-day cycles

12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

What Are the Treatments Tested in This Trial?

Interventions

• Tazemetostat

Trial Overview The study tests Tazemetostat, an FDA-approved drug thought to benefit patients with specific tumor mutations by inhibiting a protein called EZH2. The goal is to see if this drug can provide significant clinical benefits in malignancies associated with the ARID1A mutation.

How Is the Trial Designed?

Group I: Tazemetostat Experimental Treatment 1 Intervention

tazemetostat 800 mg po twice daily in continuous 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?

Prisma Health-Upstate

Lead Sponsor

Trials

91

Recruited

47,500+

Ipsen

Industry Sponsor

Trials

358

Recruited

74,600+

David Loew

Ipsen

Chief Executive Officer since 2020

BA in Business Administration and MBA from the University of St. Gallen, Switzerland

Sandra Silvestri

Ipsen

Chief Medical Officer since 2023

MD, PhD

Epizyme, Inc.

Industry Sponsor

Trials

34

Recruited

2,800+

Published Research Related to This Trial

Pemetrexed is an effective treatment for relapsed or chemotherapy-refractory non-small cell lung cancer (NSCLC), showing similar response and survival rates to taxotere but with less toxicity.

When combined with platinum analogs or other chemotherapy agents like gemcitabine or vinorelbine, pemetrexed produces equivalent responses and overall survival outcomes, suggesting it is a viable option in NSCLC treatment regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of pemetrexed in non-small cell lung cancer. Longo-Sorbello, GS., Chen, B., Budak-Alpdogan, T., et al.[2022]

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 trial involving 17 patients with advanced hepatocellular carcinoma, edatrexate showed minimal therapeutic efficacy, with no complete or partial responses and only two minor responses lasting less than 12 weeks.

While some patients experienced a decrease in serum alpha-fetoprotein levels, indicating a potential biological effect, the treatment was associated with significant grade 3 and 4 toxicities, including granulocytopenia and anemia, raising concerns about its safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of edatrexate in patients with advanced hepatocellular carcinoma. Pazdur, R., Moore, DF., Bready, B., et al.[2020]

Pemetrexed is an effective cytotoxic agent approved for first-line treatment of non-small cell lung cancer (NSCLC) in combination with cisplatin, showing promise in phase II and III trials.

The toxicity profile of pemetrexed is comparable to other NSCLC treatments, making it a safe option for patients, and its use in postinduction maintenance therapy is currently being evaluated in a phase III study.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pemetrexed as first-line therapy for non-squamous non-small cell lung cancer. Ricciardi, S., Tomao, S., de Marinis, F.[2021]

Tiragolumab, a TIGIT inhibitor, shows promise in treating solid cancers, particularly non-small cell lung cancer, based on results from phase I and II trials.

The combination of tiragolumab with the PD-L1 inhibitor atezolizumab has demonstrated statistically significant efficacy in multiple solid tumors, suggesting a potential new treatment strategy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tiragolumab Impresses in Multiple Trials. [2021]

MZ3 demonstrated strong anti-cancer activity against six leukemia cell lines, including those resistant to other drugs, indicating its potential as an effective treatment option.

The mechanism of MZ3's cytotoxicity involves inducing apoptosis through the mitochondrial pathway, characterized by DNA fragmentation, increased reactive oxygen species, and activation of caspase-3, which was confirmed in both cell cultures and a SCID mouse model of leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MZ3 induces apoptosis in human leukemia cells. Fang, L., He, Q., Hu, Y., et al.[2012]

Serdemetan, a novel compound, shows promise as a radiosensitizer in human cancer cell lines, enhancing the effectiveness of radiation therapy, particularly in p53 wild-type cells, with sensitivity-enhancement ratios of 1.18 and 1.36 in H460 and A549 cells, respectively.

In vivo studies demonstrated that Serdemetan significantly increased tumor growth delay, with dose enhancement factors of 1.9 for H460 tumors and 1.6 for A549 tumors, indicating its potential to improve cancer treatment outcomes when used alongside radiation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical assessment of JNJ-26854165 (Serdemetan), a novel tryptamine compound with radiosensitizing activity in vitro and in tumor xenografts. Chargari, C., Leteur, C., Angevin, E., et al.[2022]

The Phase Ia study of OBP-801, a class I HDAC inhibitor, involved 17 adult patients with advanced solid tumors and primarily focused on assessing safety, revealing that the drug was generally well-tolerated with no dose-limiting toxicity at the lowest dose of 1.0 mg/m2.

Among the 8 evaluable patients, 37.5% achieved stable disease, indicating some potential efficacy, but further studies are necessary to fully understand the drug's effectiveness, particularly at the 1.0 mg/m2 dose.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase Ia dose escalation study of OBP-801, a cyclic depsipeptide class I histone deacetylase inhibitor, in patients with advanced solid tumors. Heath, EI., Weise, A., Vaishampayan, U., et al.[2022]

MZ3, a novel compound derived from Combretastatin A-4, effectively induces cell cycle arrest and apoptosis in K562 leukemia cells, demonstrating its potential as a targeted treatment for leukemia.

The mechanism of action involves increasing cyclin B1 levels while decreasing cdc2 and cdc25C, leading to mitochondrial pathway activation and apoptosis through caspase-9 and caspase-3, alongside inhibition of microtubule assembly.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MZ3 can induce G2/M-phase arrest and apoptosis in human leukemia cells. Fang, L., Shen, L., Fang, Y., et al.[2021]

New vorinostat analogs with a benzoxazole ring have been developed, showing similar or improved potency against various human cancer cell lines compared to vorinostat, particularly compound 12 (GK601) with IC50 values of 1.2-2.1 μM.

Compound 12 also effectively inhibited key enzymes (HDAC1, HDAC2, and HDAC6) involved in cancer progression, demonstrating its potential as a promising antitumor agent, especially against colon cancer cell lines related to pseudomyxoma peritonei.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synthesis of benzoxazole-based vorinostat analogs and their antiproliferative activity. Mantzourani, C., Gkikas, D., Kokotos, A., et al.[2021]

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]

Pemetrexed is an effective antifolate agent approved for treating malignant pleural mesothelioma (MPM) and metastatic non-small cell lung cancer (NSCLC), with its pharmacology and mechanism of action compared favorably to methotrexate.

Premedication with steroids and vitamin supplements can reduce the side effects of pemetrexed, making it a safer option for patients, and it should be considered a standard treatment for unresectable MPM and recurrent metastatic NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pemetrexed, a novel antifolate therapeutic alternative for cancer chemotherapy. Villela, LR., Stanford, BL., Shah, SR.[2015]

The new folate analog 10-ethyl-10-deaza-aminopterin (10EdAM) is as effective as methotrexate (MTX) in inhibiting dihydrofolate reductase but is better transported and accumulates more in tumor cells, leading to greater cytotoxic effects.

In preclinical studies, 10EdAM demonstrated superior efficacy against several murine tumors and human tumor xenografts, achieving complete regressions in 10% to 40% of cases, particularly in mammary and colon carcinomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

10-Ethyl-10-deaza-aminopterin: structural design and biochemical, pharmacologic, and antitumor properties. Sirotnak, FM., Schmid, FA., Samuels, LL., et al.[2013]

In a mouse melanoma model, the novel drugs BZA1 and BZA2 demonstrated significant tumor growth delay comparable to the established drug dacarbazine, indicating their potential as effective melanoma treatments.

BZA2, in particular, may serve as an alternative treatment for melanoma patients who do not respond to dacarbazine, with a similar side effect profile but lower toxicity compared to BZA1.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alkylating benzamides with melanoma cytotoxicity: experimental chemotherapy in a mouse melanoma model. Wolf, M., Eskerski, H., Bauder-Wüst, U., et al.[2013]

A modified ChemoFx drug response marker protocol successfully allowed for the evaluation of pemetrexed's anticancer activity in 65 ex vivo lung cancer specimens, overcoming challenges posed by folate interference in standard culture media.

The study found that only 6.2% of lung specimens were classified as responsive to pemetrexed, suggesting that ChemoFx evaluation could help predict patient responses to treatment, potentially avoiding ineffective chemotherapy and its associated side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adaptation of a chemosensitivity assay to accurately assess pemetrexed in ex vivo cultures of lung cancer. Suchy, SL., Landreneau, RJ., Schuchert, MJ., et al.[2021]

Citations

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Phase II Study of Tazemetostat in Solid Tumors Harboring ... ... cancers where they are purported to play a causal role in malignancies. Tazemetostat has been shown to produce durable tumor responses in patients with B ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37228094/

Tazemetostat for tumors harboring SMARCB1/SMARCA4 or ... National Cancer Institute (U.S.); Nuclear Proteins; Rhabdoid Tumor* / diagnosis; Rhabdoid Tumor* / drug therapy; Rhabdoid Tumor* / genetics ...

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

Multi-Discipline Review - accessdata.fda.gov ... trial of tazemetostat in patients with various tumor types. The Applicant submitted the efficacy and safety results of Cohort 5, which ...

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Tazverik Receives FDA Approval as First Treatment ... Kidney Cancer, Leukemia/Lymphoma, Liver Cancer, Lung Cancer, Melanoma, Multi-site Cancers, Multiple Myeloma, Myelodysplastic Syndrome, Myeloproliferative ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8955562/

Tazemetostat: EZH2 Inhibitor - PMC The ORR was 69% in EZH2 mutant patients, compared with a response rate of 35% in the EZH2 WT cohort. Reduction in tumor volume was seen with 98% of the mutant ...

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TAZVERIK (tazemetostat) - accessdata.fda.gov The safety of TAZVERIK ... The major efficacy outcome measures were confirmed overall response rate (ORR) according to Response Evaluation Criteria in Solid ...

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Efficacy in Advanced Epithelioid Sarcoma Demonstrated efficacy of TAZVERIK® (tazemetostat) as first line of systemic therapy and in later lines in advanced epithelioid sarcoma patients.

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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.