Tazemetostat + Venetoclax for Lymphoma

Overseen By Brittany Hobbie

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Weill Medical College of Cornell University

Must not be taking: CYP3A4 modulators, P-gp inhibitors

Disqualifiers: Cardiovascular impairment, CNS involvement, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 24 months

38 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment for individuals with challenging cases of Non-Hodgkin Lymphoma (NHL) that have returned or resisted standard treatments. It combines two drugs, tazemetostat (a cancer treatment) and venetoclax, to determine the safest and most effective dose while monitoring side effects and efficacy against cancer. Participants will take pills daily and visit the clinic regularly for check-ups. Those who have already tried at least two other treatments for NHL without success might be suitable for this study. 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 it.

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

The trial protocol does not specify if you must stop all current medications, but you cannot use certain medications like moderate or strong CYP3A4 modulators, P-gp inhibitors, or warfarin. Check with the trial team for more details.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that tazemetostat and venetoclax have each been tested separately in patients with lymphoma and are considered safe. However, no studies have examined them together. This trial is the first to assess the safety of this combination for people with relapsed or refractory Non-Hodgkin Lymphoma. As a phase 1 trial, the main goal is to determine the best dose of venetoclax to use with tazemetostat and to understand the side effects when taken together.

Phase 1 trials are the initial step in testing new treatments in humans, so limited safety information is available. The trial is designed to closely monitor participants for any side effects. This approach helps ensure participant safety while researchers learn more about how the treatment works. ^{1 2 3 4}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of tazemetostat and venetoclax for treating lymphoma because it offers a unique approach compared to standard treatments like chemotherapy and radiation. Tazemetostat acts by inhibiting EZH2, an enzyme that plays a role in the growth of cancer cells, while venetoclax targets BCL-2, a protein that helps cancer cells survive. This combination targets two different pathways that contribute to cancer progression, potentially offering a more comprehensive attack on the disease. Additionally, both drugs are taken orally, which can be more convenient for patients compared to traditional intravenous therapies.

What evidence suggests that the combination of tazemetostat and venetoclax could be effective for Non-Hodgkin Lymphoma?

Research has shown that tazemetostat effectively treats follicular lymphoma, a common type of Non-Hodgkin Lymphoma (NHL). It blocks a protein called EZH2, which aids cancer cell growth. Studies have also found venetoclax promising for blood cancers, as it targets and kills certain cancer cells. In this trial, all participants will receive a combination of tazemetostat and venetoclax, which might be more effective against NHL because they attack the cancer in two different ways. While researchers are still gathering specific data on this combination, each drug alone has shown potential in fighting similar types of cancer. ^{1 2 5 6 7}

Who Is on the Research Team?

Lisa Roth, M.D.

Principal Investigator

Weill Medical College of Cornell University

Are You a Good Fit for This Trial?

This trial is for individuals with relapsed/refractory Non-Hodgkin Lymphoma who have had at least one prior treatment and are either post-autologous stem cell transplant or ineligible for it. They must be able to take pills orally, not have a history of certain conditions like major surgery recently, uncontrolled infections, or known allergies to the study drugs.

Inclusion Criteria

My lymphoma has worsened after at least one treatment.

My diagnosis of follicular lymphoma or diffuse large B-cell lymphoma is confirmed by a biopsy.

My condition worsened after a stem cell transplant, or I am not eligible for one.

Exclusion Criteria

I do not have an uncontrolled HIV or HTLV-1 infection.

My CLL has transformed into a more aggressive form.

I cannot swallow pills.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive a combination of tazemetostat and venetoclax with dose escalation to determine the maximum tolerated dose

4 weeks

Regular clinic visits for monitoring

Treatment

Participants receive the study drugs until disease progression or for up to 24 months

24 months

Regular clinic visits for blood work and imaging

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Tazemetostat
• Venetoclax

Trial Overview The trial studies how well tazemetostat and venetoclax work together in treating Non-Hodgkin Lymphoma that has come back or didn't respond to previous treatments. It aims to find the best dose, understand side effects, and see the effect on cancer over up to 24 months with regular clinic visits.

How Is the Trial Designed?

Group I: Tazemetostat and Venetoclax Experimental Treatment 2 Interventions

All participants will receive a combination of oral 800 mg tazemetostat BID and oral venetoclax. Since this is a phase 1 trial, the dose of venetoclax will be determined by the investigators per a sequential dose escalation (3+3). Participants will be provided study drug in the form of pills to take at home. Study participants will need to regularly come to the clinic for blood work, imaging, and to monitor and side effects. Participants may receive study drug until their cancer progresses or for up to 24 months.

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?

Weill Medical College of Cornell University

Lead Sponsor

Trials

1,103

Recruited

1,157,000+

Genentech, Inc.

Industry Sponsor

Trials

1,578

Recruited

569,000+

Ashley Magargee

Genentech, Inc.

Chief Executive Officer since 2024

MBA from Harvard University, BA from Princeton University

Levi Garraway

Genentech, Inc.

Chief Medical Officer since 2021

MD, PhD

Epizyme, Inc.

Industry Sponsor

Trials

34

Recruited

2,800+

Published Research Related to This Trial

Brivaracetam (BRV) was found to be an effective add-on treatment for refractory epilepsy, with 50% responder rates of 36.1% to 45.5% over 15 months in a study of 38 patients who had previously tried an average of 8.9 antiepileptic drugs.

However, the treatment was associated with a high rate of adverse events (60.5% to 85.7%), particularly psychiatric side effects, which were reported more frequently than in previous studies, indicating the need for careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brivaracetam: First Canadian Experience in an Intractable Epilepsy Population. Lafortune, J., Deacon, C., Clément, JF.[2021]

10-Ethyl-10-deazaaminopterin (EDX) was found to be significantly more effective than methotrexate (MTX) in treating various chemoresistant tumors in murine models, showing improved survival rates when administered in a high-dose regimen with delayed low-dose leucovorin (LCV) rescue.

The combination of EDX with a high-dose regimen resulted in 2-3 times greater survival compared to EDX alone, with long-term survival rates of up to 40% in certain tumor types, indicating a promising approach for treating advanced metastatic disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Markedly improved efficacy of edatrexate compared to methotrexate in a high-dose regimen with leucovorin rescue against metastatic murine solid tumors. Sirotnak, FM., Otter, GM., Schmid, FA.[2013]

In a pooled analysis of 149 children aged 4 to <16 years with focal seizures, adjunctive brivaracetam (BRV) was generally well tolerated, with a high incidence of treatment-emergent adverse events (TEAEs) reported in 94% of patients, though most were not severe.

The study indicated that BRV is a viable long-term treatment option for children with epilepsy, as it showed a favorable safety profile and did not result in significant behavioral changes, supporting its approval for use in this age group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerability of adjunctive brivaracetam in children with focal seizures: Interim analysis of pooled data from two open-label trials. Patel, AD., Badalamenti, V., Gasalla, T., et al.[2020]

In a comprehensive analysis of safety data from 1957 patients, adjunctive brivaracetam (BRV) showed a treatment-emergent adverse event (TEAE) incidence of 66.9%, slightly higher than the 62.8% observed with placebo, indicating a generally acceptable safety profile.

The most common TEAEs with BRV included somnolence, headache, dizziness, and fatigue, with psychiatric-related TEAEs occurring in 11.3% of patients, suggesting that while BRV is effective for focal seizures, monitoring for these side effects is important.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerability of adjunctive brivaracetam in epilepsy: In-depth pooled analysis. Brandt, C., Klein, P., Badalamenti, V., et al.[2020]

The glycine site antagonist MRZ 2/576 significantly increased the convulsive threshold in mice, enhancing the anticonvulsant effects of several antiepileptic drugs like carbamazepine and valproate without causing motor impairment or memory deficits.

While MRZ 2/576 improved the efficacy of antiepileptic drugs against maximal electroshock-induced seizures, it did not show a positive interaction in pentetrazole-induced seizures, indicating a selective enhancement of anticonvulsant activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Influence of the antagonist of the glycine site of NMDA receptors, MRZ 2/576, on the anticonvulsant activity of conventional antiepileptic drugs in mice. Makarska-Białek, K., Kamiński, RM., Czuczwar, SJ.[2020]

A new series of compounds designed as anticonvulsants showed 100% efficacy in preventing seizures in mice, with the most potent compounds having effective doses (ED50) significantly lower than traditional treatments like phenobarbital and ethosuximide.

The tested compounds demonstrated no neurotoxicity at maximum doses, indicating a promising safety profile alongside their strong anticonvulsant activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synthesis, molecular modeling studies, and anticonvulsant evaluation of novel 1-((2-hydroxyethyl)(aryl)amino)-N-substituted cycloalkanecarboxamides and their acetate esters. Aboul-Enein, MN., El-Azzouny, AA., Amin, KM., et al.[2019]

A new compound, N-(2,2,3,3-tetramethylcyclopropanecarboxamide)-p-phenyl-sulfonamide, showed strong anticonvulsant activity with an ED(50) value of 26 mg/kg in rat models, indicating its potential effectiveness as an antiepileptic drug.

This compound also demonstrated a high safety margin (PI > 19) compared to existing medications like valproic acid, suggesting it could be a safer alternative for treating epilepsy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synthesis and anticonvulsant activity of aromatic tetramethylcyclopropanecarboxamide derivatives. Shimshoni, JA., Bialer, M., Yagen, B.[2018]

In a study of 41 patients with advanced gastrointestinal carcinoma, the combination of trimetrexate (TMTX), fluorouracil (FU), and leucovorin (LV) showed a partial response rate of 20% in previously treated colorectal cancer patients, indicating potential efficacy for this treatment regimen.

The maximum-tolerated doses were established at 110 mg/m2 for TMTX and 500 mg/m2 for both FU and LV, with manageable toxicity levels, primarily grade 3 or 4 diarrhea in 17% of patients and hypersensitivity reactions in 26%, suggesting that the combination can be safely administered at high doses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trial of sequential trimetrexate, fluorouracil, and high-dose leucovorin in previously treated patients with gastrointestinal carcinoma. Conti, JA., Kemeny, N., Seiter, K., et al.[2017]

In a case series of nine patients, switching from levetiracetam to brivaracetam (BRV) led to a significant increase in carbamazepine-10,11-epoxide (CBZ-E) levels, which is a metabolite of carbamazepine (CBZ).

While three patients experienced clinically relevant symptoms like blurred vision and dizziness due to elevated CBZ-E levels, the majority (six patients) did not report any tolerability issues, suggesting that the impact of CBZ-E may be less significant than previously thought when BRV is used with CBZ.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Is brivaracetam-induced elevation of carbamazepine-epoxide levels common and clinically relevant? - A case series. Steinhoff, BJ., Bacher, M., Blickhan, M., et al.[2021]

In a study involving six neonates with repeated seizures, brivaracetam (BRV) was administered intravenously and showed plasma concentrations consistent with those observed in older children and adults, indicating effective pharmacokinetics in this age group.

BRV was well tolerated among the neonates, with no treatment-emergent adverse events related to the drug reported, suggesting it is a safe option for managing seizures in newborns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and safety of brivaracetam in neonates with repeated electroencephalographic seizures: A multicenter, open-label, single-arm study. Pressler, R., Boylan, G., Dempsey, E., et al.[2023]

MRZ 2/576 demonstrated a clear anticonvulsant effect in mice, with an effective dose (ED50) of 13.71 mg/kg, indicating its potential as a treatment for seizures.

When combined with other antiepileptic drugs like felbamate, oxcarbazepine, and topiramate, MRZ 2/576 significantly enhanced their effectiveness, reducing their required doses, while showing only additive interactions with these drugs in seizure suppression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interactions of MRZ 2/576 with felbamate, lamotrigine, oxcarbazepine and topiramate in the mouse maximal electroshock-induced seizure model. Luszczki, JJ., Danysz, W., Czuczwar, SJ.[2018]

A series of stiripentol analogues were synthesized and tested for their anticonvulsant properties, with two compounds (7h and (±)-13b) showing significantly improved efficacy compared to stiripentol itself, indicated by lower ED(50) values of 87 mg/kg and 110 mg/kg, respectively.

The study also included neurotoxicity evaluations, suggesting that these new analogues may offer safer alternatives for treating seizures, as they demonstrated effective anticonvulsant activity with potentially reduced side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Design and synthesis of novel stiripentol analogues as potential anticonvulsants. Aboul-Enein, MN., El-Azzouny, AA., Attia, MI., et al.[2012]

In a phase I trial involving 18 patients with advanced cancer, trimetrexate (TMTX) was administered as a continuous 5-day intravenous infusion, revealing a maximum tolerated dose of 50 mg/m2, with dose-limiting toxicities including neutropenia and thrombocytopenia.

Although no objective tumor responses were observed, six patients experienced stable disease, leading to a recommended phase II dose of 40 mg/m2 for further testing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I study of trimetrexate (NSC 352122) administered by 5-day continuous intravenous infusion. Bishop, JF., Raghavan, D., Olver, IN., et al.[2019]

Trimetrexate (TMTX) shows promising efficacy in treating relapsed T-cell lymphoma, achieving an overall response rate of 45% in a study of 20 patients, with one complete response and eight partial responses.

The treatment was associated with acceptable toxicity levels, with serious side effects like grade 3 or 4 mucositis occurring in only 4% of patients, suggesting that TMTX could be a viable option for patients resistant to methotrexate.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trimetrexate in relapsed T-cell lymphoma with skin involvement. Sarris, AH., Phan, A., Duvic, M., et al.[2016]

In a study involving 365 patients with advanced colorectal cancer, the combination of trimetrexate (TMTX) with 5-fluorouracil (5-FU) and leucovorin (LV) significantly improved progression-free survival (PFS) to 5.4 months compared to 4.1 months with 5-FU/LV alone.

The addition of TMTX did not increase toxicity or negatively impact quality of life, making it a promising first-line treatment option for advanced colorectal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trimetrexate as biochemical modulator of 5-fluorouracil/leucovorin in advanced colorectal cancer: final results of a randomised European study. Punt, CJ., Keizer, HJ., Douma, J., et al.[2020]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05618366

Tazemetostat and Venetoclax in Relapsed/Refractory Non- ... The purpose of this study is to evaluate the safety of the combination of tazemetostat and venetoclax in patients with relapsed/refractory (R/R) Follicular ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11035230/

457 A Phase I Trial of Tazemetostat and Venetoclax ... OBJECTIVES/GOALS: Primary Objective: To evaluate the safety of venetoclax plus tazemetostat in patients with relapsed and refractory (R/R) Follicular ...

3. ashpublications.org ashpublications.org/bloodadvances/article/5/8/2256/475823/Treating-lymphoma-is-now-a-bit-EZ-er

Treating lymphoma is now a bit EZ-er | Blood Advances Tazemetostat represents the first epigenetic therapy approved for the treatment of follicular lymphoma (FL). It inhibits the activity of the enhancer of zeste ...

4. ascopubs.org ascopubs.org/doi/10.1200/EDBK_320117

Incorporating Novel Targeted and Immunotherapeutic ... The novel targeted agent tazemetostat, an inhibitor of EZH2, is safe and effective in patients with relapsed/refractory follicular lymphoma.

5. aacrjournals.org aacrjournals.org/mct/article/13/4/842/91698/Selective-Inhibition-of-EZH2-by-EPZ-6438-Leads-to

Selective Inhibition of EZH2 by EPZ-6438 Leads to Potent ... Selective inhibition of EZH2 by EPZ-6438 leads to potent antitumor activity in EZH2-mutant non-Hodgkin lymphoma.

6. jcto.weill.cornell.edu jcto.weill.cornell.edu/open_clinical_trials/phase-i-trial-of-tazemetostat-in-combination-with-venetoclax-in-patients-with-relapsedrefractory-non-hodgkin-lymphoma

Phase I Trial of Tazemetostat in Combination with ... Both of these medications have been studied in patients with lymphoma and have been shown to be safe, however, they have not been used in combination. All ...

7. withpower.com withpower.com/trial/tazemetostat-venetoclax-for-lymphoma-db48c

Tazemetostat + Venetoclax for Lymphoma What safety data is available for the combination of Tazemetostat and Venetoclax in treating lymphoma? The provided research does not contain any safety data ...