Tazemetostat + Immunotherapy for Cancer

Recruiting at 2 trial locations

Overseen By Susan Chi, MD

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Susan Chi

Must not be taking: CYP3A4 agents

Disqualifiers: HIV, Hepatitis B, Hepatitis C, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 2 years

49 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of three drugs—Tazemetostat, Nivolumab, and Ipilimumab (an immunotherapy drug)—to determine their effectiveness against certain rare and challenging cancers. These cancers, such as malignant rhabdoid tumors and epithelioid sarcoma, often lack proteins that the treatment might target. Suitable participants are those diagnosed with these tumors who have completed their initial cancer treatment. As a Phase 1, Phase 2 trial, this research aims to understand how the treatment works in people and measure its effectiveness in an initial, smaller group.

Will I have to stop taking my current medications?

The trial requires that you stop taking any drugs that strongly affect CYP3A4, a liver enzyme, starting 14 days before the first dose of tazemetostat and continuing until the end of the study. If you are on such medications, you will need to discuss alternatives with your doctor.

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

Research shows that the combination of tazemetostat, nivolumab, and ipilimumab is under study to assess its safety and effectiveness for treating certain tumors. Previous studies have examined these drugs both individually and in combination.

Tazemetostat has approval for some cancers, indicating a well-understood safety profile. However, its use with nivolumab and ipilimumab remains under investigation. Nivolumab and ipilimumab effectively treat various cancers, though they can cause side effects.

A study on nivolumab and ipilimumab found them generally well-tolerated, with manageable side effects like tiredness, rash, and diarrhea. Serious side effects can occur but are less common.

While some safety information exists for tazemetostat, nivolumab, and ipilimumab individually, the combination is still under testing to determine the safest usage. This ongoing research aims to ensure participant safety, though unknown risks may exist. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Tazemetostat, Nivolumab, and Ipilimumab for cancer treatment because it combines the power of targeted therapy and immunotherapy. Tazemetostat is unique because it targets the EZH2 enzyme, which plays a role in cancer cell growth, unlike traditional chemotherapy that targets all rapidly dividing cells. Nivolumab and Ipilimumab are immune checkpoint inhibitors that help the immune system recognize and attack cancer cells, offering a different approach compared to conventional therapies that often suppress the immune response. This combination aims to enhance the body's natural defenses against cancer, potentially leading to more effective and longer-lasting results.

What evidence suggests that this trial's treatments could be effective for cancer?

Research has shown that a combination of three drugs—tazemetostat, nivolumab, and ipilimumab—may effectively treat tumors lacking certain proteins called INI-1 or SMARCA4. Tazemetostat blocks a protein known as EZH2, which can stop cancer cells from growing. Nivolumab and ipilimumab, types of immunotherapy, help the body's immune system find and fight cancer cells. Early results suggest that this combination might improve survival rates in aggressive cancers, such as brain cancers or rhabdoid tumors. These findings offer hope for treating hard-to-treat tumors. Participants in this trial will receive this combination therapy in various treatment arms to evaluate its effectiveness across different cancer types. ^{1 2 4 6 7}

Who Is on the Research Team?

Susan Chi, MD

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

This trial is for young patients aged 6 months to 21 years with specific tumors lacking INI1 or SMARCA4 proteins. Eligible participants must have completed prior treatments, be in good health otherwise, and agree to contraception if applicable. Those with uncontrolled illnesses, organ transplants, pregnancy, certain infections like HIV or hepatitis B/C, autoimmune diseases requiring treatment within the past year, or a history of allergic reactions to similar compounds are excluded.

Inclusion Criteria

My brain tumor lacks certain proteins (INI1 or SMARCA4).

I am mostly able to care for myself and carry out daily activities.

I agree to use birth control for 5 months after my last dose of treatment.

Exclusion Criteria

Subjects who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study are not eligible

I have not received a live vaccine in the last 30 days.

Subjects who have received prior solid organ transplantation are not eligible

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a combination of tazemetostat, nivolumab, and ipilimumab for up to 2 years, as long as there is benefit or no serious side effects

Up to 2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment, with follow-up visits approximately every 6 months

Up to 3 years

What Are the Treatments Tested in This Trial?

Interventions

• Ipilimumab
• Nivolumab
• Tazemetostat

Trial Overview

The study tests a combination of three drugs: Tazemetostat (TAZVERIK), Nivolumab (OPDIVO), and Ipilimumab (YERVOY) as potential treatments for malignant rhabdoid tumor and other related conditions that lack INI1/SMARCA4 proteins. The effectiveness of this drug trio will be evaluated on different patient groups based on their disease status.

How Is the Trial Designed?

Group I: Phase I b: DOSE ESCALATION (STRATUM B, NON-ATRT, NON-CNS) Experimental Treatment 3 Interventions

Part 1 will be two concurrent "rolling six" phase 1 studies starting at a different tazemetostat dose for each stratum), with one dose escalation and one dose de-escalation planned. All subjects will receive the same nivolumab and ipilimumab doses and dosing schedule

Group II: Phase I a: DOSE ESCALATION (STRATUM A, ATRT and primary CNS malignant tumor, INI/SMARCA4-deficient) Experimental Treatment 3 Interventions

Part 1 will be two concurrent "rolling six" phase 1 studies starting at a different tazemetostat dose for each stratum), with one dose escalation and one dose de-escalation planned. All subjects will receive the same nivolumab and ipilimumab doses and dosing schedule

Group III: EXP B3: TAZEMETOSTAT + NIVOLUMAB + IPILIMUMAB DOSE EXPANSION (SUBSTRATA B3) Experimental Treatment 3 Interventions

Once the MTD or RP2D of the combination is determined for each stratum, the Part 2 portion will open for that stratum, with subjects from Part 1 who are treated at the RP2D to be counted towards the enrollment numbers for Part 2. Part 2 will consist of 3 substrata per stratum based on their disease status

Group IV: EXP B2: TAZEMETOSTAT + NIVOLUMAB + IPILIMUMAB DOSE EXPANSION (SUBSTRATA B2) Experimental Treatment 3 Interventions

Once the MTD or RP2D of the combination is determined for each stratum, the Part 2 portion will open for that stratum, with subjects from Part 1 who are treated at the RP2D to be counted towards the enrollment numbers for Part 2. Part 2 will consist of 3 substrata per stratum based on their disease status

Group V: EXP B1: TAZEMETOSTAT + NIVOLUMAB + IPILIMUMAB DOSE EXPANSION (SUBSTRATA B1) Experimental Treatment 3 Interventions

Once the MTD or RP2D of the combination is determined for each stratum, the Part 2 portion will open for that stratum, with subjects from Part 1 who are treated at the RP2D to be counted towards the enrollment numbers for Part 2. Part 2 will consist of 3 substrata per stratum based on their disease status

Group VI: EXP A3: TAZEMETOSTAT + NIVOLUMAB + IPILIMUMAB DOSE EXPANSION (SUBSTRATA A3) Experimental Treatment 3 Interventions

Once the MTD or RP2D of the combination is determined for each stratum, the Part 2 portion will open for that stratum, with subjects from Part 1 who are treated at the RP2D to be counted towards the enrollment numbers for Part 2. Part 2 will consist of 3 substrata per stratum based on their disease status

Group VII: EXP A2: TAZEMETOSTAT + NIVOLUMAB + IPILIMUMAB DOSE EXPANSION (SUBSTRATA A2) Experimental Treatment 3 Interventions

Once the MTD or RP2D of the combination is determined for each stratum, the Part 2 portion will open for that stratum, with subjects from Part 1 who are treated at the RP2D to be counted towards the enrollment numbers for Part 2. Part 2 will consist of 3 substrata per stratum based on their disease status

Group VIII: EXP A1: TAZEMETOSTAT + NIVOLUMAB + IPILIMUMAB DOSE EXPANSION (SUBSTRATA A1) Experimental Treatment 3 Interventions

Once the MTD or RP2D of the combination is determined for each stratum, the Part 2 portion will open for that stratum, with subjects from Part 1 who are treated at the RP2D to be counted towards the enrollment numbers for Part 2. Part 2 will consist of 3 substrata per stratum based on their disease status

Ipilimumab is already approved in United States, European Union for the following indications:

Approved in United States as Yervoy for:

• Advanced melanoma
• Stage III unresectable melanoma
• Stage IV metastatic melanoma

Approved in European Union as Yervoy for:

• Advanced melanoma
• Stage III unresectable melanoma
• Stage IV metastatic melanoma

Who Is Running the Clinical Trial?

Susan Chi

Lead Sponsor

Trials

1

Recruited

50+

Susan Chi, MD

Lead Sponsor

Trials

1

Recruited

50+

Epizyme, Inc.

Industry Sponsor

Trials

34

Recruited

2,800+

Bristol-Myers Squibb

Industry Sponsor

Trials

2,731

Recruited

4,127,000+

Headquarters

New York City, USA

Known For

Oncology & Cardiovascular

Top Products

Eliquis, Opdivo, Revlimid, Orencia

Christopher Boerner

Bristol-Myers Squibb

Chief Executive Officer since 2023

PhD in Business Administration from the Haas School of Business, University of California, Berkeley; BA in Economics and History from Washington University in St. Louis

Deepak L. Bhatt

Bristol-Myers Squibb

Chief Medical Officer since 2024

MD from Yale University; MSc in Clinical Epidemiology from the University of Pennsylvania

Published Research Related to This Trial

In the CITYSCAPE trial involving 275 patients with chemotherapy-naive, PD-L1-positive non-small-cell lung cancer, the combination of tiragolumab and atezolizumab resulted in a significantly higher objective response rate (31.3% vs. 16.2%) and improved median progression-free survival (5.4 months vs. 3.6 months) compared to placebo plus atezolizumab.

The safety profile of tiragolumab plus atezolizumab was generally similar to that of atezolizumab alone, with serious treatment-related adverse events occurring in 21% of patients in the combination group, indicating that this combination therapy is well tolerated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tiragolumab plus atezolizumab versus placebo plus atezolizumab as a first-line treatment for PD-L1-selected non-small-cell lung cancer (CITYSCAPE): primary and follow-up analyses of a randomised, double-blind, phase 2 study. Cho, BC., Abreu, DR., Hussein, M., et al.[2022]

Nivolumab and atezolizumab, both checkpoint inhibitors, have been shown to be effective as second-line therapies for patients with non-small cell lung cancer, based on presentations from three research teams at the European Cancer Congress in 2015.

These findings suggest that checkpoint inhibitors can provide a valuable treatment option for patients who have not responded to first-line therapies, potentially improving outcomes in this challenging cancer type.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

More Benefits for Checkpoint Inhibitors in NSCLC. [2020]

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]

Atezolizumab, a monoclonal antibody targeting PD-L1, has shown significant improvements in progression-free and overall survival in patients with advanced non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC) when combined with chemotherapy, as demonstrated in the IMpower studies.

The safety profile of atezolizumab in combination with chemotherapy is acceptable, with common immune-related adverse events including rash (18-28%), hypothyroidism (8-15%), and hepatitis (5-17%), consistent with its known effects as a single agent, indicating no new safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The safety of atezolizumab plus chemotherapy for the treatment of metastatic lung cancer. Manzo, A., Carillio, G., Montanino, A., et al.[2022]

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]

Nivolumab plus ipilimumab showed durable and long-term efficacy in treating advanced non-small cell lung cancer (NSCLC) compared to chemotherapy, regardless of tumor PD-L1 expression levels.

These findings are based on updated results from part 1 of the phase 3 CheckMate 227 trial, indicating that this combination therapy could be a more effective frontline treatment option for NSCLC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab/Ipilimumab Combo Yields Durable Efficacy in Advanced NSCLC. Kahl, KL.[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]

Tazemetostat demonstrated a significantly lower risk of grade ≥3 treatment-emergent adverse events compared to several PI3K inhibitors (idelalisib, duvelisib, copanlisib, umbralisib), indicating a better safety profile for patients with relapsed/refractory follicular lymphoma.

The objective response rate (ORR) for tazemetostat was comparable to that of the PI3K inhibitors, suggesting that while tazemetostat is safer, it maintains similar efficacy in treating this type of lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Matching-Adjusted Indirect Comparison of Single-Arm Trials in Patients with Relapsed or Refractory Follicular Lymphoma Who Received at Least Two Prior Systemic Treatments: Tazemetostat was Associated with a Lower Risk for Safety Outcomes Versus the PI3-Kinase Inhibitors Idelalisib, Duvelisib, Copanlisib, and Umbralisib. Proudman, D., Nellesen, D., Gupta, D., et al.[2022]

Atezolizumab combined with chemotherapy showed promising efficacy in treating advanced, treatment-naïve non-small-cell lung cancer (NSCLC), with overall response rates of 36% to 68% across different chemotherapy regimens in a study of 76 patients.

The treatment was generally well tolerated, although common severe side effects included neutropenia and anemia, indicating a manageable safety profile for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term survival follow-up of atezolizumab in combination with platinum-based doublet chemotherapy in patients with advanced non-small-cell lung cancer. Liu, SV., Camidge, DR., Gettinger, SN., et al.[2022]

In a phase 1 study involving 115 patients with advanced solid tumors, the combination of vibostolimab and pembrolizumab was well tolerated, with no dose-limiting toxicities reported and manageable treatment-related adverse events (TRAEs) occurring in 62% of patients receiving the combination therapy.

The combination therapy showed a confirmed objective response rate (ORR) of 26% in anti-PD-1/PD-L1-naive non-small-cell lung cancer (NSCLC) patients, indicating potential antitumor activity, while monotherapy had a low ORR of 0-3% in both naive and refractory NSCLC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-in-human phase 1 study of the anti-TIGIT antibody vibostolimab as monotherapy or with pembrolizumab for advanced solid tumors, including non-small-cell lung cancer&#9734;. Niu, J., Maurice-Dror, C., Lee, DH., et al.[2022]

Citations

1.

ascopubs.org

ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.TPS10077

TAZNI: A phase I/II combination trial of tazemetostat with ...

TPS10077. Background: The prognosis for children with INI1-negative cancers is dismal, with historic 5-year overall survival <30%.

2.

clinicaltrials.gov

clinicaltrials.gov/study/NCT05407441

Tazemetostat+Nivo/Ipi in INI1-Neg/SMARCA4-Def Tumors

This trial is studying the combination of tazemetostat, nivolumab, and ipilimumab in two parts: Part 1: To find the safest dose of these three study drugs in ...

3.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC9929860/

Recent progress and novel approaches to treating atypical ...

While recent clinical trial results show that this tumor is curable, outcomes are still poor compared to other central nervous system embryonal tumors. We here ...

4.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC11845573/

Relapse-free survival in a pediatric patient with recurrent ...

We describe a pediatric patient with multiply relapsed melanoma harboring an EZH2 mutation, who achieved a prolonged relapse-free survival following adjuvant ...

5.

clinicaltrials.gov

clinicaltrials.gov/study/NCT05407441?term=AREA%5BConditionSearch%5D(%22Rhabdoid%20Tumor%20Predisposition%20Syndrome%201%22)%20AND%20AREA%5BInterventionSearch%5D(%22Nivolumab%22)&rank=2

Tazemetostat+Nivo/Ipi in INI1-Neg/SMARCA4-Def Tumors

This trial is studying the combination of tazemetostat, nivolumab, and ipilimumab in two parts: Part 1: To find the safest dose of these three study drugs ...

6.

asco.org

asco.org/abstracts-presentations/ABSTRACT377538

Update on phase 1 study of tazemetostat, an enhancer ...

Secondary endpoints included safety/tolerability, duration of response (DOR), progression-free survival (PFS), and overall survival. Selected exploratory flow ...

7.

opdivohcp.com

opdivohcp.com/safety/nsclc/opdivo-yervoy

OPDIVO® (nivolumab) + YERVOY® (ipilimumab) Safety ...

Five-year survival outcomes with nivolumab plus ipilimumab versus chemotherapy as first-line treatment for metastatic non-small-cell lung cancer in Checkmate ...