Tazemetostat + Immunotherapy for Cancer

Recruiting in Palo Alto (17 mi)

+1 other location

Overseen by Susan Chi, MD

Age: < 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: Susan Chi

Must not be taking: CYP3A4 agents

Disqualifiers: HIV, Hepatitis B, Hepatitis C, others

No Placebo Group

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This trial tests a combination of three drugs to treat children with specific hard-to-treat cancers. The drugs work by blocking cancer growth and boosting the immune system. The study aims to find the safest dose and see if the combination is effective.

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.

What data supports the effectiveness of the drug combination Tazemetostat and Immunotherapy for Cancer?

Research shows that the combination of nivolumab (Opdivo) and ipilimumab (Yervoy), which are part of the immunotherapy drugs mentioned, has demonstrated durable and long-term effectiveness in treating advanced non-small cell lung cancer (NSCLC). This suggests potential effectiveness when combined with other treatments like Tazemetostat. ^{1 2 3 4 5}

Is the combination of Tazemetostat and immunotherapy safe for humans?

Tazemetostat has been studied for safety in various cancers, including epithelioid sarcoma and B-cell lymphoma, and is generally considered safe when used as directed. It has shown a lower risk for safety issues compared to some other cancer treatments in certain studies. ^{1 6 7 8 9}

What makes the drug combination of Tazemetostat, Ipilimumab, and Nivolumab unique for cancer treatment?

This drug combination is unique because it combines Tazemetostat, which targets specific genetic changes in cancer cells, with Ipilimumab and Nivolumab, which are immune checkpoint inhibitors that help the immune system attack cancer. This approach may offer a novel way to enhance the body's immune response against cancer compared to traditional chemotherapy. ^{1 2 3 4 10}

Research Team

Susan Chi, MD

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

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

Trial Timeline

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

Treatment Details

Interventions

• Ipilimumab (Checkpoint Inhibitor)
• Nivolumab (Checkpoint Inhibitor)
• Tazemetostat (Histone Methyltransferase Inhibitor)

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.

Participant Groups

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

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

Findings from Research

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 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]

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]

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]

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]

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]

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 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]

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]

References

1. England 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. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Nivolumab/Ipilimumab Combo Yields Durable Efficacy in Advanced NSCLC. [2021]

3. United States pubmed.ncbi.nlm.nih.gov

More Benefits for Checkpoint Inhibitors in NSCLC. [2020]

4. England pubmed.ncbi.nlm.nih.gov

The safety of atezolizumab plus chemotherapy for the treatment of metastatic lung cancer. [2022]

5. England 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. [2022]

6. New Zealand pubmed.ncbi.nlm.nih.gov

Tazemetostat: First Approval. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Phase 1 study of tazemetostat in Japanese patients with relapsed or refractory B-cell lymphoma. [2021]

8. United States pubmed.ncbi.nlm.nih.gov

Initial testing (stage 1) of tazemetostat (EPZ-6438), a novel EZH2 inhibitor, by the Pediatric Preclinical Testing Program. [2022]

9. United States 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. [2022]

10. England 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;. [2022]