Tazemetostat + PD-1 Blockade for Non-Small Cell Lung Cancer

Not yet recruiting at 1 trial location

Overseen By Quillan Huang, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: VA Office of Research and Development

Must not be taking: CYP3A4 inducers/inhibitors

Disqualifiers: Neuroendocrine cancer, Cerebral metastases, Autoimmune disease, HIV, 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: 3

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of drugs, pembrolizumab and tazemetostat, to determine if they can better treat advanced non-small cell lung cancer that has worsened after previous treatments. Pembrolizumab boosts the immune system to fight cancer, while tazemetostat targets a specific protein involved in cancer growth. People with advanced non-small cell lung cancer that has not responded well to other treatments might be suitable for this trial. Participants will receive both drugs to assess if this combination can effectively slow or stop cancer progression. 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, offering participants a chance to contribute to groundbreaking cancer treatment advancements.

Do I need to stop my current medications to join the trial?

The trial does not specify if you need to stop taking your current medications. However, you cannot take medications that strongly affect the liver enzyme CYP3A4, like certain antibiotics or herbal supplements such as St. John's wort. It's best to discuss your current medications with the trial team.

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

Research has shown that using tazemetostat with pembrolizumab is generally safe and well-tolerated. In earlier studies, patients taking an 800 mg dose of tazemetostat with pembrolizumab did not experience serious safety problems. The most common side effect was a low red blood cell count. Importantly, no serious reactions emerged that would prevent increasing the dose. This suggests that the combination treatment is manageable in terms of safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Tazemetostat and Pembrolizumab for treating non-small cell lung cancer because it brings a fresh approach to tackling the disease. Unlike standard treatments like chemotherapy or singular immunotherapy, Tazemetostat specifically targets and inhibits EZH2, an enzyme that plays a role in cancer cell growth. When combined with Pembrolizumab, a PD-1 blocker that enhances the immune system's ability to fight cancer, this treatment aims to offer a powerful one-two punch by both directly stopping cancer cell proliferation and boosting the body's natural defense against tumors. This dual-action strategy could potentially improve outcomes for patients where current treatments fall short.

What evidence suggests that this trial's treatments could be effective for non-small cell lung cancer?

Research shows that pembrolizumab has promising results in treating non-small cell lung cancer, particularly in patients whose tumors have a marker called PD-L1. Studies support pembrolizumab's ability to extend these patients' lives. In this trial, participants will receive a combination of pembrolizumab and tazemetostat. Tazemetostat works by blocking a protein that aids cancer cell growth, potentially enhancing pembrolizumab's effects. Although an initial study suggested that adding tazemetostat to pembrolizumab might offer only a small benefit, the combination could yield better results than pembrolizumab alone. This combination aims to shrink or control the cancer, offering hope for patients who have not responded well to other treatments. ^{2 3 6 7 8}

Who Is on the Research Team?

Daniel S Shin, MD PhD

Principal Investigator

Michael E. DeBakey VA Medical Center, Houston, TX

Are You a Good Fit for This Trial?

This trial is for adults with advanced non-small cell lung cancer who've seen their disease progress after anti-PD-1/L1 therapy. They must have good performance status (ECOG 0-1), provide a tumor tissue sample, and have measurable disease. Adequate organ function and agreement to use contraception are required. Those with certain infections, recent major surgery, active pneumonitis or autoimmune diseases, other cancers within 3 years, or severe hypersensitivity to pembrolizumab can't participate.

Inclusion Criteria

I am not pregnant and will use birth control during the trial.

I am fully active or can carry out light work.

My cancer has worsened despite treatment with an anti-PD-1/L1 drug.

Exclusion Criteria

I have not needed treatment for an autoimmune disease in the last 2 years.

You are pregnant at the time of the study treatment.

My lung cancer is a low to intermediate grade neuroendocrine type.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Safety Lead-in Phase Ib

Safety lead-in phase using BOIN with 2 dose levels of tulmimetostat to determine recommended dose for phase II

Duration not specified

Multiple visits for dose administration and monitoring

Treatment Phase II

Combination treatment with tulmimetostat and pembrolizumab for up to 2 years

2 years

Pembrolizumab every 3 weeks, tulmimetostat daily

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year

What Are the Treatments Tested in This Trial?

Interventions

• Pembrolizumab
• Tazemetostat

Trial Overview

The study tests the combination of Tazemetostat (an EZH2 inhibitor) and Pembrolizumab (a checkpoint blockade therapy) in patients with advanced non-small cell lung cancer at multiple Veterans Affairs Medical Centers. It's an open-label phase Ib/II trial where all participants receive the same treatment without a comparison group.

How Is the Trial Designed?

Group I: combination of tulmimetostat and pembrolizumab Experimental Treatment 1 Intervention

Enrolled patients will receive combination treatment for whole study duration (2 years). For first cycle, patient will start tulmimetostat one week prior to start every 3 week pembrolizumab intravenous infusion (pembrolizumab will be given day 8 only for the first cycle, rest of cycles will be day 1 of each cycle).

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

Approved in United States as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in European Union as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in United Kingdom as KEYTRUDA for:

• Untreated metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1

Who Is Running the Clinical Trial?

VA Office of Research and Development

Lead Sponsor

Trials

1,691

Recruited

3,759,000+

VA Greater Los Angeles Healthcare System

Collaborator

Trials

53

Recruited

8,700+

Published Research Related to This Trial

A network meta-analysis of five trials showed that PD-1 inhibitors (pembrolizumab and nivolumab) had higher overall response rates (ORR) compared to the PD-L1 inhibitor (atezolizumab), particularly in patients with high PD-L1 expression.

Both pembrolizumab and nivolumab demonstrated superior overall survival (OS) benefits in various patient subgroups, but treatment decisions should also consider individual patient characteristics and safety profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative efficacy and safety of immunotherapies targeting the PD-1/PD-L1 pathway for previously treated advanced non-small cell lung cancer: A Bayesian network meta-analysis. Almutairi, AR., Alkhatib, N., Martin, J., et al.[2019]

In a phase II trial involving 15 patients with resectable non-small cell lung cancer (NSCLC), neoadjuvant treatment with pembrolizumab showed a major pathologic response in 27% of patients, indicating promising antitumor activity before surgery.

The treatment was found to be feasible and safe, with only 33% of patients experiencing moderate adverse events, and no postoperative mortality, suggesting that pembrolizumab does not compromise surgical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. Eichhorn, F., Klotz, LV., Kriegsmann, M., et al.[2022]

Pembrolizumab, a PD-1 inhibitor, has demonstrated clinical effectiveness in treating various solid tumors, particularly in patients with PD-L1-positive non-small-cell lung cancer and unresectable/metastatic melanoma.

Early-phase trials and ongoing studies are focused on further confirming the clinical benefits of pembrolizumab in thoracic malignancies, highlighting its potential as a significant treatment option in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. Karim, S., Leighl, N.[2017]

Pembrolizumab (Keytruda) was approved by the FDA for treating metastatic non-small cell lung cancer (mNSCLC) in patients with tumors expressing PD-L1, showing significant improvements in overall survival (OS) and progression-free survival (PFS) in two major clinical trials with thousands of participants.

In the KEYNOTE-024 trial, pembrolizumab demonstrated a 40% reduction in the risk of death compared to chemotherapy, while in the KEYNOTE-010 trial, it also showed a significant survival advantage over chemotherapy in patients who had previously progressed on treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for Treatment of Metastatic Non-Small Cell Lung Cancer: First-Line Therapy and Beyond. Pai-Scherf, L., Blumenthal, GM., Li, H., et al.[2022]

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]

Pembrolizumab, a PD-1 inhibitor used in cancer treatment, can lead to rare but serious immune-related adverse events, including type 1 diabetes mellitus, occurring in about 0.2% of cases.

A review of 42 cases revealed that patients may develop diabetic ketoacidosis during treatment, highlighting the need for blood glucose monitoring and awareness of this potential side effect among clinicians.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Programmed Cell Death-1 Inhibitor-Induced Type 1 Diabetes Mellitus. Clotman, K., Janssens, K., Specenier, P., et al.[2022]

In a study of 100 patients with non-small cell lung cancer (NSCLC) treated with pembrolizumab, further stratification of PD-L1 tumor proportion score (TPS) beyond 50% did not significantly affect progression-free survival (PFS).

Smoking status was associated with improved PFS, while prior radiotherapy was linked to decreased PFS, indicating that these factors, along with performance status, may serve as important biomarkers for predicting response to pembrolizumab treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab monotherapy for non-small cell lung cancer (NSCLC): can patient stratification be improved in the UK Tayside population? A retrospective cohort study. Mander, ES., Merrick, CB., Nicholson, HA., et al.[2023]

In a Phase 2 study involving 35 patients with non-small cell lung cancer, neoadjuvant pembrolizumab was found to be safe and well tolerated, with only one surgery delay due to thyroiditis and no mortality within 90 days post-surgery.

The study showed a high rate of R0 resection (88%) and a major pathologic response in 28% of patients, indicating that pembrolizumab may be more effective than standard neoadjuvant chemotherapy in this setting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Perioperative outcomes of pulmonary resection after neoadjuvant pembrolizumab in patients with non-small cell lung cancer. Tong, BC., Gu, L., Wang, X., et al.[2022]

A 68-year-old patient with stage IV lung adenocarcinoma showed an unexpected positive response to paclitaxel after failing treatment with pembrolizumab, an anti-PD-1 immunotherapy.

The patient experienced a response duration of over fourteen months with paclitaxel, suggesting that combining or sequencing chemotherapy with immunotherapy may enhance treatment effectiveness in certain cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Prolonged response with paclitaxel after immunotherapy by pembrolizumab in lung cancer]. Zapata, E., Mennecier, B., Leduc, C., et al.[2017]

An elderly male patient on pembrolizumab developed four autoimmune toxicities, including type 1 diabetes and pneumonitis, highlighting the risk of multiple immune-related adverse events associated with this treatment.

The case suggests that aging may increase susceptibility to these adverse effects, necessitating close monitoring and prompt management, including stopping the immunotherapy and using steroids for treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multiple autoimmune side effects of immune checkpoint inhibitors in a patient with metastatic melanoma receiving pembrolizumab. Kethireddy, N., Thomas, S., Bindal, P., et al.[2021]

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