Tazemetostat + Topotecan + Pembrolizumab for Small Cell Lung Cancer

Recruiting at 10 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: Immunosuppressants, Steroids

Disqualifiers: Active autoimmune disease, Pneumonitis, Uncontrolled illness, 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: 42

60 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial seeks to determine the safest and most effective dose of a new treatment combination for small cell lung cancer that has returned after treatment. The combination includes tazemetostat (also known as Tazemetostat Hydrobromide), which may inhibit tumor growth by blocking certain enzymes, topotecan, a chemotherapy drug, and pembrolizumab, an immunotherapy that aids the immune system in targeting cancer cells. Suitable candidates have small cell lung cancer that has recurred following chemotherapy and immunotherapy. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

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

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot participate if you have had chemotherapy, immune checkpoint inhibitors, or radiotherapy within 2 weeks before the study, or if you are on systemic steroid therapy or other immunosuppressive treatments within 7 days prior to the first dose of trial treatment.

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

Research shows that each treatment in this trial has undergone safety testing in humans.

For example, Tazemetostat was studied in patients with certain types of lymphoma, showing a 69% response rate in those with specific genetic changes and a 35% response rate in those without. This indicates the drug's effectiveness and prior use in humans, offering some safety information.

Pembrolizumab, another treatment in this trial, is a well-known immunotherapy drug used for various cancers, including small cell lung cancer. Research has shown it can offer long-term benefits, supporting its safety in humans.

Topotecan, a chemotherapy drug, has been used in many cancer treatments. Studies involving hundreds of patients demonstrate its common use and known side effects, aiding doctors in understanding its safety.

Overall, while this trial focuses on small cell lung cancer, these drugs are not entirely new to humans. Previous research provides a foundation for understanding their safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for small cell lung cancer, which often include chemotherapy and immunotherapy, this investigational combination uses tazemetostat, pembrolizumab, and topotecan, offering a unique approach. Tazemetostat is notable for its ability to inhibit EZH2, a protein that helps cancer cells grow, potentially enhancing the effectiveness of other treatments. Pembrolizumab, an immunotherapy, boosts the body's immune system to target cancer cells, while topotecan works by disrupting DNA replication in cancer cells. Researchers are excited about combining these mechanisms, as it could lead to more effective and targeted outcomes for patients.

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

Research has shown that tazemetostat may help shrink or control small cell lung cancer (SCLC) when combined with other treatments. This drug blocks certain enzymes that promote cancer cell growth. Pembrolizumab, a type of immunotherapy, has effectively treated SCLC by enhancing the immune system's ability to fight the cancer over an extended period. Topotecan has demonstrated strong results in patients with recurring SCLC, aiding in combating the cancer. In this trial, participants will receive a combination of tazemetostat, pembrolizumab, and topotecan, aiming to attack the cancer in different ways and offering hope for managing recurrent SCLC. ^{3 6 7 8 9}

Who Is on the Research Team?

Anish Thomas

Principal Investigator

National Cancer Institute LAO

Are You a Good Fit for This Trial?

Adults with recurrent small cell lung cancer who've had platinum-based chemotherapy can join. They must have measurable disease, stable brain metastases if present, and adequate organ function. HIV-positive patients on effective therapy are eligible. Participants need to use contraception and cannot be pregnant or breastfeeding.

Inclusion Criteria

My kidney function is within the safe range for the trial.

Your hemoglobin level is higher than 9 g/dL or 5.6 mmol/L.

Your AST and ALT liver enzymes are not more than 2.5 times the normal level.

Exclusion Criteria

My tests show genetic changes linked to MDS or MPN.

I have had T-cell lymphoblastic lymphoma or T-cell acute leukemia in the past.

I haven't had certain cancer treatments in the last 2 to 6 weeks.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose-Escalation

Patients receive tazemetostat, pembrolizumab, and topotecan to determine the maximum tolerated dose and recommended phase II dose

21 days per cycle, up to 2 years

Cycle visits every 21 days

Dose-Expansion

Evaluate safety and tolerability of the combination treatment at the recommended phase II dose

21 days per cycle, up to 2 years

Cycle visits every 21 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

Every 3 months until study closure or death

What Are the Treatments Tested in This Trial?

Interventions

• Pembrolizumab
• Tazemetostat Hydrobromide
• Topotecan Hydrochloride

Trial Overview The trial is testing the combination of Tazemetostat (an enzyme inhibitor), Topotecan (chemotherapy), and Pembrolizumab (immunotherapy) to see if it's safe and effective for treating recurrent small cell lung cancer by targeting tumor growth in various ways.

How Is the Trial Designed?

Group I: Treatment (tazemetostat, pembrolizumab, topotecan) Experimental Treatment 6 Interventions

Patients receive tazemetostat PO BID for 7 days prior to cycle 1 and then on days 1-21 of each cycle, pembrolizumab IV over 30 minutes on day 1 of each cycle, and topotecan IV over 30 minutes on days 1-3 or days 1-5 of each cycle. Cycles repeat every 21 days for 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan throughout the study and undergo biopsy and collection of blood on study.

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?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

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, an immune checkpoint inhibitor targeting the PD-1 pathway, has shown significant durability of responses in previously treated patients with extensive-stage small-cell lung cancer (ES-SCLC), leading to its accelerated approval by the FDA for second- or third-line treatment.

In a recent clinical trial, pembrolizumab combined with platinum/etoposide improved progression-free survival in previously untreated ES-SCLC patients, although it did not demonstrate a significant improvement in overall survival compared to standard treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evidence to Date: Evaluating Pembrolizumab in the Treatment of Extensive-Stage Small-Cell Lung Cancer. Riano, I., Patel, SR., Liu, SV., et al.[2021]

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 real-life study of 121 patients with advanced non-squamous non-small cell lung cancer, the combination of pembrolizumab and chemotherapy resulted in a median progression-free survival of 9 months and overall survival of 20.6 months, demonstrating its efficacy as a first-line treatment.

The treatment was generally well-tolerated, with manageable side effects; however, 17.5% of patients experienced grade 3-4 adverse events, and there were two treatment-related deaths, indicating the need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab plus pemetrexed-carboplatin combination in first-line treatment of advanced non-squamous non-small cell lung cancer: a multicenter real-life study (CAP29). Renaud, E., Ricordel, C., Corre, R., et al.[2023]

Pembrolizumab (Keytruda) is an approved treatment for metastatic or locally advanced esophageal and gastroesophageal junction cancer, indicating its efficacy in targeting these specific cancer types.

It is used in combination with platinum- and fluoropyrimidine-based chemotherapy, suggesting a synergistic approach to enhance treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab Approved for Esophageal or Gastroesophageal Cancer. Aschenbrenner, DS.[2023]

Pembrolizumab (KEYTRUDA) was approved by the FDA for treating unresectable or metastatic melanoma based on two clinical trials involving 1,374 patients, showing significant improvements in overall survival compared to ipilimumab, with hazard ratios indicating a reduced risk of death.

Patients receiving pembrolizumab also experienced significant improvements in progression-free survival, although some immune-mediated adverse reactions like hypothyroidism and pneumonitis were noted, highlighting the importance of monitoring for side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for the Treatment of Patients with Unresectable or Metastatic Melanoma. Barone, A., Hazarika, M., Theoret, MR., et al.[2022]

Pembrolizumab (Keytruda) is approved for treating advanced endometrial carcinoma that is microsatellite instability-high or mismatch repair deficient, specifically for patients whose disease has progressed after previous treatments.

This approval is significant for patients who are not candidates for curative surgery or radiation, providing a new therapeutic option for a challenging stage of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Approved Use for Keytruda. Aschenbrenner, DS.[2022]

The maximum tolerated doses (MTDs) for the combination of pembrolizumab and trametinib were established, with concurrent dosing showing a lower objective response rate (0%) compared to intermittent dosing (27%).

While the combination treatment had manageable safety profiles, with 31% of patients experiencing grade 3/4 treatment-related adverse events in the concurrent group, the overall antitumor activity was limited, suggesting that this combination may not be highly effective for solid tumors and BRAF wild-type melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

KEYNOTE-022: Pembrolizumab with trametinib in patients with BRAF wild-type melanoma or advanced solid tumours irrespective of BRAF mutation. Maio, M., Carlino, MS., Joshua, AM., et al.[2022]

In the KEYNOTE-407 study involving 1107 patients with untreated metastatic squamous non-small-cell lung cancer, the addition of pembrolizumab to chemotherapy significantly improved overall survival and quality of life without increasing severe toxicity.

Patients receiving pembrolizumab reported better health-related quality of life scores at weeks 9 and 18 compared to those receiving placebo, indicating that pembrolizumab enhances patient well-being while maintaining effective cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Health-Related Quality of Life With Carboplatin-Paclitaxel or nab-Paclitaxel With or Without Pembrolizumab in Patients With Metastatic Squamous Non-Small-Cell Lung Cancer. Mazieres, J., Kowalski, D., Luft, A., et al.[2020]

Citations

1. merck.com merck.com/news/five-year-data-for-mercks-keytruda-pembrolizumab-plus-chemotherapy-showed-sustained-survival-benefit-versus-chemotherapy-alone-in-two-studies-for-metastatic-non-small-cell-lung-cancer-nsclc/

Five-Year Data for Merck's KEYTRUDA® (pembrolizumab ... Five-year overall survival rate of 19.4% and 18.4% for KEYTRUDA plus chemotherapy in KEYNOTE-189 and KEYNOTE-407, respectively.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT02142738

NCT02142738 | Study of Pembrolizumab (MK-3475) ... This is a study to assess the efficacy and safety of pembrolizumab (MK-3475/SCH 900475) compared to standard of care (SOC) platinum-based chemotherapies.

3. sciencedirect.com sciencedirect.com/science/article/pii/S0169500225000431

Five-year efficacy and safety of pembrolizumab as first-line ... Overall, 23 patients (29.9 %) attained 5-year survival by pembrolizumab treatment in this cohort. One of the 23 patients had squamous cell carcinoma histology, ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8293071/

Evidence to Date: Evaluating Pembrolizumab in the Treatment ... Prospective trials of pembrolizumab in patients with previously treated SCLC showed significant durability of responses. These results led to ...

5. ascopubs.org ascopubs.org/doi/10.1200/jco.2015.33.15_suppl.7502

Pembrolizumab (MK-3475) in patients (pts) with extensive- ... Responses are durable, with all responders on treatment for 16+ wks with ongoing response. Conclusions: Pembrolizumab is generally well ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT02142738

NCT02142738 | Study of Pembrolizumab (MK-3475) ... This is a study to assess the efficacy and safety of pembrolizumab (MK-3475/SCH 900475) compared to standard of care (SOC) platinum-based chemotherapies.

7. merck.com merck.com/news/keytruda-pembrolizumab-demonstrates-long-term-survival-benefit-in-certain-patients-with-earlier-or-advanced-stages-of-non-small-cell-lung-cancer-nsclc/

KEYTRUDA® (pembrolizumab) Demonstrates Long-Term ... “The five-year benefit demonstrated across overall survival and event-free survival from KEYNOTE-671 supports the continued use of this ...

8. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40157574/

the phase III 3475A-D77 trial Conclusions: Overall exposure and trough concentrations of pembrolizumab s.c. 790 mg q6w were noninferior to those of pembrolizumab i.v. 400 mg q6w given with ...

9. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39952082/

Five-year efficacy and safety of pembrolizumab as first-line ... The real-world 5-year survival rate of NSCLC cases with PD-L1 ≥ 50 % treated with first-line pembrolizumab was comparable to that in a clinical trial.