Emavusertib + Pembrolizumab for Urothelial Carcinoma

Recruiting at 2 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: Immunosuppressants, Steroids

Disqualifiers: Immunodeficiency, Active autoimmune, Hepatitis, others

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

Compensation: Varies

Number of Visits: 4

Duration: Up to 2 years

27 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, if you are on chronic systemic steroid therapy or other immunosuppressive therapy, you may need to stop these before starting the trial.

What data supports the effectiveness of the drug pembrolizumab for urothelial carcinoma?

Pembrolizumab has shown significant benefits in treating advanced urothelial carcinoma, improving overall survival compared to other treatments like docetaxel and paclitaxel, especially in patients who have already received platinum-based chemotherapy. ^{1 2 3 4 5}

Is the combination of Emavusertib and Pembrolizumab safe for treating urothelial carcinoma?

Pembrolizumab has been shown to have acceptable safety in patients with advanced urothelial carcinoma, including those who are older or have progressed after platinum therapy. However, specific safety data for the combination of Emavusertib and Pembrolizumab is not provided in the available research. ^{1 4 6 7 8}

What makes the drug Emavusertib + Pembrolizumab unique for treating urothelial carcinoma?

Emavusertib + Pembrolizumab is unique because it combines a novel investigational drug, Emavusertib, with Pembrolizumab, a well-established immune checkpoint inhibitor, potentially offering a new mechanism of action for treating urothelial carcinoma. This combination may provide an alternative for patients who have limited options after standard treatments. ^{1 2 3 4 9}

What is the purpose of this trial?

This phase I trial tests the safety, side effects, best dose, and effectiveness of emavusertib (CA-4948) in combination with pembrolizumab in treating patients with urothelial cancer that has spread from where it first started to other places in the body (metastatic) and that has a resistance to PD-1/PD-L1 immune checkpoint inhibitors. CA-4948, a kinase inhibitor, may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the tumor, and may interfere with the ability of tumor cells to grow and spread. Giving CA-4948 in combination with pembrolizumab may be safe, tolerable and/or effective in treating patients with metastatic urothelial cancer that is resistant to PD-1/PD-L1 immune checkpoint inhibitors.

Research Team

Matthew D Galsky

Principal Investigator

MOUNT SINAI HOSPITAL

Eligibility Criteria

This trial is for adults with metastatic urothelial cancer resistant to PD-1/PD-L1 inhibitors. Participants need confirmed diagnosis, be in relatively good health (ECOG ≤ 2), and have adequate blood cell counts without recent transfusions. Children, those with poor performance status or insufficient organ function are excluded.

Inclusion Criteria

I can care for myself and am up more than 50% of my waking hours.

Absolute neutrophil count (ANC) ≥ 1,500/mcL

Platelets ≥ 100,000/mcL

Exclusion Criteria

Patients who are receiving any other investigational agents

Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the patient's participation for the full duration of the trial, or is not in the best interest of the patient to participate, in the opinion of the treating investigator

I have an immune system disorder or have been on high-dose steroids or other immune-weakening medicines recently.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive CA-4948 orally twice daily and pembrolizumab intravenously on day 1 of each 21-day cycle for up to 2 years

Up to 2 years

1 visit per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

Every 3 months

Treatment Details

Interventions

• CA-4948
• Pembrolizumab

Trial Overview The trial tests the combination of emavusertib (CA-4948), a kinase inhibitor that may stop tumor growth, with pembrolizumab, an immunotherapy drug. It aims to determine safety, side effects, optimal dosing and effectiveness against progressive metastatic urothelial cancer.

Participant Groups

Group I: Treatment (CA-4948, pembrolizumab) Experimental Treatment 7 Interventions

Patients receive CA-4948 orally PO BID on days 1-21 and pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection, CT, MRI, or PET throughout the study. Additionally, patients may undergo a tumor biopsy on study.

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a phase 3 study involving 487 patients with advanced urothelial carcinoma, the combination of pembrolizumab and lenvatinib did not show improved progression-free survival (4.5 months) or overall survival (11.8 months) compared to pembrolizumab with placebo.

The combination treatment resulted in a higher rate of severe adverse events (51%) compared to the placebo group (27%), leading to the conclusion that the benefit-to-risk ratio was not favorable for using lenvatinib with pembrolizumab as first-line therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab with or Without Lenvatinib as First-line Therapy for Patients with Advanced Urothelial Carcinoma (LEAP-011): A Phase 3, Randomized, Double-Blind Trial. Matsubara, N., de Wit, R., Balar, AV., et al.[2023]

In a study of 105 patients with advanced urothelial carcinoma treated with pembrolizumab, older patients (median age 72) showed a 42.5% objective response rate, while those with a poor performance status (PS) had a 0% response rate, indicating that age may not significantly affect treatment efficacy compared to PS.

Safety profiles were similar between older and younger patients, with no significant differences in immune-related adverse events; however, patients with poor PS experienced lower toxicity and significantly worse survival outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Eosinophil Changes, Efficacy and Safety of Pembrolizumab in Advanced Urothelial Carcinoma Patients with an Older Age and a Poor Performance Status. Furubayashi, N., Minato, A., Negishi, T., et al.[2022]

In a study comparing 121 patients treated with pembrolizumab to 67 patients receiving conventional chemotherapy for advanced urothelial carcinoma, pembrolizumab showed a significant improvement in overall survival with a hazard ratio of 0.63, indicating a 37% reduction in the risk of death compared to chemotherapy.

Despite the older age and poorer health status of patients receiving pembrolizumab, the treatment demonstrated a clinical benefit over traditional chemotherapy, suggesting its effectiveness as a second-line therapy in real-world settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of pembrolizumab with conventional chemotherapy after first-line platinum-based chemotherapy for advanced urothelial carcinoma in real-world practice: A multicenter retrospective study. Narita, T., Hatakeyama, S., Numakura, K., et al.[2021]

In the Phase III KEYNOTE-045 trial, pembrolizumab significantly improved overall survival in patients with second-line metastatic urothelial carcinoma compared to standard treatments like docetaxel, paclitaxel, and vinflunine.

Early results from the Phase II KEYNOTE-052 trial suggest that pembrolizumab is effective for first-line treatment in patients with metastatic urothelial carcinoma who are not eligible for cisplatin, leading to its FDA approval for these indications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in the treatment of advanced urothelial cancer. Lundgren, KT., Farina, MS., Bellmunt, J.[2018]

In a study of 69 patients with advanced urothelial carcinoma who received pembrolizumab after failing platinum-based chemotherapy, the overall response rate (ORR) was 23.2%, indicating some efficacy of the treatment.

The organ-specific response rates varied, with the highest response observed in lung metastases (31.3%) and the lowest in primary tumor sites (7.1%), suggesting that different tumor locations may respond differently to pembrolizumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Organ-Specific Tumor Response to Pembrolizumab in Advanced Urothelial Carcinoma After Platinum-Based Chemotherapy. Furubayashi, N., Negishi, T., Sakamoto, N., et al.[2022]

In a study of 105 advanced urothelial carcinoma patients treated with pembrolizumab, those who experienced immune-related adverse events (irAEs) had significantly better clinical outcomes, including higher objective response rates and longer overall survival compared to those without irAEs.

An increase in the relative eosinophil count (REC) three weeks after starting pembrolizumab was not linked to the occurrence of irAEs, suggesting that while irAEs are associated with improved survival, changes in REC may not be a reliable predictor of irAE incidence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association Between Immune-Related Adverse Events and Efficacy and Changes in the Relative Eosinophil Count Among Patients with Advanced Urothelial Carcinoma Treated by Pembrolizumab. Furubayashi, N., Minato, A., Negishi, T., et al.[2022]

In a study of 78 patients with advanced urothelial carcinoma treated with pembrolizumab, the median overall survival was 7.3 months, and the estimated survival rate at 6 months was 61.5%, indicating its efficacy in a real-life setting.

The treatment was generally well-tolerated, with the most common side effects being fatigue and gastrointestinal issues, but no severe adverse events occurred in more than 5% of patients, suggesting a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Benefit of Pembrolizumab in Advanced Urothelial Cancer Patients in Real-Life Setting: An Efficacy and Safety Monocentric Study. Dang, E., Vallée, A., Lepage-Seydoux, C., et al.[2022]

In a study of 608 patients with advanced urothelial carcinoma treated with pembrolizumab, the overall survival was similar for patients aged under 75 (7.8 months) and those aged 75 and older (10.4 months), indicating that age does not significantly impact treatment efficacy.

Older patients (≥75 years) experienced a higher rate of any-grade adverse events (55.3%) compared to younger patients (<75 years, 41.9%), suggesting that while pembrolizumab is effective across age groups, older patients may require closer monitoring for side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of pembrolizumab for older patients with chemoresistant urothelial carcinoma assessed using propensity score matching. Nishiyama, N., Kobayashi, T., Narita, S., et al.[2022]

The combination of enfortumab vedotin (EV) and pembrolizumab (Pembro) demonstrated a high confirmed objective response rate (cORR) of 64.5% in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer, indicating its efficacy as a first-line treatment option.

Patients receiving the combination therapy also experienced durable responses, with 65.4% maintaining their response at 12 months, while the safety profile showed manageable adverse events, with no new safety signals identified.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enfortumab Vedotin With or Without Pembrolizumab in Cisplatin-Ineligible Patients With Previously Untreated Locally Advanced or Metastatic Urothelial Cancer. O'Donnell, PH., Milowsky, MI., Petrylak, DP., et al.[2023]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Pembrolizumab with or Without Lenvatinib as First-line Therapy for Patients with Advanced Urothelial Carcinoma (LEAP-011): A Phase 3, Randomized, Double-Blind Trial. [2023]

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

The Eosinophil Changes, Efficacy and Safety of Pembrolizumab in Advanced Urothelial Carcinoma Patients with an Older Age and a Poor Performance Status. [2022]

3. Australia pubmed.ncbi.nlm.nih.gov

Comparison of pembrolizumab with conventional chemotherapy after first-line platinum-based chemotherapy for advanced urothelial carcinoma in real-world practice: A multicenter retrospective study. [2021]

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

Pembrolizumab in the treatment of advanced urothelial cancer. [2018]

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

Organ-Specific Tumor Response to Pembrolizumab in Advanced Urothelial Carcinoma After Platinum-Based Chemotherapy. [2022]

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

Association Between Immune-Related Adverse Events and Efficacy and Changes in the Relative Eosinophil Count Among Patients with Advanced Urothelial Carcinoma Treated by Pembrolizumab. [2022]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Clinical Benefit of Pembrolizumab in Advanced Urothelial Cancer Patients in Real-Life Setting: An Efficacy and Safety Monocentric Study. [2022]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Efficacy and safety of pembrolizumab for older patients with chemoresistant urothelial carcinoma assessed using propensity score matching. [2022]

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

Enfortumab Vedotin With or Without Pembrolizumab in Cisplatin-Ineligible Patients With Previously Untreated Locally Advanced or Metastatic Urothelial Cancer. [2023]