Pembrolizumab for Bladder Cancer

(AMBASSADOR Trial)

Not currently recruiting at 1083 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: National Cancer Institute (NCI)

Must not be taking: Corticosteroids, Immunosuppressants

Disqualifiers: Autoimmune diseases, Hepatitis, Pneumonitis, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 31

Duration: 54 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness of pembrolizumab (also known as KEYTRUDA or MK-3475), a monoclonal antibody, in treating bladder cancer that has deeply invaded the bladder wall or spread to nearby tissues or lymph nodes. Pembrolizumab aids the immune system in fighting cancer by blocking molecules that enable tumor growth. Participants will either receive pembrolizumab or join an observation group for comparison. This study suits individuals who have undergone bladder cancer surgery with no remaining signs of cancer and have not recently received certain other treatments. As a Phase 3 trial, it represents the final step before potential FDA approval, allowing participants to contribute to validating a promising treatment.

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

The trial protocol does not specify if you need to stop taking your current medications. However, it does mention that you should not have had any postoperative/adjuvant systemic therapy or treatment with any PD-1/PD-L1 axis therapy before joining the trial.

Is there any evidence suggesting that pembrolizumab is likely to be safe for humans?

Research shows that pembrolizumab is generally safe for patients. Studies have consistently found its safety to be reliable, even when combined with other treatments. Long-term use in various types of cancer has shown promise, with no unexpected side effects. Patients in earlier studies continued treatment without serious problems. However, like any medication, side effects can occur, so discussing any concerns with a doctor is important. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for bladder cancer?

Pembrolizumab is unique because it harnesses the power of the immune system to target bladder cancer. Unlike traditional chemotherapy, which attacks cancer cells directly but can also harm healthy cells, pembrolizumab is an immunotherapy that blocks the PD-1 pathway. This action helps the immune system recognize and attack cancer cells more effectively. Researchers are excited because pembrolizumab has shown promise in treating other cancers like melanoma and non-small cell lung cancer, and they hope it can offer similar benefits for bladder cancer patients, potentially with fewer side effects.

What evidence suggests that pembrolizumab could be an effective treatment for bladder cancer?

Research has shown that pembrolizumab, a monoclonal antibody, can help treat bladder cancer. In one study, about 61% of patients with high-risk bladder cancer who took pembrolizumab were still alive after three years. Another study found that about 29% of patients experienced tumor shrinkage. Additionally, 83% of patients had no detectable cancer at 12 weeks, indicating that the cancer was not visible in many of them. In this trial, some participants will receive pembrolizumab to help the body's immune system fight cancer cells, offering a promising option for those with advanced bladder cancer. Other participants will be in the observation arm, undergoing regular monitoring without receiving pembrolizumab. ^{1 3 4 6 7}

Who Is on the Research Team?

Andrea B Apolo

Principal Investigator

Alliance for Clinical Trials in Oncology

Are You a Good Fit for This Trial?

Adults with muscle-invasive bladder cancer or locally advanced urothelial cancer who've had surgery but no metastasis, no recent radiation, chemo, or major surgery. Must not be pregnant/nursing and have proper organ function. Excludes those with active hepatitis B/C, autoimmune diseases requiring steroids, prior PD-1/PD-L1 therapy, live vaccines recently taken.

Inclusion Criteria

Your hemoglobin level is 9 grams per deciliter or higher.

You have received a specific type of chemotherapy before surgery, or you have certain health issues that make you ineligible for a particular type of chemotherapy, or you have chosen not to receive a specific type of chemotherapy after surgery.

Your bilirubin levels are within a certain range, unless you have a condition called Gilbert's, in which case they can be a bit higher.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Patients receive pembrolizumab intravenously every 21 days for up to 18 cycles or undergo observation

54 weeks

18 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

Every 12 weeks

Long-term follow-up

Annual follow-up for survival and disease status

10 years

Annually

What Are the Treatments Tested in This Trial?

Interventions

• Pembrolizumab

Trial Overview

The trial is testing Pembrolizumab's effectiveness post-surgery in patients with certain types of bladder and urothelial cancers. It involves monitoring through scans and tests like CT Urography and MRI to see if this drug can prevent cancer from returning by boosting the immune system.

How Is the Trial Designed?

Group I: Arm A (pembrolizumab) Experimental Treatment 9 Interventions

Patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 18 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo a CT scan, CT urography, and/or MRI throughout the trial. Patients may also undergo a cystoscopy and blood sample collection during screening and on study.

Group II: Arm B (observation) Active Control 9 Interventions

Patients undergo observation. Patients undergo a CT scan, CT urography, and/or MRI throughout the trial. Patients may also undergo a cystoscopy and blood sample collection during screening and on study.

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

Pembrolizumab, an immune checkpoint inhibitor, showed a strong antitumor effect in a 70-year-old female patient with unresectable bladder cancer, but it also led to a grade 3 asthma attack as an immune-related adverse event.

The patient's asthma was linked to changes in immune cell markers, specifically increased CTLA-4 and TIM-3 in CD4+ T cells and a rise in Th17 cells, suggesting that these immune responses could be indicators of both adverse effects and treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A case of bronchial asthma as an immune-related adverse event of pembrolizumab treatment for bladder cancer: A case report. Hamada, K., Yoshimura, K., Oshinomi, K., et al.[2022]

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 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]

Pembrolizumab, an immunotherapy for advanced bladder cancer, led to significant tumor shrinkage after just one injection, demonstrating its efficacy in treating this type of cancer.

The patient experienced immune-related adverse events, specifically myasthenia gravis and myocarditis, which were effectively managed with early corticosteroid treatment, highlighting the importance of monitoring and addressing side effects in immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab-induced myasthenia gravis with myositis and presumable myocarditis in a patient with bladder cancer. Todo, M., Kaneko, G., Shirotake, S., et al.[2022]

In the PURE-01 study involving 50 patients with muscle-invasive bladder carcinoma, neoadjuvant treatment with pembrolizumab resulted in a pathologic complete response (pT0) in 42% of patients, demonstrating its efficacy as a pre-surgery immunotherapy.

The study found that patients with high PD-L1 expression (CPS ≥ 10%) had a significantly higher rate of pT0 (54.3%) compared to those with lower expression (13.3%), suggesting that pembrolizumab may be particularly effective in patients with PD-L1-positive tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab as Neoadjuvant Therapy Before Radical Cystectomy in Patients With Muscle-Invasive Urothelial Bladder Carcinoma (PURE-01): An Open-Label, Single-Arm, Phase II Study. Necchi, A., Anichini, A., Raggi, D., et al.[2021]

In a study of 39 patients with muscle-invasive bladder cancer, the combination of gemcitabine, cisplatin, and the immune checkpoint inhibitor pembrolizumab was effective, achieving pathologic downstaging in 56% of patients and complete pathologic response in 36%.

The treatment was generally safe, with common side effects including thrombocytopenia, anemia, and neutropenia, but no severe immune-related adverse events were reported, indicating a manageable safety profile for this neoadjuvant therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II Study of Gemcitabine and Split-Dose Cisplatin Plus Pembrolizumab as Neoadjuvant Therapy Before Radical Cystectomy in Patients With Muscle-Invasive Bladder Cancer. Rose, TL., Harrison, MR., Deal, AM., 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 PURE-01 study involving 84 patients with muscle-invasive bladder cancer, higher RNA-based immune signature scores were significantly associated with a complete response to pembrolizumab, indicating its potential effectiveness as a neoadjuvant therapy.

Unlike pembrolizumab, the same immune signatures did not predict outcomes for patients receiving standard chemotherapy, suggesting that gene expression profiling could help personalize treatment strategies for better outcomes in bladder cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of Molecular Subtyping and Immune Infiltration on Pathological Response and Outcome Following Neoadjuvant Pembrolizumab in Muscle-invasive Bladder Cancer. Necchi, A., Raggi, D., Gallina, A., et al.[2021]

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]

In a study involving 33 patients with advanced urothelial cancer, pembrolizumab demonstrated anti-tumor activity, with a 26% overall response rate, including 11% complete responses and 15% partial responses, after a median follow-up of 13 months.

The treatment was found to have an acceptable safety profile, with common side effects including fatigue and peripheral edema, and no treatment-related deaths reported, supporting further investigation in larger phase 2 and 3 trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and activity of pembrolizumab in patients with locally advanced or metastatic urothelial cancer (KEYNOTE-012): a non-randomised, open-label, phase 1b study. Plimack, ER., Bellmunt, J., Gupta, S., et al.[2022]

Pembrolizumab (Keytruda) has been approved by the FDA for treating high-risk, non-muscle invasive bladder cancer (NMIBC) in patients who are unresponsive to BCG therapy and are either ineligible for or have opted not to undergo cystectomy.

This approval specifically targets patients with carcinoma in situ (CIS) with or without papillary tumors, highlighting its role as a treatment option for those with limited surgical options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approves Pembrolizumab for BCG-Unresponsive NMIBC. Wright, KM.[2021]

Citations

1.

cancer.gov

cancer.gov/news-events/press-releases/2024/high-risk-bladder-cancer-pembrolizumab

Pembrolizumab improves outcomes in high-risk bladder ...

In preliminary data on overall survival, at three years, about 61% of patients in the pembrolizumab group were still alive, compared with about ...

2.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC6452591/

Pembrolizumab in the treatment of locally advanced or ...

An updated efficacy analysis with all patients having ⩾6 months of follow up demonstrated an ORR of 29% (95 CI, 24–34%) and a CR rate of 7%. The median time to ...

3.

merck.com

merck.com/news/keytruda-pembrolizumab-plus-padcev-enfortumab-vedotin-ejfv-significantly-improved-event-free-and-overall-survival-and-pathologic-complete-response-rate-for-certain-patients-with-muscle/

KEYTRUDA® (pembrolizumab) plus Padcev® (enfortumab ...

The trial is continuing to evaluate the secondary EFS, OS, and pCR rate endpoints for neoadjuvant and adjuvant KEYTRUDA versus surgery alone as ...

4.

ascopubs.org

ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.4509

Long-term outcomes of pembrolizumab (pembro) in ...

TMT combined with pembro was well tolerated and continues to show promising early outcomes data. A large phase 3 trial is underway to further explore this ...

5.

eu-focus.europeanurology.com

eu-focus.europeanurology.com/article/S2405-4569(22)00295-4/fulltext

Efficacy and Safety of Pembrolizumab (MK-3475) in ...

The 12-wk complete response rate was 83%, while the 1-yr metastasis-free survival rate (secondary endpoint) was 85%. Following these results, a ...

6.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/36737362/

The MK-3475-992/KEYNOTE-992 Trial

Efficacy and Safety of Pembrolizumab (MK-3475) in Combination with Chemoradiotherapy Versus Chemoradiotherapy Alone in Muscle-invasive Bladder ...

7.

clinicaltrials.gov

clinicaltrials.gov/study/NCT03711032

NCT03711032 | Efficacy and Safety of Pembrolizumab (MK ...

Efficacy and Safety of Pembrolizumab (MK-3475) in Combination With Bacillus Calmette-Guerin (BCG) in High-Risk Non-Muscle Invasive Bladder Cancer (HR NMIBC) ...