Pembrolizumab + Chemotherapy Before Surgery for Bladder Cancer

Overseen By Petros Grivas

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Washington

Must not be taking: Anti-PD-1, Anti-PD-L1

Disqualifiers: Small cell histology, Immunodeficiency, Autoimmune, others

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

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

Compensation: Varies

Number of Visits: 3

Duration: 6 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of immunotherapy and chemotherapy before surgery to determine its effectiveness in treating certain types of bladder cancer with unusual cell appearances. Pembrolizumab, an immunotherapy drug, helps the immune system attack cancer cells, while chemotherapy drugs prevent the cancer from growing and spreading. Individuals with muscle-invasive bladder cancer, without distant spread, who qualify for chemotherapy and surgery, might be suitable candidates for this study. As a Phase 2 trial, the research focuses on evaluating the treatment's effectiveness in an initial, smaller group of participants.

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 certain treatments like systemic anti-cancer therapy or immunosuppressive drugs, you may need to stop them before starting the trial. It's best to discuss your specific medications with the trial team.

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

Research has shown that pembrolizumab is generally safe and well-tolerated, with fewer treatment-related side effects compared to some other therapies. While some patients experience side effects, these are often manageable.

For the chemotherapy component, a combination of drugs called aMVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) is also considered safe. Studies have demonstrated that patients generally tolerate this treatment well, although concerns about side effects exist. These concerns sometimes lead doctors to choose different chemotherapy drugs for certain patients.

Overall, both pembrolizumab and aMVAC chemotherapy have been used in other cancer treatments, and their safety is well-documented. This makes them promising options for treating bladder cancer in this trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of pembrolizumab and chemotherapy for bladder cancer because it introduces a novel approach by pairing immunotherapy with traditional chemotherapy before surgery. Unlike standard treatments that often rely solely on chemotherapy or surgery, pembrolizumab is an immunotherapy drug that works by unleashing the body’s immune system to better recognize and attack cancer cells. This combination aims to shrink tumors more effectively before surgery, potentially leading to better outcomes and preserving more bladder function for patients. Additionally, pembrolizumab has shown promise in treating other types of cancer, which gives hope for its effectiveness in bladder cancer as part of this innovative treatment regimen.

What evidence suggests that pembrolizumab and chemotherapy before surgery might be effective for bladder cancer?

In this trial, participants will receive a combination of pembrolizumab and chemotherapy before surgery. Research has shown that pembrolizumab can significantly improve survival rates for bladder cancer patients. One study found that 61% of patients were still alive three years after starting treatment with pembrolizumab. This drug helps the immune system identify and attack cancer cells.

For the chemotherapy component, a combination called aMVAC (which includes methotrexate, vinblastine, adriamycin, and cisplatin) has proven effective. Studies indicate it works well and is safe for bladder cancer patients, helping to stop cancer cells from growing and spreading. Together, pembrolizumab and aMVAC may offer a strong approach to treating muscle-invasive bladder cancer before surgery. ^{2 4 5 6 7}

Who Is on the Research Team?

Petros Grivas

Principal Investigator

Fred Hutch/University of Washington Cancer Consortium

Are You a Good Fit for This Trial?

This trial is for adults with muscle-invasive bladder cancer that looks unusual under the microscope and hasn't spread elsewhere. They must be fit for chemotherapy, surgery to remove the bladder, and willing to provide tissue samples. Participants need functioning major organs, no severe allergies to pembrolizumab or its components, no active hepatitis B/C or HIV, not pregnant or breastfeeding, and agree to use contraception.

Inclusion Criteria

My bladder cancer has not spread, as confirmed by CT or MRI scans.

My bladder cancer is mainly not urothelial type.

My blood clotting time is normal or managed if I'm on blood thinners.

Exclusion Criteria

Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial

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

I have not had cancer treatment or experimental drugs in the last 4 weeks.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive pembrolizumab and combination chemotherapy before surgery

6 weeks

Weekly visits for IV administration

Surgery

Participants undergo standard of care radical cystectomy

1 day

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

Every 3-6 months

What Are the Treatments Tested in This Trial?

Interventions

• Combination Chemotherapy
• Pembrolizumab
• Radical Cystectomy

Trial Overview The study tests if combining pembrolizumab (an immune system-boosting drug) with chemotherapy drugs (methotrexate, vinblastine sulfate, doxorubicin hydrochloride, cisplatin) before surgery can better treat patients compared to chemotherapy alone. The goal is to see if this combination helps shrink the cancer more effectively before removing the bladder.

How Is the Trial Designed?

Group I: Treatment (pembrolizumab, aMVAC) Experimental Treatment 7 Interventions

Patients receive pembrolizumab IV over 30 minutes on day 1 of weeks 0, 3, and 6 and methotrexate IV, vinblastine IV, doxorubicin IV, and cisplatin IV on day 1 of weeks 0, 2, 4, and 6 in the absence of disease progression or unacceptable toxicity. Patients also receive pegfilgrastim SC on day 1 or 2 of weeks 0, 2, 4, and 6 in the absence of disease progression or unacceptable toxicity. Patients then undergo standard of care radical cystectomy.

Who Is Running the Clinical Trial?

University of Washington

Lead Sponsor

Trials

1,858

Recruited

2,023,000+

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Published Research Related to This Trial

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 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]

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]

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 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 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 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]

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 ... With additional follow up, the survival benefit for pembrolizumab over chemotherapy was further improved with a HR of 0.70 (95% CI 0.57–0.85) at a median follow ...

3. nejm.org nejm.org/doi/full/10.1056/NEJMoa1613683

Pembrolizumab as Second-Line Therapy for Advanced ... Pembrolizumab was associated with significantly longer overall survival (by approximately 3 months) and with a lower rate of treatment-related adverse events ...

4. merck.com merck.com/news/mercks-keytruda-pembrolizumab-significantly-improved-disease-free-survival-dfs-as-adjuvant-therapy-versus-observation-in-high-risk-patients-with-localized-muscle-invasive-and-locall/

Merck's KEYTRUDA® (pembrolizumab) Significantly ... After a median follow-up of 36.9 months, median OS was 50.9 months (95% CI, 43.8-NE) for KEYTRUDA versus 55.8 months (95% CI, 53.3-NE) for observation. “Even ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S0923753422047603

results from KEYNOTE-045 and KEYNOTE-052 after up to ... The median follow-up was 62.9 months (range 58.6-70.9 months; data cut-off 1 October 2020). At 48 months, overall survival rates were 16.7% for pembrolizumab ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/36494006/

Efficacy and safety of pembrolizumab in metastatic ... The median follow-up was 62.9 months (range 58.6-70.9 months; data cut-off 1 October 2020). At 48 months, overall survival rates were 16.7% for pembrolizumab ...

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Efficacy and safety of pembrolizumab in patients with ... Frontline pembrolizumab monotherapy exhibited clinically meaningful and generally consistent efficacy and safety in patients with advanced ...