Pembrolizumab + Radiation for Bladder Cancer

Recruiting at 93 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Glucocorticoids, Immunosuppressants

Disqualifiers: Pelvic radiation, Autoimmune disease, 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

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

Compensation: Varies

Number of Visits: 3

Duration: 4-7 weeks

160 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of treatments for bladder cancer that hasn't spread to the muscles. It compares the effects of pembrolizumab, an immunotherapy drug that helps the immune system fight cancer, combined with radiation, to traditional chemotherapy drugs (such as cisplatin, fluorouracil, gemcitabine, and mitomycin) combined with radiation. The goal is to determine if pembrolizumab with radiation can kill more cancer cells than chemotherapy with radiation. Individuals diagnosed with high-grade, non-muscle invasive bladder cancer who have had certain treatments or symptoms might be suitable candidates for this trial. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

Do I have to stop taking 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 cannot have had prior systemic chemotherapy or immunotherapy for urothelial carcinoma, and no glucocorticoids except for physiologic doses are allowed.

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

Research has shown that pembrolizumab, when used alone, is generally well-tolerated. In the KEYNOTE-052 study, 5% of patients died from causes unrelated to their disease, and a small number (1.4%) experienced serious infections like sepsis. The FDA has already approved pembrolizumab for treating some types of bladder cancer, indicating that its safety profile is well understood. Common side effects can include immune system reactions, such as inflammation in the lungs, liver, or gut, but these are usually manageable.

For chemotherapy treatments (cisplatin, gemcitabine, 5-fluorouracil, and mitomycin-C) combined with radiation, safety can vary. These drugs stop cancer cells from growing but can also cause side effects. Patients might experience nausea, fatigue, and lower blood cell counts, which can lead to infections.

This trial combines pembrolizumab with radiation to determine if this combination is as safe and effective as chemotherapy with radiation. While the treatments have known side effects, researchers closely monitor them to manage any adverse reactions. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they combine traditional therapies with new approaches to tackling bladder cancer. Most treatments for bladder cancer typically involve chemotherapy regimens like cisplatin or gemcitabine, often paired with radiation. However, one arm of the current trial offers pembrolizumab, an immunotherapy drug, which works by harnessing the body’s immune system to target cancer cells more effectively. Unlike standard chemotherapy, pembrolizumab aims to block the PD-1 pathway, potentially resulting in a more precise attack on cancer cells with fewer side effects. This innovative combination with radiation could offer a promising alternative for patients, focusing on enhancing the body's natural defenses to fight the disease.

What evidence suggests that this trial's treatments could be effective for bladder cancer?

Research has shown that using pembrolizumab with radiation therapy can effectively treat bladder cancer. In this trial, one group of participants will receive pembrolizumab combined with radiation therapy. For example, patients who received both treatments in previous studies had a much better response rate—65% compared to 19% for those who did not receive radiation. Another study found that the average time before the cancer worsened was about 5.6 months, and the average survival time was around 13.5 months. Additionally, pembrolizumab has significantly improved the time patients remain free of cancer when used as an additional treatment for urothelial cancer. This suggests that pembrolizumab, especially when combined with radiation, could be a promising treatment option for non-muscle invasive bladder cancer. ^{6 7 8 9 10}

Who Is on the Research Team?

Brian C Baumann

Principal Investigator

NRG Oncology

Are You a Good Fit for This Trial?

This trial is for patients with high-grade non-muscle invasive bladder cancer, who've had tumors removed and are recommended for cystectomy but may not be operable. They should have no nodal disease or metastasis, no pure squamous cell or adenocarcinoma of the bladder, nor neuroendocrine features.

Inclusion Criteria

My cancer does not have neuroendocrine features.

My bladder cancer re-evaluation shows no muscle invasion.

I have a specific type of bladder cancer that has not spread, and surgery was recommended.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either chemotherapy with radiation or pembrolizumab with radiation. Chemotherapy regimens include cisplatin, gemcitabine, or mitomycin with 5-fluorouracil. Pembrolizumab is administered every 6 weeks for 9 cycles. Radiation therapy is given for 20, 32, or 36 treatments over 4-7 weeks.

4-7 weeks

Multiple visits for chemotherapy/radiation administration

Follow-up

Participants are monitored for safety and effectiveness after treatment. Follow-up includes CT/MRI, blood sample collection, and optional urine sample collection.

Up to 5 years

Every 3 months for 2 years, then every 6 months for 3 years, then annually

Quality of Life Assessment

Quality of life is assessed using EORTC QLQ-C30 and Bladder Cancer Index at various time points.

Up to 2 years

What Are the Treatments Tested in This Trial?

Interventions

• Cisplatin
• Fluorouracil
• Gemcitabine
• Mitomycin
• Pembrolizumab
• Radiation Therapy

Trial Overview The PARRC Trial is comparing pembrolizumab plus radiation therapy to standard chemotherapy (cisplatin, gemcitabine, fluorouracil or mitomycin) with radiation in treating non-muscle invasive bladder cancer. It aims to see if pembrolizumab can better help the immune system attack cancer cells.

How Is the Trial Designed?

Group I: Arm 2 (Pembrolizumab and radiation) Experimental Treatment 6 Interventions

Patients receive pembrolizumab IV over 25-40 minutes on day 1 of each cycle. Cycles repeat every 6 weeks for 9 cycles in the absence of disease progression or unacceptable toxicity. Starting on day 1, patients also receive radiation therapy for 20, 32, or 36 treatments over 4-7 weeks. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients also undergo CT/MRI and blood sample collection throughout the study. Patients may also undergo optional urine sample collection on study.

Group II: Arm 1 (Chemotherapy and radiation) Active Control 9 Interventions

Patients receive one of the following chemotherapy regimens per physicians choice: 1) cisplatin IV once per week for 4 weeks, 2) gemcitabine IV on days 1, 4, 8, 11, 15, 18, 22, and 25, or 3) mitomycin IV on day 1 and 5-fluorouracil IV continuously over 120 hours on days 1-5 and 16-20. Patients receiving cisplatin or gemcitabine continue chemotherapy for 6 weeks if they are receiving radiation according to the standard hypofractionated radiation schedule. Starting on day 1, patients also receive radiation therapy for 20, 32, or 36 treatments over 4-7 weeks. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients also undergo CT/MRI and blood sample collection throughout the study. Patients may also undergo optional urine sample collection 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

The combination of pembrolizumab with chemoradiation for muscle-invasive bladder cancer (MIBC) was found to be feasible, with manageable toxicity, as only six patients experienced grade 3 or worse nonurinary adverse events out of 28 participants in the study.

The treatment showed promising efficacy, with an 88% complete response rate at 24 weeks post-chemoradiation, and favorable survival rates, including a 2-year distant metastasis-free survival rate of 78% and locoregional progression-free survival rate of 87%.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab with Chemoradiation as Treatment for Muscle-invasive Bladder Cancer: Analysis of Safety and Efficacy of the PCR-MIB Phase 2 Clinical Trial (ANZUP 1502). Weickhardt, A., Foroudi, F., Lawrentschuk, N., et al.[2023]

A 74-year-old woman with lung adenocarcinoma developed fatal immune thrombocytopenia after receiving pembrolizumab following radiotherapy, highlighting a potential risk of severe immune-related adverse events (irAEs) when combining these treatments.

Flow cytometry analysis showed increased PD-1 and Ki-67 expression in T cells post-radiotherapy, suggesting that radiotherapy may enhance immune activation and contribute to the development of irAEs in patients undergoing anti-PD-1 therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab-related Immune Thrombocytopenia in a Patient with Lung Adenocarcinoma Treated by Radiotherapy: Potential Immune-related Adverse Event Elicited by Radiation Therapy. Tamanoi, D., Saruwatari, K., Imamura, K., 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 a study of 43 patients with advanced urothelial cancer treated with pembrolizumab, 51.2% experienced immune-related adverse events (irAEs), which were linked to better survival outcomes.

Patients with grade 2 or higher irAEs had not reached median overall survival (OS) or time to treatment failure (TTF), while those with lower grade irAEs had median OS of 160 days, suggesting that the presence of irAEs may indicate a more effective response to treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of Immune-Related Adverse Events with Pembrolizumab Efficacy in the Treatment of Advanced Urothelial Carcinoma. Kobayashi, K., Suzuki, K., Hiraide, M., et al.[2020]

In a study of 98 advanced urothelial cancer patients, those who received radiotherapy to the primary tumor showed a significantly higher objective response rate to pembrolizumab (65% vs 19%) compared to those who did not receive radiotherapy.

Patients who had prior radiotherapy also experienced better overall survival rates (77% vs 50% at 12 months), suggesting that radiotherapy may enhance the effectiveness of pembrolizumab in treating advanced urothelial cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of radiotherapy to the primary tumor on the efficacy of pembrolizumab for patients with advanced urothelial cancer: A preliminary study. Fukushima, H., Kijima, T., Fukuda, S., et al.[2023]

In a study of 24 patients with advanced urothelial carcinoma, combining radiation therapy with second-line pembrolizumab showed a median overall survival of 27.7 months for those receiving curative treatment, suggesting a potential survival benefit.

The combination therapy had a clinically acceptable safety profile, with no significant difference in severe adverse events compared to patients receiving pembrolizumab alone, indicating that this approach may be safe for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Tolerability of Second-line Pembrolizumab With Radiation Therapy in Advanced Urothelial Carcinoma. Sano, T., Aizawa, R., Ito, K., et al.[2023]

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]

Citations

1. nature.com nature.com/articles/s41598-024-70182-3

Radiotherapy plus pembrolizumab for advanced urothelial ... Compared to patients who did not receive irradiation, the radiotherapy group showed a significantly higher objective response rate (65% vs 19%; ...

2. oncologynewscentral.com oncologynewscentral.com/article/real-world-data-suggest-benefit-from-sbrt-plus-pembro-in-advanced-bladder-cancer

Real-World Data Suggest Benefit From SBRT Plus Pembro ... In addition, the median progression-free survival was 5.6 months (95% CI, 4.1–8.3 months), and the median overall survival was 13.5 months (95% ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37097696/

Efficacy and Tolerability of Second-line Pembrolizumab ... Results: The median follow-up periods after pembrolizumab initiation were 15 months for the curative cohort and 4 months for the palliative cohort. The median ...

4. urotoday.com urotoday.com/conference-highlights/asco-2023/asco-2023-bladder-cancer/144881-asco-2023-long-term-outcomes-of-pembrolizumab-in-combination-with-gemcitabine-and-concurrent-hypofractionated-radiation-therapy-as-bladder-sparing-treatment-for-muscle-invasive-urothelial-cancer-of-the-bladder-a-multicenter-phase-2-trial.html

ASCO 2023: Long-Term Outcomes of Pembrolizumab in ... The study had 85% power to detect a 20% absolute improvement in 2-year bladder-intact disease-free survival rate over 60% historical rate.1 Key ...

5. 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 ... “These Phase 3 data mark the first time KEYTRUDA has shown a clinically meaningful improvement in DFS as adjuvant therapy in urothelial carcinoma,” said Dr.

6. keytrudahcp.com keytrudahcp.com/safety/adverse-reactions/urothelial-carcinoma-first-line-monotherapy/

Safety Data and Adverse Reactions for KEYNOTE-052 5% of patients (n=18/370) died from causes other than disease progression. 1.4% of patients (n=5/370) who were treated with KEYTRUDA experienced sepsis which ...

7. keytruda.com keytruda.com/advanced-urothelial-bladder-cancer/

Advanced Urothelial Bladder Cancer KEYTRUDA is an FDA-approved immunotherapy to treat certain people with advanced urothelial bladder cancer.

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

Pembrolizumab in the treatment of locally advanced or ... An interim analysis performed by the Data Safety Monitoring Committee overseeing the trial reported that patients with PD-L1 low status tumors had decreased ...

9. acsjournals.onlinelibrary.wiley.com acsjournals.onlinelibrary.wiley.com/doi/full/10.1002/cncr.35601

Efficacy and safety of pembrolizumab in patients with ... In the phase 2 KEYNOTE-052 trial, first-line pembrolizumab monotherapy was found to demonstrate antitumor activity and acceptable tolerability ...

10. fda.gov fda.gov/drugs/resources-information-approved-drugs/pembrolizumab-keytruda-advanced-or-metastatic-urothelial-carcinoma

Advanced or Metastatic Urothelial Carcinoma Immune-mediated adverse reactions, including pneumonitis, colitis, hepatitis, and endocrinopathies, were reported in the trials and were managed ...