Pembrolizumab + Radiation for Bladder Cancer

Recruiting at 27 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

Trial Summary

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.

What data supports the effectiveness of the treatment Pembrolizumab + Radiation for Bladder Cancer?

Research suggests that combining pembrolizumab (an immune therapy drug) with radiation may improve treatment outcomes for bladder cancer. Studies have shown that this combination can lead to better responses and survival rates in patients with advanced urothelial cancer. ^{1 2 3 4 5}

Is the combination of pembrolizumab and radiation therapy safe for treating bladder cancer?

Pembrolizumab, when combined with radiation therapy, can cause immune-related side effects, such as myasthenia gravis (a condition causing muscle weakness) and immune thrombocytopenia (a condition where the immune system attacks platelets, leading to bleeding). These side effects have been observed in patients with different types of cancer, including bladder cancer, and should be considered when evaluating the safety of this treatment. ^{1 2 6 7 8}

How is the treatment of pembrolizumab with radiation unique for bladder cancer?

The combination of pembrolizumab, an immune therapy drug, with radiation for bladder cancer is unique because it may enhance the immune system's ability to fight cancer by creating a synergistic effect, potentially leading to better outcomes compared to using pembrolizumab alone. ^{1 2 3 4 9}

What is the purpose of this trial?

This phase II trial compares the use of pembrolizumab and radiation therapy to chemotherapy with cisplatin, gemcitabine, 5-fluorouracil or mitomycin-C and radiation therapy for the treatment of non-muscle invasive bladder cancer. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Chemotherapy drugs, such as cisplatin, gemcitabine, 5-fluorouracil or mitomycin-C, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill cancer cells and shrink tumors. Giving pembrolizumab with radiation may kill more tumor cells than chemotherapy with radiation therapy in patients with non-muscle invasive bladder cancer.

Research Team

Brian C Baumann

Principal Investigator

NRG Oncology

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

References

1. Netherlands 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). [2023]

2. United States 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. [2023]

3. Ireland pubmed.ncbi.nlm.nih.gov

Concurrent palliative radiation with pembrolizumab for platinum-refractory urothelial carcinoma is associated with improved overall survival. [2022]

4. Greece pubmed.ncbi.nlm.nih.gov

Efficacy and Tolerability of Second-line Pembrolizumab With Radiation Therapy in Advanced Urothelial Carcinoma. [2023]

5. United States 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. [2021]

6. Australia pubmed.ncbi.nlm.nih.gov

Pembrolizumab-induced myasthenia gravis with myositis and presumable myocarditis in a patient with bladder cancer. [2022]

7. Japan 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. [2022]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Association of Immune-Related Adverse Events with Pembrolizumab Efficacy in the Treatment of Advanced Urothelial Carcinoma. [2020]

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

Exceptional response to immunotherapy in association with radiotherapy in patient with breast metastasis from urothelial carcinoma: A case report. [2020]