Pembrolizumab + Vaccine for Bladder Cancer

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Mamta Parikh

Must not be taking: Systemic steroids, Immunosuppressive therapy

Disqualifiers: HIV, Active tuberculosis, Congestive heart failure, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 30 days after last dose

30 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I trial tests the safety and side effects of a PD-L1/IDO peptide vaccine (IO102-IO103) in combination with pembrolizumab in treating patients with non-muscle invasive bladder cancer. IO102-IO103 is a novel IDO and PD-L1 peptide based immune-modulatory therapeutic. It is designed to activate the patient's own immune cells (called T-cells) to fight the tumor and stop the tumor cells escaping from the body's immune system. IO102-IO103 works to directly kill tumor cells and remove the body's immune suppressive cells, which are cells that prevent the immune system from fighting the tumor. 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. Giving IO102-IO103 in combination with pembrolizumab may make tumor cells more visible/recognizable to the immune system.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on systemic steroids or immunosuppressive therapy, you may need to stop or adjust them before starting the trial. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug pembrolizumab for bladder cancer?

Research shows that pembrolizumab, an immune checkpoint inhibitor, has improved survival in bladder cancer patients and has shown efficacy in patients with high-risk nonmuscle-invasive bladder cancer that is unresponsive to other treatments. ^{1 2 3 4 5}

Is the combination of Pembrolizumab and a vaccine generally safe for humans?

Pembrolizumab, also known as Keytruda, has been used in treating bladder cancer and is generally considered safe, but it can cause immune-related side effects like asthma. It has been approved by the FDA for certain types of bladder cancer, indicating a recognized safety profile. ^{2 6 7 8 9}

What makes the pembrolizumab and vaccine treatment for bladder cancer unique?

This treatment combines pembrolizumab, an immune checkpoint inhibitor that helps the immune system attack cancer cells, with a PD-L1/IDO peptide vaccine, which is designed to enhance the immune response specifically against bladder cancer. This combination aims to improve the effectiveness of pembrolizumab by boosting the body's immune response to the cancer. ^{2 4 7 9 10}

Research Team

Mamta Parikh

Principal Investigator

University of California, Davis

Eligibility Criteria

Adults over 18 with high-risk non-muscle invasive bladder cancer who've tried BCG treatment twice without success and aren't eligible for or have declined cystectomy. They should be in relatively good health (ECOG score 0-2) with a life expectancy of at least 6 months, adequate organ function, and no severe concurrent diseases. Pregnant women, those with certain recent treatments or vaccinations, uncontrolled diseases, or known allergies to trial drugs are excluded.

Inclusion Criteria

I cannot or do not want to undergo bladder removal surgery.

Your blood platelet count is above 50,000 per microliter within 14 days of starting the study treatment.

Your white blood cell count is not too low.

Exclusion Criteria

I have active tuberculosis.

I haven't had chemotherapy, targeted therapy, or radiotherapy in the last 2 weeks.

I have been treated with drugs targeting PD-(L)1 or CTLA-4.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive PD-L1/IDO peptide vaccine subcutaneously and pembrolizumab intravenously. Patients also undergo CT and/or CT/PET and collection of blood samples throughout the trial.

Up to 30 days after last dose

Follow-up

Participants are monitored for safety and effectiveness after treatment. Follow-up occurs every 3 months after the initial 30-day post-treatment period.

3 years

Treatment Details

Interventions

• PD-L1/IDO Peptide Vaccine
• Pembrolizumab

Trial Overview The trial is testing the combination of an immune-modulatory therapeutic called IO102-IO103 with pembrolizumab against bladder cancer. IO102-IO103 aims to activate T-cells to fight tumors and remove cells that suppress the immune system. Pembrolizumab may help the body's immune system attack cancer by making tumor cells more visible to it.

Participant Groups

Group I: Treatment (IO102-IO103, pembrolizumab) Experimental Treatment 2 Interventions

Patients receive PD-L1/IDO peptide vaccine SC and pembrolizumab IV on study. Patients also undergo CT and/or CT/PET and collection of blood samples throughout the trial.

Who Is Running the Clinical Trial?

Mamta Parikh

Lead Sponsor

Trials

7

Recruited

210+

University of California, Davis

Lead Sponsor

Trials

958

Recruited

4,816,000+

IO Biotech

Industry Sponsor

Trials

9

Recruited

750+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

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]

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 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]

The KEYNOTE-676 study aims to evaluate the safety and efficacy of pembrolizumab combined with Bacillus Calmette-Guérin (BCG) therapy in patients with high-risk nonmuscle-invasive bladder cancer (NMIBC) who have not responded to initial BCG treatment.

This Phase III trial is significant as it addresses the need for effective treatment options for patients with recurrent or BCG-unresponsive NMIBC, a group that currently has limited therapeutic alternatives.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

KEYNOTE-676: Phase III study of BCG and pembrolizumab for persistent/recurrent high-risk NMIBC. Kamat, AM., Shore, N., Hahn, N., et al.[2020]

In a study of 36 patients with locally advanced/metastatic urothelial carcinoma, the combination of the TAS0313 vaccine and pembrolizumab resulted in an objective response rate of 33.3%, indicating promising efficacy in this patient population.

The treatment was generally well-tolerated, with 94.4% of patients experiencing treatment-related adverse events, primarily mild to moderate, such as pyrexia and injection-site reactions, and no severe adverse events occurring in more than 10% of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TAS0313 Plus Pembrolizumab for Post-Chemotherapy Immune Checkpoint Inhibitor-Naïve Locally Advanced or Metastatic Urothelial Carcinoma. Nishiyama, H., Yonese, J., Kawahara, T., et al.[2023]

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]

A 67-year-old woman with metastatic renal pelvic cancer and a history of autoimmune diseases showed a significant tumor response to pembrolizumab, with complete disappearance of metastases during treatment.

Importantly, she did not experience any immune-related side effects or flare-ups of her autoimmune conditions, suggesting that pembrolizumab may be a safe and effective option for patients with urothelial carcinoma and well-controlled autoimmune diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful pembrolizumab treatment in a patient with metastatic urothelial carcinoma and underlying overlap syndrome involving systemic sclerosis and systemic lupus erythematosus. Kurokawa, M., Naito, S., Ito, 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]

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 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]

References

1. United States 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. [2022]

2. United States 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. [2022]

3. 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]

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

KEYNOTE-676: Phase III study of BCG and pembrolizumab for persistent/recurrent high-risk NMIBC. [2020]

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

TAS0313 Plus Pembrolizumab for Post-Chemotherapy Immune Checkpoint Inhibitor-Naïve Locally Advanced or Metastatic Urothelial Carcinoma. [2023]

6. England 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. [2022]

7. Australia pubmed.ncbi.nlm.nih.gov

Successful pembrolizumab treatment in a patient with metastatic urothelial carcinoma and underlying overlap syndrome involving systemic sclerosis and systemic lupus erythematosus. [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

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

10. England pubmed.ncbi.nlm.nih.gov

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