Pembrolizumab + Chemotherapy for Bladder and Prostate Cancer

Overseen By Sara Rodriguez

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Jonsson Comprehensive Cancer Center

Must be taking: Androgen deprivation therapy

Must not be taking: Live vaccines, Immunosuppressants

Disqualifiers: Active infection, Autoimmune disease, others

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

Compensation: Varies

Number of Visits: 15

Duration: 18 weeks

15 Participants Needed

Trial Summary

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

The trial protocol does not specify if you need to stop taking your current medications. However, ongoing androgen deprivation therapy and treatment for bone metastasis are allowed, and prior immunotherapy is permitted if completed more than 4 weeks before enrollment.

What data supports the effectiveness of the drug pembrolizumab in combination with chemotherapy for bladder and prostate cancer?

Pembrolizumab has shown effectiveness in treating advanced urothelial cancer, particularly in patients who cannot receive standard cisplatin-based chemotherapy, with a response rate of 28.6% in a study. It is also being evaluated in combination with chemotherapy for muscle-invasive bladder cancer, suggesting potential benefits in similar cancer types. ^{1 2 3 4 5}

Is the combination of Pembrolizumab and chemotherapy safe for treating bladder and prostate cancer?

Pembrolizumab, when used for bladder cancer, is generally well tolerated with main side effects including tiredness, low white blood cell count, anemia (low red blood cell count), muscle pain, decreased appetite, and nausea. It has been approved for use in patients who cannot tolerate cisplatin-based chemotherapy, indicating an acceptable safety profile. ^{1 5 6 7 8}

What makes the drug pembrolizumab combined with chemotherapy unique for bladder and prostate cancer?

Pembrolizumab, when combined with chemotherapy, offers a novel approach for treating bladder and prostate cancer by targeting the PD-1 pathway, which helps the immune system attack cancer cells. This combination is particularly beneficial for patients who cannot tolerate standard cisplatin-based chemotherapy, providing an alternative with potential survival benefits. ^{2 3 9 10 11}

What is the purpose of this trial?

This phase Ib trial studies how well pembrolizumab works with combination chemotherapy in treating participants with small cell/neuroendocrine cancers of the urothelium or prostate that has spread to nearby tissue or lymph nodes or that has spread to other places in the body. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as etoposide, docetaxel, cisplatin, and carboplatin, 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. Giving pembrolizumab with platinum-based chemotherapy may work better in treating participants with small cell/neuroendocrine cancers of the urothelium or prostate.

Research Team

Arnold Chin

Principal Investigator

UCLA / Jonsson Comprehensive Cancer Center

Eligibility Criteria

This trial is for adults with advanced small cell/neuroendocrine cancers of the bladder, urethra, or prostate. Participants must have adequate organ function and no recent blood transfusions. They should not have had certain cancer treatments recently and agree to use contraception. Exclusions include active autoimmune disease, known psychiatric disorders that affect participation, recent other cancer therapies, severe allergies to trial drugs, active infections like HIV or hepatitis B/C, pregnant or breastfeeding women.

Inclusion Criteria

Platelets >= 100 000/uL within 10 days prior to the start of study treatment

Hemoglobin >= 9.0 g/dL or >= 5.6 mmol/L within 10 days prior to the start of study treatment, without erythropoietin dependency and without pRBC transfusion within the last 2 weeks

Creatinine =< 1.5 x ULN OR measured or calculated creatinine clearance (GFR can also be used) >= 30 mL/min for participants with creatinine levels >1.5 x institutional ULN within 10 days prior to the start of study treatment

Exclusion Criteria

You have an ongoing autoimmune disease that has required medication in the past 2 years.

WOCBP with a positive urine pregnancy test within 72 hours prior to receiving the first dose of trial medication

You have a mental illness or addiction that could make it difficult to follow the rules of the trial.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive pembrolizumab and platinum-based chemotherapy. Pembrolizumab is administered IV over 30 minutes on day 1, and chemotherapy is administered according to cohort-specific regimens. Treatment repeats every 3 weeks for up to 6 courses.

18 weeks

6 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion. Follow-up occurs at 30 days post-treatment, then every 9-12 weeks for up to 2 years, and every 12 weeks thereafter.

Up to 3 years

Regular visits every 9-12 weeks

Treatment Details

Interventions

• Carboplatin
• Cisplatin
• Docetaxel
• Etoposide
• Pembrolizumab

Trial Overview The study tests pembrolizumab (an immune system booster) combined with chemotherapy drugs cisplatin, carboplatin, docetaxel, and etoposide in patients with specific urothelial/prostate cancers. The goal is to see if this combination is more effective than current treatments at stopping cancer growth by killing tumor cells or preventing them from dividing and spreading.

Participant Groups

Group I: Treatment (pembrolizumab, platinum-based chemotherapy) Experimental Treatment 5 Interventions

Participants receive pembrolizumab IV over 30 minutes on day 1. Courses repeat every 3 weeks for 2 years in the absence of disease progression or unacceptable toxicity. Participants also receive standard of care chemotherapy comprising either etoposide IV on days 1-3 and cisplatin IV or carboplatin IV on day 1 (Cohort 1), or etoposide IV on days 1-3, carboplatin IV on day 1, and docetaxel IV on day 1 (Cohort 2). Treatment repeats every 3 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Carboplatin is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Paraplatin for:

• Ovarian cancer
• Testicular cancer
• Lung cancer
• Head and neck cancer
• Brain cancer

Approved in European Union as Carboplatin for:

• Ovarian cancer
• Small cell lung cancer

Approved in Canada as Carboplatin for:

• Ovarian cancer
• Small cell lung cancer
• Testicular cancer

Who Is Running the Clinical Trial?

Jonsson Comprehensive Cancer Center

Lead Sponsor

Trials

373

Recruited

35,200+

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

Findings from Research

Atezolizumab and pembrolizumab received accelerated FDA approval in 2017 for treating advanced urothelial carcinoma in patients who cannot receive cisplatin, showing objective response rates of 23.5% and 28.6%, respectively, in single-arm trials with a total of 746 patients.

Due to preliminary concerns from ongoing trials, the FDA revised the indications for these drugs, now specifying they are for patients not eligible for any platinum-based chemotherapy or those with high PD-L1 expression, ensuring a more targeted treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Atezolizumab or Pembrolizumab for the Treatment of Patients with Advanced Urothelial Carcinoma Ineligible for Cisplatin-Containing Chemotherapy. Suzman, DL., Agrawal, S., Ning, YM., et al.[2020]

In a phase 2 study involving 370 patients with advanced urothelial cancer who were ineligible for cisplatin-based chemotherapy, first-line treatment with pembrolizumab resulted in a 24% objective response rate, with 83% of these responses ongoing at a median follow-up of 5 months.

Pembrolizumab demonstrated acceptable safety, with only 10% of patients experiencing serious treatment-related adverse events, making it a viable treatment option for patients with significant comorbidities or poor prognostic factors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Balar, AV., Castellano, D., O'Donnell, PH., 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]

Pembrolizumab significantly improves survival and quality of life for patients with advanced urothelial cancer who cannot tolerate cisplatin-based chemotherapy, offering an increase of approximately 2.11 to 2.16 years in overall survival and 1.71 to 1.75 quality-adjusted life years (QALYs) compared to standard treatments like carboplatin plus gemcitabine and gemcitabine monotherapy.

Despite being associated with higher costs (an increase of €90,520 compared to carboplatin plus gemcitabine), pembrolizumab is considered cost-effective at a threshold of €100,000/QALY, making it a viable first-line treatment option for this patient population in Sweden.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cost-effectiveness of Pembrolizumab for Patients with Advanced, Unresectable, or Metastatic Urothelial Cancer Ineligible for Cisplatin-based Therapy. Patterson, K., Prabhu, V., Xu, R., et al.[2022]

Urothelial carcinoma, the most common urological cancer, is primarily treated with Bacillus Calmette-Guerin (BCG) immunotherapy for superficial cases and cisplatin-based chemotherapy for metastatic disease, with vinflunine as the standard second-line option in Europe.

Novel PD-1/PD-L1 inhibitors like atezolizumab, nivolumab, and pembrolizumab have shown promise in treating bladder cancer, particularly for patients who cannot tolerate cisplatin, and are generally well tolerated with manageable side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Immunotherapy for Bladder Cancer]. Büchler, T.[2019]

In a phase 2 trial involving 22 patients with advanced urothelial cancer who had previously failed platinum-based chemotherapy, the combination of docetaxel and ifosfamide showed an objective response rate of 25%, with 20% achieving complete responses, particularly in those with lymph node-only recurrences.

The treatment was well tolerated, with mild to moderate side effects, and serious toxicities were relatively low, suggesting that this combination therapy could be a viable option for patients with specific recurrence patterns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Docetaxel and ifosfamide as second line treatment for patients with advanced or metastatic urothelial cancer after failure of platinum chemotherapy: a phase 2 study. Krege, S., Rembrink, V., Börgermann, C., et al.[2019]

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, a checkpoint inhibitor, has been shown to significantly improve overall survival in patients with locally advanced or metastatic urothelial carcinoma who have progressed after cisplatin-containing chemotherapy, compared to standard chemotherapy options.

Additionally, evidence from Phase 1 and 2 trials suggests that checkpoint inhibitors like pembrolizumab are effective as a first-line treatment for patients who cannot tolerate cisplatin-based therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of bladder cancer. Sundahl, N., Rottey, S., De Maeseneer, D., et al.[2018]

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 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]

References

1. England pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Atezolizumab or Pembrolizumab for the Treatment of Patients with Advanced Urothelial Carcinoma Ineligible for Cisplatin-Containing Chemotherapy. [2020]

2. England pubmed.ncbi.nlm.nih.gov

First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Perioperative pembrolizumab therapy in muscle-invasive bladder cancer: Phase III KEYNOTE-866 and KEYNOTE-905/EV-303. [2021]

4. 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]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Cost-effectiveness of Pembrolizumab for Patients with Advanced, Unresectable, or Metastatic Urothelial Cancer Ineligible for Cisplatin-based Therapy. [2022]

6. Czech Republic pubmed.ncbi.nlm.nih.gov

[Immunotherapy for Bladder Cancer]. [2019]

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

Docetaxel and ifosfamide as second line treatment for patients with advanced or metastatic urothelial cancer after failure of platinum chemotherapy: a phase 2 study. [2019]

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. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of bladder cancer. [2018]

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

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

11. 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]