Pemetrexed + Avelumab for Bladder Cancer

Overseen By Amishi Shah

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must be taking: Folic acid, Vitamin B12, Dexamethasone

Must not be taking: Corticosteroids, Immunosuppressives

Disqualifiers: CNS metastases, Autoimmune disease, Cardiovascular 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: 51

Duration: Up to 2 years

18 Participants Needed

Trial Summary

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, you must be able to interrupt nonsteroidal anti-inflammatory drugs (NSAIDs) around the time of pemetrexed administration. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug combination Pemetrexed and Avelumab for bladder cancer?

Avelumab has been shown to prolong overall survival in advanced urothelial carcinoma when used as a maintenance treatment after initial chemotherapy. Pemetrexed has demonstrated a favorable response rate of about 30% with minimal toxicity in advanced urothelial carcinoma, suggesting potential effectiveness when combined with other treatments. ^{1 2 3 4 5}

Is the combination of Pemetrexed and Avelumab safe for humans?

Pemetrexed has shown minimal toxicity when used alone for advanced urothelial cancer, and it has been used safely in combination with other drugs like cisplatin. Avelumab, also known as Bavencio, is generally considered safe as it is approved for use in other conditions, but specific safety data for the combination of Pemetrexed and Avelumab in bladder cancer is not provided in the available research. ^{3 6 7 8 9}

How is the drug combination of Pemetrexed and Avelumab unique for treating bladder cancer?

The combination of Pemetrexed and Avelumab is unique because it pairs a chemotherapy drug (Pemetrexed) with an immune checkpoint inhibitor (Avelumab), which may enhance the body's immune response against bladder cancer cells, potentially offering a novel approach compared to traditional chemotherapy alone. ^{1 3 6 10 11}

What is the purpose of this trial?

This phase II trial studies how well pemetrexed and avelumab work in treating patients with MTAP-deficient urothelial cancer that has spread to other places in the body. Pemetrexed may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as avelumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving pemetrexed and avelumab may work better in treating patients with MTAP-deficient urothelial cancer.

Research Team

Amishi Y. Shah

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for adults with MTAP-deficient metastatic urothelial cancer, who can stop NSAIDs as required, have measurable disease, normal organ function tests, and no severe autoimmune diseases. Participants must not be pregnant or breastfeeding and agree to use effective contraception.

Inclusion Criteria

Platelets >= 100 x 10^9/L.

I have a mild or well-controlled autoimmune condition that doesn't majorly affect my immune system.

I can stop taking NSAIDs as required around my pemetrexed treatment.

Exclusion Criteria

I haven't taken high doses of steroids or immunosuppressants in the last 2 weeks.

I have not had major surgery or am fully recovered if I did within the last 28 days.

True positive test results for hepatitis A, B, or C during screening.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive pemetrexed IV on day 1 and avelumab IV starting cycle 2, with cycles repeating every 21 days

Up to 2 years

Every 21 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

Follow-up at 30 and 120 days, then every 3 months

Treatment Details

Interventions

• Avelumab
• Pemetrexed

Trial Overview The study examines the effectiveness of combining pemetrexed (a drug that blocks enzymes needed for cell growth) with avelumab (an immunotherapy antibody) in treating patients whose cancer has spread beyond the bladder.

Participant Groups

Group I: Treatment (pemetrexed, avelumab) Experimental Treatment 2 Interventions

Patients receive pemetrexed IV over 10 minutes on day 1. Starting cycle 2, patients also receive avelumab IV over 60 minutes. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Avelumab is already approved in European Union, United States, Japan for the following indications:

Approved in European Union as Bavencio for:

• Merkel cell carcinoma
• Renal cell carcinoma
• Urothelial carcinoma

Approved in United States as Bavencio for:

• Merkel cell carcinoma
• Renal cell carcinoma
• Urothelial carcinoma

Approved in Japan as Bavencio for:

• Merkel cell carcinoma
• Renal cell carcinoma
• Urothelial carcinoma

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

Avelumab maintenance therapy after platinum-based chemotherapy in advanced urothelial carcinoma significantly improves overall response rate (ORR), progression-free survival (PFS), and overall survival (OS), especially in patients with PD-L1 positive tumors, compared to those receiving best supportive care.

While avelumab is effective, it is associated with a high rate of treatment-related adverse events (TRAEs) in 86.7% of patients, with 32.4% experiencing severe adverse events, indicating the need for careful patient monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Evaluation of Avelumab in the Treatment of Advanced Urothelial Carcinoma: Focus on Patient Selection and Outcomes. Ten Eyck, JE., Kahlon, N., Masih, S., et al.[2022]

The standard treatment for locally advanced and metastatic transitional cell carcinoma includes the four-drug combination MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) or the two-drug combination GC (gemcitabine and cisplatin).

New studies suggest that pemetrexed, either alone or in combination with gemcitabine, shows promise for improved efficacy and reduced toxicity, indicating a need for further research into these new treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pemetrexed in transitional cell carcinoma of the urothelium. von der Maase, H.[2022]

In a phase II clinical trial involving 42 patients with advanced urothelial carcinoma, the combination of pemetrexed and cisplatin resulted in a high objective response rate of 64.3%, indicating significant efficacy as a first-line treatment.

The treatment was well tolerated, with manageable toxicity; while 28.6% of patients experienced grade 3 or 4 neutropenia, there were no cases of febrile neutropenia reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of pemetrexed in combination with cisplatin in patients with advanced urothelial cancer: the PECULIAR study (KCSG 10-17). Choi, YJ., Lee, SH., Lee, JL., et al.[2018]

The combination of enfortumab vedotin (EV) and pembrolizumab (Pembro) demonstrated a high confirmed objective response rate (cORR) of 64.5% in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer, indicating its efficacy as a first-line treatment option.

Patients receiving the combination therapy also experienced durable responses, with 65.4% maintaining their response at 12 months, while the safety profile showed manageable adverse events, with no new safety signals identified.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enfortumab Vedotin With or Without Pembrolizumab in Cisplatin-Ineligible Patients With Previously Untreated Locally Advanced or Metastatic Urothelial Cancer. O'Donnell, PH., Milowsky, MI., Petrylak, DP., et al.[2023]

Immune checkpoint inhibitors like pembrolizumab and nivolumab have transformed treatment for advanced urothelial cancer, but most patients still do not respond to these therapies, highlighting a need for better predictive biomarkers.

Current PD-L1 expression levels are not consistently reliable for predicting patient responses, prompting ongoing research into resistance mechanisms and combination strategies to enhance treatment efficacy and manage side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current and Future Landscape of Immune Checkpoint Inhibitors in Urothelial Cancer. Alhalabi, O., Shah, AY., Lemke, EA., et al.[2020]

In a study of 64 patients with advanced bladder cancer, the combination of pemetrexed and gemcitabine showed an overall response rate of 20%, indicating some effectiveness but not superior to single-agent gemcitabine.

The treatment had a manageable safety profile, with significant hematologic toxicities observed in some patients, including neutropenia (38%) and anemia (19%), but overall, the combination did not demonstrate improved efficacy compared to gemcitabine alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II trial of pemetrexed plus gemcitabine in locally advanced and/or metastatic transitional cell carcinoma of the urothelium. von der Maase, H., Lehmann, J., Gravis, G., et al.[2022]

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]

Pemetrexed is a multitargeted antifolate that has demonstrated effectiveness against various solid tumors, including those in the genitourinary tract.

It shows promising results when used in combination with other chemotherapy agents like gemcitabine, suggesting potential for further research in advanced and adjuvant treatment settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brief communication: use of the multitargeted antifolate pemetrexed (Alimta) in genitourinary cancer. Misset, JL.[2022]

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]

Atezolizumab, an anti-PD-L1 monoclonal antibody, has shown durable responses in treating locally advanced and metastatic urothelial cancer, especially in patients who have failed platinum-based chemotherapy or are ineligible for cisplatin.

The treatment with atezolizumab has a more favorable toxicity profile compared to traditional cytotoxic chemotherapy, making it a promising option for patients with advanced bladder cancer, although further research is needed to identify additional predictive markers for response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atezolizumab in invasive and metastatic urothelial carcinoma. Crist, M., Balar, A.[2019]

Atezolizumab is an FDA-approved treatment for advanced bladder cancer that works by blocking the PD-L1/PD-1 immune checkpoint, enhancing T-cell immunity against tumors.

In clinical trials, atezolizumab showed a 15% objective response rate in patients whose cancer progressed after chemotherapy, and a 24% response rate in chemotherapy-naïve patients, with a favorable safety profile compared to other second-line treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atezolizumab: A PD-L1-Blocking Antibody for Bladder Cancer. Inman, BA., Longo, TA., Ramalingam, S., et al.[2022]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Clinical Evaluation of Avelumab in the Treatment of Advanced Urothelial Carcinoma: Focus on Patient Selection and Outcomes. [2022]

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

Pemetrexed in transitional cell carcinoma of the urothelium. [2022]

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

Phase II study of pemetrexed in combination with cisplatin in patients with advanced urothelial cancer: the PECULIAR study (KCSG 10-17). [2018]

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

Enfortumab Vedotin With or Without Pembrolizumab in Cisplatin-Ineligible Patients With Previously Untreated Locally Advanced or Metastatic Urothelial Cancer. [2023]

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

Current and Future Landscape of Immune Checkpoint Inhibitors in Urothelial Cancer. [2020]

6. England pubmed.ncbi.nlm.nih.gov

A phase II trial of pemetrexed plus gemcitabine in locally advanced and/or metastatic transitional cell carcinoma of the urothelium. [2022]

7. 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]

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

Brief communication: use of the multitargeted antifolate pemetrexed (Alimta) in genitourinary cancer. [2022]

9. England pubmed.ncbi.nlm.nih.gov

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

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

Atezolizumab in invasive and metastatic urothelial carcinoma. [2019]

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

Atezolizumab: A PD-L1-Blocking Antibody for Bladder Cancer. [2022]