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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to evaluate the effectiveness of combining pemetrexed and avelumab for individuals with MTAP-deficient urothelial cancer that has metastasized. Pemetrexed stops cancer cell growth, while avelumab, an immunotherapy drug, boosts the immune system to combat cancer. This trial may suit those diagnosed with MTAP-deficient metastatic urothelial carcinoma who have previously undergone treatments such as chemotherapy or specific immune therapies. As a Phase 2 trial, the research focuses on assessing the treatment's efficacy in an initial, smaller group of participants.

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.

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

Research has shown that pemetrexed is generally well-tolerated by patients, with side effects that are usually manageable. Some side effects may increase over time, but they can be controlled. Studies have found it to be moderately effective in treating urothelial cancer, a type of bladder cancer.

Avelumab, a type of immunotherapy, helps the body's immune system fight cancer. Although specific safety data for using pemetrexed and avelumab together is not available, each drug has been used separately in cancer treatments.

This trial is in a specific phase, indicating that initial safety tests have been completed, reducing the likelihood of severe side effects. However, individual experiences can vary, and some side effects might still occur. It is important to discuss potential risks and benefits with a doctor before joining a trial. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for bladder cancer?

Researchers are excited about the combination of Pemetrexed and Avelumab for bladder cancer because it offers a unique approach compared to current treatments. While traditional options like chemotherapy primarily target rapidly dividing cancer cells, Avelumab is an immunotherapy that works by enhancing the body's immune response against cancer cells. This combination aims to not only attack the cancer directly with Pemetrexed but also boost the immune system to recognize and fight the tumor more effectively. This dual-action strategy holds the promise of improved outcomes for patients with bladder cancer, potentially offering better disease control and longer-lasting effects.

What evidence suggests that pemetrexed and avelumab might be an effective treatment for bladder cancer?

Studies have shown that avelumab, when used as an initial treatment for advanced bladder cancer, can extend patient survival. For instance, some studies report that 28.9% of patients remain alive after 1, 2, and 5 years. Pemetrexed stops cancer cells from growing. In this trial, participants will receive a combination of avelumab and pemetrexed, which might enhance treatment by boosting the immune system and directly attacking cancer cells. Early research suggests this combination could benefit patients with a specific type of metastatic bladder cancer. This treatment approach is promising because it works in two ways. ^{6 7 8 9 10}

Who Is on the Research Team?

Amishi Y. Shah

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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 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]

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]

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]

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]

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]

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]

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]

Citations

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Pemetrexed and Avelumab in Treating Patients With MTAP ... 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 ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10685024/

Avelumab first-line maintenance treatment for advanced ... 10, 11, 12 For example, in patients with metastatic bladder cancer in the USA between 2000 and 2019, overall survival (OS) rates at 1, 2, and 5 years were 28.9% ...

3. asco.org asco.org/abstracts-presentations/ABSTRACT383181

A phase II trial evaluating combination pemetrexed and ... The primary objective of this trial is to evaluate response rate with sequential pemetrexed and avelumab in MTAP-deficient urothelial cancer.

4. mdanderson.org mdanderson.org/patients-family/diagnosis-treatment/clinical-trials/clinical-trials-index/clinical-trials-detail.ID2018-0576.html

A Phase II Trial to Evaluate Combination Therapy with ... 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 ...

5. aacrjournals.org aacrjournals.org/cancerrescommun/article/4/6/1609/746189/First-line-Avelumab-plus-Chemotherapy-in-Patients

Results from the Phase Ib/II JAVELIN Chemotherapy Medley ... Preliminary efficacy and safety findings with avelumab + chemotherapy in urothelial carcinoma and NSCLC were consistent with previous studies of ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12527632/

Pemetrexed Maintenance versus Observation in Patients with ... Pemetrexed, however, has shown moderate efficacy with a tolerable toxicity profile and cumulative toxicity when tested in urothelial cancer [12,13]. Pemetrexed ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT03744793?cond=%22Invasive%20Bladder%20Transitional%20Cell%20Carcinoma%22&intr=%22enzyme%20inhibitors%22&viewType=Table&rank=1

Pemetrexed and Avelumab in Treating Patients With MTAP ... 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 ...

8. ascopubs.org ascopubs.org/doi/10.1200/JCO.2022.40.16_suppl.TPS4612

A phase II trial evaluating combination pemetrexed and ... The primary objective of this trial is to evaluate response rate with sequential pemetrexed and avelumab in MTAP-deficient urothelial cancer.

9. centerwatch.com centerwatch.com/clinical-trials/listings/NCT03744793/pemetrexed-and-avelumab-in-treating-patients-with-mtap-deficient-metastatic-urothelial-cancer

Pemetrexed and Avelumab in Treating Patients With MTAP ... This phase II trial studies how well pemetrexed and avelumab work in treating patients with MTAP-deficient urothelial cancer that has spread ...

10. bcan.org bcan.org/clinicaltrials/pemetrexed-and-avelumab-in-treating-patients-with-mtap-deficient-metastatic-urothelial-cancer/

Pemetrexed and Avelumab in Treating Patients With MTAP ... 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 ...