Pemetrexed for Bladder Cancer

Overseen By Study Coordinator, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Northwestern University

Must be taking: Folic acid, Vitamin B12, Steroids

Must not be taking: Investigational agents

Disqualifiers: Prior pemetrexed, Uncontrolled illness, Cardiac 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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 5

Duration: 21 days per cycle

64 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 stop taking nonsteroidal anti-inflammatory drugs (NSAIDs) or high-dose aspirin around the time of pemetrexed treatment. There is also a 28-day washout period required after stopping any prior chemotherapy, radiation, or investigational agents before starting the trial.

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

Pemetrexed has shown effectiveness in treating various solid tumors, including bladder cancer, and has a favorable response rate of about 30% in advanced urothelial carcinoma with minimal side effects. It is also effective when combined with other drugs like gemcitabine and cisplatin for treating advanced urothelial cancer. ^{1 2 3 4 5}

Is Pemetrexed generally safe for humans?

Pemetrexed has been used to treat various cancers and is generally considered safe when kidney function is normal, but it can cause kidney damage, skin changes, and rashes in some people. ^{1 2 5 6 7}

How is the drug Pemetrexed unique for treating bladder cancer?

Pemetrexed is unique because it is a multitargeted antifolate that works by blocking several enzymes needed for cancer cell growth, and it has shown effectiveness in a variety of solid tumors, including bladder cancer. It can be used alone or in combination with other drugs like cisplatin, offering a favorable response rate with minimal toxicity. ^{1 2 4 5 8}

What is the purpose of this trial?

This phase II trial tests how well pemetrexed works in treating patients with urothelial bladder cancer and other solid tumors that have spread from where they first started (primary site) to other places in the body (metastatic) with mutations that result in a loss of function in the MLL4-protein/KMT2D-gene or UTX-protein/KDM6A-gene or MTAP enzyme. Loss of function due to a genetic mutation means a gene's activity may be reduced or eliminated. Mutations that result in a loss of function in the MLL4-protein or KMT2D-gene are found in 9.96% of all cancers including bladder carcinoma patients, esophageal squamous cell carcinoma and esophageal adenocarcinoma patients. In addition, mutations that result in a loss of function in the UTX-protein or KDM6A-gene are found in approximately 5% of all tumors, including bladder cancers, endometrial cancer, and esophagogastric cancer amongst many other tumor types. Pemetrexed is in a class of medications called antifolate antineoplastic agents. It works by stopping cells from using folic acid to make deoxyribonucleic acid and may kill tumor cells. Giving pemetrexed may increase response in patients with metastatic urothelial bladder cancer and other solid tumors with the loss of function in the MLL4-protein/KMT2D-gene or UTX-protein/KDM6A-gene or MTAP enzyme.

Research Team

Devalingam Mahalingam, MBBChBAO

Principal Investigator

Northwestern University

Eligibility Criteria

This trial is for patients with metastatic urothelial bladder cancer and other solid tumors that have spread, who also have specific genetic mutations (loss of function in MLL4-protein/KMT2D-gene or UTX-protein/KDM6A-gene or MTAP enzyme). Details on inclusion and exclusion criteria are not provided.

Inclusion Criteria

Patients of child-bearing potential and their partners must agree to adequate contraception

Patients must be able to understand and sign a written informed consent

Patients must have the ability to comply with supplemental therapies

Exclusion Criteria

Patients with uncontrolled intercurrent illnesses

Patients who received specified treatments/procedures within minimum intervals before study drug

Patients receiving other investigational agents

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive pemetrexed intravenously over 10 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

21 days per cycle

1 visit per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up every 3 months for up to 12 months.

12 months

4 visits (in-person)

Treatment Details

Interventions

• Pemetrexed

Trial Overview The trial is testing the effectiveness of Pemetrexed, a medication that inhibits tumor cells from using folic acid to create DNA, potentially killing them. It's aimed at improving treatment response in patients with certain genetic alterations.

Participant Groups

Group I: Treatment (pemetrexed) Experimental Treatment 3 Interventions

Patients receive pemetrexed IV over 10 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo blood and urine sample collection on study as well as CT throughout the trial.

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

Approved in United States as Alimta for:

• Malignant pleural mesothelioma
• Non-small cell lung cancer

Approved in European Union as Alimta for:

• Malignant pleural mesothelioma
• Non-small cell lung cancer

Who Is Running the Clinical Trial?

Northwestern University

Lead Sponsor

Trials

1,674

Recruited

989,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

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 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]

In a phase 2 trial involving 46 patients with advanced urothelial cancer, the combination of pemetrexed and gemcitabine showed moderate antitumor activity, achieving an overall response rate of 31.8%.

While the treatment resulted in a median overall survival of 13.4 months, it also caused significant side effects, with 75% of patients experiencing severe neutropenia and 11% developing febrile neutropenia, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 2 trial of pemetrexed disodium and gemcitabine in advanced urothelial cancer (E4802): a trial of the Eastern Cooperative Oncology Group. Dreicer, R., Li, H., Cooney, MM., et al.[2022]

Pemetrexed is a multitargeted antifolate that effectively inhibits key enzymes involved in cancer cell growth and is active against various solid tumors, including non-small-cell lung cancer and ovarian cancer.

A recent randomized trial found that administering pemetrexed followed by gemcitabine on specific days every 21 days resulted in the best efficacy and lowest toxicity, highlighting an optimized treatment sequence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical studies of pemetrexed and gemcitabine combinations. Adjei, AA.[2022]

In a study of 29 non-small-cell lung cancer patients treated with pemetrexed, 21% developed acute kidney injury (AKI) despite having an initial eGFR above the recommended threshold of 45 mL/min, indicating potential renal toxicity even in patients considered safe for treatment.

Patients with a baseline eGFR below 60 mL/min were more likely to experience AKI, suggesting that careful monitoring and management of renal function and risk factors are essential when administering pemetrexed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pemetrexed induced acute kidney injury in patients with non-small cell lung cancer: reversible and chronic renal damage. Rombolà, G., Vaira, F., Trezzi, M., et al.[2021]

Pemetrexed, a treatment for malignant pleural mesothelioma and non-small cell lung cancer, has been associated with a new toxicity resembling scleroderma, as seen in two cases involving painful induration and edema of the lower extremities.

This adverse effect can be mistaken for erysipelas due to similar symptoms, but it lacks fever; recognizing this toxicity is crucial for timely diagnosis and management, and folate and vitamin B12 supplementation may help reduce its incidence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Pemetrexed-induced scleroderma-like changes in the lower legs]. Corbaux, C., Marie, J., Meraud, JP., et al.[2015]

Pemetrexed is an FDA-approved anti-folate agent used to treat malignant pleural mesothelioma and previously treated non-small cell lung cancer, showing efficacy in these patient populations.

In clinical trials, rash occurred in 17-22% of patients treated with pemetrexed, and this report highlights a specific case of rash due to urticarial vasculitis, contributing to the understanding of pemetrexed's side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pemetrexed-associated urticarial vasculitis. Lopes, G., Vincek, V., Raez, LE.[2015]

Pemetrexed disodium (Alimta) was the first drug approved by the US FDA in February 2004 for treating malignant pleural mesothelioma, a rare cancer, highlighting its significance in oncology.

In August 2004, pemetrexed also received accelerated approval for use as a second-line treatment for non-small-cell lung cancer, demonstrating its efficacy in targeting folate-dependent processes crucial for cancer cell growth.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pemetrexed disodium. Gibbs, D., Jackman, A.[2019]

References

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

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

2. 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]

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

Phase 2 trial of pemetrexed disodium and gemcitabine in advanced urothelial cancer (E4802): a trial of the Eastern Cooperative Oncology Group. [2022]

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

Clinical studies of pemetrexed and gemcitabine combinations. [2022]

5. Italy pubmed.ncbi.nlm.nih.gov

Pemetrexed induced acute kidney injury in patients with non-small cell lung cancer: reversible and chronic renal damage. [2021]

6. France pubmed.ncbi.nlm.nih.gov

[Pemetrexed-induced scleroderma-like changes in the lower legs]. [2015]

7. Ireland pubmed.ncbi.nlm.nih.gov

Pemetrexed-associated urticarial vasculitis. [2015]

8. England pubmed.ncbi.nlm.nih.gov

Pemetrexed disodium. [2019]