Lurbinectedin + Avelumab for Bladder Cancer

Overseen By NCI Referral Office

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Lurbinectedin

Disqualifiers: Untreated CNS metastases, Active autoimmune, 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: 94

Duration: Up to 10 years

45 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: Small cell carcinoma of the bladder (SCCB) and other high-grade neuroendocrine tumors (HGNET) of the urinary tract are rare but aggressive cancers. Average survival for people diagnosed with SCCB or HGNET is about 1 year. Lurbinectedin and avelumab are drugs that are approved to treat other cancers. Researchers want to see if these drugs can help people with SCCB or HGNET. Objective: To test lurbinectedin with or without avelumab in people with SCCB or HGNET. Eligibility: Adults aged 18 years and older with SCBB or HGNET that returned and spread after treatment. Design: Participants will be screened. They will have a physical exam. They will have blood tests and imaging scans. They may need to have a new biopsy: A small needle will be used to collect a tissue sample from the tumor. Both study drugs are given through a tube attached to a needle inserted into a vein. If participants have already received a drug like avelumab they will receive only lurbinectedin. If patients have not been previously treated with a drug like avelumab they will receive both lurbinectedin and avelumab. All participants will receive their treatment once every 3 weeks for up to 10 years. They will also receive other drugs to relieve adverse effects. Biopsies, blood tests, and imaging scans will be repeated during some study visits. Participants may also have urine tests and tests of their heart function. Participants may remain in the study as long as the treatment is helping them. If they stop treatment, they will have safety visits 14, 30, and 90 days after their last dose. Additional follow-up visits will continue 5 to 10 years.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, if you are on systemic corticosteroids or other immunosuppressive agents, you must discontinue them at least 1 week prior to treatment initiation for recent short-term use or at least 4 weeks prior for long-term use. Hormonal therapies for other cancers may be continued if stopping them could increase the risk of disease progression.

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

Avelumab, a drug that helps the immune system fight cancer, has been shown to improve survival in patients with advanced bladder cancer, especially after chemotherapy. It has been approved for use in these cases, making it a standard treatment option. ^{1 2 3 4 5}

Is the combination of Lurbinectedin and Avelumab safe for humans?

Avelumab, used in treating advanced bladder cancer, has shown a well-tolerated safety profile in clinical trials, meaning it is generally safe for humans. However, specific safety data for the combination of Lurbinectedin and Avelumab is not provided in the available research. ^{1 2 6 7 8}

What makes the drug combination of Lurbinectedin and Avelumab unique for bladder cancer?

The combination of Lurbinectedin and Avelumab is unique because Avelumab is an immune checkpoint inhibitor that helps the immune system attack cancer cells, and it has been approved for use in advanced bladder cancer after chemotherapy. This combination may offer a novel approach by potentially enhancing the immune response against bladder cancer. ^{1 2 4 5 7}

Research Team

Andrea B Apolo, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

This trial is for adults over 18 with Small Cell Carcinoma of the Bladder (SCCB) or high-grade neuroendocrine tumors (HGNET) in the urinary tract that have worsened and spread post-treatment. Participants must be able to undergo a biopsy, blood tests, imaging scans, and possibly heart function tests.

Inclusion Criteria

I am 18 years old or older.

AST(SGOT)/ALT(SGPT) <=1.5 x institutional ULN

My cancer has spread and is getting worse.

Exclusion Criteria

Pregnant people as evaluated by a positive serum or urine beta-human chorionic gonadotropin (beta-hCG) test

I am taking low doses of steroids, not more than 10 mg of prednisone a day.

I have brain metastases that are causing symptoms or have not been treated.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive lurbinectedin with or without avelumab every 3 weeks for up to 10 years

Up to 10 years

Every 3 weeks (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 to 10 years

Every 90 days

Treatment Details

Interventions

• Avelumab
• Lurbinectedin

Trial Overview The study is examining the effectiveness of Lurbinectedin alone versus combined with Avelumab in treating SCCB or HGNET. Treatments are administered intravenously every three weeks for up to ten years, alongside drugs to mitigate side effects.

Participant Groups

Group I: Arm 2 Experimental Treatment 2 Interventions

Treatment with lurbinectedin and avelumab

Group II: Arm 1 Experimental Treatment 1 Intervention

Treatment with lurbinectedin

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?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

Avelumab, an anti-PD-L1 antibody, has received FDA accelerated approval for treating recurrent or metastatic urothelial carcinoma after first-line chemotherapy failure, highlighting its role in improving survival for patients with this aggressive cancer.

This approval marks a significant advancement in immunotherapy for urothelial carcinoma, as it is the fifth immune checkpoint inhibitor approved for this condition, indicating a growing recognition of the efficacy of immune checkpoint blockade in managing advanced bladder cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A review of avelumab in locally advanced and metastatic bladder cancer. Rao, A., Patel, MR.[2020]

Avelumab, a PD-L1 inhibitor, has been established as a new standard of care for patients with advanced or metastatic urothelial carcinoma (UC) following platinum-based chemotherapy, based on results from the JAVELIN bladder 100 trial.

The use of maintenance avelumab after initial chemotherapy has shown promise in restoring T cell responses against tumors, indicating a potential improvement in treatment outcomes for UC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Avelumab in locally advanced or metastatic urothelial carcinoma. Jackson-Spence, F., Szabados, B., Toms, C., et al.[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]

Avelumab, an anti-PD-L1 antibody, demonstrated prolonged efficacy in patients with platinum-treated advanced/metastatic urothelial carcinoma, with a confirmed overall response rate of 16.5% and a median overall survival of 7.0 months after a median follow-up of 31.9 months.

The treatment was particularly effective in high-risk subgroups, such as elderly patients and those with renal insufficiency, and early response to treatment (within 3 months) was associated with significantly longer overall survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Avelumab as second-line therapy for metastatic, platinum-treated urothelial carcinoma in the phase Ib JAVELIN Solid Tumor study: 2-year updated efficacy and safety analysis. Apolo, AB., Ellerton, JA., Infante, JR., et al.[2021]

Avelumab maintenance therapy is considered cost-effective for treating advanced or metastatic urothelial cancer (mUC) in the United States, with incremental cost-effectiveness ratios (ICERs) of $38,369.50 per QALY for the overall population and $16,150.29 per QALY for the PD-L1-positive population.

In contrast, avelumab was not deemed cost-effective in China, with ICERs of $241,610.25 and $100,528.29 per QALY for the overall and PD-L1-positive populations, respectively, exceeding the local willingness to pay threshold.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cost-Effectiveness of Avelumab Maintenance Therapy Plus Best Supportive Care vs. Best Supportive Care Alone for Advanced or Metastatic Urothelial Carcinoma. Xie, Q., Zheng, H., Chen, Y., et al.[2022]

In a study of 115 patients with metastatic urothelial carcinoma treated with atezolizumab (ATZ) after failing first-line chemotherapy, the objective response rate was 28.7%, indicating that ATZ is effective in this patient population.

The treatment was well tolerated, with 98% of patients experiencing adverse events, but only 21.2% had severe (grade 3-4) treatment-related adverse events, suggesting a manageable safety profile similar to previous clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atezolizumab in Patients with Metastatic Urothelial Carcinoma Who Have Progressed After First-line Chemotherapy: Results of Real-life Experiences. Tural, D., Ölmez, ÖF., Sümbül, AT., et al.[2022]

Avelumab demonstrated antitumor activity in patients with platinum-refractory metastatic urothelial carcinoma, achieving a complete or partial response in 17% of treated patients, including 6% with complete responses.

The safety profile of avelumab was manageable, with most treatment-related adverse events being mild (grade 1-2), although there were serious adverse events in 8% of patients, including one treatment-related death from pneumonitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial. Patel, MR., Ellerton, J., Infante, JR., et al.[2022]

Avelumab, an anti-PD-L1 antibody, has demonstrated clinical efficacy and a well-tolerated safety profile in treating metastatic and advanced urothelial carcinoma (UC) after platinum-based chemotherapy failure, leading to its FDA approval as a second-line treatment.

The mechanism of action for avelumab includes inducing antibody-dependent cellular cytotoxicity (ADCC), which helps in effectively targeting and destroying tumor cells, and it is currently being evaluated in ongoing trials for maintenance therapy and in combination with chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Which place for avelumab in the management of urothelial carcinoma? Larroquette, M., Gross-Goupil, M., Daste, A., et al.[2020]

References

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

A review of avelumab in locally advanced and metastatic bladder cancer. [2020]

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

Avelumab in locally advanced or metastatic urothelial carcinoma. [2022]

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

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

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

Avelumab as second-line therapy for metastatic, platinum-treated urothelial carcinoma in the phase Ib JAVELIN Solid Tumor study: 2-year updated efficacy and safety analysis. [2021]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Cost-Effectiveness of Avelumab Maintenance Therapy Plus Best Supportive Care vs. Best Supportive Care Alone for Advanced or Metastatic Urothelial Carcinoma. [2022]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Atezolizumab in Patients with Metastatic Urothelial Carcinoma Who Have Progressed After First-line Chemotherapy: Results of Real-life Experiences. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial. [2022]

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

Which place for avelumab in the management of urothelial carcinoma? [2020]