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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests two drugs, lurbinectedin and avelumab, to determine their effectiveness in treating aggressive bladder cancers, specifically small cell carcinoma of the bladder (SCCB) and other high-grade neuroendocrine tumors (HGNET) of the urinary tract. Researchers aim to discover if these drugs can improve survival for individuals whose cancer has returned and spread after treatment. Participants will receive treatments every three weeks; some will receive both drugs, while others will receive only lurbinectedin, based on their previous treatments. This trial may suit adults with SCCB or HGNET that has recurred and spread despite prior treatments. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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.

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

Studies have shown that both lurbinectedin and avelumab have treated other cancers and are generally safe for people. Lurbinectedin, used alone, has a known safety record, with serious side effects like severe nausea or low blood counts being less common at the usual dose of 3.2 mg/m².

Research indicates that avelumab, an immune therapy drug, is usually well-tolerated in people with advanced bladder cancer. Common side effects of avelumab include tiredness, infusion reactions (such as fever or chills), or skin issues like a rash.

When combined, studies suggest lurbinectedin and avelumab can be used together safely. However, using these drugs together may increase the chance of side effects.

Participants in these studies typically receive other medications to help manage side effects. While there might be some risks, steps are taken to make the treatment as manageable as possible. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about lurbinectedin and avelumab for bladder cancer because they offer a novel approach compared to traditional treatments like chemotherapy and immunotherapy. Lurbinectedin works by inhibiting the transcription of cancer cells, potentially reducing tumor growth, which is different from standard chemotherapy that broadly targets rapidly dividing cells. Avelumab, an immune checkpoint inhibitor, helps the immune system recognize and attack cancer cells more effectively. When combined, these treatments could enhance each other's effects, offering a potentially powerful new strategy for fighting bladder cancer.

What evidence suggests that this trial's treatments could be effective for bladder cancer?

Research has shown that lurbinectedin holds promise for treating cancers such as high-grade neuroendocrine tumors (HGNET) of the bladder. One study reported a 35% success rate for lurbinectedin in treating small cell lung cancer, which resembles HGNET. For bladder neuroendocrine cancer, it controlled the disease in 71.4% of patients who had previously received treatment. This trial will include one arm studying lurbinectedin alone and another arm examining the combination of lurbinectedin and avelumab to determine if it can improve survival rates in patients with small cell carcinoma of the bladder (SCCB). Both drugs have approval for other cancer types, suggesting potential effectiveness for SCCB and HGNET. ^{4 6 7 8 9}

Who Is on the Research Team?

Andrea B Apolo, M.D.

Principal Investigator

National Cancer Institute (NCI)

Are You a Good Fit for This Trial?

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

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

Participants must have at least one measurable site of disease, per RECIST 1.1.

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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, 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, 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 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, 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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11203258/

Durable Objective Response to Lurbinectedin in Small Cell ... We report a patient with SCBC who achieved an objective and prolonged response to lurbinectedin, which has been approved for metastatic small cell lung cancer.

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.4_suppl.601

Clinical efficacy of lurbinectedin in metastatic ... Conclusions: Lurbinectedin offers encouraging responses (DCR: 5/7, 71.4%) close to those in SCLC, in previously treated bladder mNEC. One CR was ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT06228066

NCT06228066 | Lurbinectedin With or Without Avelumab in ... Lurbinectedin was recently approved as a second line agent in small cell lung cancer, where it has shown an overall response rate of 35%.

4. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.TPS4629

A phase II study of lurbinectedin with or without avelumab ... The purpose of this study is to assess the efficacy of lurbinectedin, either alone or in combination with avelumab, in participants with SCCB or other high ...

5. pharmamar.com pharmamar.com/en/pharmamar-presents-new-results-for-lurbinectedin-at-asco-genitourinary-cancers-symposium/

PharmaMar presents new results for lurbinectedin at ASCO ... Clinical Benefit Rate was found in 56.3%, with Partial Response in 5 of 16 patients, 31%. The study concluded that lurbinectedin is a well- ...

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2020/213702s000lbl.pdf

ZEPZELCA (lurbinectedin) - accessdata.fda.gov The pooled safety population described in the WARNINGS AND PRECAUTIONS reflects exposure to ZEPZELCA as a single agent at a dose of 3.2 mg/m2 intravenously ...

7. fda.gov fda.gov/media/105933/download

PM01183 preliminary safety data from phase 2 studies has suggested that lurbinectedin given at 3.2 mg/m2 results in a lower incidence of grade 3/4 ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10972959/

Post-marketing safety evaluation of lurbinectedin This study aims to evaluate adverse events (AEs) associated with lurbinectedin using the FDA's Adverse Event Reporting System (FAERS)database.

9. pp.jazzpharma.com pp.jazzpharma.com/pi/zepzelca.en.USPI.pdf

ZEPZELCA® (lurbinectedin) for injection, for intravenous use The pooled safety population described in the WARNINGS AND PRECAUTIONS also reflects exposure to ZEPZELCA as a single agent at a dose of 3.2 mg/m2 intravenously ...