BT8009 for Bladder Cancer

Recruiting at 200 trial locations

Overseen By BicycleTx Limited

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: BicycleTx Limited

Must not be taking: CYP3A inhibitors, P-gp inhibitors

Disqualifiers: Active keratitis, High dose corticosteroids, 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: Unknown

Duration: Up to 6 years

956 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called BT8009 (a Bicycle Toxin Conjugate), both alone and with pembrolizumab, to evaluate its effectiveness and safety for people with advanced bladder cancer. The study divides participants into two groups: those without prior treatment and those who have tried at least one other treatment. Suitable candidates have advanced bladder cancer that cannot be surgically removed or has metastasized. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial requires that participants do not take strong inhibitors or inducers of CYP3A or inhibitors of P-gp while on the study. If you are on such medications, you may need to stop them. Please consult with the trial team for specific guidance.

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

Research has shown that BT8009, a type of targeted cancer treatment, has a promising safety record in ongoing studies. Some patients have experienced side effects, with about 22% having serious drug-related problems and 53% facing serious issues during treatment. However, these issues were generally manageable.

When combined with pembrolizumab (a drug that helps the immune system fight cancer), early trials suggested that BT8009 is well-tolerated. Many patients continued this combination treatment for over 16 weeks, indicating a tolerable safety profile. This is encouraging for prospective trial participants, as it suggests the treatment is generally manageable. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about BT8009 for bladder cancer because it represents a novel approach compared to traditional treatments like platinum-based chemotherapy. BT8009 is an experimental drug that targets specific cancer cells, potentially leading to fewer side effects and more precise treatment outcomes. Unlike the standard chemotherapy, which can affect healthy cells as well, BT8009 works by seeking out and binding to certain proteins found on bladder cancer cells, thereby delivering its effects directly to the tumor. Additionally, when combined with pembrolizumab, an immune checkpoint inhibitor, it may enhance the body's immune response against cancer, offering a promising new avenue for patients who may not respond well to existing therapies.

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

Research shows that BT8009, a new treatment, holds promise for bladder cancer by targeting a protein called Nectin-4. Studies have found that BT8009 effectively reaches solid tumors and has shown early signs of halting tumor growth with a good safety record. In this trial, participants in certain arms will receive BT8009 with pembrolizumab. Previous studies have shown that 65% of patients experienced a reduction in tumor size with this combination. Other participants will receive BT8009 alone, which has stabilized or reduced cancer in 61% of patients in past research. These results suggest that BT8009, whether used alone or with pembrolizumab, could be a viable option for people with advanced bladder cancer. ^{2 3 4 6 7}

Are You a Good Fit for This Trial?

This trial is for adults with advanced bladder cancer. Cohort 1 includes those who haven't had systemic therapy and can get platinum-based chemo, while Cohort 2 has had at least one systemic treatment. Key eligibility details are not provided.

Inclusion Criteria

Life expectancy ≥ 12 weeks

I am eligible for and have not received platinum-based chemotherapy.

Cohort 1: Participants must not have received prior systemic therapy for locally advanced or metastatic UC with the following exceptions: Prior local intravesical chemotherapy, local surgery when full resection is not achieved, local immunotherapy, and radiotherapy are permitted if completed at least 4 weeks prior to the initiation of study treatment and all acute toxicities have resolved. Prior neoadjuvant/adjuvant chemotherapy or monomethyl auristatin E (MMAE)-based therapy with recurrence >12 months from completion of therapy. Prior neoadjuvant/adjuvant immune checkpoint inhibitor therapy with recurrence >12 months from completion of therapy. Cohort 2: Previously Treated: Participants must have received ≥ 1 prior systemic treatment for locally advanced or metastatic UC. This includes neoadjuvant/adjuvant platinum-based chemotherapy if recurrence occurred within 12 months of completing therapy. Cohort 2: Progression or recurrence of UC during or following receipt of most recent therapy.

Exclusion Criteria

I have fully recovered from any major surgery I had recently.

I have not received a live vaccine in the last 30 days.

Cohort 2: Previously Treated: Received more than 1 prior platinum-based chemotherapy regimen for locally advanced or metastatic UC. This includes neoadjuvant/adjuvant platinum-based chemotherapy if recurrence occurred within 12 months of completing therapy. Cohort 2: Prior treatment with enfortumab vedotin or any other MMAE-based therapy

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Selection

Participants undergo a dose selection phase to determine the appropriate dosage of BT8009

8-12 weeks

Treatment

Participants receive BT8009 as monotherapy or in combination with pembrolizumab

Up to 6 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 7 years

What Are the Treatments Tested in This Trial?

Interventions

• Avelumab
• BT8009
• Gemcitabine + cisplatin Or carboplatin
• Pembrolizumab

Trial Overview The study tests BT8009 alone and combined with pembrolizumab against standard chemo (gemcitabine plus cisplatin or carboplatin) in two groups of patients based on prior treatments. It's a global study with an adaptive design to evaluate effectiveness and safety.

How Is the Trial Designed?

Group I: Cohort 2: BT8009 Arm 2 Experimental Treatment 1 Intervention

Participants will receive BT8009.

Group II: Cohort 2: BT8009 Arm 1 Experimental Treatment 1 Intervention

Participants will receive BT8009.

Group III: Cohort 2: Arm 3: BT8009 (Not Recruiting) Experimental Treatment 2 Interventions

Participants will receive BT8009 and a standard dose of pembrolizumab.

Group IV: Cohort 1: BT8009 Arm 2 Experimental Treatment 2 Interventions

Participants will receive BT8009 and a standard dose of pembrolizumab.

Group V: Cohort 1: BT8009 Arm 1 Experimental Treatment 2 Interventions

Participants will receive BT8009 and a standard dose of pembrolizumab.

Group VI: Cohort 1: Arm 3 Active Control 2 Interventions

Participants will receive Platinum-based combination chemotherapy +/- avelumab maintenance

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?

BicycleTx Limited

Lead Sponsor

Trials

5

Recruited

1,800+

Published Research Related to This Trial

This phase II study is evaluating the combination of Gemcitabine, Cisplatin, and Avelumab in treating advanced or metastatic bladder cancer, with 90 participants randomized to either the standard treatment or the combination therapy.

The study aims to determine if the addition of Avelumab increases the response rate and duration of response without significantly increasing severe toxicities, with results potentially leading to a larger phase III trial focused on overall survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Open-label randomized multi-center phase 2 study: gemcitabine cisplatin plus avelumab or gemcitabine cisplatin as first-line treatment of patients with locally advanced or metastatic urothelial bladder carcinoma: GCisAve. Gross-Goupil, M., Domblides, C., Lefort, F., 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]

In a study involving 71 patients with metastatic urothelial cancer (mUC) who were ineligible for cisplatin-based chemotherapy, avelumab demonstrated a median overall survival of 10 months, with 43% of patients alive at one year, indicating its efficacy as a first-line treatment option.

Avelumab was found to be safe, with adverse events occurring in 49.3% of patients, but no treatment-related deaths were reported, suggesting it is a tolerable option for patients who cannot receive traditional chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-line avelumab for patients with PD-L1-positive metastatic or locally advanced urothelial cancer who are unfit for cisplatin. Iacovelli, R., Ciccarese, C., Brunelli, M., et al.[2022]

Pembrolizumab significantly improves survival and quality of life for patients with advanced urothelial cancer who cannot tolerate cisplatin-based chemotherapy, offering an increase of approximately 2.11 to 2.16 years in overall survival and 1.71 to 1.75 quality-adjusted life years (QALYs) compared to standard treatments like carboplatin plus gemcitabine and gemcitabine monotherapy.

Despite being associated with higher costs (an increase of €90,520 compared to carboplatin plus gemcitabine), pembrolizumab is considered cost-effective at a threshold of €100,000/QALY, making it a viable first-line treatment option for this patient population in Sweden.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cost-effectiveness of Pembrolizumab for Patients with Advanced, Unresectable, or Metastatic Urothelial Cancer Ineligible for Cisplatin-based Therapy. Patterson, K., Prabhu, V., Xu, R., et al.[2022]

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]

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]

Urothelial carcinoma, the most common urological cancer, is primarily treated with Bacillus Calmette-Guerin (BCG) immunotherapy for superficial cases and cisplatin-based chemotherapy for metastatic disease, with vinflunine as the standard second-line option in Europe.

Novel PD-1/PD-L1 inhibitors like atezolizumab, nivolumab, and pembrolizumab have shown promise in treating bladder cancer, particularly for patients who cannot tolerate cisplatin, and are generally well tolerated with manageable side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Immunotherapy for Bladder Cancer]. Büchler, T.[2019]

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]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.TPS4619

A phase 2/3 study of Bicycle toxin conjugate BT8009 ... BT8009 has a low molecular weight and short plasma half-life, with potential to rapidly penetrate solid tumors and reduce toxicity by minimizing ...

2. urotoday.com urotoday.com/conference-highlights/asco-2025/asco-2025-bladder-cancer/160812-asco-2025-duravelo-2-a-phase-2-3-study-of-bicycle-toxin-conjugate-zelenectide-pevedotin-bt8009-targeting-nectin-4-in-patients-with-locally-advanced-or-metastatic-urothelial-cancer.html

ASCO 2025: Duravelo-2: A Phase 2/3 Study of Bicycle ... Results from the ongoing phase 1/2 clinical trial of zelenectide pevedotin (NCT04561362) indicate preliminary antitumor activity and a tolerable safety profile ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40401457/

a bicyclic peptide toxin conjugate targeting nectin-4 for the ... Preliminary data on BT8009 reveal an intriguing clinical profile, with promising efficacy and a notable safety profile. However, the design of ongoing ...

4. onclive.com onclive.com/view/first-in-class-bicycle-toxin-conjugate-targeting-nectin-4-generates-excitement-in-urothelial-carcinoma

First-in-Class Bicycle Toxin Conjugate Targeting Nectin-4 ... Additionally, the clinical benefit rate was 61%. Nine patients experienced stable disease whereas 12 patients had progressive disease. Further, ...

5. bicycletherapeutics.com bicycletherapeutics.com/wp-content/uploads/2022/07/BT8009-Triple-Meeting-Boston-vF.pdf

BT8009, a Bicycle® Toxin Conjugate targeting Nectin-4, ... BT8009 shows excellent efficacy in xenograft models expressing. Nectin-4 target and the pharmacokinetic profile enables a rapid attainment of high tumor ...

6. investors.bicycletherapeutics.com investors.bicycletherapeutics.com/news-releases/news-release-details/bicycle-therapeutics-present-pharmacokinetic-and-safety

Press Release Emerging Phase 1/2 clinical pharmacokinetic (PK) and safety data for Bicycle Toxin Conjugates (BTC) molecules BT8009 and BT5528 demonstrating differentiated ...

7. bicycletherapeutics.com bicycletherapeutics.com/wp-content/uploads/2024/05/ASCO-2024-Duravelo-2-TiP-Poster-FINAL.pdf

ASCO-2024-Duravelo-2-TiP-Poster-FINAL.pdf for updated PK and safety data from BT8009-100. OBJECTIVE. ▷ Duravelo-2/BT8009-230 (NCT06225596) is designed to measure efficacy and safety ...