BT7480 + Nivolumab for Cancer

Not currently recruiting at 8 trial locations

Overseen By Matthew Zibelman, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: BicycleTx Limited

Must not be taking: Immunotherapy, CD137 therapy

Disqualifiers: Brain metastases, Diabetes, Hypertension, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial studies a new drug, BT7480, both alone and with nivolumab (an immunotherapy), to treat advanced solid tumors that exhibit a specific marker called Nectin-4. Researchers aim to determine the safest dose of BT7480 and assess its side effects and effectiveness, particularly in individuals with kidney issues. The trial includes different groups: some will receive only BT7480, while others will receive both BT7480 and nivolumab. It seeks participants with advanced or metastatic cancer linked to Nectin-4, such as certain lung, ovarian, or breast cancers, who have no other suitable treatment options. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new drug.

Do I need to stop my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot have had cytotoxic, small molecule, or other systemic chemotherapy within 14 days, or immunotherapy within 28 days or 5 half-lives of the first dose of the study drug. Please consult with the trial team for more details.

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 cannot have had certain cancer treatments like chemotherapy or immunotherapy shortly before starting the trial.

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

Research has shown that BT7480 is generally well-tolerated on its own. Early data indicate positive effects without severe side effects in a small group of people. In one study, 39 patients received BT7480, and it proved to be safe.

When combined with nivolumab, a treatment already approved for some cancers, some safety information is available. Nivolumab can cause serious side effects, such as lung inflammation. However, early results suggest that combining it with BT7480 does not lead to unexpected severe side effects.

Since the trial is in its early stages, researchers continue to monitor safety closely to determine the best dose with the fewest side effects. Those considering participation should discuss potential risks with their healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about BT7480 and nivolumab because these treatments take a novel approach to fighting cancer. Unlike traditional chemotherapy, which attacks rapidly dividing cells broadly, BT7480 is designed to specifically target cancer cells by engaging the immune system more precisely, potentially reducing side effects. Nivolumab, an immune checkpoint inhibitor, enhances this effect by helping the immune system recognize and attack cancer cells more effectively. This combination aims to provide a more targeted and potentially more effective treatment option for patients with cancer, particularly those who haven't responded well to existing therapies.

What evidence suggests that this trial's treatments could be effective for advanced solid tumors?

Research has shown that BT7480, one of the treatments in this trial, yields promising results when used alone to treat tumors with the protein Nectin-4. Early data indicates that this treatment is generally well-tolerated and shows early signs of effectiveness, with some patients experiencing significant tumor shrinkage. Specifically, one study reported a promising 45% overall response rate in patients with certain types of cancer.

In this trial, some participants will receive a combination of BT7480 and nivolumab. This combination has demonstrated activity against tumors with both Nectin-4 and another protein, CD137. Nivolumab, already approved for treating various cancers, helps the immune system fight cancer cells. Together, these treatments are being studied for their potential to improve outcomes for people with advanced solid tumors. ^{1 2 6 7 8}

Are You a Good Fit for This Trial?

This trial is for adults with advanced solid tumors that express Nectin-4 and have not responded to standard treatments or have no suitable standard treatment options. Participants must be in relatively good health (ECOG score 0 or 1), have a life expectancy of at least 12 weeks, and provide tumor tissue samples.

Inclusion Criteria

My cancer is confirmed to be linked with Nectin-4 expression.

My advanced cancer does not respond to standard treatments.

Life expectancy ≥12 weeks

Exclusion Criteria

I have an autoimmune disease, but it's not diabetes, alopecia, thyroid disease, or vitiligo.

My diabetes is not under control, with an HbA1c level of 8% or higher.

I haven't had chemotherapy or similar treatments in the last 14 days.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1 Dose Escalation

Participants receive increasing doses of BT7480 to evaluate safety and tolerability as a monotherapy and in combination with nivolumab

6 months

Weekly visits

Phase 2 Dose Expansion

Participants receive a selected dose of BT7480 alone and in combination with nivolumab to assess clinical activity

6 months

Weekly visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 months

What Are the Treatments Tested in This Trial?

Interventions

• BT7480
• Nivolumab

Trial Overview The study tests the drug BT7480 alone and combined with nivolumab to determine safe dosages, side effects, effectiveness, how it affects the body, and its clearance. It also examines BT7480's impact on patients with reduced kidney function.

How Is the Trial Designed?

Group I: BT7480 monotherapy in patients with renal insufficiency Experimental Treatment 1 Intervention

Participants will receive a selected dose of BT7480. It is expected that approximately 12 patients will participate in this dose confirmation arm.

Group II: BT7480 monotherapy dose expansion Experimental Treatment 1 Intervention

Participants will receive a selected dose of BT7480. It is expected that approximately 45 patients will participate in this dose expansion arm in Phase 2.

Group III: BT7480 monotherapy dose escalation Experimental Treatment 1 Intervention

Participants will receive increasing doses of BT7480. It is expected that approximately 80 patients will participate in this dose escalation arm.

Group IV: BT7480 and nivolumab dose expansion Experimental Treatment 2 Interventions

Participants will receive a selected dose of BT7480 and standard dose of nivolumab. It is expected that approximately 45 patients will participate in this dose expansion arm in Phase 2.

Group V: BT7480 and nivolumab dose escalation Experimental Treatment 2 Interventions

Participants will receive increasing doses of BT7480 and standard dose of nivolumab. It is expected that approximately 12 patients will participate in this dose escalation arm.

Who Is Running the Clinical Trial?

BicycleTx Limited

Lead Sponsor

Trials

5

Recruited

1,800+

Published Research Related to This Trial

The combination of ibrutinib and nivolumab demonstrated an acceptable safety profile in 141 patients with relapsed or refractory B-cell malignancies, with only one dose-limiting toxicity reported, indicating that this treatment approach is generally safe for patients.

Preliminary results showed promising efficacy, with overall response rates of 61% in high-risk chronic lymphocytic leukaemia, 33% in follicular lymphoma, and 36% in diffuse large B-cell lymphoma, suggesting that this combination therapy could be effective for these conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and activity of ibrutinib in combination with nivolumab in patients with relapsed non-Hodgkin lymphoma or chronic lymphocytic leukaemia: a phase 1/2a study. Younes, A., Brody, J., Carpio, C., et al.[2021]

In a study of 552 non-small cell lung cancer (NSCLC) cases, PD-L1 and IDO-1 were found to be expressed in 16.9% and 42.6% of cases, respectively, and were associated with higher levels of tumor-infiltrating lymphocytes (TILs), suggesting their potential roles in immune evasion.

B7-H4 was less frequently expressed and did not show the same association with TILs, indicating that PD-L1 and IDO-1 may be more critical in the immune response to lung cancer, which could inform future treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Differential Expression and Significance of PD-L1, IDO-1, and B7-H4 in Human Lung Cancer. Schalper, KA., Carvajal-Hausdorf, D., McLaughlin, J., et al.[2021]

Nivolumab (Opdivo) significantly improves overall survival and response rates in previously-treated patients with advanced nonsquamous non-small cell lung cancer (NSCLC) compared to docetaxel, as shown in the CheckMate 057 trial.

Nivolumab has a manageable adverse event profile and is better tolerated than docetaxel, making it a valuable treatment option for patients who have progressed after chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab: A Review in Advanced Nonsquamous Non-Small Cell Lung Cancer. Keating, GM.[2018]

In the CheckMate 142 study involving 119 patients with previously treated MSI-H/dMMR metastatic colorectal cancer, the combination of nivolumab and low-dose ipilimumab showed a high objective response rate (ORR) of 55% and a promising 12-month overall survival (OS) rate of 85%.

Most treatment-related adverse events (sTRAEs) were manageable, occurring early and resolving quickly, with comparable efficacy outcomes between patients with and without sTRAEs, indicating a favorable benefit-risk profile for this treatment regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of Nivolumab plus Low-Dose Ipilimumab in Previously Treated Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer. Morse, MA., Overman, MJ., Hartman, L., et al.[2020]

Nivolumab, an anti-PD-1 antibody, was administered to a 63-year-old female patient with metastatic melanoma after renal transplantation, highlighting the potential for anti-tumor activity in high-risk patients, despite the challenges of concurrent immunosuppression.

The patient experienced acute renal allograft rejection and renal failure shortly after starting nivolumab, indicating significant risks associated with this treatment in transplant recipients, but she later showed a positive clinical response after re-challenging with nivolumab while on hemodialysis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor activity of nivolumab on hemodialysis after renal allograft rejection. Ong, M., Ibrahim, AM., Bourassa-Blanchette, S., et al.[2023]

In the Asian subpopulation with advanced non-small cell lung cancer (NSCLC) and PD-L1 expression ≥1%, patients treated with nivolumab plus ipilimumab showed significantly improved overall survival (OS) and progression-free survival (PFS) compared to those receiving chemotherapy, with a 3-year OS rate of 53% versus 37%.

The safety profile of nivolumab plus ipilimumab was manageable, with grade 3-4 treatment-related adverse events occurring in 40% of patients, similar to the 36% in the chemotherapy group, indicating no new safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-line nivolumab + ipilimumab in advanced NSCLC: CheckMate 227 subpopulation analyses in Asian patients. O'Byrne, KJ., Lee, KH., Kim, SW., et al.[2022]

In a study of 45 patients with metastatic melanoma treated with the combination of nivolumab and ipilimumab, the disease control rate was 54% and the objective response rate was 29%, indicating moderate efficacy in a real-world setting.

The treatment had a high toxicity profile, with 88% of patients experiencing adverse events, and 44% discontinuing treatment due to these events, highlighting the need for careful monitoring and management of side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world efficacy and toxicity of combined nivolumab and ipilimumab in patients with metastatic melanoma. Parakh, S., Randhawa, M., Nguyen, B., et al.[2019]

Nivolumab, an immune checkpoint inhibitor, significantly improves overall survival and progression-free survival in patients with advanced stage squamous cell non-small cell lung cancer (NSCLC) compared to docetaxel, as shown in the CHECKMATE 017 study.

The safety and tolerability of nivolumab are favorable, and interestingly, the expression of the PD-L1 ligand does not predict treatment outcomes, suggesting that other factors may influence the effectiveness of this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab in the treatment of metastatic squamous non-small cell lung cancer: a review of the evidence. Lim, JS., Soo, RA.[2018]

In a study of 1255 patients with metastatic non-small cell lung cancer (NSCLC), first-line treatment with nivolumab plus ipilimumab (NIVO+IPI) showed a high incidence of treatment-related adverse events (TRAEs), with 78% experiencing any-grade TRAEs and 34% experiencing severe (grade 3 or 4) TRAEs, but the treatment was generally well tolerated.

Patients who discontinued NIVO+IPI due to TRAEs still had a favorable long-term survival rate, with a 3-year overall survival of 50%, indicating that stopping treatment because of side effects did not negatively impact their long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of First-Line Nivolumab Plus Ipilimumab in Patients With Metastatic NSCLC: A Pooled Analysis of CheckMate 227, CheckMate 568, and CheckMate 817. Paz-Ares, LG., Ciuleanu, TE., Pluzanski, A., et al.[2023]

Nivolumab, an immune checkpoint inhibitor, significantly improved overall survival and progression-free survival compared to docetaxel in patients with advanced squamous non-small cell lung cancer (NSCLC) in the CheckMate 017 trial.

Nivolumab was better tolerated than docetaxel, with manageable adverse effects, making it a promising treatment option for patients who have already undergone chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab: a review in advanced squamous non-small cell lung cancer. Keating, GM.[2022]

The bispecific antibody described in patent US2019161548 targets both PD-1 and CTLA-4, which are important immune checkpoints in cancer, and has been shown to enhance the activation and proliferation of CD8+ T cells and stimulate CD4+ T cells.

Clinical trials are currently underway to assess the safety and effectiveness of this bispecific antibody, with hopes that it may outperform the existing combination therapy of nivolumab and ipilimumab in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bispecific anti-PD-1/CTLA-4 antibody for advanced solid tumors. Perez-Santos, M.[2021]

Nivolumab and pembrolizumab are FDA-approved monoclonal antibodies that target PD-1, helping to enhance T cell activity against cancer by blocking the PD-1/PD-L1 interaction, which allows cancer cells to escape immune detection.

Both drugs have shown efficacy across multiple cancer types, including melanoma and non-small cell lung cancer, and are considered interchangeable options for treating these conditions, which may help manage the rising costs of cancer therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab and pembrolizumab: Monoclonal antibodies against programmed cell death-1 (PD-1) that are interchangeable. Prasad, V., Kaestner, V.[2022]

Citations

1. onclive.com onclive.com/view/bt7480-shows-preliminary-activity-in-nectin-4-cd137-tumors

BT7480 Shows Preliminary Activity in Nectin-4+, CD137+ ... The Nectin-4/CD137 Bicycle–targeted immune cell agonist BT7480 had antitumor activity in patients with Nectin-4– and CD137-expressing tumors.

2. bicycletherapeutics.com bicycletherapeutics.com/wp-content/uploads/2024/09/ESMO-2024-BT7480-Clin-Update-and-Biomarkers-Poster-FINAL.pdf

BT7480 ▷ Presented here are the results of the monotherapy dose escalation part of the Phase 1/2 study (NCT05163041) of BT7480 ± nivolumab in patients.

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/34725211/

BT7480, a novel fully synthetic Bicycle tumor-targeted ... BT7480 is a highly potent Nectin-4-dependent CD137 agonist that produces complete regressions and antitumor immunity with only intermittent drug exposure in ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT03907488

NCT03907488 | Immunotherapy (Nivolumab or ... The addition of nivolumab or brentuximab vedotin to combination chemotherapy may shrink the cancer or extend the time without disease symptoms coming back.

5. opdivohcp.com opdivohcp.com/efficacy

Efficacy Information | OPDIVO® (nivolumab) OPDIVO® (nivolumab), alone or in combination, is approved in 25 indications. Discover the robust evidence behind the use of OPDIVO from earlier to advanced ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05163041

NCT05163041 | Study BT7480-100 in Patients With ... This clinical study is evaluating a drug called BT7480 alone and in combination with nivolumab in participants with advanced solid tumors associated with ...

7. opdivohcp.com opdivohcp.com/safety

Safety Information | OPDIVO® (nivolumab) Fatal adverse reactions occurred in 16 (2.0%) patients who were treated with OPDIVO in combination with chemotherapy; these included pneumonitis (4 patients), ...

8. bicycletherapeutics.com bicycletherapeutics.com/wp-content/uploads/2023/05/B261_Poster_AACR_April-2023_JG-collab-JE_BT740-TiP.pdf

Phase 1/2 study of the safety, pharmacokinetics, and ... Combination: BT7480 will be given at the RP2D in combination with nivolumab 240 mg administered as a 30-min IV infusion once every 2 weeks. •. Disease ...