Evaluation of BT8009 Monotherapy and BT8009 with Pembrolizumab Versus Chemotherapy in Locally Advanced or Metastatic Urothelial Cancer
- Trial ID
- 2023-504231-41-01
- Protocol
- BT8009-230
- Sponsor
- Bicycletx Limited
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of BT8009 in combination with pembrolizumab compared to chemotherapy (cisplatin or carboplatin with gemcitabine and maintenance avelumab, if indicated) in participants with locally advanced or metastatic urothelial cancer. This is measured by progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) assessed by blinded independent central review (BICR). The clinical relevance of this objective lies in determining the potential of BT8009 as a more effective treatment option, which could lead to improved management and outcomes for patients with this type of cancer.
The secondary objectives include:
- Comparing the clinical activity of BT8009 in combination with pembrolizumab versus chemotherapy, as measured by the objective response rate (ORR) per RECIST v1.1 assessed by BICR and by the Investigator.
- Comparing overall survival (OS) of participants treated with BT8009 in combination with pembrolizumab versus chemotherapy.
- Evaluating the clinical activity of each study treatment regimen, as measured by duration of response (DoR) per RECIST v1.1 assessed by BICR and by the Investigator.
- Evaluating DoR per RECIST v1.1 assessed by BICR in Cohort 2.
- Evaluating ORR per RECIST v1.1 assessed by the Investigator in Cohort 2.
- Evaluating DoR per RECIST v1.1 assessed by the Investigator in Cohort 2.
Participants
The clinical trial involves a total of **588 participants** diagnosed with **locally advanced or metastatic urothelial cancer**. The study population includes both male and female subjects, aged 18 years and older, with a confirmed histological or cytological diagnosis of the disease. Participants were selected based on their ability to provide informed consent and meet specific health criteria, including adequate organ function and a life expectancy of at least 12 weeks. The trial population encompasses individuals with measurable disease as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Lifestyle factors such as diet and physical activity were not specified as part of the selection criteria. The study includes a vulnerable population, indicating that additional ethical considerations were taken into account during the selection process. Key inclusion criteria required participants to have a dominant transitional cell pattern in cases of mixed histologies and to provide archival or fresh tumor tissue for central laboratory submission.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of **BT8009** as monotherapy or in combination with other treatments in participants with locally advanced or metastatic urothelial cancer. This study is a randomized, open-label, Phase 2/3 trial. The trial will assess the progression-free survival (PFS) and overall response rate (ORR) as primary endpoints, with secondary endpoints including overall survival (OS) and duration of response (DoR). The trial is expected to conclude by December 31, 2030, with recruitment starting on September 15, 2024.
Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on inclusion criteria such as age, histological confirmation of the disease, and adequate organ function. Following successful screening, participants will be randomized into different cohorts to receive either BT8009 in combination with **pembrolizumab** or chemotherapy (cisplatin or carboplatin with **gemcitabine** and maintenance **avelumab**, if indicated), or BT8009 monotherapy. The trial will include regular follow-up visits to monitor treatment efficacy and safety, with assessments conducted according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
The expected duration of participant involvement varies depending on the treatment cohort, with a maximum treatment period of up to 48 weeks for BT8009. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, or withdrawal of consent. The end-of-study visit will occur after the final treatment cycle, where comprehensive evaluations will be conducted to assess the overall outcomes of the trial. Participants will be required to adhere to specific contraceptive measures throughout the study and for a defined period following the last dose of the investigational products.
Treatment
The clinical trial involves the administration of several **experimental medications** and comparator treatments. **BT8009** is the primary investigational drug, administered as a **solution for infusion**. It is a **protein-based** entity developed by BICYCLETX LIMITED. The maximum daily dose is 6 mg/m², with a total dose not exceeding 1040 mg/m² over a treatment period of up to 48 weeks. The administration route is **intravenous infusion**.
**Cisplatin** is used as a comparator treatment in the trial. It is provided as a **concentrate for solution for infusion**. The active substance is of **chemical origin**, with a maximum daily dose of 70 mg/m² and a total dose limit of 420 mg/m² over a maximum treatment period of 18 weeks. The administration is via **intravenous infusion**.
**Avelumab** is another comparator, also administered as a **concentrate for solution for infusion**. It is a **biological entity** with a maximum daily dose of 800 mg and a total dose limit of 77,000 mg over a treatment period of up to 45 weeks. The route of administration is **intravenous infusion**.
**Carboplatin** is included as a comparator treatment, provided as a **concentrate for solution for infusion**. It is a **chemical entity** with a maximum daily dose of 750 mg and a total dose limit of 4500 mg over a maximum treatment period of 18 weeks. Administration is conducted via **intravenous infusion**.
**Pembrolizumab** is used in combination with BT8009 and is administered as a **concentrate for solution for injection**. It is a **biological entity** with a maximum daily dose of 200 mg and a total dose limit of 7000 mg over a treatment period of up to 24 weeks. The administration route is **intravenous infusion**.
**Gemcitabine** is another comparator treatment, provided as a **concentrate for solution for infusion**. It is a **chemical entity** with a maximum daily dose of 1000 mg/m² and a total dose limit of 12,000 mg/m² over a maximum treatment period of 18 weeks. The administration is via **intravenous infusion**.
Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial aims to evaluate the efficacy of BT8009 both as a monotherapy and in combination with pembrolizumab, compared to standard chemotherapy regimens involving cisplatin or carboplatin with gemcitabine and maintenance avelumab, if indicated.
Efficacy
Efficacy in this clinical trial will be assessed using several key endpoints. The primary efficacy endpoint for **Cohort 1** is progression-free survival (PFS), which is defined as the length of time from the date of randomization to the date of first documentation of disease progression per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1), as assessed by blinded independent central review (BICR), or death from any cause, whichever occurs first. For **Cohort 2**, the primary endpoint is the overall response rate (ORR), measured by the percentage of participants who achieve either a confirmed complete response (CR) or partial response (PR) per RECIST v1.1, also assessed by BICR.
Secondary endpoints for **Cohort 1** include ORR, overall survival (OS), and duration of response (DoR). ORR is measured by the percentage of participants achieving a confirmed CR or PR per RECIST v1.1, assessed by both BICR and the investigator. OS is defined as the time from randomization to death from any cause. DoR is measured from the first documentation of objective response to the first documentation of objective tumor progression or death, assessed by both BICR and the investigator. For **Cohort 2**, secondary endpoints include DoR and ORR, with assessments conducted by both BICR and the investigator.
The efficacy assessments will be conducted at specified intervals throughout the trial, with the use of validated criteria such as RECIST v1.1 to ensure consistency and reliability in the evaluation of tumor response. The data collected will be analyzed to determine the efficacy of BT8009 as monotherapy or in combination with pembrolizumab, compared to chemotherapy regimens in participants with locally advanced or metastatic urothelial cancer.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Able to understand the study procedures and agree to participate in the study by providing written informed consent.
- ≥ 18 years of age on day of signing informed consent.
- Histologically or cytologically confirmed locally advanced (unresectable) or metastatic UC of the renal pelvis, ureter, bladder, or urethra. a. Participants with mixed histologies are required to have a dominant transitional cell pattern (≥ 50%).
- Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. a. Target lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions post irradiation.
- Archival or fresh tumor tissue comprising primary or metastatic UC should be available for submission to central laboratory.Tissue samples from a bladder biopsy showing only non-muscle invasive UC is not permitted. Cytology specimens are not permitted.
- Life expectancy ≥ 12 weeks.
- Adequate organ function: a. Total bilirubin ≤ 1.5 × upper limit of normal (ULN) or ≤ 3 × ULN for participants with Gilbert disease b. Serum albumin ≥ 2.5 g/dL c. Aspartate aminotransferase (AST) ≤ 2.5 × ULN or ≤ 5 × ULN in the presence of liver metastases d. Alanine aminotransferase (ALT) ≤ 2.5 × ULN or ≤ 5 × ULN in the presence of liver metastases e. Alkaline phosphatase ≤ 2.5 × ULN or ≤ 5 × ULN in the presence of liver or bone metastases f. Estimated glomerular filtration rate (eGFR) ≥ 30 mL/min (using the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] creatinine equation adjusted by the patient’s body surface area)
- International normalized ratio (INR)/prothrombin time (PT) ≤ 1.5 × ULN unless participant is receiving a stable dose of anticoagulant therapy and PT or activated partial thromboplastin time or partial thromboplastin time (aPTT/PTT; per laboratory standard of care) is within therapeutic range of intended use of the appropriate anticoagulants.
- Negative pregnancy test for women of childbearing potential (WOCBP) (negative serum test at Screening and negative urine or serum test within 72 hours prior to the first dose).
- WOCBP and male participants willing to follow highly effective contraception at least as conservative as Clinical Trial Facilitation Group (CTFG, 2020) recommendations of < 1% failure rate starting at Screening, throughout the study period, and for at least 1 month following the last dose of avelumab, 4 months following the last dose of pembrolizumab, 6.5 months following the last dose of zelenectide pevedotin (BT8009), and 6 months following the last dose of platinum treatment or gemcitabine, whichever comes last.
- Fertile male participants must agree to refrain from sperm donation from first dose until at least 1 month following the last dose of avelumab, 4 months following the last dose of pembrolizumab, 6.5 months following the last dose of zelenectide pevedotin (BT8009), and 6 months following the last dose of platinum treatment or gemcitabine, whichever comes last. Women must not breastfeed or donate eggs from first dose until 1 month following the last dose of avelumab, 4 months following the last dose of pembrolizumab, 6.5 months following the last dose of zelenectide pevedotin (BT8009), and 6 months following the last dose of platinum treatment or gemcitabine, whichever comes last.
- Additional cohort specific inclusion criteria may apply (see synopses)
Exclusion Criteria
- Active keratitis or corneal ulcerations.
- Requirement, while receiving study medications, for treatment with strong inhibitors or strong inducers of human cytochrome P450 3A (CYP3A) or inhibitors of P-glycoprotein (P-gp) including herbal- or food-based inhibitors.
- Any condition requiring current treatment with high dose corticosteroids (> 10 mg daily prednisone or equivalent).
- Known hypersensitivity or allergy to any of the ingredients of any of the study interventions, or to MMAE.
- Has not adequately recovered from recent major surgery (excluding placement of vascular access, in the opinion of the Investigator.
- Receipt of live or attenuated vaccine within 30 days of first dose.
- Known active carcinomatous meningitis or untreated central nervous system (CNS) metastases. a. Participants with treated brain metastases may participate in the study if they are stable based on at least 2 scans done at least 4 weeks apart, either without the use of steroids or on stable or decreasing dose of ≤ 10 mg daily prednisone or equivalent and are without any symptoms.
- Uncontrolled diabetes, defined as hemoglobin A1C (HbA1c) ≥ 8%.
- National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade ≥ 2 peripheral neuropathy.
- Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently).
- Uncontrolled hypertension (HTN) (systolic blood pressure (BP) ≥ 150 mm mercury (Hg) or diastolic BP ≥ 95 mm Hg) prior to first dose.
- Prior allogeneic stem cell or solid organ transplantation.
- Active interstitial lung disease or pneumonitis, or a history of interstitial lung disease or pneumonitis requiring treatment with steroids or other immunosuppressive medications.
- Prior treatment with an agent directed to another stimulatory or co-inhibitory T-cell receptor, including, but not limited to TIGIT therapy, CD137 agonists, OX-40 agonist or CTLA-4 inhibitors.
- Prior treatment with any systemic anticancer therapy within 2 weeks or 5 half-lives, whichever is longer, prior to initiation of study treatment; the following exceptions are permitted: a. Palliative radiotherapy for UC-related bone or soft tissue metastasis completed > 7 days prior to baseline imaging. b. Androgen deprivation therapy using gonadotropin-releasing hormone (GnRH) agonists. c. Females with hormone receptor-positive breast cancer who are receiving tamoxifen or aromatase inhibitors adjuvant therapy ≥ 3 years. d. Treatment with any systemic anticancer immunotherapy > 28 days prior to initiation of study treatment.
- Treatment with any other investigational agent or participation in another clinical study with therapeutic intent within 2 weeks or 5 half-lives, whichever is longer, prior to first dose of study treatment.
- Has an active autoimmune disease that has required systemic treatment in past 2 years (ie, with use of disease modifying agents, corticosteroids, or immunosuppressive drugs).
- Any prior Grade ≥ 3 immune-related adverse event while receiving immune checkpoint inhibitor.
- Known human immunodeficiency virus (HIV) or acquired immune deficiency syndrome (AIDS). a. Well controlled HIV will be allowed if the participant meets all the following criteria at inclusion**: i. Cluster of differentiation (CD4+) counts ≥ 350 cells/uL; ii. HIV viral load < 400 copies/mL; iii. Without a history of opportunistic infection within the last 12 months; iv. On established antiretroviral therapy (ART) for at least 4 weeks. **Not applicable in China. Participants with known HIV or AIDS in China are excluded.
- Known active hepatitis B, defined as positive surface antigen (HBsAg) and/or anti-hepatitis B core antibody (anti-HBc) and a positive hepatitis B polymerase chain reaction (a detectable hepatitis B viral load).
- Known active hepatitis C infection with positive viral load (detectable hepatitis C virus [HCV RNA]) if HCV is antibody positive (if antibody is negative then viral load is not applicable). Participants who have been treated for hepatitis C infection can be included if HCV RNA is undetectable for ≥ 12 weeks.
- History or another active malignancy that would interfere with the safety or efficacy evaluation of the clinical study.
- Suspicion of relevant and recent systemic viral syndrome or need for quarantine/isolation that is not resolved prior to initiation of study treatment in the opinion of the Investigator.
- History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant’s ability to take part in the full duration of the study, or is not in the best interest of the participant to take part, in the opinion of the Investigator. Participants with history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, congestive heart failure or symptoms of New York Heart Association (NYHA) Class III or IV (Appendix 2) documented within 6 months prior to first dose of study treatment or: a. Mean resting corrected QT interval (QTc) > 470 msec by Fridericia QT correction. b. Any factors that increase the risk of QTc prolongation such as congenital long QT syndrome, or family history of long QT syndrome. c. Any clinically important abnormalities (as assessed by the Investigator) in rhythm, conduction, or morphology of resting ECGs, eg, complete left bundle branch block, third degree heart block.
- Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study.
- Prior Stevens-Johnson syndrome (SJS)/ toxic epidermal necrolysis (TEN)/drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), erythema multiforme, symmetric drug-related intertriginous and flexural exanthema (SDRIFE), or Baboon syndrome.
- Active systemic infection or fever not attributable to underlying malignancy requiring therapeutic oral or IV antibiotics within 14 days prior to start of study treatment. Participants receiving prophylactic antibiotics are eligible.
- Additional cohort-specific exclusion criteria may apply.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 15 Sept 2024 | 15 |
 Belgium | Not Recruiting | 15 Sept 2024 | 10 |
 Bulgaria | Not Recruiting | 15 Sept 2024 | 25 |
 Czechia | Not Recruiting | 15 Sept 2024 | 20 |
 Denmark | Not Recruiting | 15 Sept 2024 | 15 |
 France | Not Recruiting | 15 Sept 2024 | 13 |
 Germany | Not Recruiting | 15 Sept 2024 | 1 |
 Greece | Not Recruiting | 15 Sept 2024 | 24 |
 Hungary | Not Recruiting | 15 Sept 2024 | 2 |
 Ireland | Not Recruiting | 15 Sept 2024 | 20 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Zelenectide Pevedotin | Test | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 6 | 48 | PRD12666060 |
AVELUMAB | Comparator | — | CONCENTRATE FOR SOLUTION FOR INFUSION | 800 | 45 | SUB180078 |
CARBOPLATIN | Comparator | — | CONCENTRATE FOR SOLUTION FOR INFUSION | 750 | 18 | SUB06614MIG |
GEMCITABINE | Comparator | — | CONCENTRATE FOR SOLUTION FOR INFUSION | 1000 | 18 | SUB07892MIG |
PEMBROLIZUMAB | Test | — | CONCENTRATE FOR SOLUTION FOR INFUSION | 200 | 24 | SUB167136 |
BT8009 | Test | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 6 | 48 | PRD10891228 |
CISPLATIN | Comparator | — | CONCENTRATE FOR SOLUTION FOR INFUSION | 70 | 18 | SUB07483MIG |