Phase 2 Evaluation of Zelenectide Pevedotin in NECTIN4 Amplified Advanced Breast Cancer with BT8009 Infusion
- Trial ID
- 2024-517868-33-00
- Protocol
- BT8009, Duravelo-3
- Sponsor
- Bicycletx Limited
Trial statistics
Objectives
The primary objective of this Phase 2 study is to assess the **clinical activity** of zelenectide pevedotin in participants with **NECTIN4 amplified advanced breast cancer**. This will be measured by the objective response rate (ORR) according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, as assessed by the Investigator. The clinical relevance of this objective lies in determining the efficacy of zelenectide pevedotin in targeting NECTIN4 amplified tumors, which could potentially lead to improved treatment options for patients with this specific subtype of advanced breast cancer.
Secondary objectives include evaluating the safety and tolerability of zelenectide pevedotin in participants with NECTIN4 amplified tumors. Additionally, the study aims to assess clinical activity through various parameters such as duration of response (DoR), disease control rate (DCR), clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS), and time to progression (TTP), all assessed per RECIST v1.1 by the Investigator. These secondary objectives are crucial for understanding the broader impact of the treatment on patient outcomes and its potential role in clinical practice.
Participants
The clinical trial involves a total of **36 participants** diagnosed with **NECTIN4 Amplified Advanced Breast Cancer**. The study population includes both male and female subjects, aged 18 years and older, with a confirmed diagnosis of recurrent unresectable or metastatic triple-negative breast cancer (TNBC) or hormone receptor-positive (HR+)/HER2-negative breast cancer. Participants were selected based on specific criteria, including confirmed NECTIN4 gene amplification and measurable disease as per RECIST v1.1 guidelines. The trial includes individuals with an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less, indicating a relatively stable general health status. Lifestyle considerations such as diet and physical activity are not specified, but participants must have adequate organ function and a life expectancy of at least 12 weeks. The trial also includes vulnerable populations, ensuring comprehensive representation. Key inclusion criteria require participants to have adequate bone marrow function and organ function, and women of childbearing potential must have a negative pregnancy test. The trial aims to assess the clinical activity of zelenectide pevedotin in this specific patient population.
Plans and Procedures
The clinical trial is designed to evaluate the **clinical activity** of zelenectide pevedotin in participants with NECTIN4 amplified advanced breast cancer. This is a Phase 2, randomized, double-blind, controlled study. The trial aims to assess the objective response rate (ORR) as the primary endpoint, with secondary endpoints including the incidence of adverse events, duration of response (DoR), disease control rate (DCR), clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS), and time to progression (TTP). The study is expected to commence recruitment on May 1, 2025, and conclude by December 30, 2028.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, confirmed NECTIN4 gene amplification, and adequate organ function. The screening visit will also include a negative pregnancy test for women of childbearing potential and a requirement for participants to agree to effective contraception. Following the screening, participants will receive the investigational product, BT8009, administered as a solution for infusion. The maximum treatment period is 48 weeks, with a maximum daily dose of 6 mg/m² and a total dose not exceeding 1656 mg.
Study visits will be scheduled at regular intervals to monitor the participants' health status, assess the response to treatment, and record any adverse events. These visits will include laboratory tests, electrocardiograms (ECGs), and vital sign assessments. The end-of-study visit will occur after the completion of the treatment period or upon early termination. Participants may be withdrawn from the study if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The expected length of participant involvement is approximately 48 weeks, with additional follow-up as necessary to assess long-term outcomes.
Treatment
The clinical trial involves the administration of **BT8009**, an experimental medication developed by BICYCLETX LIMITED. BT8009 is formulated as a **solution for infusion** and is classified as a chemical entity with a protein origin. The active substance, also named BT8009, is administered via **intravenous infusion**. The dosing regimen for BT8009 is specified as a maximum daily dose of 6 mg/m², with a total maximum dose of 1656 mg over a treatment period not exceeding 48 weeks. The administration schedule and participant compliance are closely monitored to ensure adherence to the protocol.
In this study, BT8009 is the primary investigational product, and no additional non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified. The trial's main objective is to evaluate the clinical activity of BT8009 in participants with NECTIN4 amplified advanced breast cancer, as measured by the objective response rate according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The study does not include a pediatric formulation, and BT8009 is not designated as an orphan drug. The trial is conducted under strict compliance with regulatory standards to ensure the safety and efficacy of the investigational product.
Efficacy
The efficacy of zelenectide pevedotin in participants with NECTIN4 amplified advanced breast cancer will be assessed primarily through the **Objective Response Rate (ORR)**. This will be measured by the percentage of participants who achieve either a confirmed complete response (CR) or partial response (PR) according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as evaluated by the investigator. Secondary endpoints include the incidence of adverse events, duration of response (DoR), disease control rate (DCR), clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS), and time to progression (TTP). These secondary endpoints will also be assessed using RECIST v1.1 criteria.
Inclusion and Exclusion Criteria
Inclusion Criteria
- ≥ 18 years of age on day of signing informed consent
- Histologically or cytologically confirmed recurrent unresectable or metastatic TNBC or HR+/HER2-negative breast cancer as defined in cohort specific criteria.
- Confirmed NECTIN4 gene amplification by an analytically validated clinical trial assay (CTA).
- 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 comprised TNBC or HR+/HER2-negative invasive breast cancer should be available for submission to central laboratory if not provided during pre-screening
- Life expectancy ≥ 12 weeks.
- ECOG PS of ≤ 1
- Oxygen saturation of ≥93% on room air.
- 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 (ALP) ≤ 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 and individualized by the participant's BSA)
- International normalized ratio (INR)/prothrombin time (PT) ≤ 1.5 × ULN unless participant is receiving a stable dose of anticoagulant therapy and PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of the appropriate anticoagulants.
- Adequate bone marrow function including the following: a. Hemoglobin ≥ 9 g/dL b. Absolute neutrophil count (ANC) ≥ 1500 cells/ mm3 c. Platelet count ≥ 100,000 cells/mm3.
- 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 must be willing to follow highly effective contraception at least as conservative as Clinical Trial Facilitation Group (CTFG) recommendations of < 1% failure rate starting at Screening, throughout the study period, and for at least 6.5 months following the last dose of zelenectide pevedotin
- Fertile male participants must agree to refrain from sperm donation from first dose until at least 6.5 months following the last dose of zelenectide pevedotin. Women must not breastfeed or donate eggs from first dose until 6.5 months following the last dose of zelenectide pevedotin.
- Able to understand the study procedures and agree to participate in the study by providing written informed consent.
- Please refer to the study protocol for additional cohort specific criteria that may apply.
Exclusion Criteria
- Prior treatment with any ADC containing an MMAE (vedotin) payload or other MMAE-based therapy.
- Uncontrolled hypertension (systolic blood pressure (BP) ≥ 150 mm mercury (Hg) or diastolic BP ≥ 95 mm Hg) prior to first dose.
- Active interstitial lung disease or pneumonitis requiring ongoing treatment with steroids (>10 mg per day of prednisone or equivalent) or other immunosuppressive medications.
- Ongoing clinically significant toxicity (Grade ≥ 2) associated with prior treatment for breast cancer (including radiotherapy or surgery) with the exception of well controlled immuno-oncology related endocrine disorders on supportive therapy and alopecia.
- 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/μL; 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.
- Known active hepatitis B, defined as positive surface antigen and/or anti-hepatitis B core antibody or positive hepatitis B polymerase chain reaction assay (a detectable hepatitis B viral load).
- Known active hepatitis C infection with positive viral load if hepatitis C virus 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 they have documented sustained virologic response of ≥ 12 weeks.
- Active systemic infection or fever not attributable to underlying malignancy requiring therapeutic oral or IV antibiotics within 14 days prior to first dose of study treatment. Participants receiving prophylactic antibiotics are eligible.
- Suspicion of relevant and recent systemic viral syndrome or need for quarantine/isolation that is not resolved prior to first dose 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 any of the following: a. A 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 documented within 6 months prior to first dose of study treatment b. Mean resting corrected QT interval (QTc) ≥ 450 msec for males, and ≥ 470 msec for females by Fridericia QT correction, except in cases of right bundle branch block or when prolongation is caused by implanted pacemaker function. c. Any factors that increase the risk of QTc prolongation such as congenital long QT syndrome, or family history of long QT syndrome. d. 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).
- Previously tested HER2-positive (IHC 3+ or ISH+) on prior pathology testing (per ASCO-CAP guidelines)
- 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.
- History or another active malignancy that would interfere with the safety or efficacy evaluation of the clinical study.
- Requirement, while on study, 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.
- Receipt of live or attenuated vaccine within 30 days of first dose
- Prior treatment with any systemic anticancer therapy within 28 days or 5 half-lives, whichever is shorter, prior to first dose of study treatment; the following exceptions are permitted: a. Palliative radiotherapy for bone or soft tissue metastasis completed > 7 days prior to baseline imaging.
- Active keratitis or corneal ulcerations.
- 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).
- 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 for at least 4 weeks prior to the first dose, either without the use of steroids or on stable or decreasing dose of ≤ 10 mg daily prednisone or equivalent and are without any symptoms that would confound the evaluation of neurologic or other adverse events (AEs).
- 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).
- Treatment with any other investigational agent or participation in another clinical study with therapeutic intent within 28 days or 5 half-lives, whichever is shorter, prior to first dose of study treatment.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 01 May 2025 | 6 |
 France | Not Recruiting | 01 May 2025 | 6 |
 Italy | Not Recruiting | 01 May 2025 | 8 |
 Spain | Not Recruiting | 01 May 2025 | 10 |
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 |
|---|---|---|---|---|---|---|
BT8009 | Test | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENIOUS INFUSION | 6 | 48 | PRD10891228 |
Zelenectide Pevedotin | Test | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENIOUS INFUSION | 6 | 48 | PRD12666060 |