Phase 2 Evaluation of Zelenectide Pevedotin in NECTIN4-Amplified Advanced or Metastatic Non-Small Cell Lung Cancer
- Trial ID
- 2025-521115-40-00
- Protocol
- BT8009-202
- Sponsor
- Bicycletx Limited
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase 2 study is to assess the **clinical activity** of zelenectide pevedotin in participants with **NECTIN4 amplified tumors** by evaluating the objective response rate (ORR) according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, as assessed by the Investigator. This is clinically relevant as it provides insight into the efficacy of zelenectide pevedotin in treating advanced or metastatic non-small cell lung cancer, potentially offering a new therapeutic option for patients with this specific genetic amplification.
Secondary objectives include:
- Evaluating the safety and tolerability of zelenectide pevedotin in participants with NECTIN4 amplified tumors.
- Assessing clinical activity by duration of response (DoR), disease control rate (DCR), clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS), and time to progression (TTP) per RECIST v1.1, as assessed by the Investigator.
These secondary objectives aim to provide a comprehensive understanding of the treatment's impact on various clinical outcomes, further informing its potential role in managing this cancer subtype.
Participants
The clinical trial involves a total of **44 participants** diagnosed with **Advanced or Metastatic Non-small Cell Lung Cancer**. The study population includes both male and female subjects, aged 18 years and older, who are not part of a vulnerable population. Participants were selected based on specific criteria, including histologically or cytologically confirmed advanced or metastatic non-small cell lung cancer (NSCLC) and confirmed NECTIN4 gene amplification. The trial does not specify any particular lifestyle considerations such as diet or physical activity. Participants must have a life expectancy of at least 12 weeks and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating they are in relatively good health despite their condition. The selection process ensures that participants have not received more than three prior lines of systemic therapy in the advanced/metastatic setting, and they must have measurable disease as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Adequate organ function and bone marrow function are also required for participation.
Plans and Procedures
The clinical trial is designed to evaluate the **clinical activity** of **zelenectide pevedotin** in participants with **NECTIN4 amplified advanced or metastatic non-small cell lung 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 treatment-emergent 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 August 31, 2025, and conclude by February 28, 2029.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically or cytologically confirmed advanced or metastatic non-small cell lung cancer, confirmed NECTIN4 gene amplification, and adequate organ function. The screening visit will also involve obtaining informed consent and conducting baseline assessments. Following the screening, participants will be randomized to receive the investigational product, **BT8009**, administered as an intravenous infusion. The maximum treatment period is 54 weeks, with a maximum daily dose of 6 mg/m² and a total dose not exceeding 432 mg.
Study visits will include regular follow-up assessments to monitor safety, efficacy, and any adverse events. These visits will involve laboratory tests, imaging studies, and clinical evaluations as per the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. The end-of-study visit will occur after the completion of the treatment period or upon early termination. Participants are expected to be involved in the study for the entire treatment period unless they experience disease progression, unacceptable toxicity, or withdraw consent, which may lead to early termination from the study.
Participants must adhere to specific conditions, such as using effective contraception and refraining from donating sperm or eggs during the study and for 6.5 months following the last dose of zelenectide pevedotin. The study is not a low-intervention trial and is categorized as therapeutic exploratory. The trial is conducted under the sponsorship of BICYCLETX LIMITED, with the investigational product being a bicyclic peptide formulated as a powder for concentrate for solution for infusion.
Treatment
The clinical trial involves the administration of **zelenectide pevedotin**, an investigational medicinal product, under the sponsor product code BT8009. This compound is formulated as a **powder for concentrate for solution for infusion**. The active substance, zelenectide pevedotin, is a bicyclic peptide that selectively binds to NECTIN4, fused to monomethyl auristatin E (MMAE) via a sarcosine decamer with a beta-alanine N-terminus and a valine-citrulline-PABC self-immolating spacer. The pharmaceutical form is specifically designed for intravenous infusion, ensuring direct delivery into the bloodstream. The dosing regimen for this trial specifies a maximum daily dose of 6 mg/m², with a total maximum dose of 432 mg over a treatment period not exceeding 54 days. The administration schedule is determined by the investigator, adhering to the trial protocol to optimize therapeutic outcomes while monitoring for adverse effects.
In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus remains solely on evaluating the efficacy and safety of zelenectide pevedotin in participants with previously-treated NECTIN4 amplified advanced or metastatic non-small cell lung cancer. Participant compliance with the dosing schedule is monitored through regular assessments and documentation by the clinical trial team, ensuring adherence to the protocol and accurate evaluation of the investigational product's clinical activity.
Efficacy
The efficacy of **zelenectide pevedotin** in the clinical trial will be assessed primarily through the **Objective Response Rate (ORR)**, which is defined as 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. This primary endpoint will provide a direct measure of the drug's clinical activity in participants with NECTIN4 amplified tumors.
Secondary endpoints will include several additional measures of efficacy: the **Duration of Response (DoR)**, which is the time from the first documentation of objective response to the first documentation of disease progression or death; the **Disease Control Rate (DCR)**, which includes the percentage of participants with CR, PR, or stable disease (SD); the **Clinical Benefit Rate (CBR)**, defined as the proportion of participants with CR, PR, or SD lasting at least 16 weeks; **Progression-Free Survival (PFS)**, which measures the time from the first day of study drug administration to disease progression or death; **Overall Survival (OS)**, which is the time from the first day of study drug administration to death from any cause; and **Time to Progression (TTP)**, defined as the time from the first dose until disease progression.
These efficacy parameters will be assessed at various timepoints throughout the study, with evaluations conducted according to the RECIST v1.1 criteria. The assessments will be performed by the investigator, ensuring a consistent and standardized approach to measuring the clinical outcomes of the treatment. The trial is designed to provide comprehensive data on the efficacy of zelenectide pevedotin in treating advanced or metastatic non-small cell lung cancer with NECTIN4 amplification.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Able to understand the study procedures and agree to participate in the study by providing written informed consent.
- Life expectancy ≥ 12 weeks.
- ECOG PS of ≤ 1.
- 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 Note: Red blood cells (RBCs) should not be given 4 weeks prior to bone marrow function assessment and platelet transfusions or growth factors should not be given 2 weeks prior to bone marrow function assessment.
- 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).
- 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 adjusted by participant’s body surface area, or as measured by 24-hour urine collection).
- ≥ 18 years of age on day of signing informed consent.
- Histologically or cytologically confirmed advanced or metastatic NSCLC. a. Cohort A: Histologically or cytologically confirmed non-squamous NSCLC. b. Cohort B: Histologically or cytologically confirmed squamous NSCLC
- Confirmed NECTIN4 gene amplification by an analytically validated clinical trial assay (CTA).
- Participants must not have received more than 3 prior lines of systemic therapy in the advanced/metastatic setting. • Participants with no known actionable genomic alterations must have received both platinum based therapy and immunotherapy given either sequentially or in combination for advanced/metastatic NSCLC. • Those with known actionable genomic alterations (eg, EGFR, ALK, BRAF, MET, ROS1, NTRK1/2/3, RET) are eligible provided they have received or are not candidates for available standard targeted therapy in the advanced/metastatic setting.
- 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.
- Adequate archival or fresh tumor tissue comprised of advanced or metastatic NSCLC should be available for submission to central laboratory, if not provided during pre-screening.
- 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.
Exclusion Criteria
- Evidence of mixed small cell lung cancer (SCLC) and NSCLC histology.
- 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.
- 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 13.3) 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 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).
- Ongoing clinically significant toxicity (Grade ≥ 2) associated with prior treatment for NSCLC (including radiotherapy or surgery), with the exception of well-controlled immuno-oncology related endocrine disorders on supportive or replacement therapy, and alopecia.
- Active keratitis or corneal ulcerations.
- 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 3 months 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).
- Known active hepatitis B, defined as positive surface antigen and/or anti-hepatitis B core antibody and positive polymerase chain reaction (PCR) assay.
- 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.
- Uncontrolled diabetes, defined as hemoglobin A1C (HbA1c) ≥ 8%.
- National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade ≥ 2 peripheral neuropathy.
- 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.
- 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.
- 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.
- Active interstitial lung disease (ILD) or pneumonitis requiring ongoing treatment with steroids (>10 mg per day of prednisone or equivalent) or other immunosuppressive medications; or any prior history of ILD or non-infectious pneumonitis requiring high-dose glucocorticoids.
- Known diffusing capacity of the lung for carbon monoxide (DLCO) < 50% or FEV1 % <50% predicted.
- Known human immunodeficiency virus (HIV) or acquired immune deficiency syndrome (AIDS). Well-controlled HIV will be allowed if the participant meets all the following criteria at inclusion: a. Cluster of differentiation (CD4+) counts ≥ 350 cells/μL b. HIV viral load < 400 copies/mL c. Without a history of opportunistic infection within the last 12 months d. On established antiretroviral therapy (ART) for at least 4 weeks.
- Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently).
- Uncontrolled hypertension (systolic blood pressure (BP) ≥ 150 mm mercury (Hg) or diastolic BP ≥ 95 mm Hg) prior to first dose.
- Prior treatment with MMAE (vedotin) based therapy.
- 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.
- 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.
- 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 |
|---|---|---|---|
 France | Not Recruiting | 31 Aug 2025 | 10 |
 Germany | Not Recruiting | 31 Aug 2025 | 4 |
 Italy | Not Recruiting | 31 Aug 2025 | 2 |
 Spain | Not Recruiting | 31 Aug 2025 | 12 |
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 | 54 | PRD12666060 |
BT8009 | Test | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENIOUS INFUSION | 6 | 54 | PRD10891228 |