Phase I Study of Becotatug Vedotin for Safety and Efficacy in EGFR-Positive Pediatric Relapsed/Refractory or Metastatic Solid Tumors

A Phase I Clinical Study to Explore the Safety and Efficacy of Becotatug Vedotin in Pediatric Patients With EGFR-Positive Relapsed/Refractory or Metastatic Solid Tumors

There is a significant unmet medical need for effective therapies for pediatric relapsed/refractory solid tumors. EGFR is highly and stably expressed in multiple pediatric solid tumor subtypes, and adult Phase I data of Becotatug Vedotin demonstrated a manageable safety profile and promising antitumor activity in EGFR-positive advanced solid tumors.This is a multicenter, non-randomized, single-arm, open-label Phase I clinical trial sponsored by Sun Yat-sen University Cancer Center (SYSUCC). The trial evaluates the safety, tolerability, pharmacokinetics (PK), immunogenicity, and preliminary efficacy of Becotatug Vedotin-an EGFR-targeted antibody-drug conjugate (ADC)-in pediatric patients with EGFR-positive relapsed/refractory or metastatic solid tumors.

Pediatric relapsed/refractory solid tumors represent a major unmet medical need, with conventional chemotherapy and immunotherapy showing limited efficacy and significant toxicities in this population. EGFR is highly and stably expressed in multiple pediatric solid tumor subtypes. Becotatug Vedotin consists of a humanized anti-EGFR monoclonal antibody conjugated to monomethyl auristatin E (MMAE), a potent microtubule inhibitor, via a cleavable valine-citrulline linker. Adult Phase I data demonstrated a manageable safety profile and promising antitumor activity in EGFR-positive advanced solid tumors, with an objective response rate (ORR) of 29% in nasopharyngeal carcinoma and 31% in head and neck squamous cell carcinoma. This trial extends these findings to the pediatric population.The trial evaluates the safety, tolerability, pharmacokinetics (PK), immunogenicity, and preliminary efficacy of Becotatug Vedotin-an EGFR-targeted antibody-drug conjugate (ADC)-in pediatric patients with EGFR-positive relapsed/refractory or metastatic solid tumors.

Inclusion Criteria:

• All participants must meet all of the following criteria to be eligible for enrollment:

Informed Consent: The patient (and/or legal guardian, as age-appropriate) fully understands the study, voluntarily agrees to participate, and signs a written informed consent form (ICF). A separate biomarker consent form is required for EGFR testing prior to screening.

Age: 2 to 18 years old at the time of consent. Life Expectancy: Estimated overall survival of at least 3 months.

Histologically Confirmed Disease: Pathologically confirmed relapsed/refractory or metastatic EGFR-positive solid tumor, belonging to one of the following subtypes:

Head and neck squamous cell carcinoma, nasopharyngeal carcinoma, or lymphoepithelial carcinoma that progressed during or after at least one line of platinum-based chemotherapy and PD-1/PD-L1 inhibitor therapy Rhabdomyosarcoma Neuroblastoma Medulloblastoma Wilms tumor Atypical teratoid/rhabdoid tumors (AT/RTs) Diffuse intrinsic pontine gliomas (DIPGs) Other EGFR-positive solid tumor subtypes deemed eligible by the investigator Measurable Disease: At least one measurable tumor lesion by computed tomography (CT) or magnetic resonance imaging (MRI) per RECIST v1.1 criteria (longest diameter ≥10 mm; pathological lymph node short axis ≥15 mm).

Performance Status: Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2.

Adequate Bone Marrow Function:

Absolute neutrophil count (ANC) ≥1.5 × 10⁹/L Platelet count ≥75 × 10⁹/L Hemoglobin ≥80 g/L Exception for patients with bone marrow involvement: ANC ≥1.0 × 10⁹/L, platelets ≥50 × 10⁹/L, hemoglobin ≥75 g/L

Adequate Hepatic and Renal Function:

Serum creatinine ≤1.5 × upper limit of normal (ULN) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × ULN Total bilirubin ≤1.5 × ULN Exception for patients with liver involvement: AST/ALT ≤5 × ULN, total bilirubin ≤3 × ULN

Exclusion Criteria:

• Participants will be excluded from the study if they meet any of the following criteria:

Hypersensitivity: Known hypersensitivity to any component of Becotatug Vedotin (MRG003) or its excipients.

Symptomatic CNS Metastases: Presence of symptomatic central nervous system (CNS) metastases.

Prior Malignancies: History of other primary malignant tumors, except for:

Locally excised basal cell or squamous cell carcinoma of the skin Cervical carcinoma in situ Any prior malignancy that has been in complete remission for ≥3 years without treatment Note: Melanoma (any stage) is explicitly excluded

Significant Liver Disease: Clinically significant liver disease, including:

Positive hepatitis C virus (HCV) antibody Chronic active hepatitis B (HBV DNA >20,000 IU/mL) HIV Infection: Known human immunodeficiency virus (HIV) infection. Severe Ocular Abnormalities: History of severe ophthalmologic conditions, such as severe dry eye syndrome or exposure keratitis.

Uncontrolled Systemic Diseases: Severe or uncontrolled medical conditions, including:

Interstitial lung disease or pneumonitis Active autoimmune diseases requiring systemic immunosuppressive therapy

Cardiac Disease: Clinically significant cardiac dysfunction or cardiac disease, including:

Congestive heart failure (New York Heart Association Class ≥II) Uncontrolled arrhythmias QTc interval prolongation >450 ms (males) or >470 ms (females) Recent Antitumor Therapy: Received any systemic antitumor therapy (chemotherapy, biological therapy, immunotherapy, targeted therapy) within 3 weeks prior to the first dose of study drug, and have not recovered to CTCAE v4.03 Grade ≤1 (except alopecia).

Recent Major Surgery: Underwent major surgical procedure within 3 weeks prior to the first dose of study drug.

Planned Surgery: Planned surgical procedure during the study period, or any surgery deemed necessary by the investigator.

Prior EGFR Therapy Toxicity: History of severe skin toxicity caused by prior EGFR-targeted therapy, or chronic skin disease requiring ongoing oral or intravenous treatment.

Other Significant Risks: Any other concurrent medical condition that, in the investigator's judgment, would increase the risk of toxicity or compromise the patient's ability to complete the study.