DEPECA-1 – DEfeating PEnile CAncer 1 – A Phase II study to evaluate a first-line systemic therapy with enfortumab vedotin plus avelumab for advanced and metastatic penile carcinoma

The primary objective is to evaluate the efficacy of the combination of enfortumab vedotin plus avelumab in patients with locally advanced or metastatic penile squamous cell carcinoma. This objective addresses the clinical need for effective first-line systemic therapy in this rare malignancy, where treatment options remain limited and outcomes are generally poor.

The secondary objectives include:

• To evaluate the efficacy of the combination of enfortumab vedotin plus avelumab
• To evaluate the safety and tolerability of the combination of enfortumab vedotin plus avelumab
• To assess the quality of life

The sponsor did not provide information regarding the total number of participants for this clinical trial. The study population consists exclusively of **male patients** aged **18 years and older** with histologically confirmed **locally advanced or metastatic penile squamous cell carcinoma**. Participants must have an **Eastern Cooperative Oncology Group (ECOG) performance status** of 2 or less and a life expectancy of at least 3 months. Eligible patients are those considered non-eligible for curative surgical management, including individuals with distant metastatic disease or specific staging criteria based on the UICC/AJCC 8th edition TNM classification. Participants must have measurable disease per **RECIST 1.1 criteria** and adequate hematologic, hepatic, and renal function, including **absolute neutrophil count** greater than 1,500 cells/μL, **platelet count** of at least 100 x 10⁹/L, **hemoglobin** of at least 9 g/dL, and **creatinine clearance** of at least 30 mL/min. No prior systemic therapy for metastatic or locally advanced disease in the palliative setting is permitted, although neoadjuvant or adjuvant systemic therapy without immunotherapy is allowed if completed at least 6 months before enrollment. Participants must not have other active malignancies within the past 3 years, except adequately treated **basal cell carcinoma** or **squamous cell carcinoma** of the skin, and must have no history of significant cardiovascular disease within the last 6 months.

This is a Phase II clinical trial evaluating the efficacy and safety of combination therapy with **enfortumab vedotin** and **avelumab** in patients with **locally advanced or metastatic penile squamous cell carcinoma**. The study employs a single-arm, open-label design to assess first-line systemic treatment in patients who are not eligible for curative surgical management. The trial is designed to enroll adult male patients aged 18 years or older with histologically confirmed diagnosis of penile squamous cell carcinoma and measurable disease according to **RECIST 1.1 criteria**. Eligible participants must have an **Eastern Cooperative Oncology Group** performance status of 2 or less and adequate hematologic, hepatic, and renal function. Patients with prior systemic therapy for metastatic or locally advanced disease in the palliative setting are excluded, although neoadjuvant or adjuvant systemic therapy without immunotherapy is permitted if administered at least 6 months before enrollment.

The investigational medicinal products consist of **Bavencio** (avelumab 20 mg/mL concentrate for solution for infusion) and **Padcev** (enfortumab vedotin 30 mg powder for concentrate for solution for infusion), both administered via **intravenous** route. The maximum daily dose of avelumab is 1200 mg, with a maximum total dose of 38400 mg over the treatment period. Enfortumab vedotin is administered at a maximum daily dose of 1.25 mg/kg, with a maximum total dose of 80 mg/kg. The maximum treatment period for both agents is 24 months. The primary endpoint is **Objective Response Rate** in first-line treatment as assessed by investigators, defined as the proportion of patients achieving **complete response** or **partial response** according to RECIST 1.1 criteria. Secondary endpoints include **progression-free survival**, defined as time from treatment initiation to first documented disease progression or death; **overall survival**, defined as time from treatment start to death from any cause; **duration of response**, measured from first documented response to progression or death; and **disease control rate**, defined as the proportion of patients achieving complete response, partial response, or **stable disease** for at least 12 weeks.

Safety assessments include monitoring the incidence and severity of **adverse events** and **serious adverse events**, graded according to the **Common Terminology Criteria for Adverse Events** version 5.0. Patient-reported quality of life will be evaluated using the **EQ-5D-5L** and **EQ-HWB-S** questionnaires along with additional bolt-on questions. The estimated recruitment start date is September 2025, with an estimated study completion date of November 2030. The expected duration of participant involvement is up to 24 months of active treatment, with subsequent follow-up visits for survival and disease status assessment. Participants may be withdrawn from the study early due to disease progression, unacceptable toxicity, withdrawal of consent, significant protocol violations, or investigator decision based on clinical judgment. Male patients with female partners of childbearing potential must use effective contraception during the study and for 4 months after the last dose of enfortumab vedotin or at least 30 days after the last administration of avelumab, whichever occurs last.

The investigational treatment regimen consists of two experimental medications administered in combination. The first experimental medication is **Bavencio**, which contains **avelumab** as the active substance. Avelumab is a recombinant human monoclonal IgG1 antibody against programmed death ligand-1. The product is supplied as a 20 mg/mL **concentrate for solution for infusion** and is administered as a **solution for infusion** via the **intravenous route**. The maximum daily dose is **1200 mg**, with a maximum total dose of **38400 mg** over the treatment period. The maximum treatment duration is **24 months**.

The second experimental medication is **Padcev**, which contains **enfortumab vedotin** as the active substance. The product is supplied as a 30 mg **powder for concentrate for solution for infusion** and is administered as a **solution for infusion** via the **intravenous route**. The dosage is weight-based, with a maximum daily dose of **1.25 mg/kg** and a maximum total dose of **80 mg/kg** over the treatment period. The maximum treatment duration is **24 months**.

Both experimental medications are protein-based therapeutic agents and are administered to patients with locally advanced or **metastatic penile squamous cell carcinoma**. The combination therapy aims to evaluate efficacy in this patient population receiving first-line systemic treatment.

Efficacy will be assessed through multiple endpoints evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The primary efficacy endpoint is Objective Response Rate (ORR), defined as the proportion of patients achieving a complete response (CR) or partial response (PR) as assessed by investigators. Secondary efficacy endpoints include progression-free survival (PFS), defined as the time from the start of treatment to the first documented disease progression according to RECIST 1.1 criteria or death from any cause, whichever occurs first. Overall survival (OS) will be measured as the time from the start of treatment to death from any cause. Duration of response (DoR) will be evaluated as the time from the first documented response (CR or PR) to disease progression or death from any cause, whichever occurs first. Disease Control Rate (DCR) will be determined as the proportion of patients achieving CR, PR, or stable disease (SD) for at least 12 weeks according to RECIST 1.1 criteria. Patient-reported quality of life will be assessed using the EQ-5D-5L and EQ-HWB-S questionnaires along with a set of bolt-on questions.