Phase 2 Trial of Pucotenlimab and Becotatug Vedotin Induction Therapy Versus Becotatug Vedotin Alone in Locally Advanced Head and Neck Squamous Cell Carcinoma

The primary objective of this randomized Phase 2 trial is to compare the **objective response rate (ORR)** in patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC) treated with induction therapy of EGFR-ADC MRG003 combined with anti-PD-1 Pucotenlimab versus EGFR-ADC MRG003 alone, prior to chemoradiotherapy. This comparison is clinically relevant as it aims to determine the efficacy of the combination therapy in enhancing tumor response, which could potentially lead to improved treatment outcomes for patients with LA-HNSCC.

Secondary objectives include:

• Comparing the complete response (CR) rate at 6 months post-chemoradiotherapy between the two treatment arms.
• Assessing progression-free survival (PFS) between the two arms.
• Evaluating failure-free survival (FFS) between the two arms.
• Comparing overall survival (OS), including OS rates at 24 and 36 months, between the two arms.
• Evaluating and comparing treatment compliance between the arms.
• Assessing and comparing adverse events graded by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 between the two arms.

The clinical trial involves participants diagnosed with **locally advanced head and neck squamous cell carcinoma**. The study population includes both male and female subjects, aged between 18 and 75 years, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating they are in relatively good health. The trial does not include a vulnerable population. Participants were selected based on specific inclusion criteria, such as having a histologically confirmed diagnosis of previously untreated locally advanced squamous cell carcinoma of the head and neck, suitable for definitive chemoradiotherapy. The trial does not provide information on the total number of participants or specific lifestyle considerations such as diet or physical activity. The sponsor has not disclosed the total number of participants involved in the study.

The clinical trial is a **randomized**, **controlled**, and **double-blind** Phase 2 study designed to evaluate the efficacy of induction treatment with **EGFR-ADC MRG003** alone or in combination with the **anti-PD-1** agent **pucotenlimab**, followed by chemoradiotherapy in patients with **locally advanced head and neck squamous cell carcinoma** (LA-HNSCC). The primary objective is to compare the objective response rate (ORR) of patients treated with the combination therapy versus the monotherapy before chemoradiotherapy. The trial is expected to commence recruitment on June 2, 2025, and conclude by June 29, 2029.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, performance status, and tumor characteristics. Eligible participants will be randomized to receive either the combination of MRG003 and pucotenlimab or MRG003 alone. The treatment phase will involve intravenous administration of the investigational products, with MRG003 administered at a maximum daily dose of 2.3 mg/kg and pucotenlimab at 200 mg, over a maximum treatment period of 9 and 33 weeks, respectively. Follow-up visits will be scheduled to monitor treatment response and adverse events, with radiological imaging conducted according to RECIST version 1.1 criteria to assess the best objective response rate at the end of the induction phase.

The expected duration of participant involvement in the trial is approximately four years, including treatment and follow-up periods. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, withdrawal of consent, or any other reason deemed appropriate by the investigator. Secondary endpoints include progression-free survival, failure-free survival, overall survival, treatment compliance, and the incidence and severity of adverse events. The trial will adhere to rigorous ethical standards and regulatory requirements to ensure the safety and well-being of all participants.

The clinical trial involves the administration of two experimental medications, **HX008** and **MRG003**, both provided in the form of a **solution for infusion**. **HX008** contains the active substance **pucotenlimab**, a protein-based compound developed by LEPU BIOPHARMA CO., LTD. This medication is administered via **intravenous injection**. The dosing regimen for **HX008** involves a maximum daily dose of 200 mg, with a total maximum dose of 2200 mg over a treatment period of up to 33 weeks. The administration schedule is designed to ensure optimal therapeutic exposure while monitoring for any adverse effects. Participant compliance is monitored through regular assessments and documentation of infusion sessions.

**MRG003** is another investigational product used in this trial, containing the active substance **becotatug vedotin**, also a protein-based compound. This medication is similarly administered as a **solution for infusion** via **intravenous injection**. The dosing for **MRG003** is calculated based on body weight, with a maximum daily dose of 2.3 mg/kg and a total maximum dose of 6.9 mg/kg over a treatment period of up to 9 weeks. The administration of **MRG003** is carefully scheduled to align with the trial's objectives, ensuring that participants receive the appropriate dosage while maintaining safety and efficacy standards. Compliance is monitored through detailed records of dosing and participant response to the treatment.

No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are utilized in this study. The trial's primary objective is to evaluate the efficacy of the combination of **HX008** and **MRG003** compared to **MRG003** alone in patients with locally advanced head and neck squamous cell carcinoma. The trial design includes rigorous monitoring of participant adherence to the dosing schedule and assessment of therapeutic outcomes to ensure the integrity and reliability of the study results.

Efficacy in this clinical trial will be assessed primarily through the **objective response rate (ORR)** of patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC). The ORR will be evaluated by investigators using head and neck radiological imaging according to RECIST version 1.1 criteria. This assessment will occur at the end of the induction phase of treatment with EGFR-ADC MRG003 combined with anti-PD-1 Pucotenlimab or with EGFR-ADC MRG003 alone, approximately 21 ± 7 days after the Day 1 of the last cycle of induction treatment. Objective response includes both complete and partial responses.

Secondary endpoints for efficacy include progression-free survival (PFS), failure-free survival (FFS), and overall survival (OS). PFS is defined as the time from randomization to the first progression or death from any cause, or the date of the last follow-up for patients without progression or death. FFS is measured from randomization to the first event of locoregional/metastatic progression after completion of chemoradiotherapy (CRT) or failure to receive CRT, or death from any cause. OS is defined as the time between randomization and death from any cause or the date of the last follow-up for patients who are alive.

Additional assessments will include compliance with treatment protocols, including radiotherapy and administration of anti-PD-1, EGFR-ADC, and cisplatin. This will involve reporting the total tumor dose, number of fractions, treatment duration, and any major deviations. For drug treatments, the number of cycles/injections, total dose, treatment duration, dose intensity, and relative dose intensity will be documented. Treatment interruptions, reductions, and discontinuations, along with their reasons, will also be reported. The incidence and severity of adverse events, serious adverse events, and laboratory abnormalities will be graded according to the National Cancer Institute - Common Terminology Criteria of Adverse Events (NCI-CTCAE) version 5.0, from randomization to one month after the end of adjuvant treatment.