Becotatug Vedotin Plus Pucotenlimab in Locally Advanced Head and Neck Squamous Cell Carcinoma With Suboptimal Response to Induction Immunochemotherapy
A Prospective, Multicenter, Single-Arm, Phase II Clinical Study of Becotatug Vedotin Combined With Pucotenlimab in Patients With Locally Advanced Head and Neck Squamous Cell Carcinoma With Suboptimal Response to Induction Immunochemotherapy
Patients with locally advanced head and neck squamous cell carcinoma (HNSCC) may receive chemotherapy combined with immunotherapy before surgery to reduce tumor size. However, some patients do not respond adequately to this initial treatment, and additional treatment options are needed.
This study aims to evaluate the effectiveness and safety of combining becotatug vedotin (MRG003), an antibody-drug conjugate that targets the epidermal growth factor receptor (EGFR), with pucotenlimab (HX008), a PD-1 immune checkpoint inhibitor, in patients whose disease remains stable or progresses after induction immunotherapy combined with platinum-based chemotherapy.
This is a prospective, multicenter, single-arm, phase II clinical trial. Eligible patients with locally advanced, resectable HNSCC will receive two cycles of becotatug vedotin plus pucotenlimab, administered every three weeks before surgery. After treatment, patients will undergo tumor response assessment followed by curative-intent surgery and appropriate postoperative treatment.
The primary objective is to evaluate the objective response rate (ORR), defined as the proportion of patients achieving complete or partial tumor response. The study will also assess pathological response, surgical outcomes, treatment safety, and long-term survival.
The study seeks to determine whether this additional preoperative treatment strategy may improve tumor response and provide further opportunities for organ preservation in patients who have not benefited adequately from initial induction immunochemotherapy.
Обзор исследования
Статус
Вмешательство/лечение
Подробное описание
**Background and Rationale**
Locally advanced head and neck squamous cell carcinoma (HNSCC) often requires extensive surgical resection, which may significantly impair speech, swallowing, appearance, and quality of life. Although induction immunochemotherapy combining platinum-based chemotherapy with programmed cell death protein 1 (PD-1) inhibitors has demonstrated promising antitumor activity, a proportion of patients experience stable disease (SD) or progressive disease (PD). These patients may have limited opportunities for tumor downstaging and organ preservation before definitive surgery.
Becotatug vedotin (MRG003) is an epidermal growth factor receptor (EGFR)-targeting antibody-drug conjugate (ADC) that delivers a cytotoxic payload to tumor cells. Pucotenlimab (HX008) is a PD-1 inhibitor that enhances antitumor immune responses. The combination may provide complementary antitumor mechanisms and represents a potential treatment strategy for patients with inadequate responses to previous induction immunochemotherapy.
**Study Design and Treatment**
This is a prospective, multicenter, open-label, single-arm, phase II clinical study designed to evaluate the efficacy and safety of becotatug vedotin combined with pucotenlimab as an adaptive neoadjuvant treatment strategy.
Eligible participants will have histologically confirmed, locally advanced (stage III-IVA), resectable HNSCC with SD or PD following at least two cycles of induction immunochemotherapy containing platinum-based chemotherapy and a PD-1 inhibitor, as assessed according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Resectability will be confirmed by a multidisciplinary team.
Participants will receive becotatug vedotin at 2.0 mg/kg intravenously and pucotenlimab at 200 mg intravenously, administered every three weeks for two cycles.
Following completion of study treatment, radiological tumor response will be assessed before curative-intent surgery. Postoperative adjuvant treatment, including radiotherapy with or without chemotherapy, will be administered according to standard clinical practice.
**Study Objectives and Assessments**
The primary objective is to evaluate the objective response rate (ORR) according to RECIST v1.1 after adaptive neoadjuvant therapy.
Secondary assessments include pathological complete response, major pathological response, R0 resection, organ preservation, safety, perioperative complications, and survival outcomes, including event-free survival, disease-free survival, and overall survival.
Exploratory analyses of tumor tissue and peripheral blood samples will investigate potential biomarkers associated with treatment response and mechanisms underlying resistance to induction immunochemotherapy.
**Statistical Design**
A Simon's two-stage minimax design will be employed, with a null ORR of 10%, a target ORR of 35%, a one-sided significance level of 0.05, and 80% statistical power.
In the first stage, 11 evaluable participants will be enrolled. If no more than one participant achieves a complete or partial response, the study will be stopped early for insufficient efficacy. If at least two participants achieve an objective response, an additional seven evaluable participants will be enrolled, resulting in a total of 18 evaluable participants.
If at least five of the 18 evaluable participants achieve an objective response, the regimen will be considered to have sufficient antitumor activity to warrant further investigation.
Allowing for approximately 15% attrition or non-evaluable participants, up to 22 participants are planned to be enrolled.
**Safety and Follow-up**
Adverse events, serious adverse events, immune-related adverse events, and perioperative complications will be monitored throughout the study. Participants will undergo postoperative follow-up, including imaging assessments for disease recurrence and long-term survival evaluation, according to the study protocol.
Тип исследования
Регистрация (Оцененный)
Фаза
- Фаза 2
Контакты и местонахождение
Контакты исследования
- Имя: Yujie Liang, PhD
- Номер телефона: +86 13242879610
- Электронная почта: liangyj35@mail.sysu.edu.cn
Учебное резервное копирование контактов
- Имя: Bin Zeng, PhD
- Номер телефона: +86 18819472975
- Электронная почта: zengb29@mail.sysu.edu.cn
Места учебы
-
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Guangdong
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Guangzhou, Guangdong, Китай
- Sun Yat-sen University Cancer Center
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Контакт:
- Puyun Ouyang, PhD
- Номер телефона: +86 20 87343571
- Электронная почта: ouyangpy@sysucc.org.cn
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Главный следователь:
- Puyun Ouyang, PhD
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Guangzhou, Guangdong, Китай, 510055
- Hospital of Stomatology, Sun Yat-sen University
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Контакт:
- Yujie Liang, PhD
- Номер телефона: +86 13242879610
- Электронная почта: liangyj35@mail.sysu.edu.cn
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Главный следователь:
- Yujie Liang, PhD
-
Младший исследователь:
- bin zeng, PhD
-
Guangzhou, Guangdong, Китай
- The Third Affiliated Hospital of Sun Yat-sen University
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Контакт:
- Zhanhong Chen, PhD
- Номер телефона: +86 20 85253333
- Электронная почта: chenanonz@163.com
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Главный следователь:
- Zhanhong Chen, PhD
-
Shenzhen, Guangdong, Китай
- Longgang District People's Hospital of Shenzhen
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Контакт:
- Jun Li, PhD
- Номер телефона: +86 755 28932833
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Главный следователь:
- Jun Li, PhD
-
-
Критерии участия
Критерии приемлемости
Возраст, подходящий для обучения
Принимает здоровых добровольцев
Полы, имеющие право на обучение
Описание
**Inclusion Criteria:**
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Voluntarily provides written informed consent before undergoing any study-specific procedures.
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Aged 18 to 70 years, regardless of sex.
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Histologically confirmed locally advanced (stage III-IVA, AJCC 8th edition) head and neck squamous cell carcinoma (HNSCC).
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Has received at least two cycles of induction immunochemotherapy comprising platinum-based chemotherapy and a PD-1 inhibitor.
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Has achieved stable disease (SD) or progressive disease (PD) as the best response to induction immunochemotherapy according to RECIST v1.1. A multidisciplinary team (MDT) considers that additional adaptive neoadjuvant therapy may reduce tumor burden, decrease the extent of surgical resection, or improve the opportunity for organ preservation.
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The interval between completion of induction immunochemotherapy and the first dose of study treatment does not exceed 28 days.
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Disease remains amenable to curative-intent surgery with an anticipated R0 resection, as confirmed by an MDT including an experienced head and neck surgeon.
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Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
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At least one measurable lesion according to RECIST v1.1 before initiation of study treatment.
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Adequate organ function, as assessed within 7 days before the first study dose:
- Absolute neutrophil count ≥1.5 × 10⁹/L.
- Platelet count ≥100 × 10⁹/L.
- Hemoglobin ≥90 g/L.
- Total bilirubin ≤1.5 × upper limit of normal (ULN).
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN (≤5 × ULN in the presence of liver metastases).
- Serum creatinine ≤1.5 × ULN or creatinine clearance ≥60 mL/min (Cockcroft-Gault formula).
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Women of childbearing potential and men whose partners are women of childbearing potential agree to use effective contraception throughout the study and for at least 6 months after the last dose.
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Willing and able to comply with study treatment, follow-up visits, laboratory examinations, and other protocol-required procedures.
**Exclusion Criteria:**
- Primary nasopharyngeal carcinoma.
- History of severe hypersensitivity to becotatug vedotin, pucotenlimab, or any of their excipients.
- Previous anticancer treatment for HNSCC other than the protocol-specified induction immunochemotherapy, including surgery, radiotherapy, other chemotherapy, targeted therapy, or biological therapy.
- Unresectable disease due to invasion of critical anatomical structures (e.g., carotid sheath involvement) or other factors, or medical contraindications to curative-intent surgery, as determined by the MDT.
- Distant metastatic disease (M1).
- Active autoimmune disease or a history of autoimmune disease requiring systemic immunosuppressive treatment within the previous 2 years, except for permitted conditions such as vitiligo or stable hypothyroidism.
- Active central nervous system (CNS) metastases and/or carcinomatous meningitis.
- Requirement for long-term immunosuppressive therapy or use of systemic corticosteroids at immunosuppressive doses (>10 mg/day prednisone or equivalent) within 7 days before the first study dose.
- Human immunodeficiency virus (HIV) infection; untreated active hepatitis B infection (HBsAg-positive with HBV DNA >1,000 IU/mL); or hepatitis C infection (HCV antibody-positive with detectable HCV RNA).
- Pregnancy or breastfeeding.
- Severe or uncontrolled systemic disease, including clinically significant cardiovascular, pulmonary, infectious, or endocrine disorders.
- Major surgery or severe trauma within 4 weeks before the first study dose.
- Severe bleeding tendency or coagulation disorder, or clinically significant active bleeding within 1 month before the first study dose.
- Any other condition that, in the investigator's opinion, may compromise participant safety, study compliance, or interpretation of study results.
Учебный план
Как устроено исследование?
Детали дизайна
- Основная цель: Уход
- Распределение: Н/Д
- Интервенционная модель: Одногрупповое задание
- Маскировка: Нет (открытая этикетка)
Оружие и интервенции
Группа участников / Армия |
Вмешательство/лечение |
|---|---|
|
Экспериментальный: Adaptive Neoadjuvant Therapy
Patients with locally advanced, resectable head and neck squamous cell carcinoma who have achieved stable disease or progressive disease following induction immunochemotherapy will receive becotatug vedotin (MRG003) at 2.0 mg/kg and pucotenlimab (HX008) at 200 mg intravenously every three weeks for two cycles, followed by curative-intent surgery and standard postoperative treatment as clinically indicated. |
Becotatug vedotin (MRG003) is an epidermal growth factor receptor (EGFR)-targeting antibody-drug conjugate (ADC). It will be administered intravenously at a dose of 2.0 mg/kg on Day 1 of each 21-day cycle for two cycles, in combination with pucotenlimab. Pucotenlimab (HX008) is a humanized monoclonal antibody targeting programmed cell death protein 1 (PD-1). It will be administered intravenously at a fixed dose of 200 mg on Day 1 of each 21-day cycle for two cycles, in combination with becotatug vedotin. |
Что измеряет исследование?
Первичные показатели результатов
Мера результата |
Мера Описание |
Временное ограничение |
|---|---|---|
|
Objective Response Rate (ORR)
Временное ограничение: From baseline to preoperative tumor assessment after two treatment cycles (approximately 6-10 weeks after the first dose)
|
The proportion of participants achieving a complete response (CR) or partial response (PR), as assessed by investigators using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), based on radiological assessments before and after adaptive neoadjuvant treatment. The ORR will be reported with an exact 95% confidence interval using the Clopper-Pearson method. |
From baseline to preoperative tumor assessment after two treatment cycles (approximately 6-10 weeks after the first dose)
|
Вторичные показатели результатов
Мера результата |
Мера Описание |
Временное ограничение |
|---|---|---|
|
Pathological Complete Response Rate (pCR)
Временное ограничение: At curative-intent surgery, approximately 6-12 weeks after the first study dose
|
The proportion of participants with no residual viable invasive tumor cells in the primary tumor bed and all regional lymph nodes, as determined by histopathological examination of surgical specimens. |
At curative-intent surgery, approximately 6-12 weeks after the first study dose
|
|
Major Pathological Response Rate (MPR)
Временное ограничение: At curative-intent surgery, approximately 6-12 weeks after the first study dose
|
The proportion of participants with 10% or less residual viable tumor cells in the resected tumor tissue, as assessed by histopathological examination. |
At curative-intent surgery, approximately 6-12 weeks after the first study dose
|
|
R0 Resection Rate
Временное ограничение: At curative-intent surgery, approximately 6-12 weeks after the first study dose
|
The proportion of participants undergoing curative-intent surgery who achieve microscopically negative surgical margins (R0 resection), as confirmed by histopathological examination. |
At curative-intent surgery, approximately 6-12 weeks after the first study dose
|
|
Organ Preservation Rate
Временное ограничение: From baseline surgical assessment to definitive surgery, approximately 6-12 weeks after the first study dose
|
Among participants assessed by a multidisciplinary team before study enrollment as requiring function-ablative surgery, the proportion who undergo organ-function-preserving surgery while achieving R0 resection after adaptive neoadjuvant treatment. |
From baseline surgical assessment to definitive surgery, approximately 6-12 weeks after the first study dose
|
|
Incidence of Adverse Events (AEs)
Временное ограничение: From first study drug administration through the protocol-defined safety follow-up period (up to 48 months)
|
The incidence and severity of adverse events, serious adverse events, and immune-related adverse events, graded according to NCI CTCAE version 6.0. Treatment-related events, events leading to dose modification or discontinuation, and perioperative complications will also be assessed. |
From first study drug administration through the protocol-defined safety follow-up period (up to 48 months)
|
|
Event-Free Survival (EFS) Rate at 1 and 2 Years
Временное ограничение: At 1 year and 2 years after the first study dose
|
The estimated proportion of participants remaining event-free at 1 year and 2 years after initiation of adaptive neoadjuvant therapy, calculated using the Kaplan-Meier method according to the protocol-defined event criteria. |
At 1 year and 2 years after the first study dose
|
|
Disease-Free Survival (DFS) Rate at 1 and 2 Years
Временное ограничение: At 1 year and 2 years after curative-intent surgery
|
The estimated proportion of participants remaining disease-free at 1 year and 2 years following curative-intent surgery, calculated using the Kaplan-Meier method. |
At 1 year and 2 years after curative-intent surgery
|
|
Overall Survival (OS) Rate at 1 and 2 Years
Временное ограничение: At 1 year and 2 years after the first study dose
|
The estimated proportion of participants alive at 1 year and 2 years after initiation of adaptive neoadjuvant therapy, calculated using the Kaplan-Meier method. |
At 1 year and 2 years after the first study dose
|
|
Clinicopathological Downstaging Rate
Временное ограничение: From baseline staging to postoperative pathological assessment, approximately 6-12 weeks after the first study dose
|
The proportion of participants whose postoperative pathological TNM stage (pTNM) is lower than the clinical TNM stage (cTNM) assessed after induction immunochemotherapy and before adaptive neoadjuvant treatment. |
From baseline staging to postoperative pathological assessment, approximately 6-12 weeks after the first study dose
|
Соавторы и исследователи
Спонсор
Соавторы
Следователи
- Главный следователь: Yujie Liang, PhD, Hospital of Stomatology, Sun Yat-Sen University
Даты записи исследования
Изучение основных дат
Начало исследования (Оцененный)
Первичное завершение (Оцененный)
Завершение исследования (Оцененный)
Даты регистрации исследования
Первый отправленный
Впервые представлено, что соответствует критериям контроля качества
Первый опубликованный (Действительный)
Обновления учебных записей
Последнее опубликованное обновление (Действительный)
Последнее отправленное обновление, отвечающее критериям контроля качества
Последняя проверка
Дополнительная информация
Термины, связанные с этим исследованием
Ключевые слова
Дополнительные соответствующие термины MeSH
Другие идентификационные номера исследования
- GHKQ-202608-L001
Планирование данных отдельных участников (IPD)
Планируете делиться данными об отдельных участниках (IPD)?
Описание плана IPD
There is currently no plan to share de-identified individual participant data (IPD) with researchers outside the study team. Study data will be managed in accordance with the approved protocol, informed consent, institutional ethics requirements, and applicable Chinese regulations. Aggregate study findings may be disseminated through scientific publications.
Информация о лекарствах и устройствах, исследовательские документы
Изучает лекарственный продукт, регулируемый FDA США.
Изучает продукт устройства, регулируемый Управлением по санитарному надзору за качеством пищевых продуктов и медикаментов США.
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