A Prospective, Exploratory Clinical Study of Becotatug Vedotin Combined With Putlimab as Neoadjuvant Therapy Prior to Surgery and Adjuvant Radiotherapy After Surgery in Locally Advanced Head and Neck Squamous Cell Carcinoma
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 35
- 试验地点
- 1
- 主要终点
- Pathologic response
研究概览
简要总结
This is a prospective, exploratory, non-registration, multi-center clinical study to evaluate the efficacy and safety of becotatug vedotin (EGFR-ADC) combined with putlimab and radiotherapy in the perioperative treatment of locally advanced resectable head and neck squamous cell carcinoma (HNSCC).
**Neoadjuvant Phase** (3-week cycle, 2 cycles):
- Putlimab (HX008): 200 mg, Q3W, D1, IV
- Becotatug vedotin (MRG003): 2.0 mg/kg, Q3W, D1, IV
**Adjuvant/Maintenance Phase:** Surgery within 2-4 weeks post-neoadjuvant; surgical approach at investigator discretion.
**Group A (Postoperative pCR):**
- Putlimab (HX008): 200 mg, Q3W, D1, IV, up to 1 year
- Adjuvant RT: 40 Gy/5 weeks
**Group B (Postoperative MPR):**
- Putlimab (HX008): 200 mg, Q3W, D1, IV, up to 1 year
- Adjuvant RT: 50 Gy/5 weeks
**Group C (Postoperative Partial/No Response):**
- Low-risk (no extracapsular nodal extension [ENE] and negative margins): Putlimab 200 mg Q3W (up to 1 year) + RT 60 Gy/6 weeks
- High-risk (ENE and/or positive margins): Putlimab 200 mg Q3W (up to 1 year) + RT 60-66 Gy/6-6.6 weeks + Cisplatin 60 mg/m², Q3W, D1, IV, for 2 cycles
RT timing, field, and fractionation may be adjusted by investigators based on individual disease status.
Imaging assessment every 2 cycles (±7 days) until disease recurrence, initiation of new anti-tumor therapy, withdrawal of informed consent, death, or up to 21 cycles, whichever occurs first. Additional imaging may be performed at any time if clinically indicated.
详细描述
Neoadjuvant Phase (3-week cycle, 2 cycles):
Putlimab (HX008): 200 mg, Q3W, D1, IV infusion (60 ± 15 min, first cycle ≥ 60 min), for 2 cycles Becotatug vedotin (MRG003): 2.0 mg/kg, Q3W, D1, IV infusion (60 ± 10 min, first cycle ≥ 60 min), administered at least 30 min after completion of putlimab infusion, for 2 cycles For subjects unable to tolerate 60-min infusion, the infusion time may be extended to 120 min. Efficacy assessment will be performed every cycle until completion of 2 cycles followed by surgical resection or occurrence of discontinuation events (clinical progression, investigator-confirmed radiographic progression per RECIST 1.1, unacceptable toxicity, withdrawal of informed consent, or meeting criteria for intervention discontinuation).
Adjuvant/Maintenance Phase (3-week cycle):
Surgical resection within 2-4 weeks post-neoadjuvant; surgical approach at investigator discretion. Postoperative pathological response (pCR and MPR) will be determined based on the percentage of residual visible tumor relative to total tumor bed area on H&E-stained slides. Postoperative maintenance treatment will be administered in 3-week cycles. Adjuvant treatment will be selected based on pathological response: Group A (postoperative pCR); Group B (postoperative MPR); Group C (postoperative partial response/no response), further stratified into low/intermediate-risk (no extracapsular nodal extension [ENE] and negative margins) and high-risk (ENE and/or positive margins). All patients will receive putlimab (PD-1) maintenance therapy for a total duration of up to 1 year.
Post-discontinuation Standard Therapy:
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Diagnosis of any malignancy other than gastric cancer within 5 years prior to the first dose, with the exception of adequately treated cutaneous basal cell carcinoma, cutaneous squamous cell carcinoma, and/or radically resected carcinoma in situ;
- •Known endoscopic evidence of active bleeding in the target lesion;
- •Concurrent participation in another interventional clinical study, or receipt of any investigational medicinal product or use of investigational device within 4 weeks prior to the first dose;
- •Prior exposure to any of the following therapies: anti-PD-1, anti-PD-L1, or anti-PD-L2 agents; agents targeting other stimulatory or co-inhibitory T-cell receptors (including but not limited to CTLA-4, OX-40, and CD137); or antibody-drug conjugates (ADCs) with MMAE or MMAF payloads;
- •Systemic administration of Chinese proprietary medicines with anti-tumor indications or immunomodulatory agents (including thymosin, interferon, and interleukins, except for local administration to control pleural effusion) within 2 weeks prior to the first dose;
- •Active autoimmune disease requiring systemic therapy (e.g., disease-modifying antirheumatic drugs, corticosteroids, or immunosuppressants) within 2 years prior to the first dose. Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement for adrenal or pituitary insufficiency) is not considered systemic therapy;
- •Receipt of systemic corticosteroid therapy (excluding intranasal, inhaled, or other topical corticosteroids) or any other form of immunosuppressive therapy within 7 days prior to the first dose; *Note: Physiologic doses of corticosteroids (prednisone ≤10 mg/day or equivalent) are permitted;*
- •History of allogeneic organ transplantation (corneal transplantation excluded) or allogeneic hematopoietic stem cell transplantation;
- •Known hypersensitivity to pucotenlimab, MRG003, or any of their excipients;
- •Failure to recover adequately from toxicities and/or complications of prior interventions (i.e., to Grade ≤1 or to baseline, excluding fatigue and alopecia) prior to initiation of study treatment;
- •Known history of human immunodeficiency virus (HIV) infection (HIV-1/2 antibody positive);
- •Untreated active hepatitis B infection (defined as HBsAg positivity with HBV-DNA copy number above the upper limit of normal of the local laboratory); *Note: Subjects with hepatitis B may be enrolled if they meet the following criteria:* 1) HBV viral load <1,000 copies/mL (200 IU/mL) prior to the first dose; subjects must receive prophylactic anti-HBV therapy throughout the study treatment period to prevent viral reactivation; 2) Subjects with anti-HBc (+), HBsAg (-), anti-HBs (-), and undetectable HBV viral load are not required to receive prophylactic anti-HBV therapy but require close monitoring for viral reactivation;
- •Active hepatitis C infection (HCV antibody positive with HCV-RNA level above the lower limit of quantification);
- •Receipt of a live vaccine within 30 days prior to Cycle 1 Day 1; *Note: Inactivated injectable influenza vaccines for seasonal influenza are permitted within 30 days prior to the first dose; intranasal live-attenuated influenza vaccines are not permitted;*
- •Pregnancy or breastfeeding;
- •Presence of any serious or uncontrolled systemic condition, including but not limited to:
- •1) Resting ECG demonstrating significant, symptomatic, and poorly controlled abnormalities in rhythm, conduction, or morphology, including complete left bundle branch block, second-degree or higher atrioventricular block, ventricular arrhythmias, or atrial fibrillation; 2) Unstable angina pectoris, congestive heart failure, or chronic heart failure of New York Heart Association (NYHA) Class ≥2; 3) Any arterial thrombosis, embolism, or ischemic event (e.g., myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack) within 6 months prior to enrollment; 4) Inadequately controlled hypertension (systolic blood pressure >140 mmHg or diastolic blood pressure >90 mmHg); 5) History of non-infectious pneumonitis requiring corticosteroid therapy within 1 year prior to the first dose, or currently clinically active interstitial lung disease; 6) Active pulmonary tuberculosis; 7) Active or uncontrolled infection requiring systemic antimicrobial therapy; 8) Clinically active diverticulitis, intra-abdominal abscess, or gastrointestinal obstruction; 9) Hepatic conditions including cirrhosis, decompensated liver disease, or acute or chronic active hepatitis; 10) Poorly controlled diabetes mellitus (fasting blood glucose >10 mmol/L); 11) Urinalysis demonstrating urine protein ≥2+ with confirmed 24-hour urine protein >1.0 g; 12) Psychiatric disorder that would preclude compliance with study requirements;
- •17. Any medical condition, laboratory abnormality, or concurrent therapy that, in the Investigator's opinion, may interfere with study assessments, compromise subject safety, or render the subject unsuitable for study participation.
排除标准
- •Presence of distant metastatic lesions;
- •History of Grade ≥3 immune-related adverse events or treatment-related adverse events that have not recovered to Grade ≤1;
- •Receipt of surgery, chemotherapy, targeted small molecule therapy, or radiotherapy for another invasive malignancy within the past 5 years;
- •Autoimmune disease requiring systemic corticosteroid therapy within the past 3 months, history of clinically significant autoimmune disease, or syndrome requiring systemic corticosteroid therapy;
- •Active infection requiring systemic treatment;
- •Prior receipt of any form of anti-tumor therapy for the primary tumor or metastatic lymph nodes, including chemotherapy, radiotherapy, targeted therapy, anti-PD-1 or anti-PD-L1 therapy, or surgery (biopsy excluded);
- •History of other malignancies;
- •History of organ transplantation;
- •History of autoimmune disease, or other conditions requiring long-term systemic corticosteroid or immunosuppressive therapy;
- •Positive for human immunodeficiency virus (HIV);
- •Active hepatitis B or hepatitis C infection (HBV DNA or HCV RNA above the upper limit of normal);
- •Total white blood cell count <3.5×10⁹/L, absolute lymphocyte count <0.8×10⁹/L, neutrophil count <1.5×10⁹/L, platelet count <100×10⁹/L, or hemoglobin <90 g/L; total bilirubin >1.5× upper limit of normal (ULN), transaminases (AST, ALT) >3× ULN (>5× ULN if hepatic metastases present), serum creatinine >1.5× ULN; coagulation abnormalities with international normalized ratio (INR) or prothrombin time (PT) >1.5× ULN;
- •Serious cardiovascular, respiratory, or major immune system comorbidities; including urinary tract obstruction, myocardial infarction, arrhythmia, obstructive or restrictive lung disease, or other conditions that the Investigator considers may increase subject risk;
- •Pregnant or lactating women;
- •Refusal to use effective contraception during the treatment period and for 3 months thereafter;
- •Concurrent participation in another clinical study;
- •Critically ill patients unable to complete the study assessments;
- •History of psychiatric disorders (e.g., schizophrenia, mania, anxiety disorder, depression, phobia, etc.) or subjects/spouses diagnosed with psychiatric illness at the time of study enrollment;
- •Subjects or spouses with communication barriers or inability to provide normal responses due to altered consciousness, aphasia, intellectual disability, or other causes;
- •Any other condition that the Investigator considers renders the subject unsuitable for enrollment or may interfere with subject participation or completion of the study.
结局指标
主要结局
Pathologic response
时间窗: Periprocedural
次要结局
- Overall survival(2 years after surgery)
- Major pathological response(Periprocedural)
- Objective Response Rate(At the end of Cycle 2 (each cycle is 21 days))
- Disease Control Rate(At the end of Cycle 2 (each cycle is 21 days))
- Event-Free Survival(2 years after surgery)
- Safety(At the end of every 2 treatment cycles (21-day cycle))
研究者
Lirong Wu
Professor
Jiangsu Cancer Institute & Hospital