A Prospective, Single-Arm Clinical Study of Intranasal Recombinant Adenovirus Vaccine WSK-IM05 Combined With Tislelizumab as Neoadjuvant Therapy for HPV-Positive Oropharyngeal Squamous Cell Carcinoma
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 9
- 试验地点
- 1
- 主要终点
- Incidence of Dose-Limiting Toxicities (DLTs)
研究概览
简要总结
This phase I, open-label, single-arm trial uses a "3+3" dose-escalation design to evaluate the safety, tolerability, and preliminary efffcacy of intranasal WSK-IM05 vaccine combined with tislelizumab as neoadjuvant therapy in patients with resectable HPV-positive oropharyngeal squamous cell carcinoma. Participants receive two cycles of WSK-IM05 (intranasal) and tislelizumab (200 mg IV) on day 1 of each 3-week cycle, followed by surgery. After surgery, patients receive standard of care (chemoradiotherapy or radiotherapy as indicated) plus 15 cycles of adjuvant tislelizumab. The main outcomes include dose-limiting toxicities and treatment-related adverse events.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •1. Age ≥ 18 years, male or female.
- •Histologically confirmed oropharyngeal squamous cell carcinoma meeting all of the following criteria: Newly diagnosed, HPV-positive, without distant metastases; Confirmed p16 positive by immunohistochemistry (defined as ≥70% moderate to strong nuclear and cytoplasmic staining of tumor cells)；Assessed by head and neck surgery as resectable; Willing to undergo surgical treatment.
- •Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1.
- •Adequate organ and bone marrow function, defined as:Hematology: neutrophil count (NEUT) ≥ 1.5×10⁹/L; platelet count (PLT) ≥ 80×10⁹/L; hemoglobin ≥ 8 g/dL; Liver function: AST, ALT, ALP ≤ 2.5×upper limit of normal (ULN); total bilirubin (TBIL) ≤ 1.5×ULN; Albumin ≥ 2.8 g/dL.Renal function: serum creatinine (Cr) ≤ 1.5×ULN or creatinine clearance (CCr) > 60 mL/min; Coagulation: international normalized ratio (INR) ≤ 1.5; activated partial thromboplastin time (APTT) ≤ 1.5×ULN; Adenovirus type 5(Ad5) neutralizing antibody titer ≤ 1:200.
- •Willing to voluntarily sign the informed consent form and able to comply with protocol-required visits and procedures.
排除标准
- •1. History of other malignancies (except for adequately treated and with no recurrence within 5 years:basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer,cervical carcinoma in situ, intramucosal gastrointestinal carcinoma, or other malignancies deemed eligible by the investigator).
- •Any active autoimmune disease or history of autoimmune disease,including but not limited to immune-related neurological disorders, multiple sclerosis, autoimmune(demyelinating) neuropathy, Guillain-Barré syndrome, myasthenia gravis, systemic lupus erythematosus(SLE), connective tissue disease, scleroderma, inflammatory bowel disease (including Crohn's disease and ulcerative colitis), autoimmune hepatitis, toxic epidermal necrolysis (TEN), or Stevens-Johnson syndrome (excluding type I diabetes mellitus managed with stable insulin doses).
- •History of allergic disease, severe drug allergy, or known allergy to any component of large molecule protein preparations,PD-1 monoclonal antibody injections, or the intranasal recombinant adenovirus vaccine (note: severe allergy is defined as requiring hospitalization).
- •Prior receipt of any of the following treatments:a. Prior use of PD-1 antibody, PD-L1 antibody, PD-L2 antibody, CTLA-4 antibody, EGFR antibody, or EGFR-TKI.b. Prior receipt of an antitumor vaccine.c. Use of any active vaccine against infectious diseases (e.g.,inffuenza vaccine, varicella vaccine) within 4 weeks before first dose or planned during the study period.d. Major surgery or severe trauma within 4 weeks before first dose.e. Prior antitumor toxicity not recovered to ≤ CTCAE v5.0 grade 1 (excluding alopecia or sequelae of prior platinum-related neuropathy) or to the levels specified in inclusion/exclusion criteria.
- •Presence of severe medical conditions, such as: Cardiac dysfunction grade II or higher (NYHA criteria), ischemic heart disease (e.g., myocardial infarction or angina), clinically significant supraventricular or ventricular arrhythmias; Poorly controlled diabetes (fasting blood glucose ≥ 10 mmol/L); Poorly controlled hypertension (systolic blood pressure > 150 mmHg and/or diastolic blood pressure > 100 mmHg); Echocardiography showing ejection fraction < 50%; QTc interval: > 450 msec in males, > 470 msec in females; Any ECG abnormality that, in the investigator's opinion, poses additional risk for the study drug.
- •History of interstitial lung disease, non-infectious pneumonitis, or high suspicion of interstitial lung disease; or conditions that might interfere with detection or management of suspected drug-related pulmonary toxicity. Patients with a prior history of drug-induced or radiation-induced non-infectious pneumonitis who are asymptomatic may be enrolled. Active tuberculosis or past tuberculosis that remains uncontrolled after treatment.
- •Patients with hyperthyroidism or organic thyroid disease. Hypothyroidism managed with a stable dose of thyroid replacement hormone may be enrolled (as conffrmed by the investigator and/or endocrinologist).
- •Active infection, or unexplained fever within 48 hours before first dose, or use of systemic antibiotics within 1 week before signing informed consent.
- •Active hepatitis B (HBV DNA ≥ 2000 IU/mL or 10⁴ copies/mL) or active hepatitis C (positive HCV antibody with HCV RNA above the lower limit of detection), or known positive HIV test or known acquired immunodeffciency syndrome (AIDS).
- •Clear history of neurological or psychiatric disorders, such as epilepsy or dementia.
- •Clear history of drug abuse or alcohol abuse within 3 months.
- •Pregnant or breast feeding women; participants (and their partners) who plan to conceive within 3 months after the study period, have unprotected sexual intercourse, or are unwilling to use adequate contraceptive measures (e.g., condom,intrauterine device, or partner sterilization).
- •Receipt of any investigational drug within 4 weeks before first dose, or concurrent enrollment in another clinical study, unless it is an observational (non-interventional) study or the follow-up phase of an interventional study.
- •Any other condition that,in the investigator's judgment, might interfere with the study, including inability to complete study treatment and follow-up.
研究组 & 干预措施
WSK-IM05 (4×10^10 vp) + Tislelizumab
Participants receive two cycles (each cycle = 3 weeks) of neoadjuvant treatment. On day 1 of each cycle: intranasal WSK-IM05 vaccine at a dose of 4×10^10 vp and tislelizumab 200 mg intravenously. After two cycles, patients undergo radical surgery followed by standard postoperative therapy plus 15 cycles of adjuvant tislelizumab (200 mg every 3 weeks). Dose-limiting toxicity (DLT) is assessed during the first 21 days after the first dose.
干预措施: WSK-IM05 (1.6x10^11 vp) (Biological)
Arm 2: WSK-IM05 (8×10^10 vp) + Tislelizumab
Participants receive two cycles (each cycle = 3 weeks) of neoadjuvant treatment. On day 1 of each cycle: intranasal WSK-IM05 vaccine at a dose of 8×10^10 vp and tislelizumab 200 mg intravenously. After two cycles, patients undergo radical surgery followed by standard postoperative therapy plus 15 cycles of adjuvant tislelizumab (200 mg every 3 weeks). Dose-limiting toxicity (DLT) is assessed during the first 21 days after the first dose.
干预措施: WSK-IM05 (1.6x10^11 vp) (Biological)
WSK-IM05 (4×10^10 vp) + Tislelizumab
Participants receive two cycles (each cycle = 3 weeks) of neoadjuvant treatment. On day 1 of each cycle: intranasal WSK-IM05 vaccine at a dose of 4×10^10 vp and tislelizumab 200 mg intravenously. After two cycles, patients undergo radical surgery followed by standard postoperative therapy plus 15 cycles of adjuvant tislelizumab (200 mg every 3 weeks). Dose-limiting toxicity (DLT) is assessed during the first 21 days after the first dose.
干预措施: WSK-IM05 (4×10^10 vp) (Biological)
Arm 3: WSK-IM05(1.6×10^11 vp) + Tislelizumab
Participants receive two cycles (each cycle = 3 weeks) of neoadjuvant treatment. On day 1 of each cycle: intranasal WSK-IM05 vaccine at a dose of 1.6×10^11 vp and tislelizumab 200 mg intravenously. After two cycles, patients undergo radical surgery followed by standard postoperative therapy plus 15 cycles of adjuvant tislelizumab (200 mg every 3 weeks). Dose-limiting toxicity (DLT) is assessed during the first 21 days after the first dose.
干预措施: Tislelizumab (Drug)
Arm 2: WSK-IM05 (8×10^10 vp) + Tislelizumab
Participants receive two cycles (each cycle = 3 weeks) of neoadjuvant treatment. On day 1 of each cycle: intranasal WSK-IM05 vaccine at a dose of 8×10^10 vp and tislelizumab 200 mg intravenously. After two cycles, patients undergo radical surgery followed by standard postoperative therapy plus 15 cycles of adjuvant tislelizumab (200 mg every 3 weeks). Dose-limiting toxicity (DLT) is assessed during the first 21 days after the first dose.
干预措施: WSK-IM05 (8×10^10 vp) (Biological)
Arm 3: WSK-IM05(1.6×10^11 vp) + Tislelizumab
Participants receive two cycles (each cycle = 3 weeks) of neoadjuvant treatment. On day 1 of each cycle: intranasal WSK-IM05 vaccine at a dose of 1.6×10^11 vp and tislelizumab 200 mg intravenously. After two cycles, patients undergo radical surgery followed by standard postoperative therapy plus 15 cycles of adjuvant tislelizumab (200 mg every 3 weeks). Dose-limiting toxicity (DLT) is assessed during the first 21 days after the first dose.
干预措施: WSK-IM05 (1.6x10^11 vp) (Biological)
结局指标
主要结局
Incidence of Dose-Limiting Toxicities (DLTs)
时间窗: First 21 days after first dose of WSK-IM05
Proportion of participants experiencing DLTs within the DLT observation period (first 21 days after the first dose), as defined per protocol.
Incidence and Severity of Treatment-Related Adverse Events (TRAEs)
时间窗: From first dose through 30 days after last dose of WSK-IM05
Type, incidence, severity (grade 1-5 according to CTCAE v5.0), and causality assessment of all treatment-related adverse events.
Incidence of Serious Adverse Events (SAEs)
时间窗: From first dose through 30 days after last dose
Including immune-related adverse events (irAEs), injection/administration site reactions, allergic reactions, etc.
次要结局
- Major Pathological Response (MPR)(At time of surgery (approx. Week 6-10))
- Pathological Complete Response (pCR)(At time of surgery (approx. Week 6-10))
- Objective Response Rate (ORR)(After 2 cycles of neoadjuvant therapy (prior to surgery, approx. Week 5-9))
- Event-Free Survival (EFS)(From first dose up to approximately 3 years)
研究者
Xingchen Peng
Professor
West China Hospital