A Single-Arm Study of Adjuvant Immunotherapy Plus Anlotinib in Patients With Locally Advanced Esophageal Squamous Cell Carcinoma With Non-Major Pathological Response and ypN-Positive Disease After Neoadjuvant Chemoimmunotherapy and Surgery
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 入组人数
- 75
- 主要终点
- 1-Year Disease-Free Survival Rate
研究概览
简要总结
The goal of this clinical trial is to learn whether postoperative immunotherapy combined with anlotinib can help prevent or delay cancer recurrence in adults aged 18 to 75 years with locally advanced esophageal squamous cell carcinoma. Eligible participants must have previously received chemotherapy combined with anti-PD-1 immunotherapy, followed by complete surgical removal of the cancer. Examination of the surgical specimens must show more than 10% viable tumor remaining in the original tumor bed and cancer cells remaining in regional lymph nodes.
The main questions this trial aims to answer are:
- What proportion of participants are alive without cancer recurrence or a second primary cancer 12 months after enrollment?
- How long do participants remain free of cancer recurrence, and how long do they survive?
- What treatment-related medical problems occur during treatment with anti-PD-1 immunotherapy plus anlotinib?
- Where does the cancer recur if recurrence occurs? All participants will receive the same study treatment; there is no comparison group.
Participants will:
- Receive an anti-PD-1 immunotherapy medicine by intravenous infusion once every 3 weeks, generally using the same anti-PD-1 medicine received before surgery
- Take anlotinib by mouth once daily for 14 days, followed by 7 days without anlotinib, in each 21-day treatment cycle
- Continue treatment for up to 15 cycles unless the cancer returns, unacceptable side effects occur, consent is withdrawn, or another reason for stopping treatment arises
- Undergo regular clinic visits, laboratory tests, physical examinations, and safety assessments during treatment
- Undergo imaging examinations approximately every 3 months to check for cancer recurrence
- Be followed for disease recurrence and survival for up to 5 years after surgery Stored surgical tumor tissue will also be studied to explore whether features of the tumor immune environment are associated with treatment outcomes.
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
- •Age 18 to 75 years, inclusive.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 to
- •Histologically confirmed locally advanced esophageal squamous cell carcinoma.
- •Prior treatment with 2 to 4 cycles of neoadjuvant chemotherapy combined with an anti-PD-1 monoclonal antibody, followed by radical surgery with pathologically confirmed R0 resection.
- •An interval of no more than 10 weeks between completion of the last neoadjuvant chemotherapy or immunotherapy treatment and radical surgery.
- •Postoperative pathological assessment showing non-major pathological response, defined as more than 10% residual viable tumor cells in the primary tumor bed, and viable tumor metastasis in at least one resected regional lymph node (ypN-positive disease).
- •Enrollment within 10 weeks after esophagectomy.
- •Ability to swallow and tolerate oral medication, without severe dysphagia, chronic diarrhea, intestinal obstruction, or another condition that may substantially affect oral drug absorption.
- •Adequate organ function, based on laboratory tests performed within 7 days before the first dose and without blood transfusion, erythropoietin, granulocyte colony-stimulating factor, or similar supportive treatment within the preceding 14 days, meeting all of the following criteria:
- •Absolute neutrophil count ≥1.5 × 10^9/L.
- •Platelet count ≥100 × 10^9/L.
- •Hemoglobin ≥90 g/L.
- •Total bilirubin ≤1.5 × the upper limit of normal (ULN).
- •Alanine aminotransferase and aspartate aminotransferase ≤2.5 × ULN.
- •Serum creatinine ≤1.5 × ULN or creatinine clearance ≥60 mL/min.
- •Urine protein negative or 1+ on routine urinalysis. If urine protein is 2+ or higher, 24-hour urinary protein must be ≤1.0 g.
- •International normalized ratio ≤1.5, prothrombin time no more than 4 seconds above ULN, and activated partial thromboplastin time ≤1.5 × ULN.
- •Systolic blood pressure <140 mmHg and diastolic blood pressure <90 mmHg, without antihypertensive medication or while receiving no more than two antihypertensive medications.
- •Thyroid-stimulating hormone within the normal range. Participants with abnormal thyroid-stimulating hormone may be eligible if free triiodothyronine and free thyroxine are within the normal ranges and the investigator determines that systemic immunosuppressive treatment is not required and that observation, stable endocrine replacement therapy, or symptomatic treatment is sufficient.
- •Fasting blood glucose ≤10 mmol/L or glycated hemoglobin ≤8%. Participants with diabetes must have stable glycemic control with medication.
- •Left ventricular ejection fraction ≥50% and resting corrected QT interval <480 milliseconds.
- •No myocardial infarction or severe or unstable angina within 6 months before the first dose; no clinically symptomatic severe arrhythmia; and no congestive heart failure of New York Heart Association Class II or higher.
- •Ability to understand the study and voluntarily provide written informed consent.
排除标准
- •Esophageal cancer with a pathological type other than squamous cell carcinoma.
- •Distant organ or distant lymph node metastasis identified by preoperative imaging, intraoperative exploration, or postoperative pathological examination, corresponding to M1 disease according to the American Joint Committee on Cancer staging system, Eighth Edition.
- •No prior neoadjuvant therapy, or prior neoadjuvant therapy other than chemotherapy combined with immunotherapy, including neoadjuvant chemotherapy alone or neoadjuvant chemoradiotherapy.
- •Use of an anti-PD-L1 antibody or another immune checkpoint inhibitor other than an anti-PD-1 antibody during neoadjuvant treatment.
- •One or fewer, or more than four, cycles of neoadjuvant chemoimmunotherapy.
- •A Grade 4 or higher immune-related adverse event, Grade 3 or higher immune-related pneumonitis, or Grade 2 or higher immune-related myocarditis during prior neoadjuvant treatment, according to the Common Terminology Criteria for Adverse Events, Version 5.
- •Substantial extranodal extension, fixed or matted regional lymph nodes, or involvement of important surrounding tissues or organs found during surgery that, in the investigator's judgment, prevented complete oncological resection or created a clear risk of residual disease; or postoperative evidence of R1 or R2 resection.
- •Major pathological response or pathologically negative regional lymph nodes (ypN0) after neoadjuvant treatment.
- •A severe postoperative complication of Grade 3 or higher that has not recovered to Grade 1 or lower or to the preoperative baseline before planned adjuvant treatment or within 10 weeks after surgery; or a postoperative complication that, in the investigator's judgment, has substantially reduced the participant's performance status and is expected to prevent tolerance of adjuvant treatment.
- •Poor nutritional status or a Patient-Generated Subjective Global Assessment score ≥
- •An unhealed wound, ulcer, or fracture.
- •Any Grade 2 or higher bleeding event within 4 weeks before the first dose.
- •Evidence of a bleeding diathesis; current thrombolytic therapy or therapeutic anticoagulation; or use of an antiplatelet drug, such as clopidogrel, or high-dose aspirin >325 mg/day within 14 days before the first dose. Low-dose aspirin ≤100 mg/day for cardiovascular prevention is permitted.
- •An arterial or venous thromboembolic event within 6 months before the first dose, including cerebrovascular accident, transient ischemic attack, deep vein thrombosis, or pulmonary embolism.
- •A concurrent second primary malignancy or a history of another malignancy within the previous 5 years, except completely cured cervical carcinoma in situ, basal cell carcinoma of the skin, or squamous cell carcinoma of the skin.
- •Active autoimmune disease, or a history of autoimmune disease that currently requires systemic immunosuppressive treatment. Stable thyroid dysfunction that does not require systemic immunosuppression, including hypothyroidism controlled with hormone replacement or stably controlled hyperthyroidism, is permitted.
- •An active infection requiring systemic treatment; active tuberculosis; or a history of tuberculosis without adequate treatment and with current evidence of active disease. A participant with latent tuberculosis infection may be enrolled only after assessment by an infectious disease or respiratory specialist confirms that enrollment is safe.
- •An uncontrolled active viral or sexually transmitted infection, including hepatitis B surface antigen positivity with hepatitis B virus DNA above the institutional lower limit of detection when standard antiviral therapy has not been initiated or cannot be administered following specialist assessment; uncontrolled hepatitis C virus RNA positivity; known HIV infection without standard antiviral treatment or with inadequate virological control; or active syphilis.
- •Known severe hypersensitivity to an active ingredient or excipient of either study treatment.
研究组 & 干预措施
Experimental Arm
Participants will receive an anti-PD-1 monoclonal antibody by intravenous infusion on Day 1 of each 21-day cycle, generally using the same anti-PD-1 agent administered during neoadjuvant treatment. Anlotinib will be administered orally at a starting dose of 12 mg once daily on Days 1-14 of each 21-day cycle. Study treatment must begin within 10 weeks after surgery and will continue for up to 15 cycles unless disease recurrence, unacceptable toxicity, withdrawal of consent, or another protocol-defined reason for discontinuation occurs. Protocol-specified treatment interruptions and dose reductions of anlotinib to 10 mg or 8 mg are permitted for toxicity. Dose reduction of the anti-PD-1 agent is not permitted.
干预措施: Anti-PD-1 Monoclonal Antibody (Drug)
Experimental Arm
Participants will receive an anti-PD-1 monoclonal antibody by intravenous infusion on Day 1 of each 21-day cycle, generally using the same anti-PD-1 agent administered during neoadjuvant treatment. Anlotinib will be administered orally at a starting dose of 12 mg once daily on Days 1-14 of each 21-day cycle. Study treatment must begin within 10 weeks after surgery and will continue for up to 15 cycles unless disease recurrence, unacceptable toxicity, withdrawal of consent, or another protocol-defined reason for discontinuation occurs. Protocol-specified treatment interruptions and dose reductions of anlotinib to 10 mg or 8 mg are permitted for toxicity. Dose reduction of the anti-PD-1 agent is not permitted.
干预措施: Anlotinib (Drug)
结局指标
主要结局
1-Year Disease-Free Survival Rate
时间窗: At 12 months after enrollment
The Kaplan-Meier estimated percentage of participants who are alive without local or regional recurrence, distant metastasis, or a second primary malignancy at 12 months after enrollment. Disease-free survival is measured from the date of enrollment to the first occurrence of disease recurrence, a second primary malignancy, or death from any cause, whichever occurs first.
次要结局
- Disease-Free Survival(From enrollment through 5 years after surgery)
- Overall Survival(From enrollment through 5 years after surgery)
- Patterns of Disease Recurrence(From enrollment through 5 years after surgery)
- Percentage of Participants With Treatment-Related Adverse Events(From the first dose through completion or discontinuation of study treatment, up to 15 cycles (each cycle is 21 days).)
研究者
Jun Liu
Professor
Shanghai Chest Hospital