Low-Dose Radiotherapy Combined With Retlirafusp Alfa and Chemotherapy as Neoadjuvant Therapy for Resectable Locally Advanced Esophageal Squamous Cell Carcinoma: An Exploratory Phase II Study
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 96
- 试验地点
- 1
- 主要终点
- Pathological Complete Response (pCR)
研究概览
简要总结
This study aims to evaluate the efficacy and safety of neoadjuvant low-dose radiotherapy combined with Retlirafusp alfa and chemotherapy in the treatment of resectable locally advanced esophageal squamous cell carcinoma.
详细描述
Esophageal squamous cell carcinoma (ESCC) is the predominant subtype of esophageal cancer in China, accounting for approximately 90% of cases. Most patients are diagnosed at locally advanced stages. Although standard neoadjuvant chemoradiotherapy can achieve a pathological complete response (pCR) rate of around 43%, over 30% of patients still experience postoperative recurrence, and non-pCR patients have a poor prognosis. Immunotherapy has opened new avenues for locally advanced ESCC, with neoadjuvant immunochemotherapy achieving pCR rates of approximately 20%-35%, indicating room for further improvement.
Low-dose radiotherapy (LDRT, 8 Gy/4 fractions) can remodel the tumor immune microenvironment, promoting the conversion of "cold tumors" to "hot tumors" and enhancing the antitumor efficacy of immune checkpoint inhibitors. Retlirafusp alfa is an anti-PD-L1/TGF-βRII bifunctional fusion protein developed by Hengrui Medicine, which simultaneously blocks both the PD-L1 and TGF-β signaling pathways, thereby activating T-cell-mediated tumor killing. This study innovatively combines low-dose radiotherapy, Retlirafusp alfa, and chemotherapy to explore its value in the neoadjuvant setting for resectable locally advanced ESCC.
This is a prospective, cohort, phase II clinical trial planned to enroll 96 patients with previously untreated resectable locally advanced ESCC (AJCC 9th edition stage T1-4aN1-3M0 or T3-4aN0M0). Cohort A receives low-dose radiotherapy (8 Gy/4 fractions) combined with Retlirafusp alfa and nab-paclitaxel plus cisplatin/carboplatin for 2 cycles; Cohort B receives Retlirafusp alfa plus nab-paclitaxel and cisplatin/carboplatin (without radiotherapy). Radical surgery is performed 4-6 weeks after neoadjuvant therapy. The primary endpoint is pCR rate. Secondary endpoints include major pathological response (MPR), R0 resection rate, objective response rate (ORR), event-free survival (EFS), overall survival (OS), and safety. This study will provide important evidence for the "low-dose radiotherapy + immunotherapy + chemotherapy" neoadjuvant treatment model in locally advanced ESCC, with the potential to further improve pCR rates and long-term patient survival.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 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
- •Voluntary participation with written informed consent.
- •Age 18-75 years, male or female.
- •Histologically or cytologically confirmed thoracic esophageal squamous cell carcinoma (ESCC).
- •Clinical stage T1-4aN1-3M0 or T3-4aN0M0 (AJCC 9th edition): T stage determined by CT combined with MRI or endoscopic ultrasound; nodal involvement confirmed by biopsy, EBUS/EUS, or mediastinoscopy, or imaging showing lymph node short-axis diameter ≥2.0 cm; distant metastasis (M1) excluded by FDG-PET/CT or chest/abdominal/brain CT/MRI; no suspicious metastatic lymph nodes on cervical ultrasound.
- •Potentially resectable thoracic esophageal lesion with anticipated R0 resection.
- •No prior systemic therapy for esophageal tumor (chemotherapy, targeted therapy, immunotherapy, radiotherapy, etc.).
- •ECOG performance status 0-
- •At least one measurable lesion per Japanese Classification of Esophageal Cancer, 12th edition.
- •Agreement to provide archived tumor tissue or undergo biopsy for biomarker analysis.
- •Adequate organ function (within 14 days prior to first dose, without blood products or growth factors):
- •Hematology: WBC ≥4×10⁹/L, ANC ≥2×10⁹/L, hemoglobin ≥90 g/L, platelets ≥90×10⁹/L.Hepatic: total bilirubin ≤1.5×ULN (≤3×ULN for Gilbert's syndrome), AST and ALT ≤2.5×ULN (≤5×ULN for liver metastases), alkaline phosphatase ≤3×ULN (≤5×ULN for liver/bone metastases), albumin ≥30 g/L. Renal: serum creatinine ≤1.5×ULN or CrCl ≥60 mL/min (Cockcroft-Gault formula). Coagulation: INR ≤1.5 (without anticoagulation).
- •Body weight >35 kg, with no >10% weight loss in the past 3 months.
- •Life expectancy >12 months.
- •Women of childbearing potential and men must use effective contraception during the study and for 3 months after the last dose; non-lactating; negative serum/urine HCG within 7 days before first dose for women of childbearing potential.
排除标准
- •1.History of hypersensitivity to any component of Retlirafusp alfa, paclitaxel, carboplatin, or other platinum agents.
- •2,Cervical esophageal cancer, esophageal adenocarcinoma, or other pathological types.
- •3.Clinical stage I/IIA, T4b unresectable, or distant metastasis (M1) confirmed by imaging.
- •4.History of other malignancies within 5 years, except cured basal cell carcinoma of the skin, cervical carcinoma in situ, etc.
- •5.Prior or current receipt of any of the following:
- •Any radiotherapy, chemotherapy, or other anti-tumor therapy for malignancy.
- •Use of immunosuppressive agents or systemic corticosteroids for immunosuppressive purposes (dose >10 mg/day prednisone or equivalent) within 2 weeks prior to first study drug administration. Inhaled or topical steroids and adrenal hormone replacement at doses >10 mg/day prednisone or equivalent are permitted in the absence of active autoimmune disease.
- •Receipt of live-attenuated vaccine within 4 weeks prior to first study drug administration.
- •Major surgery or severe trauma within 4 weeks prior to first study drug administration.
- •6.Active or history of autoimmune disease, including but not limited to: interstitial pneumonia, enteritis, hepatitis, hypophysitis, vasculitis, nephritis, hyperthyroidism, hypothyroidism (may be considered after hormone replacement therapy). Patients with psoriasis or childhood asthma/allergy that has fully resolved and requires no intervention in adulthood may be considered; however, those requiring bronchodilators for medical intervention are excluded.
- •7.Immunodeficiency, including HIV positivity, other acquired or congenital immune deficiencies, or history of organ or allogeneic bone marrow transplantation.
- •8.Poorly controlled cardiac conditions, including but not limited to: (1) NYHA class ≥II heart failure, (2) unstable angina, (3) myocardial infarction within 1 year, (4) clinically significant supraventricular or ventricular arrhythmias uncontrolled despite intervention.
- •9.Severe infection (CTCAE grade ≥2) within 4 weeks prior to first study drug administration, such as severe pneumonia requiring hospitalization, bacteremia, or infectious complications; active pulmonary inflammation on baseline chest imaging; signs/symptoms of infection or need for oral/IV antibiotics within 14 days prior to first dose (except prophylactic antibiotics).
- •10.Active pulmonary tuberculosis by history or CT, history of active tuberculosis within 1 year prior to enrollment, or history of active tuberculosis >1 year ago without adequate treatment.
- •11.Active hepatitis B (HBV DNA ≥2000 IU/mL or 10⁴ copies/mL), or hepatitis C (HCV antibody positive with HCV RNA above the lower limit of detection).
- •12.Diagnosis of other malignancy within 5 years prior to first study drug administration, except those with low risk of metastasis or death (5-year survival >90%), such as adequately treated basal cell or squamous cell skin cancer, or cervical carcinoma in situ.
- •13.Pregnant or lactating women. 14.Other conditions deemed by the investigator to potentially necessitate premature study termination, such as other serious diseases (including psychiatric disorders) requiring concomitant treatment, alcoholism, drug abuse, or family/social factors that may affect patient safety or compliance.
结局指标
主要结局
Pathological Complete Response (pCR)
时间窗: Assessed via pathological examination of surgical specimens within 2 weeks post-surgery; follow-up up to 6 months.
pCR is defined as the absence of residual invasive carcinoma cells in both the resected primary tumor and lymph nodes.
次要结局
- Major Pathological Response (MPR)(Assessed via pathological examination of surgical specimens within 2 weeks post-surgery; follow-up up to 6 months.)
- R0 Resection Rate(Assessed via pathological examination of surgical specimens within 2 weeks post-surgery; follow-up up to 6 months.)
- Objective Response Rate (ORR)(Assessed via imaging after completion of neoadjuvant therapy; follow-up up to 6 months.)
- Disease Control Rate (DCR)(Assessed via imaging after completion of neoadjuvant therapy; follow-up up to 6 months.)
- Event-Free Survival (EFS)(From enrollment to first event, assessed every 3 months; follow-up up to 36 months.)
- Overall Survival (OS)(From enrollment to death or last follow-up, assessed every 3 months; follow-up up to 36 months.)
- Adverse Event Rate(Continuous monitoring from informed consent to 90 days after the last dose; follow-up up to 36 months.)
- Quality of Life Assessment Score(Assessed at screening, Cycle 1 Day 1, Cycle 2 Day 1（each cycle is 21 days）, and at 1, 3, 6, and 12 months post-surgery (7 time points in total); follow-up up to 12 months.)
- Biospecimen collection time points (tissue and blood samples)(Tissue and blood samples were collected at four time points: before treatment, after radiotherapy, during combination therapy (Cycle 1 Day 1 to Cycle 2 Day 1; 21 days per cycle), and before surgery; follow-up continued up to 6 months.)
研究者
Hang Yin
Chief Physician
Harbin Medical University