Hypofractionated Radiotherapy Combined With Immunochemotherapy for Conversion Treatment of Gastroesophageal Junction Adenocarcinoma

Официальное название

A Phase Ib/II Study of Hypofractionated Radiotherapy Combined With Immunochemotherapy as Conversion Therapy for Locally Advanced Gastroesophageal Junction Adenocarcinoma

Обзор

The purpose of this study is to investigate the safety and efficacy of conversion therapy using HFRT combined with ICT in locally advanced or metastatic unresectable GEJA.

Подробное описание

The aim of this study is to investigate whether hypofractionated radiotherapy (HFRT) combined with a PD-1 inhibitor (Sintilimab) and chemotherapy based on the SOX regimen is a safe and well-tolerated conversion strategy for patients with locally advanced or metastatic unresectable gastroesophageal junction adenocarcinoma (GEJA), and whether it can improve the objective response rate (ORR) compared to immunochemotherapy alone.

Вмешательства

• Лучевая терапия hypofractionated radiotherapy
  In Phase Ib, HFRT will be administered at one of three dose levels: 3 Gy × 5 fractions, 4 Gy × 5 fractions, or 5 Gy × 5 fractions. The recommended dose determined in Phase Ib will be used in Phase II (delivered as 5 fractions).
• Препарат SOX Chemotherapy
  SOX chemotherapy regimen: Oxaliplatin 130 mg/m² administered by intravenous infusion on Day 1; S-1 administered orally for 14 consecutive days followed by a 7-day rest period. The dosage of S-1 is based on body surface area (BSA): 40 mg twice daily for BSA ≤1.5 m², 50 mg twice daily for BSA between 1.5-1.6 m², and 60 mg twice daily for BSA ≥1.6 m². Each cycle is repeated every 3 weeks.
• Препарат PD-1 inhibitor
  Sintilimab 200 mg administered by intravenous infusion on Day 1 of each 3-week cycle.

Первичные конечные точки

• Safety and tolerability in Phase Ib [Срок оценки: within 3 months after the HFRT]
• ORR rate in Phase II [Срок оценки: approximately 4 weeks after the resection of primary lesion]

Вторичные конечные точки (6)

• R0 resection rate [Срок оценки: approximately 2 weeks after the resection of primary lesion]
• DOR (Duration of Response) [Срок оценки: Up to 3 years]
• PFS (Progression-Free Survival) [Срок оценки: Up to 3 years]
• OS (Overall Survival) [Срок оценки: Up to 3 years]
• Adverse Events (AEs) [Срок оценки: From the first dose through 90 days after the last dose]
• Quality of Life (QoL) - EORTC QLQ-C30 [Срок оценки: At baseline, during treatment, and at predefined follow-up visits]

Критерии участия

Критерии включения

Participants must meet all of the following criteria:

• Histologically and/or cytologically confirmed diagnosis of locally advanced gastroesophageal junction adenocarcinoma (GEJA), Siewert type I-III, with staging of cT3-4, any N, M0 or cT2 N+, M0, according to the AJCC 8th edition.
• Resectable locally advanced disease as determined by multidisciplinary team (MDT) assessment.
• Age ≥18 years, regardless of sex.
• ECOG performance status of 0 or 1.
• Estimated life expectancy of ≥3 months.
• No prior anti-tumor therapy.
• At least one measurable lesion per RECIST v1.1, defined as:

• Lesion ≥1 cm in longest diameter on spiral CT, or
• Lesion ≥2 cm in longest diameter on conventional CT or MRI.
• Imaging must be performed within 28 days prior to enrollment.
• Adequate organ function within 14 days prior to treatment, as defined below (Note: No RBC or platelet transfusion or use of G-CSF within 14 days prior to hematology testing):

Hematologic:

• Hemoglobin ≥9 g/dL (without transfusion)
• ANC ≥1.5 × 10⁹/L
• WBC ≥3.0 × 10⁹/L (without G-CSF)
• Platelets ≥75 × 10⁹/L (without IL-11 or TPO)

Biochemical:

• Total bilirubin ≤1.5 × ULN
• AST and ALT ≤2.5 × ULN
• Serum creatinine ≤1.5 × ULN or creatinine clearance ≥60 mL/min (Cockcroft-Gault formula)
• Albumin ≥25 g/L (2.5 g/dL)

Coagulation (within 7 days prior to enrollment):

• INR <1.5
• APTT <1.5 × ULN
• INR or PT ≤1.5 × ULN
• For patients with active hepatitis B or C:

• Antiviral therapy must be initiated ≥14 days before enrollment
• HBV DNA ≤500 IU/mL or ≤2500 copies/mL; HCV RNA undetectable
• Must agree to continue antiviral therapy during the study
• Left ventricular ejection fraction (LVEF) ≥50% by echocardiography.
• Women of childbearing potential:

• Negative serum or urine pregnancy test within 7 days prior to enrollment
• Agree to use effective contraception during the study and for at least 3 months after the last dose
• Must not breastfeed or donate/retrieve ova within 60 days after the last dose
• Effective contraception must be continued for at least 6 months after last dose of chemotherapy
• Men must be surgically sterile or agree to use effective contraception during the study and for at least 3 months after the last dose.
• Voluntarily signed informed consent with good compliance and willingness to complete study procedures and follow-up.

Критерии исключения

Participants who meet any of the following conditions will be excluded:

• Diagnosed as mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) by immunohistochemistry or gene testing.
• Evidence of peritoneal or multi-organ metastatic disease, as confirmed by chest and abdominal CT, bone scan, or MRI (in cases with suspected osseous lesions).
• History of or concurrent other malignancies within the past 5 years, excluding cured basal cell carcinoma, squamous cell carcinoma of the skin, or carcinoma in situ of the cervix.
• Known allergy to any component of the investigational drugs, history of severe hypersensitivity, or any contraindication to study drugs.
• Clinically significant upper gastrointestinal bleeding within 30 days prior to enrollment or randomization.
• History of congenital pulmonary fibrosis, drug-induced pneumonitis, active pulmonary tuberculosis, or CT-confirmed active pneumonia; interstitial lung disease requiring steroid treatment.
• Active autoimmune or inflammatory diseases requiring immunosuppressive therapy within 2 years prior to treatment, including but not limited to:

• Inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis, diverticulitis),
• Systemic lupus erythematosus,
• Sarcoidosis,
• Tuberculosis,
• Wegener's granulomatosis,
• Myasthenia gravis,
• Graves' disease,
• Rheumatoid arthritis,
• Hypophysitis,
• Uveitis,
• Glomerulonephritis,
• Nephrotic syndrome,
• Fanconi syndrome, or renal tubular acidosis. Exceptions: type 1 diabetes, hypothyroidism controlled by hormone replacement, and non-systemically treated dermatologic conditions (e.g., vitiligo, psoriasis, alopecia).
• History of immunodeficiency, HIV infection (positive HIV 1/2 antibodies), congenital or acquired immunodeficiency disorders, or history of organ transplantation.
• Active hepatitis B (HBsAg positive) or active hepatitis C infection. Patients with past or controlled HBV/HCV infection may be eligible.
• Use of systemic corticosteroids or immunosuppressants within 2 weeks prior to study treatment.

• Inhaled or topical corticosteroids and adrenal replacement doses (equivalent to ≤10 mg/day prednisone) are permitted.
• Short-term (<7 days) corticosteroids are allowed for non-autoimmune conditions or prophylaxis (e.g., contrast allergy).
• Uncontrolled or serious comorbidities, including:

• Poorly controlled hypertension (SBP ≥150 mmHg or DBP ≥100 mmHg despite medication)
• Myocardial infarction, ischemia (grade II or above), acute coronary syndrome within 6 months, arrhythmia (e.g., QTc ≥480 ms, atrial fibrillation), or uncontrolled angina
• NYHA class III-IV heart failure, LVEF <50%, severe valvular disease, cardiomyopathy of any cause
• History of stroke or transient ischemic attack within screening period
• Active or uncontrolled infection
• Severe liver disease (e.g., cirrhosis, decompensated liver disease, chronic active hepatitis) affecting tolerability to treatment
• Poorly controlled diabetes (fasting glucose >10 mmol/L)
• Proteinuria ≥++ on dipstick or >1.0 g/24 h on urine protein quantification
• Coagulation disorders (INR >1.5 or APTT >1.5 × ULN), bleeding tendency, or current use of thrombolytics or anticoagulants.

• Known hereditary or acquired bleeding/thrombotic conditions (e.g., hemophilia, coagulopathy, thrombocytopenia, hypersplenism).
• History of significant hemoptysis (≥2.5 mL/day) or massive bleeding within 2 months.
• Gastrointestinal bleeding, bleeding gastric ulcer, positive fecal occult blood (++ or above), vasculitis, or active bleeding within 3 months.
• Long-term use of warfarin/heparin or high-dose antiplatelet therapy (aspirin ≥300 mg/day or clopidogrel ≥75 mg/day).
• Major surgery (e.g., craniotomy, thoracotomy, or laparotomy) within 4 weeks prior to the first dose, or planned major surgery during the study period.
• Gastrointestinal perforation and/or fistula within 6 months prior to enrollment; history of arterial/venous thrombotic events such as stroke (excluding clinically stable infarction per investigator), deep vein thrombosis, or pulmonary embolism.
• Unhealed wounds or fractures of clinical significance.
• Severe gastrointestinal conditions that may impair oral medication absorption (e.g., dysphagia, chronic diarrhea, intestinal obstruction).
• Severe malnutrition.
• Pregnant or breastfeeding women, or subjects (male or female within one year of menopause) unwilling to use effective contraception.
• History of substance abuse or uncontrolled psychiatric disorders.
• Unwilling or unable to comply with study procedures.
• Participation in another interventional clinical trial within 30 days prior to first dose or planning to do so during the current study.
• Any other condition deemed by the investigator to pose significant risk to patient safety or interfere with study conduct.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Китай · 4 центра

• West China Xiamen Hospital, Sichuan University — Xiamen
• The Seventh People's Hospital of Chengdu — Чэнду
• West China Hospital, Sichuan University — Чэнду
• West China Shangjin Nanfu Hospital, Sichuan University — Чэнду

Идентификаторы

NCT: NCT07072351 · GEJA-ICRT-2025-05

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗