Advanced Esophageal Squamous Cell Carcinoma
Conditions
Brief summary
A Randomized, Open-Label, Parallel-Controlled, Multicenter Phase III Clinical Trial to Evaluate the Safety and Efficacy of Anlotinib Hydrochloride Combined with Benmelstobart versus Toripalimab Combined with Chemotherapy as First-Line Treatment for Advanced Esophageal Squamous Cell Carcinoma Harboring Specific Gene Mutations
Interventions
DRUGanlotinib combined with benmelstobart
Benmelstobart injection 1200 mg will be diluted in 250 mL normal saline (0.9% sodium chloride) and administered via intravenous infusion over 60 ± 10 minutes on Day 1 of each 21-day cycle until disease progression, unacceptable toxicity, or a maximum of 24 months. Anlotinib hydrochloride capsules 12 mg will be administered orally once daily before breakfast at approximately the same time each day on a schedule of 2 weeks on and 1 week off in 21-day cycles until disease progression or unacceptable toxicity.
DRUGToripalimab Combined with Chemotherapy
Induction Phase (maximum 6 cycles):Toripalimab injection 240 mg will be administered intravenously over 60 minutes on Day 1 of each 21-day cycle after dilution in 100 mL normal saline (0.9% sodium chloride). Chemotherapy regimen will be determined prior to randomization based on individual patient characteristics. Patients will receive one of the following chemotherapy regimens per local treatment standards: Cisplatin 60-75 mg/m² intravenously on Day 1 plus paclitaxel 150-175 mg/m² intravenously over \>3 hours, both administered every 3 weeks; or cisplatin 60-75 mg/m² intravenously on Day 1 plus fluorouracil 700-850 mg/m² daily by continuous intravenous infusion over 24 hours on Days 1-5, repeated every 3 weeks. Maintenance Phase :Toripalimab injection 240 mg will be administered intravenously over 60 minutes on Day 1 of each 21-day cycle after dilution in 100 mL normal saline (0.9% sodium chloride).
Sponsors
The First Affiliated Hospital of Zhengzhou University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* (1) Histologically or cytologically confirmed unresectable locally advanced, recurrent, or metastatic esophageal squamous cell carcinoma (excluding adenosquamous carcinoma); (2) No prior systemic therapy, or recurrence more than 6 months after completion of (neo)adjuvant therapy or definitive chemoradiotherapy; (3) Age: ≥18 years (calculated from the date of informed consent signature); ECOG PS score: 0-1; estimated life expectancy \>3 months; (4) Presence of TP53 mutation or FAT1 mutation, and absence of NOTCH3 mutation; (5) At least one measurable lesion as confirmed by RECIST 1.1 criteria; measurable lesions should not have received prior local treatment such as radiotherapy (lesions within prior radiation fields may be selected as target lesions if progression is confirmed); (6) Adequate major organ function meeting the following criteria: * Hemoglobin ≥90 g/L; * Absolute neutrophil count (ANC) ≥1.5 × 10\^9/L; * Platelets ≥75 × 10\^9/L; * Total bilirubin ≤1.5 × upper limit of normal (ULN); * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN (≤5 × ULN if liver metastases present); * Serum creatinine ≤1.5 × ULN or creatinine clearance ≥60 mL/min; * Prothrombin time (PT), activated partial thromboplastin time (APTT), and international normalized ratio (INR) ≤1.5 × ULN (for patients not receiving anticoagulation); * Thyroid-stimulating hormone (TSH) ≤ULN (if TSH abnormal, normal free T3 and free T4 are acceptable); (7) Women of childbearing potential must agree to use effective contraception during the study and for 6 months after study completion, with negative serum or urine pregnancy test within 7 days prior to enrollment; men must agree to use effective contraception during the study and for 6 months after study completion, see Section 5.4 for details; (8) Voluntary participation in this study with signed informed consent and good compliance.
Exclusion criteria
* (1) Other malignancies within 3 years prior to first dose or currently concurrent malignancies, except:Other malignancies treated with surgery alone with continuous disease-free survival (DFS) of ≥5 years;Cured cervical carcinoma in situ, non-melanomatous skin cancer, and superficial bladder tumors \[Ta (non-invasive), Tis (carcinoma in situ), and T1 (tumor invades lamina propria)\]; (2) Conditions affecting intravenous injection or blood collection, or factors affecting oral drug administration (e.g., inability to swallow, chronic diarrhea, intestinal obstruction); (3) Prior treatment-related adverse events not resolved to ≤Grade 1 per CTCAE v5.0, except Grade 2 alopecia, Grade 2 peripheral neuropathy, Grade 2 anemia, clinically non-significant and asymptomatic laboratory abnormalities, and hypothyroidism stable on hormone replacement therapy judged by investigator as having no safety risk; (4) Major surgery, significant traumatic injury within 4 weeks prior to first dose, or anticipated need for major surgery during study treatment (except protocol-required surgery), or presence of non-healing wounds or fractures. \[Major surgery defined as Grade 3 or higher per National Surgical Classification Directory 2022\]; (5) Esophageal squamous cell carcinoma with active bleeding from primary lesion within 2 months; hematemesis or melena with daily blood loss ≥2.5 mL within 3 months prior to screening, or any bleeding event ≥CTCAE Grade 3, or any bleeding signs or history regardless of severity judged by investigator as unsuitable for enrollment; (6) Arterial or venous thrombotic events within 6 months prior to first dose, including cerebrovascular accident (including transient ischemic attack), deep vein thrombosis, or pulmonary embolism; (7) Active viral hepatitis with inadequate control. Eligible if: HBsAg-positive subjects: HBV DNA \<2000 IU/mL (or 1×10⁴ copies/mL) or receiving anti-HBV treatment for ≥1 week prior to study with ≥1 log reduction in viral load, with willingness to continue anti-HBV therapy throughout study; HCV-infected subjects (HCV Ab or HCV RNA positive): judged by investigator as stable or receiving approved antiviral treatment at enrollment with plan to continue; (8) Active syphilis infection requiring treatment; (9) Active tuberculosis, history of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, radiation pneumonitis requiring treatment, or symptomatic active pneumonia; (10) History of psychoactive substance abuse with inability to abstain, or psychiatric disorder; (11) Prior or planned allogeneic bone marrow or solid organ transplantation; (12) History of hepatic encephalopathy; (13) Significant cardiovascular disease, including any of the following: 1. New York Heart Association (NYHA) Class II or greater heart failure or left ventricular ejection fraction (LVEF) \<50% by echocardiography; 2. History of clinically significant ventricular arrhythmia (e.g., sustained ventricular tachycardia, ventricular fibrillation, torsades de pointes) or arrhythmia requiring continuous antiarrhythmic medication; 3. Unstable angina pectoris; 4. Myocardial infarction within 12 months; 5. Fridericia-corrected QT interval (QTcF) \>450 msec for males or \>470 msec for females (if abnormal, three consecutive measurements ≥2 minutes apart, use average); 6. Congenital long QT syndrome or family history; 7. History of deep vein thrombosis, pulmonary embolism, or other serious thromboembolism within 3 months prior to randomization (implanted port or catheter-related thrombosis, or superficial venous thrombosis not considered "serious"); 8. Current use or recent use (within 7 days prior to study treatment) of aspirin (\>325 mg/day), dipyridamole, ticlopidine, clopidogrel, or cilostazol; (14) Active or uncontrolled severe infection (≥CTCAE Grade 2); (15) Renal failure requiring hemodialysis or peritoneal dialysis; (16) History of immunodeficiency, including HIV positivity or other acquired or congenital immunodeficiency disorders; (17) Use of immunosuppressants or systemic or absorbable topical corticosteroids for immunosuppressive purposes within 7 days prior to first dose (except prednisone ≤10 mg daily or equivalent); (18) Epilepsy requiring treatment; (19) Tumor-related symptoms and treatment: <!-- --> 1. Cytotoxic chemotherapy, immunotherapy within 3 weeks, or radiotherapy or small molecule targeted therapy within 2 weeks prior to first dose, or within 5 half-lives of drug (whichever is shorter) from last treatment; (prior radiotherapy: target lesions should not be within radiation field, or if within field, progression must be confirmed); 2. Traditional Chinese medicines with anti-tumor indications approved by NMPA within 2 weeks prior to first dose (including Compound Cantharis Capsules, Kang'ai Injection, Kanglaite Capsules/Injection, Aidi Injection, Brucea Javanica Oil Injection/Capsules, Xiaoaiping Tablets/Injection, Huachansu Capsules, etc.); 3. Imaging evidence of significant tumor invasion into adjacent organs (aorta or trachea) with increased risk of bleeding or fistula; ulcerative ESCC with increased bleeding risk due to proximity to vessels; 4. Known complete esophageal obstruction requiring interventional relief; 5. Post-esophageal or tracheal stent placement; 6. Uncontrolled pleural effusion, pericardial effusion, or moderate to severe ascites requiring repeated drainage (investigator judgment); 7. Known spinal cord compression, carcinomatous meningitis, or brain metastasis with symptoms or symptom control \<4 weeks; (20) Known hypersensitivity to study drug excipients; (21) Prior treatment with anlotinib hydrochloride or other anti-angiogenic agents, or any anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibody; (22) Participation in other interventional clinical trials with investigational drug use within 4 weeks prior to first dose; (23) Pregnancy, lactation, or planned pregnancy during study period; (24) Any condition that, in the opinion of the investigator, would pose significant safety risk to the subject or interfere with completion of the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| PFS | about 2 years | The time from randomization to the first occurrence of disease progression or death due to any cause, whichever occurs first, as determined by the investigator according to RECIST v1.1. |
| OS | about 2 years | The time from randomization to death due to any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| ORR | about 2 years | The percentage of subjects with complete response (CR) or partial response (PR) as determined by the investigator according to RECIST 1.1. |
| DCR | about 2 years | The percentage of subjects with complete response (CR), partial response (PR), or disease stabilization (SD) for ≥6 weeks as determined by the investigator according to RECIST 1.1. |
| DOR | about 2 years | The time from the first documented confirmed objective response to disease progression or death due to any cause, whichever occurs first, as determined by the investigator according to RECIST v1.1. |
| AE | about 2 years | The incidence and severity of adverse events, with severity graded according to the NCI CTCAE v5.0 scale. |
Countries
China
Contacts
CONTACTfeng wang
Outcome results
None listed