A Study of Simmitinib Plus Irinotecan in Advanced Esophageal Squamous Cell Carcinoma

The experiment was divided into two stages. The first stage is dose escalation stage. Rapid titration and "3+3" dose escalation design were used to observe DLT of simmitinib plus irinotecan liposome, and MTD was determined. The second stage is a randomized controlled study. After RP2D was determined in the first stage, participants were randomly assigned to 3 groups in a 1:1:1 ratio, including simmitinib plus irinotecan liposome, irinotecan liposome, and irinotecan.

Inclusion criteria

• Have fully understood and voluntarily sign the ICF for this study;
• Age of 18-70 years (inclusive), male or female;
• Esophageal squamous cell carcinoma confirmed histologically or cytologically
• Second-line patients with disease progression after only first-line standard therapy（Standard treatment: chemotherapy with platinum plus fluorouracil or taxane combined with immunosuppressive regimen .Progression during adjuvant/neoadjuvant therapy or within 6 months of the last dose is considered a first-line standard treatment failure）
• At least one measurable lesion according to RECIST 1.1;
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0-1;
• Expected survival is more than 3 months
• Adequate organ function, defined as:

Absolute Neutrophil count (ANC) ≥ 1.5 × 10^9/L; Platelet count (PLT) ≥ 75× 10^9/L; Hemoglobin (Hb) ≥ 90 g/L; Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × upper limit of normal (ULN) (≤ 5.0 × ULN for patients with liver metastases); Serum total bilirubin (TBIL) ≤ 1.5 × ULN; Serum creatinine ≤ 1.5 × ULN and Creatinine clearance (CCr)≥60mL/min; Prothrombin time (PT)、activated partial thromboplastin time (APTT)、international normalized ratio(INR)≤1.5 × ULN;

• Male and female patients of childbearing age must agree to take effective contraceptive measures during treatment and within 6 months after the last dose of treatment.

Exclusion criteria

• Patients who have previously received any anti-tumor therapy within 4 weeks prior to the first dose;
• Patients who have previously received any live attenuated vaccine within 4 weeks before the first use of the study treatment or are expected to received any live attenuated vaccine during the study;
• Prior systemic treatment with anti-VEGF drugs, irinotecan, or any other topoisomerase I inhibitor
• LVEF <50%；
• BMI≤18.5 kg/m^2
• Symptomatic central nervous system (CNS) metastases or meningeal metastases;
• Patients with other types of malignant tumors within 5 years prior to the screening, except for radically resected, non-recurrent skin basal cell carcinoma, skin squamous cell carcinoma, superficial bladder cancer, cervical cancer in situ, or other carcinoma in situ;
• Patients with bleeding tendency; active bleeding or a history of heavy bleeding within the past 6 months;
• Urine protein ≥ ++ and 24 h urine protein > 1.0g at screening period;
• Presence of any severe and/or uncontrolled disease before starting treatment;
• Severe lung disease within 6 months before first dosing ；
• Any active infection requiring antibiotics or hormones systemic treatment by intravenous infusion within 14 days prior to the first dose;
• Inability to swallow drugs orally, or presence of clinically significant gastrointestinal disorders