A Study of SYS6010, Enlonstobart, and Chemotherapy for First-Line Treatment of Esophageal Squamous Cell Carcinoma.

A Phase II/III Study to Evaluate the Efficacy and Safety of SYS6010 in Combination With SG001 With or Without 5-FU/Capecitabine in Subjects With First-Line Advanced/Metastatic Esophageal Squamous Cell Carcinoma.

This is a multicenter phase 2/3 clinical study to evaluate the efficacy and safety of SYS6010 plus SG001±5-FU/Capecitabine as first-line treatment, in patients with advanced/metastatic esophageal squamous cell carcinoma.

Phase II study comprises a safety lead-in stage, a dose expansion stage, and a randomized treatment stage. The Phsae III study is randomized controlled trial.

Phase II (safety lead-in stage): the safety lead-in stage employs a 3+3 design. It aims to evaluate the safety and tolerability of combination therapy-comprising capecitabine/5-FU administered at a descending dose level starting from DL0 alongside fixed doses of SYS6010 and SG001-in previously untreated patients with unresectable locally advanced or metastatic ESCC. The primary objectives are to determine the Maximum Tolerated Dose (MTD) and the Recommended Phase II Dose (RP2D).

Phase II (dose expansion stage): Upon completion of the safety evaluation and confirmation of tolerability for a dose cohort in the safety lead-in phase, expansion of that cohort may be initiated, with plans to expand 1-2 dose cohorts.

Phase II (randomized treatment stage): Upon determination of the RP2D based on prior data, a randomized controlled study will be conducted in a first-line advanced/metastatic esophageal squamous cell carcinoma (ESCC) patient population. Patients will be randomly assigned to three arms: Arm 1: SYS6010+SG001+ capecitabine/5-FU; arm2: investigator's choice of SOC; arm3: SYS6010+SG001.

Phase III is a randomized, controlled, open-label, multicenter study designed to evaluate the efficacy of SYS6010+SG001+capecitabine/5-FU versus investigator's choice of treatment as first-line therapy for advanced/metastatic esophageal squamous cell carcinoma. The Phase III trial design will be finalized based on Phase II results. The preliminary plan is to randomized patients in a 1:1 ratio to either the investigational arm or the control arm. Investigational arm: SYS6010+SG001+capecitabine/5-FU; control arm: investigator's choice of SOC.

Inclusion Criteria:

1. Be able to understand and voluntarily sign the written ICF;
2. Age 18-75 (inclusive) years, male or female;
3. With histologically/cytologically confirmed esophageal squamous cell carcinoma that is either locally advanced unresectable or metastatic, with no prior systemic antitumor therapy administered for the recurrent/metastatic disease setting. Have at least one measurable lesion that meets the RECIST v 1.1 criteria at baseline;
4. Eastern Cooperative Oncology Group (ECOG) performance status score: 0-1;
5. Life expectancy ≥ 3 months;

Exclusion Criteria:

1. Prior treatment involving topoisomerase I inhibitors (including ADC drugs that contain topoisomerase I inhibitors as toxins);
2. Prior treatment with immune checkpoint inhibitors or other agents targeting T-cell co-stimulatory/co-inhibitory pathways (e.g., anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4, anti-CD137 antibodies)
3. With a history of ≥Grade 3 allergic reactions to monoclonal antibodies, or with known hypersensitivity or intolerance to SYS6010, SG001, paclitaxel, carboplatin, cisplatin, fluorouracil, or any of their excipients;
4. With dihydropyrimidine dehydrogenase (DPD) deficiency.