A Study of CS1001 in Subjects With Esophageal Squamous Cell Carcinoma

Study Overview
=================
Brief Summary
-----------------
Phase III Study to Investigate the Efficacy and Safety of CS1001 or Placebo in Combination with FP as First-Line Therapy in Subjects with Unresectable Locally Advanced, Recurrent or Metastatic Esophageal Squamous Cell Carcinoma

Official Title
-----------------
A Multi-Center, Double-Blind, Randomized, Phase III Study to Investigate the Efficacy and Safety of CS1001 in Combination With Fluorouracil and Cisplatin (FP) Compared to Placebo in Combination With FP as First-Line Therapy in Subjects With Unresectable Locally Advanced, Recurrent or Metastatic Esophageal Squamous Cell Carcinoma (ESCC)

Conditions
-----------------
Unresectable Locally Advanced, Recurrent or Metastatic Esophageal Squamous Cell Carcinoma

Intervention / Treatment
-----------------
* Drug: CS1001+ Fluorouracil+Cisplatin
* Drug: Placebo+ Fluorouracil+Cisplatin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria ≥ 18 years and ≤ 75 years on the day of signing informed consent form (ICF). Fully informed of the study, with good compliance and willing to provide written ICF. The ICF must be signed before performing any protocol-related procedure (that is not a part of subject's routine medical care). Subjects with pathohistologically or cytologically confirmed unresectable locally advanced, relapsed or metastatic ESCC (based on American Joint Committee on Cancer [AJCC] Guideline version 8, see Appendix 14.2) Subjects must not be eligible for radical therapy such as radical chemoradiotherapy or surgery. Subjects who have not received any systemic anti-neoplastic therapy as the main regimen for locally advanced or metastatic ESCC. (Subjects who received prior neoadjuvant, adjuvant or radical chemoradiotherapy for ESCC but had relapse or progression of disease 6 months after the completion of these treatments are allowed.) ECOG PS 0 or 1. Life expectancy ≥ 3 months. Subjects have at least one measurable lesion as evaluated by the investigator according to RECIST v1.1, and the baseline imaging assessment must be performed within 28 days prior to the first dose of investigational product. Target lesions in the past radiation fields, if confirmed as radiological progression, are considered as measurable lesions. Palliative treatment (e.g. radiotherapy) for local lesion must be completed ≥ 14 days prior to the first dose of investigational product. Subjects must provide tumor tissue samples (formalin fixed-paraffin embedded [FFPE] tissue block or unstained tumor tissue sections) for biomarker analysis, in order to determine the expression of PD-L1. Subjects must have adequate organ function as assessed in the following laboratory tests (subjects must not receive any blood transfusion or any hematopoietic growth factor within 7 days prior to the test) Female subjects with childbearing potential (unless with documentation of sterilization surgery or being post-menopausal) must have negative serum pregnancy test result at screening. Female subject with childbearing potential (unless with documentation of sterilization surgery or being post-menopausal) or male subjects and their partners must agree to use an effective contraceptive measure from the day of signing ICF till at least 6 months after the last dose of investigational product. Exclusion criteria Adenocarcinoma, mixture of adenocarcinoma and squamous cell carcinoma, or other pathological type of esophageal cancer. Subjects with active central nervous system (CNS) metastasis and/or carcinomatous meningitis (that is symptomatic, or requires treatment, or no radiological evidence confirming the stability of the lesion within 28 days prior to the first dose of investigational product). With another active primary malignancy in the past 5 years, except local curable cancers that have undergone curative therapy, e.g. basal cell carcinoma of skin, squamous cell carcinoma of skin, superficial bladder cancer, prostate cancer in situ, breast cancer in situ or cervical cancer in situ. Known history of positive human immunodeficiency virus (HIV) test result or acquired immunodeficiency syndrome (AIDS). Any severe or uncontrolled systemic disease, e.g., diabetes mellitus or hypertension, that may increase the risk associated with participation in the study or investigational product administration, or compromise subject's ability to receive investigational product, as per investigator's judgment. Subjects who have previously received any treatment of antibody or drug that targets at T-cell coregulatory pathways or immune checkpoint pathways, e.g., antibodies targeting at programmed death receptor-1 (PD-1), programmed death receptor-ligand 1 (PD-L1), cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), OX-40, CD137, T cell immunoglobulin mucin molecule 3 (TIM-3), lymphocyte activation gene 3 (LAG-3), etc. Subjects who have received cell-based immunotherapy (e.g., cytokine-induced killer cell [CIK], chimeric antigen receptor T cell [CAR-T] immunotherapy, etc.). All toxicities except for alopecia and fatigue that are caused by the prior anti-neoplastic treatment has recovered to Grade 1 (according to National Cancer Institute Common Toxicity Criteria for Adverse Events [NCI CTCAE] v5.0). Subjects with history of allogenic stem cell or solid organ transplantation. Subjects with any condition that in the investigator's opinion are not suitable for participating in this study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CS1001+ Fluorouracil+Cisplatin<br> | Drug: CS1001+ Fluorouracil+Cisplatin<br>* CS1001 1200 mg, intravenous infusion on the first day of each cycle (3 weeks) (Q3W). Fluorouracil: 800 mg/m2/day, continuous intravenous infusion on Day 1 to Day 4 of each cycle Cisplatin: 80 mg/m2, intravenous infusion on the first day of each cycle.<br>|
| Active Comparator: Placebo+ Fluorouracil+Cisplatin<br> | Drug: Placebo+ Fluorouracil+Cisplatin<br>* Placebo 1200 mg, intravenous infusion on the first day of each cycle (3 weeks) (Q3W). Fluorouracil: 800 mg/m2/day, continuous intravenous infusion on Day 1 to Day 4 of each cycle Cisplatin: 80 mg/m2, intravenous infusion on the first day of each cycle.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) assessed by Blinded Independent Central Review (BICR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | PFS was defined as the time from randomization to the first documented progressive disease (PD) per RECIST 1.1 as assessed by BICR, or death due to any cause, whichever occurred first. | Approximately 43 months from the time of randomization | 
| Overall survival (OS) | OS was defined as the time from randomization to death due to any cause. | Approximately 43 months from the time of randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS assessed by investigators according to RECIST v1.1 | PFS was defined as the time from randomization to the first documented progressive disease (PD) per RECIST 1.1 as assessed by investigators, or death due to any cause, whichever occurred first. | Approximately 43 months from the time of randomization | 
| Objective response rate (ORR) assessed by BICR and investigators according to RECIST v1.1 | ORR was defined as the percentage of participants in the analysis population who had a Complete Response (CR) or a Partial Response (PR) per RECIST 1.1. | Approximately 43 months from the time of randomization | 
| Duration of response (DoR) assessed by BICR and investigators according to RECIST v1.1 | DOR was defined as the time from first documented evidence of confirmed CR or PR until PD or death due to any cause, whichever occurred first. | Approximately 43 months from the time of randomization |