Sintilimab or Placebo With Chemotherapy in Esophageal Squamous Cell Carcinoma ( ORIENT-15 )

Study Overview
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Brief Summary
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This is a randomized, double-blind multi-center, phase III study comparing the efficacy and safety of sintilimab or placebo in combination with chemotherapy as first-line treatment in subjects with unresectable, locally advanced recurrent or metastatic esophageal squamous cell carcinoma. After the interim analysis conducted by the iDMC, an open-label assignment of experimental arm therapy will continue in regions outside of China, in order to further evaluate the efficacy and safety of sintilimab in combination with chemotherapy in subjects representing the western population with advanced esophageal squamous cell carcinoma

Official Title
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A Multicenter, Double-Blind, Randomized Phase 3 Clinical Trial Evaluating the Efficacy and Safety of Sintilimab vs. Placebo, in Combination With Chemotherapy, for First-Line Treatment of Unresectable, Locally Advanced, Recurrent, or Metastatic Esophageal Squamous Cell Carcinoma (ORIENT-15)

Conditions
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Esophageal Squamous Cell Carcinoma

Intervention / Treatment
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* Biological: Sintilimab
* Drug: Cisplatin
* Drug: Paclitaxel
* Drug: Fluorouracil
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Histopathologically confirmed unresectable, locally advanced, recurrent or metastatic ESCC (excluding mixed adenosquamous carcinoma and other histological subtypes) ECOG PS of 0 or 1 Subject must be unsuitable for definitive treatment, such as definitive chemoradiotherapy and/or surgery. For subjects who have received (neo)adjuvant or definitive chemotherapy/radiochemotherapy, time from the completion of last treatment to disease recurrence must be > 6 months Could provide archival or fresh tissues for PD-L1 expression analysis with obtainable results Have at least one measurable lesion as per RECIST v1.1 Key exclusion Criteria: ESCC with endoscopy-confirmed near-complete obstruction requiring interventional therapy Post stent implantation in the esophagus or trachea with risk of perforation Received systemic treatment for advanced or metastatic ESCC. Received a cumulative dose of cisplatin ≥ 300 mg/m2 and the last cisplatin dose was within 12 months of randomization or the first dose of study treatment in the open-label phase. High risk of hemorrhage or perforations due to tumor invasion in adjacent organs (aorta or trachea), or have fistula formation. Hepatic metastasis > 50% of the total liver volume. Received palliative therapy for a local lesion within 2 weeks prior to the first dose. Received systemic treatment with Chinese traditional medicines with anti-cancer indications or immunomodulators (including thymosins, interferons, and interleukins) within 2 weeks prior to the first dose of study treatment. Received systemic immunosuppressants within 2 weeks prior to randomization, excluding local use of glucocorticoids administered by nasal, inhaled, or other routes, and systemic glucocorticoids at physiological doses (no more than 10 mg/day of prednisone or equivalents), or glucocorticoids to prevent allergies to contrast media.

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

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Randomized Part: Experimental: Sintilimab + chemotherapy<br>Sintilimab in combination with investigator's choice of chemotherapy TP regimen: Cisplatin + paclitaxel or CP regimen: Cisplatin + fluorourcil | Biological: Sintilimab<br>* For weight <60kg, 3mg/kg IV Q3W day 1, and for weight≥60kg, 200mg IV Q3W day 1<br>Drug: Cisplatin<br>* 75mg/m^2 IV Q3W day 1<br>Drug: Paclitaxel<br>* 87.5 mg/m^2 IV Q3W day 1, day 8 for first cycle and 175mg/m^2 IV Q3W day 1 after first cycle<br>Drug: Fluorouracil<br>* 800 mg/m^2 IV continuous infusion over 24 hours daily on Days 1-5 Q3W<br>|
| Active Comparator: Randomised Part: Active Comparator: Placebo + chemotherapy<br>Placebo in combination with investigator's choice of chemotherapy TP regimen: Cisplatin + paclitaxel or CP regimen: Cisplatin + fluorourcil | Drug: Cisplatin<br>* 75mg/m^2 IV Q3W day 1<br>Drug: Paclitaxel<br>* 87.5 mg/m^2 IV Q3W day 1, day 8 for first cycle and 175mg/m^2 IV Q3W day 1 after first cycle<br>Drug: Fluorouracil<br>* 800 mg/m^2 IV continuous infusion over 24 hours daily on Days 1-5 Q3W<br>Drug: Placebo<br>* For weight <60kg, 3mg/kg IV Q3W day 1, and for weight≥60kg, 200mg IV Q3W day 1<br>|
| Experimental: Open-label part: Sintilimab+ chemotherapy<br>Sintilimab in combination with investigator's choice of chemotherapy TP regimen: Cisplatin + paclitaxel or CP regimen: Cisplatin + fluorourcil | Biological: Sintilimab<br>* For weight <60kg, 3mg/kg IV Q3W day 1, and for weight≥60kg, 200mg IV Q3W day 1<br>Drug: Cisplatin<br>* 75mg/m^2 IV Q3W day 1<br>Drug: Paclitaxel<br>* 87.5 mg/m^2 IV Q3W day 1, day 8 for first cycle and 175mg/m^2 IV Q3W day 1 after first cycle<br>Drug: Fluorouracil<br>* 800 mg/m^2 IV continuous infusion over 24 hours daily on Days 1-5 Q3W<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| OS in overall population | To compare the overall survival of sintilimab vs. placebo, in combination with chemotherapy, for first-line treatment in subjects with unresectable, locally advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC) | From date of randomization until the date of death from any cause, assessed up to 40 months. | 
| OS in PD-L1 positive population | To compare the OS of sintilimab vs. placebo, in combination with chemotherapy, for first-line treatment in subjects with PD-L1 positive, unresectable, locally advanced, recurrent or metastatic ESCC | From date of randomization until the date of death from any cause, assessed up to 40 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ORR in overall population | To compare the objective response rate between the two treatment arms in ITT population | From date of randomization up to 28 months. | 
| PFS in overall populationsubjects in ITT population | To compare the progression-free survival between the two treatment arms in ITT population | From date of randomization up to 28 months | 
| DCR in overall population | To compare the disease control rate between the two treatment arms in ITT population | From date of randomization up to 28 months | 
| DoR in overall population | To compare the duration of response between the two treatment arms in ITT population | From date of randomization up to 28 months | 
| ORR - PD-L1 positive | To compare the objective response rate between the two treatment arms in PD-L1 positive subjects in ITT population | From date of randomization up to 28 months | 
| DCR - PD-L1 positive | To compare the disease control rate between the two treatment arms in PD-L1 positive subjects in ITT population | From date of randomization up to 28 months | 
| DoR - PD-L1 positive | To compare the duration of response between the two treatment arms in PD-L1 positive subjects in ITT population | From date of randomization up to 28 months | 
| PFS - PD-L1 positive | To compare the progression-free survival between the two treatment arms in PD-L1 positive subjects in ITT population | From date of randomization up to 28 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ESCC, Esophageal Cancer, Esophageal Neoplasms, Esophageal Neoplasms Malignant, Esophageal Squamous Cell Carcinoma, Neoplasms, Squamous Cell, Esophageal Diseases, Carcinoma, Squamous Cell, Gastrointestinal Diseases, Paclitaxel, Cisplatin, Fluorouracil, Antineoplastic Agents, Anti-PD-1, Sintilimab