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

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)

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

Study Overview

• Status: Completed
• Conditions: Esophageal Squamous Cell Carcinoma
• Intervention / Treatment: Biological: Sintilimab; Drug: Cisplatin; Drug: Paclitaxel; Drug: Fluorouracil; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 746
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • East Albury, New South Wales, Australia, 2640
      • Border Medical Oncology
  • South Australia
    • Woodville South, South Australia, Australia, 5011
      • The Queen Elizabeth Hospital
  • Victoria
    • Heidelberg, Victoria, Australia, 3079
      • Austin Hospital
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Sir Charles Gairdner Hospital
    • Subiaco, Western Australia, Australia, 6008
      • St John of God Subiaco Hospital
• Belgium
  • Brussels, Belgium, 1000
    • Institut Jules Bordet
  • Verviers, Belgium, 4800
    • Centre Hospitalier Regional de Verviers
  • Corneel Heymanslaan 10
    • Gent, Corneel Heymanslaan 10, Belgium, 9000
      • University Hospital Gent
  • Herestraat 49
    • Leuven, Herestraat 49, Belgium, 3000
      • Universitair Ziekenhuis Leuven
  • Hippocrate 10
    • Bruxelles, Hippocrate 10, Belgium, 1200
      • Cliniques Universitaires Saint-Luc Av.
• China
  • Beijing, China
    • Beijing Cancer Hospital
• France
  • Bettancourt La Ferree, France, 25000
    • Hopital Jean Minjoz
  • Bordeaux, France, 33000
    • Institut Bergonie
  • Caen, France, 14000
    • Centre Francois Baclesse
  • Clermont Ferrand, France, 63000
    • CHU Estaing
  • Clermont Ferrand, France, 63100
    • CHU Estaing
  • Dijon, France, 21000
    • Faculté de médecine
  • Dijon, France, 21079
    • Universite de Bourgogne - Faculte de Medecine - INSERM U866
  • Lille, France, 59020
    • Oscar Lambret Centre
  • Marseille, France, 13005
    • CHU Hôpital de la Timone
  • Paris, France, 75015
    • Hôpital Européen Georges Pompidou
  • Poitiers, France, 86021
    • CHU De Poitiers
  • Rouen, France, 76000
    • Hôpital Charles-Nicolle de Rouen
  • Vandœuvre-lès-Nancy, France, 54500
    • Institut de Cancerologie de Lorraine
• Hungary
  • Ráth György U. 7-9
    • Budapest, Ráth György U. 7-9, Hungary, 1122
      • Orszagos Onkologiai Intezet
  • Szent István U. 68
    • Nyíregyháza, Szent István U. 68, Hungary, 4400
      • Jósa András Oktatókórház
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitario Vall d'Hebron
  • Barcelona, Spain, 08001
    • Hospital Del Mar
  • Fuenlabrada, Spain, 28942
    • Hospital Universitario de Fuenlabrada
  • Girona, Spain
    • Hospital Universitari de Girona Doctor Josep Trueta
  • Lleida, Spain, 25198
    • Hospital Universitari Arnau de Vilanova de Lleida
  • Madrid, Spain, 28046
    • Hospital Universitario La Paz
  • Madrid, Spain
    • Hospital Universitario Ramon y Cajal
  • Madrid, Spain, 280402
    • Hospital Universitario Fundacion Jimenez Diaz
  • Pamplona, Spain, 31008
    • Clinica Universidad de Navarra
  • Sabadell, Spain, 08208
    • Parc Tauli Sabadell Hospital Universitari
  • Santiago De Compostela, Spain, 15706
    • Complexo Hospitalario Universitario De Santiago
  • Sevilla, Spain, 41003
    • Hospital Universitario Virgen Macarena
  • Valencia, Spain, 46016
    • Consorci Hospital General Universitari de València
  • Zaragoza, Spain, 50009
    • Hospital Universitario Miguel Servet
  • Cantabria
    • Santander, Cantabria, Spain, 39008
      • University Hospital Marqués de Valdecilla
• United States
  • California
    • Anaheim, California, United States, 92835
      • St. Joseph Heritage Healthcare - Virginia K. Crosson Cancer Center
    • Orange, California, United States, 92868
      • UC Irvine
  • Colorado
    • Denver, Colorado, United States, 80218
      • Rocky Mountain Cancer Centers, LLP
  • Georgia
    • Columbus, Georgia, United States, 31904
      • IACT Health - John B. Amos Cancer Center
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Stephenson Cancer Center
  • Texas
    • Austin, Texas, United States, 78705
      • Texas Oncology, P.A.
  • Washington
    • Vancouver, Washington, United States, 98684
      • Northwest Cancer Specialists, P.C.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Innovent Biologics (Suzhou) Co. Ltd.
• Collaborators: Fortrea

Publications and helpful links

General Publications

• Lu Z, Wang J, Shu Y, Liu L, Kong L, Yang L, Wang B, Sun G, Ji Y, Cao G, Liu H, Cui T, Li N, Qiu W, Li G, Hou X, Luo H, Xue L, Zhang Y, Yue W, Liu Z, Wang X, Gao S, Pan Y, Galais MP, Zaanan A, Ma Z, Li H, Wang Y, Shen L; ORIENT-15 study group. Sintilimab versus placebo in combination with chemotherapy as first line treatment for locally advanced or metastatic oesophageal squamous cell carcinoma (ORIENT-15): multicentre, randomised, double blind, phase 3 trial. BMJ. 2022 Apr 19;377:e068714. doi: 10.1136/bmj-2021-068714.

Study record dates

Study Major Dates

• Study Start (Actual): December 24, 2018
• Primary Completion (Actual): September 9, 2021
• Study Completion (Actual): July 29, 2023

Study Registration Dates

• First Submitted: November 12, 2018
• First Submitted That Met QC Criteria: November 18, 2018
• First Posted (Actual): November 20, 2018

Study Record Updates

• Last Update Posted (Actual): October 24, 2023
• Last Update Submitted That Met QC Criteria: October 22, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Cisplatin; Anti-PD-1; Fluorouracil; Gastrointestinal Diseases; Antineoplastic Agents; Esophageal Cancer; Paclitaxel; Esophageal Diseases; Esophageal Squamous Cell Carcinoma; ESCC; Sintilimab; Esophageal Neoplasms; Neoplasms, Squamous Cell; Carcinoma, Squamous Cell; Esophageal Neoplasms Malignant
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Head and Neck Neoplasms; Esophageal Diseases; Neoplasms, Squamous Cell; Esophageal Neoplasms; Carcinoma; Carcinoma, Squamous Cell; Esophageal Squamous Cell Carcinoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Paclitaxel; Fluorouracil
• Other Study ID Numbers: CIBI308A301; 2020-000533-40 (Registry Identifier: EudraCT)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No