Clinical Trials Register

Summary
EudraCT Number:	2020-000533-40
Sponsor's Protocol Code Number:	CIBI308A301
National Competent Authority:	Hungary - National Institute of Pharmacy
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2020-05-05
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Hungary - National Institute of Pharmacy

A.2

EudraCT number

2020-000533-40

A.3

Full title of the trial

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)

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Randomized Clinical Trial of Sintilimab in Combination with Chemotherapy for Treatment of Unresectable, Locally Advanced, Recurrent, or Metastatic Esophageal Squamous Cell Carcinoma

A.3.2

Name or abbreviated title of the trial where available

ORIENT-15

A.4.1

Sponsor's protocol code number

CIBI308A301

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Innovent Biologics (Suzhou) Co., Ltd.
B.1.3.4	Country	China
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Innovent Biologics (Suzhou) Co., Ltd.
B.4.2	Country	China
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Innovent Biologics (Suzhou) Co., Ltd.
B.5.2	Functional name of contact point	Winnie Leung
B.5.3	Address:
B.5.3.1	Street Address	No. 168 Dongping Street, Suzhou Industrial Park, Jiangsu, China
B.5.3.2	Town/ city	Suzhou
B.5.3.3	Post code	215123
B.5.3.4	Country	China
B.5.4	Telephone number	+86 180 3609 5522
B.5.5	Fax number	+86 0512 6956 6088 8269
B.5.6	E-mail	cibi308a301_eu@innoventbio.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Tyvyt®
D.2.1.1.2	Name of the Marketing Authorisation holder	Innovent Biologics (Suzhou) Co., Ltd.
D.2.1.2	Country which granted the Marketing Authorisation	China
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Sintilimab
D.3.2	Product code	IBI308
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	SINTILIMAB
D.3.9.1	CAS number	2072873-06-2
D.3.9.2	Current sponsor code	IBI308
D.3.9.4	EV Substance Code	SUB195564
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Esophageal Squamous Cell Carcinoma

E.1.1.1

Medical condition in easily understood language

Esophageal Squamous Cell Carcinoma

E.1.1.2

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	25.1
E.1.2	Level	PT
E.1.2	Classification code	10030187
E.1.2	Term	Oesophageal squamous cell carcinoma recurrent
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	PT
E.1.2	Classification code	10058527
E.1.2	Term	Oesophageal squamous cell carcinoma metastatic
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	25.1
E.1.2	Level	PT
E.1.2	Classification code	10061534
E.1.2	Term	Oesophageal squamous cell carcinoma
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

- To compare the overall survival (OS) of sintilimab vs. placebo, in combination with chemotherapy, as first-line treatment in subjects with unresectable, locally advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC);
- To compare the OS of sintilimab vs. placebo, in combination with chemotherapy, as first-line treatment in subjects with PD-L1 positive (CPS ≥10, i.e.,
combined positive score), unresectable, locally advanced, recurrent or metastatic ESCC.

E.2.2

Secondary objectives of the trial

- To compare progression-free survival (PFS), objective response rate (ORR), progression-free survival (PFS), disease control rate (DCR), and duration of response (DoR) between two treatment arms in overall population;
- To compare the objective response rate (ORR), progression-free survival (PFS), disease control rate (DCR), and duration of response (DoR) between two treatment arms in subjects with PD-L1 positive (CPS ≥10) ESCC.
- To compare the safety between the two treatment arms.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Histopathologically confirmed unresectable, locally advanced, recurrent or metastatic ESCC (excluding mixed adenosquamous carcinoma and other histological subtypes).
2. Aged ≥ 18.
3. ECOG PS of 0 or 1.
4. 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 recurrencne must be > 6 months.
5. Could provide archival or fresh tissues for PD-L1 expression analysis with obtainable results.
6. Have at least one measurable lesion as per RECIST v1.1.
7. Adequate organs and bone marrow functions, as defined below:
1) Complete blood count: absolute neutrophil count (ANC) ≥ 1.5 × 109/L, platelet (PLT) count ≥ 100 × 109/L, hemoglobin (HGB) ≥ 9.0 g/dL. Note: Subjects cannot receive blood transfusion, erythropoietin (EPO), or Granulocyte-colony stimulating factor (GSF) within 7 days prior to the blood collection.
2) Hepatic function: total bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN in subjects without hepatic metastasis; TBIL ≤ 1.5 × ULN, ALT and AST ≤ 5 × ULN in subjects with hepatic metastasis.
3) Renal function: urine protein < 2+ from random sample or < 1 g from 24-hour urine collection, and creatinine clearance rate (Ccr) ≥ 60 mL/min by Cockcroft-Gault formula.
The calculations of Ccr for one subject must use the same formula throughout the entire study.
4) Adequate coagulation function, defined as international normalized ratio (INR) ≤ 1.5 or prothrombin time (PT) ≤ 1.5 × ULN; if the subject is receiving anticoagulant therapy, the results of coagulation tests need to be within the acceptable range for anticoagulants.
Expected survival ≥ 12 weeks.
9. Subject (female subjects of childbearing age or male subjects whose partners are of childbearing age) must take effective contraceptive measures during the entire course of the trial and until 180 days after the last dose.
10. Signed the informed consent form (ICF) and be able to comply with the scheduled follow-up visits and related procedures required in the protocol.

E.4

Principal exclusion criteria

1. ESCC with endoscopy-confirmed near-complete obstruction requiring interventional therapy.
2. Post stent implantation in the esophagus or trachea with risks of perforation.
3. Received systemic treatment for advanced or metastatic ESCC.
4. 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
5. High risk of hemorrhage or perforations due to tumor invasion in adjacent organs (aorta or trachea), or have fistula formation.
6. Load of hepatic metastasis > 50% of the total liver volume.
7. Received treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug that specifically targets T-cell co-stimulation or immune checkpoint pathways.
8. Enrolled in another interventional clinical study, unless only involved in an observational study (non-interventional) or in the follow-up phase of an interventional study.
9. Received palliative therapy for local lesion within 2 weeks prior to the first dose.
10. 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.
11. Received systemic immunosuppressants within 2 weeks prior to
randomization or the first dose of study treatment in the
open-label phase, excluding local use of glucocorticoids and systemic
glucocorticoids at physiological doses (no more than 10 mg/day of
prednisone or equivalents), or glucocorticoids to prevent allergies to
contrast media
12. Received a live attenuated vaccine within 4 weeks prior to the first dose of study treatment or be scheduled to receive live attenuated vaccine during the study period.
Note: Seasonal inactivated influenza virus vaccines within 4 weeks prior to the first dose of study treatment are permitted, but attenuated influenza vaccines are not.
13. Received major surgery (craniotomy, thoracotomy, or laparotomy) within 4 weeks prior to the first dose of study treatment or is scheduled to receive major surgery during the course of the trial.
14. Any toxicity (excluding alopecia, events that are not clinically significant, or asymptomatic laboratory abnormalities) due to prior anti-tumor therapy that has not yet resolved to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0 grade 0 or 1 prior to the first dose of study treatment.
15. Known symptomatic central nervous system (CNS) metastasis or carcinomatous meningitis.
16Clinically significant ascites, including ascites that could be detected on physical examination, has been treated with a prior procedure, or currently requires treatment. Asymptomatic subjects with a small amount of ascitic fluid demonstrated by imaging can be enrolled.
17. Moderate bilateral pleural effusion or large unilateral pleural effusion, or effusion resulting in respiratory dysfunction and requiring drainage.
18. Subjects with bone metastases at risk of paraplegia.
19. Known active autoimmune disease requiring treatment or previous disease history within 2 years (subjects with vitiligo, psoriasis, alopecia, or Graves' disease not requiring systemic treatment, hypothyroidism only requiring thyroid replacement, or type I diabetes only requiring insulin can be enrolled).
20. Known history of primary immunodeficiency diseases.
21. Known active pulmonary tuberculosis.
Known history of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation.
23. Known allergy to any monoclonal antibody or any formulation or excipient of chemotherapy agents (e.g. paclitaxel, fluorouracil, or cisplatin) in that the subjects is inappropriate to receive TP or CF regimen.
24. HIV-infected subjects (positive anti-HIV antibody).
25. Active or poorly controlled serious infections.
26. Symptomatic congestive heart failure (NYHA Class II–IV) or symptomatic or poorly controlled arrhythmia.
27. Uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 100 mmHg) despite of standard treatment.
28. Any arterial thromboembolic event within 6 months prior to enrollment, including myocardial infarction, unstable angina, cerebrovascular accident, or transient cerebral ischemic attack.
29. Significant malnutrition, such as those requiring continuous parenteral nutrition ≥7 days; excluding those having received intravenous treatment for malnutrition for more than 4 weeks before the first dose of study treatment.
30. History of deep venous thrombosis, pulmonary embolism, or other serious thromboembolic events within 3 months prior to enrollment (implantable port or catheter-related thrombosis, or superficial venous thrombosis are not considered as "serious" thromboembolisms).

For a complete overview of the exclusion criteria refer to the protocol.

E.5 End points

E.5.1

Primary end point(s)

- OS (Overall survival) in the ITT population;
- OS in PD-L1 positive subjects in the ITT population.

E.5.1.1

Timepoint(s) of evaluation of this end point

Assessments will be performed at timepoints described in the protocol.

E.5.2

Secondary end point(s)

- Key secondary endpoints:
-ORR (Objective response rate), PFS (Progression free survival) in the ITT population;
-ORR. PFS in PD-L1 positive subjects in the ITT population.
- Other secondary endpoints:
- DCR (Disease control rate), DoR (Duration of response)in the ITT population;
- DCR, DoR in PD-L1 positive subjects in the ITT population.

E.5.2.1

Timepoint(s) of evaluation of this end point

Assessments will be performed at timepoints described in the protocol.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

added an open-label phase after completion of enrollment in the randomisation phase of the study

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Australia

China

United States

Belgium

France

Hungary

Spain

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

The trial is completed if the last remaining subject has completed the
safety follow-up following completion of therapy (up to 24 months
treatment), or the sponsor decides to discontinue the trial early based
on the advice from the iDMC and/or the agreement between sponsor
and health authority, whichever is earliest.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

468

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

278

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

127

F.4.2.2

In the whole clinical trial

746

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Upon completion of this study the patient will return to standard care, however there are no approved treatments available.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2020-08-18

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-06-03

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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