Clinical Trials Register

Summary
EudraCT Number:	2018-002374-46
Sponsor's Protocol Code Number:	UC-0110/1807
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2018-08-24
Trial results	View 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

France - ANSM

A.2

EudraCT number

2018-002374-46

A.3

Full title of the trial

A randomised phase II trial assessing REGorafenib combined with IRInotecan as second-line treatment in patients with metastatic gastro-oesophageal adenocarcinomas.

A.3.1

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

A.3.2

Name or abbreviated title of the trial where available

REGIRI

A.4.1

Sponsor's protocol code number

UC-0110/1807

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	UNICANCER
B.1.3.4	Country	France
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Laboratoire BAYER
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	UNICANCER
B.5.2	Functional name of contact point	Project Manager, Laure MONARD
B.5.3	Address:
B.5.3.1	Street Address	101, rue de Tolbiac
B.5.3.2	Town/ city	Paris cedex 13
B.5.3.3	Post code	75654
B.5.3.4	Country	France
B.5.4	Telephone number	33173 79 73 09
B.5.5	Fax number	33171 93 61 66
B.5.6	E-mail	l-monard@unicancer.fr

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Comparator
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	CAMPTO
D.2.1.1.2	Name of the Marketing Authorisation holder	PFIZER HOLDING FRANCE
D.2.1.2	Country which granted the Marketing Authorisation	France
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	Irinotecan
D.3.4	Pharmaceutical form	Concentrate for 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	IRINOTECAN
D.3.9.1	CAS number	97682-44-5
D.3.9.4	EV Substance Code	SUB08295MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	180
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	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	No
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.IMP: 2
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	Stivarga
D.2.1.1.2	Name of the Marketing Authorisation holder	BAYER AG
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Regorafenib
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	REGORAFENIB
D.3.9.1	CAS number	755037-03-7
D.3.9.3	Other descriptive name	REGORAFENIB
D.3.9.4	EV Substance Code	SUB73090
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	40
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	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	No
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Patients aged ≥18 years old with metastatic gastro-oesophageal adenocarcinomas after failure of a first-line fluoropyrimidine and platinum-based chemotherapies.

E.1.1.1

Medical condition in easily understood language

Patients with advanced gastro-oesophageal cancer after failure of a first-line chemotherapy.

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

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 evaluate the efficacy of regorafenib combined with irinotecan (REGIRI), compared to irinotecan (IRI) alone, as second-line treatment in patients with metastatic gastro-oesophageal adenocarcinomas. The efficacy will be evaluated in terms of overall survival (OS).

E.2.2

Secondary objectives of the trial

• To evaluate the efficacy of regorafenib combined with irinotecan (REGIRI) versus irinotecan (IRI) alone, in terms of:
-the overall survival rate
-the progression-free survival (PFS)
-the progression-free survival rate
-the disease control rate (DCR)
-the objective response rate (ORR)
• To assess treatment-related toxicity (NCI CTCAE v5.0)
• To evaluate the effect of treatment on quality of life

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

• To evaluate the pharmacokinetics of regorafenib and its metabolites M2 and M5, as well as that of irinotecan and SN-38
• To study the pharmacogenetics: cyclin D1 polymorphisms
• To identify tumour factors predictive of response to regorafenib and irinotecan combination using immunochemistry

E.3

Principal inclusion criteria

1. Patient must have signed a written informed consent form prior to any study specific procedures
2. Patients aged ≥18 years old
3. Histologically confirmed diagnosis of gastro-oesophageal adenocarcinomas: gastroesophageal junction (Siewert II and III) and gastric adenocarcinomas
4. Asymptomatic primary tumour
5. Metastatic disease
6. At least one target lesion (according to RECIST 1.1):
• Unidimensionally measurable on cross-sectional imaging
• In an area not previously irradiated
7. Disease progression after a fluoropyrimidine and platinum agent-based chemotherapy (5-FU or 5-FU prodrugs combined with cisplatin or oxaliplatin). For example, docetaxel combined with FOLFOX, PD-L1/PD1 inhibitors combined with FOLFOX, LV5-FU2-cisplatin or 5-FU-cisplatin are acceptable prior therapies.
8. ECOG performance status ≤1
9. Life expectancy >3 months
10. Amylase ≤1.5 x ULN and lipase ≤1.5 x ULN
11. Adequate liver function:
- Total bilirubin ≤1.5 x ULN
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3.0 x ULN (≤5 x ULN for patients with liver metastasis)
- Alkaline phosphatase (ALP) ≤2.5 x ULN (≤5.0 x ULN for patients with liver or bone metastases)
12. Platelet count ≥100,000/mm3; haemoglobin (Hb) ≥9 g/dL; absolute neutrophil count (ANC) ≥1,500/mm3. The use of blood transfusion(s) to meet the inclusion criteria will not be allowed
13. International normalised ratio (INR) ≤1.5 x ULN and partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) ≤1.5 x ULN unless receiving treatment with therapeutic anticoagulation. Patients being treated with anticoagulant, e.g., heparin, are eligible if there is no evidence of an underlying abnormality with these parameters and if a close monitoring of at least weekly evaluations was performed until INR and PTT are stable based on a pre-dose measurement as defined by the local standard of care.
14. Creatinine clearance (CLcr) ≥50 mL/min estimated by Cockcroft-Gault equation
15. Women of childbearing potential and men must agree to use adequate contraception during the study and for at least 8 weeks after the last study drug administration.
16. Patients affiliated to the social security system

E.4

Principal exclusion criteria

1. Symptomatic brain metastases or carcinomatous meningitis
2. Bone-only metastasis
3. Known and documented UGT1A1 deficiency
4. History of Gilbert’s syndrome
5. Previous or concurrent cancer with a distinct primary site, other than oesogastric cancer, within 5 years prior to randomisation (except for curatively treated cervical cancer in situ, non-melanoma skin cancer, and superficial bladder tumours)
6. Persistent proteinuria >3.5 g/24 h measured by urine protein-creatinine ratio from a random urine sample (grade ≥3, NCI-CTCAE v 5.0)
7. Interstitial lung disease with ongoing signs and symptoms at inclusion
8. Known hypersensitivity to any of the study drugs, study drug classes, or excipients
9. Non-healing wound, non-healing ulcer, or non-healing bone fracture
10. Patients with evidence or history of any bleeding diathesis, irrespective of severity
11. Any haemorrhage or bleeding event grade ≥3 (NCI-CTCAE v.5.0) within 4 weeks before starting of the study treatment
12. Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 6 month before starting the study treatment (except for adequately treated catheter-related venous thrombosis occurring more than one month before the start of study medication)
13. Previous major surgical procedure, significant traumatic injury, or radiotherapy within the 4 weeks before inclusion
14. Uncontrolled hypertension (systolic blood pressure >140 mmHg or diastolic pressure >90 mmHg) despite optimal medical management. Congestive heart failure: New York Heart Association (NYHA) ≥ class 2
15. Unstable angina (angina symptoms at rest), new-onset angina (that started within the last 3 months)
16. Myocardial infarction less than 6 months before starting the study treatment
17. Uncontrolled cardiac arrhythmias
18. History of epileptic seizures requiring long-term anticonvulsant therapy
19. History of organ transplantation with use of immunosuppression therapy
20. Ongoing bacterial or fungal infection (grade >2 by NCI-CTCAE v.5.0)
21. Known history of human immunodeficiency virus (HIV) infection
22. Active hepatitis B or C, or chronic hepatitis B or C requiring treatment with antiviral therapy
23. Use of CYP 3A4 inducers or inhibitors
24. Pregnant or breast-feeding women
25. Bowel malabsorption or extended bowel resection that could affect the absorption of regorafenib, occlusive syndrome, inability to take oral medications
26. Inflammatory bowel disease with chronic diarrhoea
27. Participation in another clinical trial within the 30 days before inclusion
28. Concurrent treatment with another investigational product or anticancer therapy (other than irinotecan or regorafenib)
29. Person kept in detention or incapable of giving consent
30. Patient unwilling or unable to comply with the medical follow-up required by the study because of geographic, social, or psychological reasons

E.5 End points

E.5.1

Primary end point(s)

Overall Survival (OS), defined as the time from the date of randomisation until death of any cause. If a patient is alive at the database cut-off date, then the patient will be censored at the last date of follow-up.

E.5.1.1

Timepoint(s) of evaluation of this end point

Time from the date of randomisation until death of any cause.

E.5.2

Secondary end point(s)

• The efficacy will be assessed using the following endpoints (tumour response assessed by RECIST v1.1):
-Overall survival rates at 6 and 12 months, estimated by the Kaplan-Meier method.
-Progression-free survival (PFS), defined as the time from the date of randomisation to date of disease progression (radiological or clinical) or death of any cause, whichever occurs first. Patients without tumour progression or death at the time of analysis will be censored at the date of their last tumour assessment.
-PFS rates at 3 and 6 months, estimated by the Kaplan-Meier method
-Disease control rate (DCR), defined as the percentage of patients, with complete response (CR), partial response (PR), or stable disease (SD) as best response at the database cut-off date.
-Objective response rate (ORR), defined as the percentage of patients with CR or PR. Patients who discontinue treatment without a tumour assessment will be considered non-responders for the analysis.
• Frequency and severity of adverse events assessed by NCI CTCAE v5.0
• Health-related quality of life will be assessed using the EORTC QLQ-C30 and the oesophago-gastric cancer questionnaire (EORTC QLQ-OG25)
• Pharmacokinetic study of regorafenib and its metabolites M2 and M5, as well as that of irinotecan and SN-38
• Pharmacogenetic study of the impact of cyclin D1 polymorphisms
• Immunochemistry analyses to identify tumour factors predictive of response to regorafenib and irinotecan combination

E.5.2.1

Timepoint(s) of evaluation of this end point

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

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

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Effect of treatment on quality of life.
Biomarkers study.

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

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

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

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

LVLS

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

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:

124

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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

154

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)

none

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

2018-10-10

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-11-09

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2022-05-19

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