Clinical Trials Register

Summary
EudraCT Number:	2018-002231-24
Sponsor's Protocol Code Number:	PROICM2018-01NEX
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2018-06-22
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

France - ANSM

A.2

EudraCT number

2018-002231-24

A.3

Full title of the trial

A randomized phase III trial assessing a regorafenib-irinotecan combination (REGIRI) versus regorafenib alone in metastatic colorectal cancer patients after failure of standard therapies, according to the A/A genotype of Cyclin D1

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

NEXT-REGIRI

A.4.1

Sponsor's protocol code number

PROICM2018-01NEX

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	Institut régional du Cancer de Montpellier
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
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Institut régional du Cancer de Montpellier
B.5.2	Functional name of contact point	Dr Jean Pierre BLEUSE
B.5.3	Address:
B.5.3.1	Street Address	208 rue des apothicaires
B.5.3.2	Town/ city	montpellier
B.5.3.3	Post code	34298
B.5.3.4	Country	France
B.5.4	Telephone number	0033467612344
B.5.5	Fax number	0033467613023
B.5.6	E-mail	drci-icm105@icm.unicancer.fr

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	STIVARGA
D.2.1.1.2	Name of the Marketing Authorisation holder	BAYER HEALTHCARE SAS
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	REGORAFENIB
D.3.2	Product code	REGIRI ( Irinotecan+regorafenib)
D.3.4	Pharmaceutical form	Cachet
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.3.9.1	CAS number	755037-03-7
D.3.9.3	Other descriptive name	REGORAFENIB
D.3.9.4	EV Substance Code	SUB73090
D.3.11 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	No
D.2.1.1.1	Trade name	IRINOTECAN
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.3.2	Product code	REGIRI ( Irinotecan+regorafenib)
D.3.4	Pharmaceutical form	Solution for injection
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.3.11 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: 3
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	STIVARGA
D.2.1.1.2	Name of the Marketing Authorisation holder	BAYER HEALTHCARE SAS
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	REGORAFENIB
D.3.4	Pharmaceutical form	Cachet
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.3.9.1	CAS number	755037-03-7
D.3.9.3	Other descriptive name	REGORAFENIB
D.3.9.4	EV Substance Code	SUB73090
D.3.11 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

Metastatic colorectal cancer

E.1.1.1

Medical condition in easily understood language

Metastatic colorectal cancer

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.0
E.1.2	Level	PT
E.1.2	Classification code	10052358
E.1.2	Term	Colorectal cancer metastatic
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

Comparison of overall survival in the Regorafenib and REGIRI combination (Regorafenib + Irinotecan) arms in mCRC patients of Cyclin D1 A/A genotype.

E.2.2

Secondary objectives of the trial

Study of:
-Progression-free survival
-Objective response rate
-Disease control rate according to Recist criteria (version 1.1)
-Toxicity (according to the NCI-CTCAE v5.0)
-Quality of life (EORTC QLQ-C30)

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

Investigation any association between cyclin D1 protein expression and response to treatment.

E.3

Principal inclusion criteria

1. Signed informed consent obtained before any study specific procedures
2. Male or female ≥ 18 years of age
3. Histological or cytological documentation of adenocarcinoma of the colon or rectum
4. Patients with metastatic colorectal cancer
5. Progression during or within 3 months following the last administration of approved standard therapies, which must include a fluoropyrimidine (or raltitrexed), oxaliplatin, irinotecan, anti VEGF therapy and an anti EGFR therapy (for RAS wild-type tumors)
6. ECOG performance status ≤1
7. Life expectancy of at least 3 months
8. Patients with A/A CCND1 genotype of rs603965 CCND1
9. Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements conducted within 7 days of starting study treatment:Amylase and lipase ≤1.5 x ULN, Total bilirubin ≤ 1.5 x ULN, Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 x ULN (≤ 5 x ULN for patients with liver involvement of their cancer), Alkaline phosphatase (ALP) ≤ 2.5 x ULN (≤ 5.0 x ULN for patients with liver involvement for their cancer and/or have bone metastases), Platelet count ≥ 100,000/mm3; Hemoglobin (Hb) ≥ 9 g/dL; Absolute neutrophil count (ANC) ≥ 1,500/ mm3. Transfusion to meet the inclusion criterion, Serum creatinine ≤ 1.5 x ULN
10. International normalized 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, will be allowed to participate provided no prior evidence of an underlying abnormality in these parameters exists. Close monitoring of at least weekly evaluations will be performed until INR and PTT are stable based on a pre-dose measurement as defined by the local standard of care
11. Women of childbearing potential must have a blood or urine pregnancy test performed a maximum of 7 days before start of study treatment, and a negative result must be documented before start of study treatment
12. Women of childbearing potential and men must agree to use adequate contraception before entering the study until at least 8 weeks after the last study drug administration of Regorafenib and 12 weeks after the last study drug administration of Irinotecan. The investigator or a designated associate is requested to advise the patient on how to achieve an adequate birth control. Adequate contraception is defined in the study as any medically recommended method (or combination of methods) as per standard of care.

E.4

Principal exclusion criteria

1. Patients with A/G or G/G CCND1 genotype of rs603965 CCND1
2. Prior treatment with regorafenib or sorafenib
3. Prior treatment with TAS 102
4. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before start of study drug
5. Pregnant or breast-feeding subjects. Women of childbearing potential must have a pregnancy test performed a maximum of 7 days before start of treatment, and a negative result must be documented before start of study drug
6. Congestive heart failure ≥ New York Heart Association (NYHA) class 2
7. Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months)
8. Myocardial infarction less than 6 months before start of study drug
9. Cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted)
10. Uncontrolled hypertension. (Systolic blood pressure > 140 mmHg or diastolic pressure > 90 mmHg despite optimal medical management)
11. Pleural effusion or ascites that causes respiratory compromise (≥ NCI-CTCAE V5.0 Grade 2 dyspnea)
12. Ongoing infection > Grade 2 NCI-CTCAE V5.0
13. Known history of human immunodeficiency virus (HIV) infection
14. Active hepatitis B or C, or chronic hepatitis B or C requiring treatment with antiviral therapy
15. Patients with seizure disorder requiring medication
16. History of organ allograft
17. Patients with evidence or history of any bleeding diathesis, irrespective of severity
18. Any hemorrhage or bleeding event ≥ NCI-CTC V5.0 Grade 3 within 4 weeks prior to the start of study medication
19. Non-healing wound, ulcer, or bone fracture
20. Dehydration NCI-CTCAE V5.0 Grade ≥ 1
21. Substance abuse, medical, psychological or social conditions that may interfere with the subject’s participation in the study or evaluation of the study results
22. Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation
23. Any illness or medical conditions that are unstable or could
jeopardize the safety of the subject and his/her compliance in the study
24. Persistent proteinuria of NCI-CTCAE V5.0 Grade 3 (> 3.5g/24 hours)
25. Patients unable to swallow oral medications
26. Any malabsorption condition
27. Chronic inflammatory bowel disease and / or bowel obstruction
28. Unresolved toxicity higher than NCI-CTCAE V.5.0 Grade 1 attributed to any prior therapy/procedure excluding alopecia, hypothyroidism and oxaliplatin induced neurotoxicity ≤ Grade 2
29. Concomitant participation or participation within the last 30 days in another clinical trial
30. Systemic anticancer therapy during this trial or within 4 weeks before randomization

E.5 End points

E.5.1

Primary end point(s)

Overall survival presented with its median and confidence interval at 95%, estimated from randomization date to the date of death, whatever the cause, using the Kaplan-Meier method

E.5.1.1

Timepoint(s) of evaluation of this end point

At the end of the study

E.5.2

Secondary end point(s)

The secondary efficacy endpoint include:
- Progression-free survival (PFS), defined as the time (days) from date of randomization to date of first observed disease progression (investigator’s radiological or clinical assessment) or death due to any cause, if death occurs before progression is documented. Patients without tumor progression or death at the time of analysis will be censored at their last date of tumor assessment.
- Disease control rate (DCR), defined as the rate of patients, whose best response was not progressive disease (i.e., CR, PR or SD), to all randomized patients in the treatment group
- Objective response rate (OOR), defined as the rate of patients with CR or PR, to all randomized patients in the treatment group. Patients prematurely discontinuing without an assessment will be considered non-responders for the analysis.
- Safety will be evaluated using the NCI-CTCAE version 5.0 scale; at each visit for the duration of the treatment.
-Quality of life will be evaluated, using the EORTC QLQ-C30 questionnaire.
The expected benefit is an overall survival improvement of this treatment in patients with metastatic colorectal cancer who have received all standard treatments except TAS-102 and Regorafenib.

E.5.2.1

Timepoint(s) of evaluation of this end point

At the end of the study

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

E.6.6

Pharmacokinetic

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

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)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Regorafenib alone

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

the last visit of the last subject undergoing the trial

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:

312

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

312

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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

312

F.4.2

For a multinational trial

F.4.2.1

In the EEA

312

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

2018-08-06

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-07-10

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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