Clinical Trials Register

Summary
EudraCT Number:	2013-004385-34
Sponsor's Protocol Code Number:	ICM_2013/09
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2015-08-24
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

2013-004385-34

A.3

Full title of the trial

Activity of Regorafenib in combination with modified Gemcitabine - Oxaliplatin Chemotherapy (mGEMOX) in patients with advanced Biliary Tract Cancer (BTC): A Phase Ib-II trial

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

BREGO

A.4.1

Sponsor's protocol code number

ICM_2013/09

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 - Montpellier - Val d'Aurelle
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	Institut régional du Cancer - Montpellier - Val d'Aurelle
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	Institut régional du Cancer - Montpellier - Val d'Aurelle
B.5.2	Functional name of contact point	Jean Pierre BLEUSE
B.5.3	Address:
B.5.3.1	Street Address	208 rue des Apothicaires
B.5.3.2	Town/ city	Montpellier Cedex 5
B.5.3.3	Post code	34298
B.5.3.4	Country	France
B.5.4	Telephone number	04 67 61 23 44 / 31 02
B.5.5	Fax number	04 67 61 30 23
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 Pharma 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.3.4	Pharmaceutical form	Coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
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	GEMCITABINE
D.2.1.1.2	Name of the Marketing Authorisation holder	ACTAVIS GROUP PTC EHF
D.2.1.2	Country which granted the Marketing Authorisation	Iceland
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.3.4	Pharmaceutical form	Powder 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	GEMCITABINE
D.3.9.1	CAS number	95058-81-4
D.3.9.4	EV Substance Code	SUB07892MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	up to
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.IMP: 3
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	OXALIPLATINE
D.2.1.1.2	Name of the Marketing Authorisation holder	ACTAVIS GROUP PTC EHF
D.2.1.2	Country which granted the Marketing Authorisation	Iceland
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.3.4	Pharmaceutical form	Powder 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	OXALIPLATIN
D.3.9.1	CAS number	61825-94-3
D.3.9.4	EV Substance Code	SUB09490MIG
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	5
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

advanced Biliary Tract Cancer

E.1.1.1

Medical condition in easily understood language

Biliary 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	17.0
E.1.2	Level	PT
E.1.2	Classification code	10055111
E.1.2	Term	Biliary 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

For Phase 1b:
The main objective for this dual-center open-label phase Ib study is to determine the RD for the phase II trial of Regorafenib administered in combination with mGEMOX in patients with advanced biliary tract cancer.
For phase 2 :
Evaluating the treatment efficacy of the recommended dose of Regorafenib and mGEMOX by assessing the progression free survival according RECIST criteria (version 1.1).

E.2.2

Secondary objectives of the trial

To evaluate Objective Response,
To evaluate the duration of overall response (complete or partial) according RECIST criteria (version 1.1),
To evaluate the non-progression rate (OR+SD) according RECIST criteria (version 1.1),
To evaluate the feasibility and safety profile of the combination of mGEMOX and Regorafenib according to the NCI-CTCAE, version 4.03,
To evaluate the overall survival.

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

• Assessment of KRAS BRAF mutational status using IntPlex test,
• Interest of 18F-FDG--PET/CT in early assessment of tumor response (only phase II),
• Pharmacokinetic of Regorafenib (20 patients, only phase II).

E.3

Principal inclusion criteria

1. Adenocarcinoma of the biliary tract (gallbladder, intra and/or extrahepatic bile ducts, or ampulla of Vater):
Cytologically or histologically proven adenocarcinoma of the biliary tract. In case of uncertain biliary tract origin (e.g., intrahepatic, peripheral cholangiocarcinomas), inclusion is possible if i) extensive search for primary origin (thoracic and abdominopelvic Computed Tomography scanner (CT scan), upper digestive endoscopy) is negative; and ii) histological examination is consistent with bile duct adenocarcinoma (ImmunoHistoChemistry (IHC) should ideally be performed and be consistent with biliary primary disease, e.g., positive for cytokeratin 7 and negative for cytokeratin 20).
2. Metastatic disease with no curative surgery option or metastatic recurrence after resection.
3. At least one measurable lesion in a non-irradiated area according to Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1).
4. No biliary obstruction.
5. Age between 18 and 75 years.
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
7. Life expectancy higher than 3 months.
8. No prior chemotherapy for advanced disease. Previous adjuvant chemotherapy including Gemcitabine and/or platinum based is allowed if completed at least 6 months previously and relapsing after completion of the last dose.
9. Total bilirubin ≤ 2.5 times the upper limit of the normal range (ULN). Patients with jaundice or evidence of bile duct obstruction, in whom the biliary tree can be decompressed by endoscopic or percutaneous endoprothesis (at least 15 days before inclusion) with subsequent reduction in total bilirubin ≤ 3 ULN, will be eligible for the study.
10. Aminotransferases (AST, ALT) ≤ 2.5 ULN (≤ 5 ULN in case of diffuse hepatic involvement), INR < 1.5 (following vitamin K1 injection in patients with current or recent history of jaundice or bile duct obstruction), Glomerular Filtration Rate (GFR) > 50 mL/min/1.73m² according to the Modification of Diet in Renal Disease (MDRD) formula, neutrophils ≥ 1.5.10^9/L, platelets ≥ 100.10^9/L, hemoglobin ≥ 9 g/dL (red blood cell transfusion is allowed if needed).
11.Signed informed consent obtained before any study specific procedures.
12.Patients must be affiliated to a Social Security System.

E.4

Principal exclusion criteria

1. Known central nervous system metastases.
2. Known history of human immunodeficiency virus (HIV) infection
3. Contraindication or history of allergic reaction to one of the treatment components.
4. Previous irradiation (external radiotherapy or brachytherapy) within 30 days prior to study treatment.
5. Major surgery within 30 days prior to study treatment.
6. Participation in another clinical trial within 30 days prior to study treatment.
7. Concomitant systemic immunotherapy, chemotherapy, antitumor hormone therapy, targeted therapy or any experimental therapy.
8. Active uncontrolled infection, peripheral neuropathy grade ≥ 2, acute or subacute bowel obstruction, history of inflammatory bowel disease, interstitial pneumonitis, respiratory failure, renal failure, dysphagia or any malabsorption condition.
9. Symptomatic coronary heart disease or myocardial infarction in the past 6 months, congestive heart failure (NYHA class II), prior cerebrovascular accident.
10.Uncontrolled hypertension (systolic blood pressure (BP) > 150 mmHg or diastolic pressure > 90 mmHg despite optimal medical management).
11.Proteinuria of National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) ≥ grade 2 (i.e. urinary protein ≥ 1.0 g/24 hrs).
12.Patients with current or anticipated need for strong Cytochrome P450 3A4 (CYP3A4) inhibitors or inducers.
13.Pregnancy (or positive β-HCG dosage at inclusion), breast-feeding, or lack of effective contraception in male or female patients of reproductive potential.
14.Other malignancies either currently active or in the last 5 years, except adequately treated in situ carcinoma of the cervix and basal or squamous cell skin carcinoma.
15.Legal incapacity or physical, psychological or mental status interfering with the patient's ability to sign the informed consent or to terminate the study.

E.5 End points

E.5.1

Primary end point(s)

For phase 1b :
Limiting Toxicities during and within 6 weeks (2 cycles) after the beginning of the treatment. DLT definition.

For phase 2 :
Progression-free survival (according RECIST v1.1).

E.5.1.1

Timepoint(s) of evaluation of this end point

Not applicable

E.5.2

Secondary end point(s)

For phase 2 :
• Objective response (OR) rate
• Disease control rate
• Safety profile (assessed by CTCAE v 4.03)
• Overall survival (OS)

E.5.2.1

Timepoint(s) of evaluation of this end point

Not applicable

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

Yes

E.6.10

Pharmacogenetic

Yes

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)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

1b : determining the recommended dose level for phase 2.

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

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

MGEMOX whitout Regorafenib is standard arm

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:

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

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

2014-05-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-01-27

P. End of Trial
P.	End of Trial Status	Ongoing

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