Clinical Trials Register

Summary
EudraCT Number:	2017-002330-23
Sponsor's Protocol Code Number:	9794
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:	2017-10-20
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

2017-002330-23

A.3

Full title of the trial

HEPATIC ARTERIAL INFUSION OF GEMCITABINE-OXALIPLATIN FOR SECOND-LINE THERAPY IN NON-METASTATIC UNRESECTABLE INTRA-HEPATIC CHOLANGIOCARCINOMA: A MULTICENTRIC SINGLE-ARM PHASE II STUDY

TRAITEMENT INTRA-ARTERIEL HEPATIQUE PAR GEMCITABINE-OXALIPLATINE DANS LES CHOLANGIOCARCINOMES INTRA-HEPATIQUES NON RÉSÉCABLES, NON MÉTASTASTATIQUES EN 2ème LIGNE : ESSAI MULTICENTRIQUE MONOBRAS DE PHASE II

A.3.1

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

EVALUATION OF THE EFFICACY AND TOLERANCE OF A CHEMOTHERAPY BY GEMCITABINE AND OXALIPLATIN ADMINISTERED IN THE LIVER, BY THE HEPATIC ARTERY, ON A CHOLANGIOCARCINOME

EVALUATION DE L'EFFICACITE ET DE LA TOLERANCE D'UNE CHIMIOTHERAPIE PAR GEMCITABINE ET OXALIPLATINE ADMINISTREE DANS LE FOIE, PAR L'ARTERE HEPATIQUE, SUR UN CHOLANGIOCARCINOME

A.3.2

Name or abbreviated title of the trial where available

GEMOXIA-02

A.4.1

Sponsor's protocol code number

9794

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	University hospital of 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	University hospital of Montpellier
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	University Hospital of Montpellier
B.5.2	Functional name of contact point	CADENE Anne
B.5.3	Address:
B.5.3.1	Street Address	DRI- Pav 32 - 39 avenue Charles Flahault
B.5.3.2	Town/ city	Montpellier
B.5.3.3	Post code	34295
B.5.3.4	Country	France
B.5.4	Telephone number	0033467330814
B.5.5	Fax number	0033467339172
B.5.6	E-mail	a-cadene@chu-montpellier.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.2.1.2	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.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intrahepatic use (Noncurrent)
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.3.9.2	Current sponsor code	gemcitabine
D.3.9.3	Other descriptive name	gemcitabine
D.3.9.4	EV Substance Code	SUB07892MIG
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	1000
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.2.5	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	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intraarterial 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.3.9.2	Current sponsor code	oxaliplatine
D.3.9.3	Other descriptive name	oxaliplatine
D.3.9.4	EV Substance Code	SUB09490MIG
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	100
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

The combination of gemcitabine and oxaliplatin intra-arterial as second-line therapy can greatly improve the Objective Response Disorder (ORT) at 4 months

L’association de la gemcitabine et de l’oxaliplatine par voie intra-artérielle comme traitement de seconde ligne peut fortement améliorer le Trouble de Réponse Objective (TRO) à 4 mois.

E.1.1.1

Medical condition in easily understood language

The combination of gemcitabine and oxaliplatin intra-arterial as second-line therapy can greatly improve the Objective Response Disorder (ORT) at 4 months

L’association de la gemcitabine et de l’oxaliplatine par voie intra-artérielle comme traitement de seconde ligne peut fortement améliorer le Trouble de Réponse Objective (TRO) à 4 mois.

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	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10036706
E.1.2	Term	Primary liver cancer non-resectable
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The main objective is to evaluate the objective response rate (complete or partial response) 4 months after inclusion using RECIST 1.1 evaluation

L'objectif principal est d'évaluer le taux de réponse objectif (réponse complète ou partielle) 4 mois après l'inclusion en utilisant l'évaluation RECIST 1.1

E.2.2

Secondary objectives of the trial

The secondary objectives are:
• Safety (NCI-CTCAE version 4.0)
• Quality of life (QLQ-C30)
• Secondary resectability rate
• Overall survival
• Progression-free survival

Les objectifs secondaires sont les suivants:
• Sécurité (NCI-CTCAE version 4.0)
• Qualité de vie (QLQ-C30)
• Taux de resecabilité secondaire
• La survie globale
• La survie sans progression

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Patients eligible for inclusion in this study have to meet all the following criteria:
• Histologically-proven intrahepatic cholangiocarcinoma previously treated by first-line systemic therapy
• Absence of extra-hepatic metastasis or peritoneal carcinomatosis (as demonstrated by CT-scan)
• Age  18 years
• General health status PS 0, 1
• Estimated life expectancy > 3 months
• Disease that is not suitable for resection with a curative intent, as validated by a multidisciplinary committee with at least one senior hepatic surgeon
• At least one measurable lesion according to RECIST 1.1 criteria
• Platelets ≥100,000/mm3, polynuclear neutrophils ≥1000/mm3 , hemoglobin  9g/dL (even transfused patients can be included)
• Creatininemia < 1.5N
• Bilirubinemia ≤2 N (after biliary drainage if necessary)
• ASAT and ALAT ≤ 5N
• Reference hepatic MRI (according to the foreseen protocol) done during the 30 days preceding the 1st cycle of treatment
• Written informed consent
• National health insurance cover

Les patients admissibles pour cette étude doivent satisfaire à tous les critères suivants:
• Cholangiocarcinome intrahépatique histologiquement prouvé préalablement traité par thérapie systémique de première ligne
• Absence de métastase extra-hépatique ou de carcinomatose péritonéale (comme l'ont démontré la tomodensitométrie)
• Âge  18 ans
• État de santé général PS 0, 1
• Estimation de l'espérance de vie> 3 mois
• Maladie qui ne convient pas à la résection avec intention curative, validée par un comité multidisciplinaire avec au moins un chirurgien hépatique senior
• Au moins une lésion mesurable selon les critères RECIST 1.1
• Plaquettes ≥100 000 / mm3, neutrophiles polynucléaires ≥1000 / mm3, hémoglobine  9g / dL (même les patients transfusés peuvent être inclus)
• Créatininémie <1,5N
• Bilirubinémie ≤2 N (après drainage biliaire si nécessaire)
• ASAT et ALAT ≤ 5N
• L'IRM hépatique de référence (selon le protocole prévu) effectuée au cours des 30 jours précédant le 1er cycle de traitement
• Consentement écrit en connaissance de cause
• Couverture de l'assurance maladie nationale

E.4

Principal exclusion criteria

Patients eligible for this study must not meet any of the following criteria:
• Patients with cholangiocarcinoma of the gallbladder or common bile duct or those with hepatocholangiocarcinoma or a Klatskin tumor
• Patients who are eligible for surgical resection or liver transplantation
• Extra-hepatic metastases [Pulmonary micronodules <7mm without uptake on PET are not a contra-indication]
• Presence of clinical ascites
• History of intra-arterial therapy or more than one line of systemic treatment
• Contra-indication or grade 3-4 allergy to any of the treatment drugs
• Grade  2 peripheral neuropathy
• Ongoing participation or participation within the 21 days prior to inclusion in the study in another therapeutic trial with an experimental drug
• Concomitant systemic treatment with immunotherapy, chemotherapy or hormone therapy
• Serious non-stabilized disease, active uncontrolled infection or other serious underlying disorder likely to prevent the patient from receiving the treatment
• Pregnancy, breast-feeding or the absence of effective contraception for women of child-bearing age
• Another cancer in the 5 years preceding or at the time of inclusion in the trial (except for in situ cervical cancer or basal cell carcinoma of the skin)
• Allergy to iodine contrast agents
• Treatment with anticoagulants (heparin or AVK) that cannot be interrupted for 12 hours
• Treatment with anti-platelets that cannot be interrupted for 5 days for aspirin or Plavix.
• Contra-indication for use of an intra-arterial approach (severe arteriopathy)
• Legal incapacity (persons in custody or under guardianship)
• Impossibility to sign the informed consent document or to adhere to the medical follow-up of the trial for geographical, social or psychological reasons

Les patients admissibles pour cette étude ne doivent satisfaire à aucun des critères suivants:
• Patients atteints de cholangiocarcinome de la vésicule biliaire ou de la voie biliaire ou ceux atteints d'hépatocholangiocarcinome ou d'une tumeur Klatskin
• Patients admissibles à une résection chirurgicale ou à une transplantation hépatique
• Les métastases extra-hépatiques [Les micronodules pulmonaires <7 mm sans absorption sur le PET ne sont pas une contraindication]
• Présence d'ascite clinique
• Histoire de la thérapie intra-artérielle ou plus d'une ligne de traitement systémique
• Contra-indication ou allergie de grade 3-4 à l'un des médicaments de traitement
• Neuropathie périphérique de grade  2
• Participation ou participation continue dans les 21 jours précédant l'inclusion dans l'étude dans un autre essai thérapeutique avec un médicament expérimental
• Traitement systémique concomitant avec immunothérapie, chimiothérapie ou hormone thérapeutique
• Maladie grave non stabilisée, infection non contrôlée active ou autre trouble sous-jacent grave susceptible d'empêcher le patient de recevoir le traitement
• Grossesse, allaitement maternel ou absence de contraception efficace pour les femmes en âge de procréer
• Un autre cancer dans les 5 années précédant ou au moment de l'inclusion dans l'essai (à l'exception du cancer du col de l'utérus ou du carcinome basocellulaire de la peau)
• Allergie aux agents de contraste d'iode
• Traitement avec des anticoagulants (héparine ou AVK) qui ne peut être interrompu pendant 12 heures
• Traitement avec anti-plaquettes qui ne peuvent pas être interrompus pendant 5 jours pour l'aspirine ou Plavix.
• Contra-indication pour l'utilisation d'une approche intra-artérielle (artériopathie sévère)
• Invalidité légale (personnes en détention ou sous tutelle)
• Impossibilité de signer le document de consentement éclairé ou d'adhérer au suivi médical du procès pour des raisons géographiques, sociales ou psychologiques

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is the percentage of patients with an objective response (defined as partial or complete response) 4 months after inclusion (using RECIST v1.1 criteria)

Le critère d'évaluation principal est le pourcentage de patients ayant une réponse objective (définie comme réponse partielle ou complète) 4 mois après l'inclusion (en utilisant les critères RECIST v1.1)

E.5.1.1

Timepoint(s) of evaluation of this end point

4 months after inclusion

E.5.2

Secondary end point(s)

Secondary endpoints will be:
• Safety (NCI-CTCAE version 4.0)
• Quality of life (QLQ-C30 questionnaire). The time to a final deterioration in the global health score (decrease of 5 points or more with no further improvement before death). The delay will be calculated from date of the first cycle to QoL evaluation or date of death or date of last news if the patient has no deterioration
• Secondary resectability rate (as evaluated by an experienced hepatic surgeon)
• Overall survival (estimated by the time between the date of inclusion and the date of death or date of last news for alive patients)
• Progression-free survival by CT-scan/MRI according to the investigator's opinion (defined as the time between the date of inclusion and the date of first progression or death [whichever occurs first] or date of last news for patients alive without any progression)

Les critères secondaires seront:
• Tolérance (NCI-CTCAE version 4.0)
• Qualité de vie (questionnaire QLQ-C30). Le temps d'une détérioration finale du score de santé mondial (diminution de 5 points ou plus sans amélioration avant la mort). Le délai sera calculé à partir de la date du premier cycle jusqu'à l'évaluation de la qualité de vie ou la date du décès ou la date des dernières nouvelles si le patient n'a aucune détérioration
• Taux de réséchebilité secondaire (évalué par un chirurgien hépatique expérimenté)
• La survie globale (estimée par le moment entre la date d'inclusion et la date de décès ou la date des dernières nouvelles pour les patients vivants)
• La survie sans progression par tomodensitométrie / IRM selon l'opinion de l'enquêteur (définie comme le temps entre la date d'inclusion et la date de la première progression ou la mort [la première éventualité] ou la date des dernières nouvelles pour les patients vivants sans progression )

E.5.2.1

Timepoint(s) of evaluation of this end point

4 months after inclusion

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

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)

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

E.8.1.1

Randomised

E.8.1.2

Open

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

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

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

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

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
G.4 Investigator Network to be involved in the Trial: 1

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2017-10-10

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-11-24

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

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