Clinical Trials Register

Summary
EudraCT Number:	2007-005796-34
Sponsor's Protocol Code Number:	CC-GEMSO-2007
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2008-01-07
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

Germany - BfArM

A.2

EudraCT number

2007-005796-34

A.3

Full title of the trial

A randomized, double-blind, multicenter phase II trial with gemcitabine plus sorafenib versus gemcitabine plus placebo in patients with chemo-naive advanced or metastatic adenocarcinoma of the biliary tract

A.3.1

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

Multicenter clinical trial for patients with chemo-naive advanced or metastatic adenocarcinoma of the biliary tract

A.3.2

Name or abbreviated title of the trial where available

CC-GEMSO-2007

A.4.1

Sponsor's protocol code number

CC-GEMSO-2007

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	Universität Mainz, I. Medizinische Klinik und Poliklinik
B.1.3.4	Country	Germany
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	Universität Mainz, I. Medizinische Klinik und Poliklinik
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Universität Mainz, I. Medizinische Klinik und Poliklinik
B.5.2	Functional name of contact point	Peter R. Galle
B.5.3	Address:
B.5.3.1	Street Address	Langenbeckstr. 1
B.5.3.2	Town/ city	Mainz
B.5.3.3	Post code	D-55131
B.5.3.4	Country	Germany
B.5.4	Telephone number	+49613117-7275
B.5.5	Fax number	+49613117-5595

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	Nexavar 200mg Filmtabletten
D.2.1.1.2	Name of the Marketing Authorisation holder	Bayer HealthCare AG, D-51368 Leverkusen, Deutschland
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	Film-coated 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	sorafenib
D.3.9.1	CAS number	475207-59-1
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	200
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	Gemzar 1g Pulver zur Herstellung einer Infusionslösung
D.2.1.1.2	Name of the Marketing Authorisation holder	Lilly Deutschland GmbH, Teichweg 3, D-35396 Gießen, Deutschland
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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.3.10	Strength
D.3.10.1	Concentration unit	g gram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1
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	Gemzar 200 mg Pulver zur Herstellung einer Infusionslösung
D.2.1.1.2	Name of the Marketing Authorisation holder	Lilly Deutschland GmbH, Teichweg 3, D-35396 Gießen, Deutschland
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	200
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Patients with Adenocarcinoma of the gallbladder or intrahepatic bile ducts or histologically proven hepatic metastases of an earlier resected and histologically proven biliary tract cancer

E.1.1.1

Medical condition in easily understood language

Patients with Adenocarcinoma of the gallbladder or intrahepatic bile ducts or histologically proven hepatic metastases of an earlier resected and histologically proven biliary tract 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	13.1
E.1.2	Level	LLT
E.1.2	Classification code	10008593
E.1.2	Term	Cholangiocarcinoma
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

The primary objective is to evaluate the antitumor activity of a combination therapy consisting of gemcitabine plus sorafenib compared to gemcitabine plus placebo as first line therapy of advanced biliary tract cancer in terms of progression free survival

E.2.2

Secondary objectives of the trial

The secondary objectives are:

Safety and toxicity of a combination therapy of gemcitabine and sorafenib.

Efficacy of gemcitabine in combination with sorafenib on overall survival (OS)

Efficacy of gemcitabine in combination with sorafenib on tumor response

Efficacy of gemcitabine in combination with sorafenib on tumor control

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Male and female patients aged 18 years and older
- Signed and dated informed consent before the start of specific protocol procedures
- Adenocarcinoma of the gallbladder or intrahepatic bile ducts or histologically proven hepatic metastases of an earlier resected and histologically proven biliary tract cancer
o Not amenable to curative surgical resection
o With at least one unidimensionally measurable target lesion in non-irradiated (or treated by photodynamic therapy, PDT) area (largest diameter >/= 1 cm (spiral CT scan or MRI) or >/= 2 cm (conventional CT scan),
o With pain and biliary obstruction controlled
o Cytologically or histologically confirmed

Note : in case of uncertain biliary tract origin (e.g., intrahepatic CCs), inclusion is possible if

iv) extensive search for primary (thoracic and abdomino pelvic CT scan, colonoscopy, upper digestive endoscopy, serum PSA level for men or mammography for women, and FDG-PET if possible) is negative
v) histological examination is consistent with bile duct adenocarcinoma, with IHC positive for cytokeratin 7 and 19 and negative for cytokeratin 20 [Shimonishi, 2000].
vi) No histologically evidence of hepatocellular carcinoma (HCC)
- No prior palliative (radio)-chemotherapy (gemcitabine or fluoropyrimidine-based chemotherapy)
Note:
iii) previous adjuvant chemotherapy is allowed (completed since ≥ 6 months if containing gemcitabine or platinum salts);
iv) previous irradiation (external radiotherapy, brachytherapy, chemoembolization) and PDT are allowed provided that there is at least one unidimensionally measurable target lesion in untreated area
- Resolution of all side effects of prior surgical procedures to grade ≤ 1 (except for the laboratory values specified below)
- At least 4 weeks from any major surgery (at first dose of study drug)
- ECOG Performance Status of 0-2
- Life expectancy of at least 12 weeks
- Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements to be conducted within 7 days prior to screening:
- Hemoglobin > 9.0 g/dl
- Absolute neutrophil count (ANC) >1,500/mm3
- Platelet count ≥ 100,000/μl
- Total bilirubin < 3 times the upper limit of normal
- ALT and AST < 5 x upper limit of normal
- prothrombin rate > 60% or INR < 1.5
Note:
iii) intravenous vitamin K1 should be administered to patients with current or recent history of jaundice or bile duct obstruction and abnormal prothrombin rate or INR prior to assess prothrombin rate or INR
iv) Patients who are being therapeutically anticoagulated with an agent such as coumadin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in these parameters exists

- Alkaline phosphatase < 4 x ULN
- Lipase/Amylase < 2.5 x upper limit of normal
- Serum creatinine < 1.5 x upper limit of normal; creatinin clearance at least 45 ml/min
- Patients must be able to swallow sorafenib capsules
- Patients who understand the nature of the trial and are willing and able to comply with scheduled visits, treatment plans, laboratory tests and other study procedures
- Female patients who are capable of bearing children must have a negative pregnancy test result (serum or urine) at study entry. All women included in the study must be surgically sterile or postmenopausal or agree to employ adequate birth control measures for the duration of the study and two months post-dosing. Male patients must be surgically sterile or must agree to use effective contraception during the study and six months post-dosing.

E.4

Principal exclusion criteria

- Surgery (except diagnostic biopsy), external radiotherapy, brachytherapy, or PDT within 30 days prior to start of treatment
- Other tumor type than adenocarcinoma (e.g. leiomyosarcoma, lymphoma) or a second cancer except in patients with squamous or basal cell carcinoma of the skin or carcinoma in situ of the cervix which has been effectively treated. Patients curatively treated and disease free for at least 5 years will be discussed with the sponsor before inclusion
- History of cardiac disease: congestive heart failure >NYHA class 2; active CAD (MI more than 6 months prior to study entry is allowed); cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted) or uncontrolled hypertension
- Any of the following within the 12 months prior to starting the study treatment:, coronary/peripheral artery bypass graft, cerebrovascular accident or transient ischemic attack, or pulmonary embolism
- Ongoing cardiac dysrhythmias of grade >/=2, atrial fibrillation of any grade, or QTc interval >450 msec for males or >470 msec for females
- Hypertension that cannot be controlled by medications (>150/100 mmHg despite optimal medical therapy)
- History of HIV infection
- Active clinically serious infections (> grade 2 NCI-CTC version 3.0)
- Known Central Nervous System tumors including metastatic brain disease
- Patients with seizure disorder requiring medication (such as steroids or anti-epileptics)
- History of organ allograft
- Patients with evidence or history of bleeding diasthesis
- Active disseminated intravascular coagulation, or patients prone to thromboembolism
- Patients undergoing renal dialysis
- Pregnant or breast-feeding patients
- Substance abuse, medical, psychological or social conditions that may interfere with the patient’s participation in the study or evaluation of the study results
- Any condition that is unstable or could jeopardize the safety of the patient and their compliance in the study
- Known or suspected allergy to the investigational agent or any agent given in association with this trial

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is defined as progression-free survival (PFS)

E.5.1.1

Timepoint(s) of evaluation of this end point

when progression occurs

E.5.2

Secondary end point(s)

Overall survival (OS)
Best overall response according to RECIST
Time to objective response according to RECIST
Duration of overall response according to RECIST
Duration of stable disease according to RECIST
QLQ-C30 quality of life questionnaire

E.5.2.1

Timepoint(s) of evaluation of this end point

when progression occurs

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

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

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

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

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

see protocol

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

Number of subjects for this age range:

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)

not applicable

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

2008-02-01

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2008-03-19

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2011-07-20

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