Clinical Trials Register

Summary
EudraCT Number:	2013-003976-11
Sponsor's Protocol Code Number:	HSG-1-13
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2014-06-06
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

Denmark - DHMA

A.2

EudraCT number

2013-003976-11

A.3

Full title of the trial

Effects of S-1 and capecitabine in combination with oxaliplatin on the coronary artery blood flow in patients metastatic gastrointestinal tract adenocarcinoma

A.3.1

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

Effect of two cancer drugs (S-1 and capecitabine) on the blood circulation of the heart.

A.3.2

Name or abbreviated title of the trial where available

Fluo Heart

A.4.1

Sponsor's protocol code number

HSG-1-13

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	Helsinki University Central Hospital
B.1.3.4	Country
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	Nordic Drugs Ab
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Helsinki University Central Hospital
B.5.2	Functional name of contact point	Department of Oncology
B.5.3	Address:
B.5.3.1	Street Address	Haartmaninkatu 4
B.5.3.2	Town/ city	Helsinki
B.5.3.3	Post code	FIN-00290
B.5.4	Telephone number	358947173200
B.5.5	Fax number	358947174202
B.5.6	E-mail	heikki.joensuu@hus.fi

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	Teysuno is a medicine that contains the active substances tegafur, gimeracil and oteracil.
D.2.1.1.2	Name of the Marketing Authorisation holder	Nordic Group B.V.
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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	S1
D.3.4	Pharmaceutical form	Capsule, hard
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	TEGAFUR
D.3.9.1	CAS number	17902-23-7
D.3.9.4	EV Substance Code	SUB10870MIG
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	50
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	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	Xeloda (Capecitabine) is a "prodrug" that is converted to 5-fluorouracil (5-FU) in the body, but more is converted in tumor cells than in normal tissues
D.2.1.1.2	Name of the Marketing Authorisation holder	Accord Healthcare Limited
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Xeloda
D.3.9.3	Other descriptive name	CAPECITABINE
D.3.9.4	EV Substance Code	SUB12474MIG
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	2000
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)	Yes
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	Oxaliplatin
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	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/m2 milligram(s)/square meter
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	130
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 gastrointestinal tract adenocarcinoma

E.1.1.1

Medical condition in easily understood language

Malignant tumor disease arising from gastrointestinal tract (e.g. stomach, intestine) belonging to the adenocarcinoma group of tumors

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	10063916
E.1.2	Term	Metastatic gastric cancer
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 frequency of subclinical coronary artery dysfunction, as assessed with the CFR, as compared with the baseline CFR

E.2.2

Secondary objectives of the trial

•The CFR between the chemotherapy groups.
•The coronary flow response to the CPT as compared to the baseline values and between the chemotherapy groups.
•The presence of left ventricle regional wall motion abnormalities or global systolic dysfunction
•Cardiac arrhythmias in Holter registration between the 2 groups and as compared to the baseline.
•Plasma sensitive troponin concentration between the 2 groups and as compared to the baseline.
•Frequency and severity of cardiac symptoms and chest pain during treatment.
•Adverse events (Common Terminology Criteria for Adverse Events [CTCAE] version 4.0) between the 2 treatment groups.
•Response rate of cancer to chemotherapy between the 2 treatment groups (RECIST v. 1.1).
•Patient preference of chemotherapy (assessed at the completion of chemotherapy when ≥ 3 cycles were given)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Has given written informed consent.
2.Is >18 years of age.
3.Has advanced or metastatic gastrointestinal tract adenocarcinoma.
4.No previous cancer chemotherapy for cancer.
5.Measurable or evaluable lesions according to RECIST v1.1 criteria.
6.Is able to take medications orally.
7.Has ECOG performance status 0 or 1 on Cycle 1, Day 1 (see Appendix A).
8.Has a life expectancy of at least 3 months.
9.Serum troponin T or I and creatine phosphokinase (CPK)-MB values < upper limit of normal (ULN) for the institution.
10.Has adequate organ function as defined by the following criteria:
a.Aspartate aminotransferase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) ≤2 x ULN; if liver function abnormalities are due to underlying liver metastasis, AST (SGOT) and ALT (SGPT) ≤6 x ULN.
b.Total serum bilirubin of ≤1.5 x ULN.
c.Absolute neutrophil count of ≥1,500/mm3 (i.e., ≥1.5 x 109/L by International Units [IU])
d.Platelet count ≥100,000/mm3 (IU: ≥100 x 109/L) (excluding measurements obtained within 7 days after transfusion).
e.Hemoglobin value of ≥11.0 g/dL.
f.Creatinine < 1.5 x ULN. I creatinine clearance is measured, this should be ≥60 mL/min based on calculated creatinine clearance (Cockcroft-Gault13 formula, see Appendix D) or 24-hour urine collection.
g.Is willing and able to comply with scheduled visits, treatment plan, lab tests and other study procedures

E.4

Principal exclusion criteria

1.Has had treatment with any of the following within the specified time frame prior to study drug administration:
a.Cancer considered operable without prior chemotherapy.
b.Prior chemotherapy to cancer.
c.Previous therapy with fluoropyrimidines or anthracyclines for any indication.
d.Inability to swallow tablets.
e.Patients with known DPD deficiency.
f.Any investigational agent received either concurrently or within the last4 weeks.
g.Current enrollment in another interventional clinical study.
2.Has a serious illness or medical condition(s) including, but not limited to, the following:
a.Known brain metastasis or leptomeningeal metastasis.
b.Patient with a history of myocardial infarction within the last 6 months, or with a history of coronary surgery or stenting, severe/unstable angina, coronary/peripheral artery bypass graft, cerebrovascular accident or transient ischemic attack, pulmonary embolism, or deep vein thrombosis within the last 12 months.
c.Symptomatic congestive heart failure (New York Heart Association [NYHA] class III or IV (see Appendix E).
d.Ongoing cardiac dysrhythmias (≥Grade 2), atrial fibrillation (any grade), or prolongation of QTc interval (>450 msec for males; >470 msec for females).
e.Patients with any cardiac disease that requires regular medication (medication for vascular diseases such as hypertension is allowed).
f.Hypertensive crisis or severe hypertension that is not controlled.
g.Known acute systemic infection.
h.Chronic nausea, vomiting, or diarrhea considered to be clinically significant in the opinion of the Investigator.
i.≥Grade 1 peripheral neuropathy.
j.Recent hemoptysis, coagulopathy and other bleeding disorders considered by the Investigator to be clinically significant.
k.Known nephrotic syndrome (proteinuria >2 g/24 hours).
l.Known clinically significant interstitial lung disease or pulmonary fibrosis.
m.Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness.
n.Organ allografts with immunosuppressive therapy required.
o.Major surgery within 3 weeks prior to study treatment start, or lack of complete recovery from the effects of surgery.
p.Clinically significant malabsorption syndrome
q.Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the Investigator would make the patient inappropriate for entry into this study.
3.Is receiving concomitant treatment with short-acting nitroglycerins, or one or more of the following drugs that may interact with S-1or capecitabine:
a.Sorivudine, brivudine, uracil, eniluracil, cimetidine, folinate/folinic acid, and dipyridamole (may enhance S-1or capecitabine activity).
b.Nitroimidazoles, including metronidazole and misonidazole (may enhance S-1 activity)
c.Clozapine (may increase risk and severity of hematologic toxicity)
d.Allopurinol (may diminish S-1 activity).
e.Phenytoin (S-1 may enhance phenytoin activity).
f.Flucytosine, a fluorinated pyrimidine antifungal agent (may enhance S-1 activity).
4.Is a pregnant or lactating female.
5.Female patients of childbearing potential must have negative pregnancy test before initiation of study drug dosing. Postmenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential. Male and female patients of reproductive potential must agree to employ an effective barrier method of birth control throughout the study and for up to 3 months following discontinuation of study drug.
6.The cardiac arterial flow tests cannot be done

E.5 End points

E.5.1

Primary end point(s)

The frequency of subclinical coronary artery dysfunction, as assessed with the CFR, as compared with the baseline CFR

E.5.1.1

Timepoint(s) of evaluation of this end point

Each chemotherapy cycle

E.5.2

Secondary end point(s)

E.5.2.1

Timepoint(s) of evaluation of this end point

Each chemotherapy cycle

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

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

Yes

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

Yes

E.8.2.3.1

Comparator description

capecitabine, oxaliplatin

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

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.1.1.1

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.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

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)

Therapy by the physician's choice

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

2014-09-24

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-09-08

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2017-04-25

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