Clinical Trials Register

Summary
EudraCT Number:	2011-003553-26
Sponsor's Protocol Code Number:	C-II-009
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:	2012-02-03
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

2011-003553-26

A.3

Full title of the trial

A single arm study in metastatic colorectal cancer patients treated with pharmacokinetically (PK) dose adjusted weekly or biweekly 5-fluorouracil (5-FU) regimes.

Eine einarmige Studie bei Patienten mit metastasiertem kolorektalem Karzinom (CRC) unter pharmakokinetisch (PK) angepasstem, ein- oder zweiwöchigem 5-Fluorouracil (5-FU) Behandlungsschema.

A.3.1

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

Eine klinische Studie in Patienten mit fortgeschrittenem Darmkrebs welche eine einwöchige- oder zweiwöchige Therapie mit individuell angepasster 5-Fluorouracil Dosierung erhalten.

A.3.2

Name or abbreviated title of the trial where available

C-5FU-TDM

A.4.1

Sponsor's protocol code number

C-II-009

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	CESAR Central European Society for Anticancer Drug Research-EWIV
B.1.3.4	Country	Austria
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	Saladax Biomedical
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	CESAR Central European Society for Anticancer Drug Research-EWIV
B.5.2	Functional name of contact point	Sponsor
B.5.3	Address:
B.5.3.1	Street Address	Hanglüssgasse 4/1-3
B.5.3.2	Town/ city	Vienna
B.5.3.3	Post code	1150
B.5.3.4	Country	Austria
B.5.4	Telephone number	00431522309312
B.5.5	Fax number	00431522309314
B.5.6	E-mail	berta.moritz@cesar.or.at

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	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.3.1	Product name	5-Fluorouracil
D.3.2	Product code	5-FU
D.3.4	Pharmaceutical form	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	FLUOROURACIL
D.3.9.1	CAS number	51-21-8
D.3.9.2	Current sponsor code	5-FU
D.3.9.3	Other descriptive name	5-Fluorouracil
D.3.9.4	EV Substance Code	SUB07721MIG
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

metastasiertes kolorektales Karzinom

E.1.1.1

Medical condition in easily understood language

Fortgeschrittener Darmkrebs

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	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10052362
E.1.2	Term	Metastatic colorectal 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

To determine whether pharmacokinetically-guided dose adjustment of 5-FU provides a stable intrapatient dose level of 20-30 mg.h /l. The primary analysis will be the comparison of the proportion of patients with AUC within 20 to 30 mg.h/L after the first 5-FU application versus the fourth application.

Das Primärziel der C-II-009 Studie ist, mittels Anwendung eines vordefinierten Dosierungsalgorithmus, die 5-FU Konzentration innerhalb der in der Literatur beschriebenen optimalen Area-under-the-curve (AUC) von 20-30 mg*h/l zu halten.

E.2.2

Secondary objectives of the trial

To determine whether pharmacokinetically-guided dose adjustment of 5-FU is able to reduce treatment-related toxicities.

Das sekundäre Ziel dieser Studie ist, die Häufigkeit von behandlungsbezogenen Toxizitäten zu reduzieren.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

(1) Capable of understanding the protocol requirements and risks, and providing written informed consent.
(2) Patients with histologically confirmed metastatic colorectal cancer.
(3) ECOG Performance Status (ECOG-PS) status ≤ 2.
(4) Female or male patients of 18 years of age or older
(5) Life expectancy > 3 months
(6) Women of child-bearing potential (i.e., women who are pre-menopausal or not surgically sterile) must use acceptable contraceptive methods (intrauterine device [IUD], oral contraceptive or double barrier method of contraception), and must have a negative serum pregnancy test within 1 week prior to beginning treatment on this trial. Nursing patients are excluded. Sexually active male patients must also use acceptable contraceptive methods (condom).
(7) An absolute neutrophil count >1.5/nl
(8) Platelet count > 100/nl.
(9) Total bilirubin ≤ 2 x upper limit of normal.
(10) AST and ALT ≤ 2.5 x upper limit of normal, or ≤ 5 x upper limit of normal in case of liver metastases.
(11) Serum creatinine ≤ 2x upper limit of normal
(12) Hemoglobin ≥ 9 g/dl (may be corrected by transfusion prior to 5-FU treatment with investigator approval).

(1) Der Patient muss in der Lage sein, etwaige Risiken sowie die Protokoll-Anforderungen zu verstehen und die Patienteninformation und Einwilligung zu unterschreiben.
(2) Patienten mit einem histologisch abgesicherten, metastasierenden kolorektalen Karzinom.
(3) Patienten, welche für eine palliative Erst- oder Zweitlinien Chemotherapie mit 5-FU in Frage kommen.
(4) ECOG Performance Status (ECOG-PS) Status ≤ 2.
(5) Weiblicher oder männliche Patienten, welcher zur Zeit der Randomisierung älter als 18 Jahre ist.
(6) Lebenserwartung von > 3 Monaten.
(7) Gebärfähige Frauen, (z.B. Prämenopausale Frauen oder nicht chirurgisch sterilisierte Frauen) müssen akzeptable kontrazeptive Methoden (Intrauterinpessar, Orale Kontrazeptiva, Doppelbarrieren Methoden) verwenden, sowie einen negativen Serum-Schwangerschaft Test, innerhalb einer Woche vor dem Beginn der Behandlung, machen. Stillende Patientinnen sind von der Studie ausgeschlossen. Sexuell aktive Männer müssen ebenfalls akzeptable Verhütungsmethoden verwenden (Kondom).
(8) Eine absolute Zahl der Neutrophilen von > 1,500 cells/ mm3 (= 1.5 G/l; = 1,5/nl)
(9) Zahl der Thrombozyten > 100/nl.
(10) Totales Bilirubin ≤ 2 x Obergrenze des Normalbereichs.
(11) AST und ALT ≤ 2.5 x Obergrenze des Normalbereichs, oder ≤ 5 x Obergrenze des Normalbereichs im Fall von Lebermetastasen.
(12) Serum Kreatinin ≤ 2x Obergrenze des Normalbereichs.
(13) Hämoglobin ≥ 9 g/dl (es ist erlaubt den Hämoglobin Wert mittels Transfusion vor der 5-FU Behandlung und nach Genehmigung durch den Prüfarzt zu korrigieren).

E.4

Principal exclusion criteria

(1) Symptomatic brain metastasis.
(2) Serious concomitant systemic disorders (e.g., active infection) that, in the opinion of the investigator, would compromise the safety of the patient or compromise the patient’s ability to complete the study.
(3) Unwilling or unable to follow protocol requirements or to give informed consent.
(4) Any treatment with cytotoxic or biologic agents within the 4weeks prior to beginning treatment on this study. At least 4 weeks must have elapsed from any prior surgery or radiation.
(5) Unresolved toxicity from prior chemotherapy (including approved and experimental drugs) greater than grade I.
(6) Known Dihydropyrimidine dehydrogenase (DPD) deficiency

(1) Symptomatische Gehirnmetastasen.
(2) Schwerwiegende systemische Begleiterkrankungen (z.B. aktive Infektionen), welche in den Augen des Prüfarztes die Sicherheit des Patienten, bzw. dessen Fähigkeit die Studie zu beenden, beeinflusst.
(3) Der Patient ist unfähig oder unwillens die Protokoll Anforderungen zu verstehen bzw. sein Einverständnis zur Teilnahme an dieser Studie zu geben.
(4) Behandlung mit zytotoxischen oder biologischen Substanzen innerhalb von 4 Wochen vor Behandlungsbeginn dieser Studie. Operationen bzw. Bestrahlungen müssen mindestens 4 Wochen in der Vergangenheit liegen.
(5) Fortbestehende ≥ Grad 1 Toxizitäten von vorherigen Chemotherapien (zugelassen oder experimentell).
(6) Bekannter Dihydropyrimidine Dehydrogenase (DPD) Mangel.

E.5 End points

E.5.1

Primary end point(s)

To determine whether pharmacokinetically-guided dose adjustment of 5-FU provides a stable intrapatient dose level of 20-30 mg.h /l.

E.5.1.1

Timepoint(s) of evaluation of this end point

The primary analysis will be the comparison of the proportion of patients with AUC within 20 to 30 mg.h/L after the first 5-FU application versus the fourth application.

E.5.2

Secondary end point(s)

To determine whether pharmacokinetically-guided dose adjustment of 5-FU is able to reduce treatment-related toxicities.

E.5.2.1

Timepoint(s) of evaluation of this end point

Treatment related toxicities will be assesst throughout 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

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

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)

E.7.4

Therapeutic use (Phase IV)

Yes

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

Last patient last visit.

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.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)

According to local practice.

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

2012-02-28

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-03-15

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2014-09-17

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