Clinical Trials Register

Summary
EudraCT Number:	2012-000522-22
Sponsor's Protocol Code Number:	ISO-CC-002
National Competent Authority:	Sweden - MPA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-02-08
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

Sweden - MPA

A.2

EudraCT number

2012-000522-22

A.3

Full title of the trial

A Single-blind, Randomized Phase I/II study of Pharmacokinetic and Pharmacodynamic investigation of Modufolin® (60 or 200 mg/m2) compared to Levoleucovorin (60 or 200 mg/m2) in tumour, adjacent mucosa and plasma for patients with colon cancer.

Farmakokinetisk och farmakodynamisk undersökning av Modufolin® och Levoleucovorin i tumör, närliggande tarmslemhinna och plasma hos patienter med cancer i tjocktarm.

A.3.1

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

Study of the absorption and elimination of Modufolin® and Levoleucovorin on tumor, adjacent mucosa and plasma in patients with colon cancer.

Undersökning av hur Modufolin® och Levoleucovorins omsätts i tumör, närliggande tarmslemhinna och plasma hos patienter med cancer i tjocktarmen.

A.3.2

Name or abbreviated title of the trial where available

PK/PD study of Modufolin® in plasma, tumour and adjacent mucosa in patients with colon cance

N/A

A.4.1

Sponsor's protocol code number

ISO-CC-002

A.5.4

Other Identifiers

Name:

N/A

Number:

N/A

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	Isofol Medical AB
B.1.3.4	Country	Sweden
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Isofol Medical AB
B.4.2	Country	Sweden
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Sahlgrenska University Hospital
B.5.2	Functional name of contact point	Principal Investigator
B.5.3	Address:
B.5.3.1	Street Address	Sahlgrenska University Hospital/Östra
B.5.3.2	Town/ city	Göteborg
B.5.3.3	Post code	SE-416 85
B.5.3.4	Country	Sweden
B.5.4	Telephone number	+46(0)313434219
B.5.5	Fax number	+46(0)313436169
B.5.6	E-mail	kristoffer.derwinger@vgregion.se

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	No
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	Modufolin®
D.3.2	Product code	N/A
D.3.4	Pharmaceutical form	Lyophilisate for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous bolus use (Noncurrent)
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Modufolin API
D.3.9.2	Current sponsor code	Modufolin API
D.3.9.3	Other descriptive name	(6R)-5,10-methylene-tetrahydrofolic acid
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	10
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	Isovorin
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer AB
D.2.1.2	Country which granted the Marketing Authorisation	Sweden
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	Isovorin
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	Intravenous bolus use (Noncurrent)
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	CALCIUM LEVOFOLINATE
D.3.9.1	CAS number	80433-71-2
D.3.9.2	Current sponsor code	Levoleucovorin
D.3.9.4	EV Substance Code	SUB06054MIG
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	10
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

Colon cancer

E.1.1.1

Medical condition in easily understood language

Colon 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	16.0
E.1.2	Level	PT
E.1.2	Classification code	10009944
E.1.2	Term	Colon 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 compare [6R] 5,10-methylene-THF, 5-formyl-THF, 5-methyl-THF and THF concentration in the tumor tissue and adjacent mucosa for the different treatment groups

E.2.2

Secondary objectives of the trial

• To explore if there is a difference in other pharmacokinetic parameters of [6R] 5,10-methylene-THF, 5-formyl-THF, 5-methyl-THF and THF calculated from plasma concentration.
• To study safety in terms of adverse events and laboratory measurements; haematology, clinical chemistry and urinalysis.
• To study gene expression in tumor and mucosa and its correlation to tissue concentration.
• To study homocystein and serum folate levels.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Patients must have operable colon cancer that is amenable to curative surgery.

2. Performance status of 0 to 1 on the Eastern Cooperative Oncology Group (ECOG). Performance Status scale. (See Protocol Attachment 2.)

3. Patients without contra indications for undergoing surgery.

4. For women: Must be surgically sterile, postmenopausal, or compliant with a contraceptive regimen during and for 3 months after treatment; must have a negative serum or urine pregnancy test (within 7 days before enrolment) and must not be lactating.

5. For men: Must be surgically sterile or compliant with a contraceptive regimen during and for 3 months after treatment.

6. Patients must sign an informed consent document.

7. Patient legally competent and able to communicate effectively with the study personnel as judged by the investigator.

8. Patient likely to co-operate during the study.

9. Patients must be at least 18 years of age.

E.4

Principal exclusion criteria

1. Concurrent administration of any other anti-tumor therapy.

2. Treatment within the last 30 days with a drug/device that has not received regulatory approval for any indication at the time of study entry.

3. Any intake of medication which could influence homocysteine, folate, and vitamin B12 status, within 30 days of surgery

4. Serious concomitant systemic disorders (e.g., active infection including HIV, cardiac disease) that in the opinion of the investigator would compromise the patient's ability to complete the study.

5. Are pregnant or breast-feeding.

6. Second primary malignancy that is clinically detectable at the time of consideration for study enrollment.

7. History of significant neurological or mental disorder, including seizures or dementia.

8. Presence of clinically relevant (i.e., detectable by physical examination) third-space fluid collection (e.g., ascites, pleural effusion) that cannot be controlled by drainage or other procedures prior to study entry.

9. Inability or unwillingness to be given Modufolin® or Levoleucovorin (Isovorin®).

E.5 End points

E.5.1

Primary end point(s)

An exploratory evaluation of the tumor and mucosa concentrations of [6R] 5,10-methylene-THF, 5-formyl-THF, 5-methyl-THF and THF will be done respectively for comparisons between treatments.

E.5.1.1

Timepoint(s) of evaluation of this end point

At the time of biopsy

E.5.2

Secondary end point(s)

An exploratory evaluation of the pharmacokinetic parameters of [6R] 5,10-methylene-THF, 5-formyl-THF, 5-methyl-THF and THF will be done respectively for comparisons between treatments.

Correlation between AUC(0-2h) calculated from plasma concentration and tissue concentration in the tumor and adjacent mucosa will be explored.

Change over time in homocystein and serum folate levels will be explored.

Gene expression in tumor and mucosa and correlation to tissue concentration will be explored.

Assessment of safety will be based mainly on the frequency of adverse events and on the number of laboratory values that fall outside of pre-determined ranges. Other safety data (e.g. electrocardiogram, vital signs) will be considered as appropriate.

E.5.2.1

Timepoint(s) of evaluation of this end point

PK: t = 0, 5 min, 10 min, 20 min, 40 min, 60 min, 90 min, 120 min, 180 min, 240 min, 360 min, and 24 h

Homocystein and serum folate: t = screening, t = 24 h and t = 5 days (end of study visit)

Correlation between plasma and tissue concentration: 0 - 2 h

Biopsies for studying gene expression in tumor and mucosa will be collected during surgery.

Safety assessments will start at t = 0 and continue througout the study (incl. 5 days post surgery).

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

E.6.4

Safety

Yes

E.6.5

Efficacy

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

Yes

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

PK/PD

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

Yes

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

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)

Yes

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

Yes

E.8.4

The trial involves multiple sites in the 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 visit of the last subject

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)

All subjects will recieve treatment according to routine care of the specific condition.

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

2012-04-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-05-30

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2013-08-29

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