Clinical Trials Register

Summary
EudraCT Number:	2018-001210-15
Sponsor's Protocol Code Number:	MOU-2017-02
National Competent Authority:	Czechia - SUKL
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2018-11-19
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

Czechia - SUKL

A.2

EudraCT number

2018-001210-15

A.3

Full title of the trial

Rational Anti-EGFR therapy Selection for the first-line treatment of patients with metastatic KRAS/NRAS wild type colorectal cancer based on the use of molecular predictor miR-31-5p (RASmiR)

Racionální výběr Anti-EGFR terapie v první linii léčby pacientů s metastazujícím kolorektálním karcinomem wild-type KRAS / NRAS na základě použití molekulárního prediktoru miR-31-5p

A.3.1

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

Rational Anti-EGFR therapy Selection for the first-line treatment of patients with metastatic KRAS/NRAS wild type colorectal cancer based on the use of molecular predictor miR-31-5p (RASmiR)

Racionální výběr Anti-EGFR terapie v první linii léčby pacientů s metastazujícím kolorektálním karcinomem wild-type KRAS / NRAS na základě použití molekulárního prediktoru miR-31-5p

A.3.2

Name or abbreviated title of the trial where available

RASmiR

A.4.1

Sponsor's protocol code number

MOU-2017-02

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	Masarykův onkologický ústav
B.1.3.4	Country	Czech Republic
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	Ministry of Health
B.4.2	Country	Czech Republic
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Masaryk Memorial Cancer Institute
B.5.2	Functional name of contact point	Clinical trials unit
B.5.3	Address:
B.5.3.1	Street Address	Zluty kopec 7
B.5.3.2	Town/ city	Brno
B.5.3.3	Post code	65653
B.5.3.4	Country	Czech Republic
B.5.4	Telephone number	+420543136232
B.5.6	E-mail	studie@mou.cz

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	Avastin 25 mg/ml concentrate for solution for infusion
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Czech Republic
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 infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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)	Yes
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	Vectibix 20 mg/mL concentrate for solution for infusion
D.2.1.1.2	Name of the Marketing Authorisation holder	Amgen Eur ope B.V
D.2.1.2	Country which granted the Marketing Authorisation	Czech Republic
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 infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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)	Yes
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	Erbitux 5 mg/mL solution for infusion
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck KGaA
D.2.1.2	Country which granted the Marketing Authorisation	Czech Republic
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 infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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)	Yes
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

inoperable, untreated, wild type RAS (wt KRAS/wtNRAS), metastatic colorectal cancer (mCRC)

inoperabilní, neléčený, RAS nemutovaný (wt KRAS/ wtNRAS), metastatický kolorektální karcinom (mCRC)

E.1.1.1

Medical condition in easily understood language

inoperable, untreated, wild type RAS (wt KRAS/wtNRAS), metastatic colorectal cancer (mCRC)

inoperabilní, neléčený, RAS nemutovaný (wt KRAS/ wtNRAS), metastatický kolorektální karcinom (mCRC)

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

• Progression-Free Survival (PFS) in patients with low verus high miR-31-5p expression: Compare the predictive value of miR-31-5p expression as measured progression free survival. PFS is defined as the time from the date of randomization to the date of the first objectively documented tumor progression as assessed according to RECIST 1.1 or death due to any cause. Subjects who die without a reported prior progression will be considered to have progressed on the date of their death. Subjects who did not progress or die will be censored on the date of their last tumor assessment. Subjects who started any subsequent anti-cancer therapy without a prior reported progression will be censored.

Primárním cílem studie je zhodnocení PFS (doba přežití bez návratu onemocnění) u pacientů s nízkou nebo vysokou expresí miR-31-5p. Porovnání prediktivní hodnoty miR-31-5p exprese.

E.2.2

Secondary objectives of the trial

• Progression-Free Survival (PFS) in all groups
• Overall Survival (OS) in all goups
• Overall Response Rate (ORR) in all groups

1) Zhodnocení PFS (doba přežití bez návratu onemocnění) u všech skupin pacientů.
2) Zhodnocení OS (celkového přežití) pacientů u všech skupin.
3) Zhodnocení ORR (objektivní odpovědi nádoru) u všech skupin
pacientů dle RECIST 1.1.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. The subject, prior to any study-related procedures, has provided Independent Ethics Committee approved written Informed Consent as per national regulations
2. The subject is male or female, aged 18 years or older.
3. The subject has histologically confirmed wild type KRAS and NRAS (at least in codons: 12, 13, 59, 61, 117, 146 / both genes) mCRC.
4. The subject has metastatic lesion measurable by RECIST 1.1.
5. The subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and life expectancy > 3 months.
6. If subject is female of childbearing potential, subject has documentation of negative pregnancy test prior to enrollment.
7. Subject (men and women) of childbearing potential must agree to use adequate contraception beginning at the signing of the ICF until at least 90 days after the last dose of systemic drugs.

1. Podepsaní informovaný souhlas studie před první studijní procedurou
2. Pacient straší 18 let
3. Histologicky potvrzený KRAS a NRAS nemutovaný (genetické vyšetření kodonů: 12,13, 59, 61, 117, 146) karcinom tlustého střeva nebo rekta
4. Metastatické a měřitelné onemocnění dle RECIST 1.1
5. ECOG 0-1 a předpokládaná doba přežití více jak 3 měsíce.
6. Ženy ve fertilním věku musí mít před randomizací negativní těhotenský test.
7. Pacient ve fertilním věku musí souhlasit s adekvátní antikoncepcí započatou s podpisem informovaného souhlasu a do doby 90 dní po poslední systémové medikaci.

E.4

Principal exclusion criteria

1. The subject must not receive prior systemic anticancer treatment in adjuvant administration for colorectal cancer in the previous 6 months.
2. Disorders of intestinal patency:
a) Acute or sub-acute ileus
b) Therapy-insensitive diarrhea of grade G3 and above, especially due to short bowel syndrome
3. Patients who at the time of diagnosis of mCRC are indicated for surgical treatment, because their primary tumor and/or metastases are radically resectable.
4. The subject has primary Central Nervous System (CNS) malignancies or CNS metastases; exception: subjects with brain metastasis treated with radiotherapy or surgery will be allowed if their ECOG status is 0-1.
5. The subject has any of the following hematologic abnormalities:
• ANC 1,5 x 109/L
• Platelet count < 100 x 109/L
6. The subject has any of the following serum chemistry abnormalities:
• Total bilirubin > 2.5 x ULN
• Serum albumin < 20 g/L
• Calculated creatinine clearance < 30mL/min/1.73m2
• Proteinuria > 2+; protein greater than 2+ must have 24 hour urine collection
7. Cardiovascular disease limiting the overall condition of the patient (PS 2 and above): symptomatic heart failure, uncontrolled hypertension G2 and more (systole> = 140-159 mmHg / diastole> = 90-99 mmHg, or signs of hypertensive crisis), uncontrolled / symptomatic cardiac arrhythmia.
8. Acute thromboembolic disease or untreated and/or clinically symptomatic thromboembolic disease occurring 6 months before screening for the study
9. Significant bleeding disease of severity> G2 6 months before the first medication in the study.
10. Female subject is pregnant or lactating.
11. The subject has peripheral neuropathy > Grade 2.
12. The subject is participating in another interventional protocol.

Vylučující kritéria:
1. Pacient nesmí obdržet předchozí systémovou protinádorovou léčbu v adjuvantním podání pro kolorektální karcinom v předchozích 6 měsících
2. Poruchy střevní průchodnosti:
a) Akutní nebo subakutní ileus
b) Terapeuticky neovlivnitelný průjem stupně G3 a vyšší, zejména z důvodu syndromu krátké střevní kličky
3. Pacienti, kteří mohou podstoupit radikální resekci všech metastáz v době screeningu do studie.
4. Přítomné metastázy mozku, s výjimkou ošetřených metastáz pomocí radioterapie nebo operace při současném splnění podmínky PS ECOG 0-1.
5. Laboratorní hematologické abnormality:
Absolutní neutrofily 1,5 x 109 /l
Trombocyty < 100 x 109 /l
6. Laboratorní biochemické abnormality:
Celkový bilirubin > 2,5 x ULN
Sérový albumin < 20g/l
Kreatinin clearance < 30ml/min/1.73m 2
Proteinurie > 2+ (více jak 2+ nutný 24 hodinový sběr moči)
7. Kardiovaskulární onemocnění omezující celkový stav pacienta (PS 2 a více): symptomatické srdeční selhávání, nekontrolovatelná hypertenze G2 a více (systola >=140 – 159 mmHg / diastola >= 90 - 99 mmHg, nebo známky hypertenzní krize), nekontrolovaná/symptomatická srdeční arytmie.
8. Akutní trombembolické onemocnění nebo nezaléčené a/nebo klinicky symptomatické trombembolické onemocnění vzniklé 6 měsíců před screeningem do studie.
9. Signifikantní krvácivé onemocnění závažnosti > G2 6 měsíců před podáním první medikace ve studii.
10. Kojící nebo těhotné ženy.
11. Periferní neuropatie > G2.
12. Pacient, který se účastní jiného klinického hodnocení.
13. Pacient s jiným aktivním nádorovým onemocnění než mCRC
Kritéria pro předčasné ukončení účasti:
1. Radiologická progrese onemocnění
2. Neakceptovatelná toxicita léčby
3. Těhotenství
4. Rozhodnutí lékaře v zájmu pacienta anebo v důsledku klinické progrese
5. Nutná závažná, původně nepředpokládaná, operační intervence
6. Závažné porušení protokolu
7. Odmítnutí léčby
8. Ztráta kontaktu s pacientem
9. Úmrtí

E.5 End points

E.5.1

Primary end point(s)

PFS A vs PFS B (PFS A > PFS B with ≥ 25 %)

E.5.1.1

Timepoint(s) of evaluation of this end point

with ending of follow-up period

na konci období follow-up

E.5.2

Secondary end point(s)

Median PFS in all groups
Median OS in all groups
Percentage of participants with an ORR in all groups

Medián PFS ve všech ramenech
Medián OS ve všech ramenech
Procento subjektů s ORR ve všech ramenech

E.5.2.1

Timepoint(s) of evaluation of this end point

with ending of follow-up period

na konci období follow-up

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

E.6.5

Efficacy

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

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

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.8.3

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

posledná návštěva posledního pacienta

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:

300

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

375

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)

Treatment or care after the subject has ended the participation in the
trial is not different from the expected normal treatment of the
condition

Léčba po ukočnení účasti subjektu KH v KH se neliší od běžné léčby
tohoto onemocnění

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	CZECRIN
G.4.3.4	Network Country	Czech Republic

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2018-11-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-10-10

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

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Orphan Designation Number:
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