Clinical Trials Register

Summary
EudraCT Number:	2014-001126-15
Sponsor's Protocol Code Number:	CRICKET
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2014-05-16
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2014-001126-15

A.3

Full title of the trial

A phase II single-arm study of cetuximab plus irinotecan
as rechallenge 3rd-line treatment of kras, nras and braf wild-type irinotecan-pretreated metastatic colorectal cancer patients progressing after an initial response to a 1st-line cetuximab-containing therapy and a standard 2nd-line

studio di fase II, a singolo braccio, di terapia di III linea con rechallenge di cetuximab ed irinotecano in pazienti con carcinoma colorettale metastatico kras, nras e braf wild-type e irinotecano-pretrattati progrediti, dopo aver ottenuto un’ iniziale risposta, ad una terapia di prima linea contenente cetuximab

A.3.1

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

study to investigate cetuximab plus irinotecan
as rechallenge 3rd-line treatment of kras, nras and braf wild-type irinotecan-pretreated metastatic colorectal cancer patients progressing after an initial response to a 1st-line cetuximab-containing therapy and a standard 2nd-line.

studio per valutare un ritrattamento con cetuximab e irinotecano in pazienti con tumore del colon-retto metastatico KRAS, NRAS e BRAF wild-type, irinotecano resistenti, progrediti ad una prima linea a base di irinotecano (FOLFIRI o FOLFOXIRI) contenente cetuximab dalla quale abbiano ricevuto un iniziale beneficio

A.3.2

Name or abbreviated title of the trial where available

CRICKET

A.4.1

Sponsor's protocol code number

CRICKET

A.5.1

ISRCTN (International Standard Randomised Controlled Trial) Number

ISRCTN99999999

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT99999999

A.5.3

WHO Universal Trial Reference Number (UTRN)

U9999-9999-9999

A.5.4

Other Identifiers

Name:

Number:

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	G.O.N.O. (Gruppo Oncologico Nord Ovest)
B.1.3.4	Country	Italy
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	Merck Serono SpA
B.4.2	Country	Italy
B.4.1	Name of organisation providing support	G.O.N.O. (Gruppo Oncologico Nord Ovest)
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Azienda Ospedaliero-Universitaria Pisana
B.5.2	Functional name of contact point	U.O. Oncologia Medica Universit 2
B.5.3	Address:
B.5.3.1	Street Address	via Roma 67
B.5.3.2	Town/ city	Pisa
B.5.3.3	Post code	56126
B.5.3.4	Country	Italy
B.5.4	Telephone number	0039050992192
B.5.5	Fax number	0039050992069
B.5.6	E-mail	trials.office.pisa@gmail.com

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	Italy
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	Irinotecan
D.3.2	Product code	Irinotecan
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	IRINOTECAN
D.3.9.1	CAS number	97682-44-5
D.3.9.4	EV Substance Code	SUB08295MIG
D.3.10	Strength
D.3.10.1	Concentration unit	g/ml gram(s)/millilitre
D.3.10.2	Concentration type	not less then
D.3.10.3	Concentration number	20
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	Erbitux 5mg/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	Italy
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	Cetuximab
D.3.2	Product code	Cetuximab
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	CETUXIMAB
D.3.9.1	CAS number	205923-56-4
D.3.9.4	EV Substance Code	SUB01178MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	not less then
D.3.10.3	Concentration number	5
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)	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	Yes
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	Yes
D.3.11.13.1	Other medicinal product type	Cetuximab is a chimeric IgG1 monoclonal antibody (moAb) producted by DNA mammifer cell line recombinant.

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 colonrectal cancer KRAS, NRAS and BRAF wild type.

carcinoma colon retto metastatico NRAS,KRAS e BRAF non mutato.

E.1.1.1

Medical condition in easily understood language

metastatic tumor of colon-rectum without mutation of genes KRAS, NRAS and BRAF

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	LLT
E.1.2	Classification code	10052362
E.1.2	Term	Metastatic colorectal cancer
E.1.2	System Organ Class	100000004864

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 evaluate, in terms of Overall Response Rate (ORR), the activity of cetuximab plus irinotecan as rechallenge third line treatment of RAS (K- and N-RAS, codons 12, 13, 59, 61, 117, 146) and BRAF (V600E) wild-type, irinotecan-resistant, mCRC patients progressing after an initial response to a first-line irinotecan- and cetuximab-containing therapy and a second-line with FOLFOXIRI/FOLFOX/XELOX plus bevacizumab.

E.2.2

Secondary objectives of the trial

the duration of progression-free survival (PFS);
the duration of overall survival (OS);
the safety profile;
the evaluation of potential predictive and/or prognostic biomarkers

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Histologically proven diagnosis of colorectal adenocarcinoma;
RAS and BRAF wild-type status of primary colorectal cancer and/or related metastasis;
First-line irinotecan-based (FOLFIRI or FOLFOXIRI) cetuximab-containing therapy producing at least a partial response;
First-line progression-free survival in response to cetuximab-containing therapy ≥6 months;
Documentation of progression to first-line cetuximab within 4 weeks after last cetuximab administration;
Time between the end of first-line therapy and the start of third-line treatment with cetuximab plus irinotecan ≥4 months;
Second-line oxaliplatin-based (FOLFOXIRI, FOLFOX or XELOX) bevacizumab-containing therapy;
Documentation of progression to second-line treatment;
Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST criteria, vers.1.1);
Have tumor tissue (of primary tumor and metastases or at least one of the two) available for biomarker analysis;
Male or female, aged > 18 years of age;
ECOG Performance Status ≤ 2;
Life expectancy of at least 3 months;
Adequate bone marrow, liver and renal function assessed within 14 days before starting study treatment;
Signed informed consent obtained before any study specific procedures.

E.4

Principal exclusion criteria

Active uncontrolled infections or active disseminated intravascular coagulation;
Past or current history of malignancies other than colorectal carcinoma, except for curatively treated basal or squamous cell carcinoma of the skin or in situ carcinoma of the cervix;
Fertile women (<12 months after last menstruation) and men of childbearing potential not willing to use effective means of contraception
Woman who are pregnant or are breastfeeding
Previous Grade 3/4 infusion related reaction to cetuximab.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint of this study is overall response rate (ORR)
ORR is defined as the percentage of patients, relative to the total of enrolled subjects, achieving a complete (CR) or partial (PR) response, according to RECIST 1.1 criteria. The determination of clinical response will be based on investigator-reported measurements. Responses will be evaluated with a chest and abdominal computed tomography (CT) scan every 8 weeks. Patients who do not have an on-study assessment will be included in the analysis as non-responders.

E.5.1.1

Timepoint(s) of evaluation of this end point

computed tomography (CT) scan every 8 weeks.

E.5.2

Secondary end point(s)

Progression-free survival (PFS) is defined as the time from the start of therapy until the first documentation of objective disease progression or death due to any cause, whichever occurs first. PFS will be censored on the date of the last evaluable on-study tumor assessment documenting absence of progressive disease for patients who are alive, on study and progression-free at the time of the analysis, or if lost to follow-up. Alive patients having no tumor assessments after baseline will have time to event endpoint censored on the date of treatment start .
The determination of disease progression will be based on investigator-reported measurements. Disease status will be evaluated according to RECIST 1.1 criteria.
Overall survival (OS) is defined as the time from the start of therapy until the date of death due to any cause. For patients still alive at the time of analysis, or if lost to follow up, the OS time will be censored on the last date the patients were known to be alive.
Toxicity rate is defined as the percentage of patients, relative to the total of enrolled subjects, experiencing a specific adverse event, according to National Cancer Institute Common Toxicity V 4.03

E.5.2.1

Timepoint(s) of evaluation of this end point

For PFS from start treatment to disease progression or death due to any other causes.
for OS from start treatment to death.

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

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)

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

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.8.2.4

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

Planned accrual time is 18 months for a total study duration of 24 months.
LVLS October 2016.

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)

subjects in disease progression will be follow up to overall survival and at subsequent anti-cancer treatment.

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

2014-10-03

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-04-09

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

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