Clinical Trials Register

Summary
EudraCT Number:	2019-001328-36
Sponsor's Protocol Code Number:	na
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:	2021-05-24
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

2019-001328-36

A.3

Full title of the trial

Multicenter prospective single-arm study investigating the efficacy and safety of second-line cetuximab plus chemotherapy treatment in initially RAS-mt mCRC patients who converted to RAS-wt at the time of first progression

Studio di fase II a singolo braccio di terapia di II linea con cetuximab e chemioterapia in pazienti con carcinoma colorettale metastatico KRAS e NRAS mutato alla diagnosi con assenza di mutazioni di KRAS/NRAS su plasma alla progressione da prima linea

A.3.1

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

A.3.2

Name or abbreviated title of the trial where available

KAIROS

A.4.1

Sponsor's protocol code 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	UMBERTO I - POLICLINICO DI ROMA
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.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Enrico Cortesi
B.5.2	Functional name of contact point	Oncologia B
B.5.3	Address:
B.5.3.1	Street Address	Viale del Policlinico Umberto I
B.5.3.2	Town/ city	Roma
B.5.3.3	Post code	00161
B.5.3.4	Country	Italy
B.5.4	Telephone number	064462982
B.5.5	Fax number	064463686
B.5.6	E-mail	thekairostrial@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.2.1.1.1	Trade name	ERBITUX - 5 MG/ML SOLUZIONE PER INFUSIONE - USO ENDOVENOSO- FLACONCINO (VETRO) 100 ML 1 FLACONCINO
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck Europe B.V
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	Erbitux
D.3.2	Product code	[DE_BW_01_GMP_2018_0139]
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.3.9.2	Current sponsor code	NA
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	500
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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	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

patients with RAS-mt mCRC at diagnosis (based on tumor tissue) who convert to RAS-wt disease (based on ctDNA) at progression after first-line treatment

Tumore del colon retto metastatico RAS mutato in progressione dopo una prima linea terapeutica con riscontro di assenza di mutazione di RAS su ctDNA

E.1.1.1

Medical condition in easily understood language

patients with metastatic colon rectal cancer bearing RAS mutation at progression after first-line treatment who convert to RAS-wt disease (based on ctDNA)

Pazienti con tumore del colon retto metastatico portatori di mutazione a carico di RAS in progressione dopo terapia di prima linea con riscontro di assenza di mutazioni di Ras all'analisi di ctDNA

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	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10079136
E.1.2	Term	Adenocarcinoma of colon metastatic
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

Overall response rate (ORR) to cetuximab plus chemotherapy according to RECIST v1.1., that means the rate of patients with confirmed complete response (CR) or partial response (PR) as best response to treatment.

Gli studi dimostrano elevata concordanza tessuto/plasma al basale (90%), quelli discordanti sono legati alla scarsa quantità di ctDNA rilasciato in pazienti resecati o senza metastasi epatiche. Tale concordanza al basale esula dall’obiettivo primario che è verificare l’efficacia di cetuximab in seconda linea in pazienti con tumori del colon-retto metastatici RAS mutati su biopsia tissutale alla diagnosi (non candidabili a trattamento con EGFRi) e RAS wt su plasma alla progressione da prima linea. La conversione dello stato mutazionale al momento della PD non dipende dal trattamento di prima linea o dal processo di evoluzione clonale del cancro. L’eventuale discordanza al basale (mutazioni di RAS su tessuto e assenza di mutazioni su plasma) non modificherebbe il razionale dello studio; i pazienti non sarebbero candidabili ad un trattamento con cetuximab. Tale concordanza al basale della prima linea comporterebbe un allungamento dei tempi dello studio >12 mesi ed un incremento dei costi.

E.2.2

Secondary objectives of the trial

Progression free survival (PFS): measured as the time from the start of study treatment (second line therapy) until the first observation of disease progression or death due to any cause
Overall survival (OS): calculated as the time from the start of the study treatment (second line therapy) until death from any cause
Safety profile: adverse events graded according to NCI CTCAE v5.0

Sopravvivenza libera da progressione: intesa come l'intervallo di tempo tra l'inizio del trattamento in studio fino alla progressione di malattia o morte per qualsiasi causa
Sopravvivenza globale: intesa come l'intervallo di tempo tra l'inizio del trattamento in studio fino alla morte per qualsiasi causa
Profilo di sicurezza: valutazione di eventi avversi secondo NCI CTCAE v5.0

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Histologically proven diagnosis of colorectal adenocarcinoma;
- KRAS/NRAS-mt status of primary colorectal cancer and/or related metastasis; at the time of the initial diagnosis
- Radiological evidence of progression of disease (PD) after first-line therapy with chemotherapy plus bevacizumab;
- Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST criteria, vers.1.1);
- Male or female, aged > 18 years of age;
- ECOG Performance Status = 2;
- Adequate bone marrow, liver and renal function assessed within 14 days before starting study treatment;
Adequate bone marrow function (without hematopoietic growth factor or transfusion support within 14 days prior to study enrollment), including:
a. Absolute Neutrophil Count (ANC) ¿1,500/mm3 or ¿1.5 x 109/L.
b. Platelets ¿100,000/mm3 or ¿100 x 109/L.
c. Hemoglobin ¿9 g/dL (¿5.6 mmol/L).
Female patients of childbearing potential must have negative serum pregnancy or
urine pregnancy test at screening.

Adequate renal function defined by an estimated creatinine clearance ¿30 mL/min
according to the Cockcroft-Gault formula as:
•¿CLCR={[(140–age) × weight)]/(72 x SCR)} × 0.85 (if female), where CLCR
(creatinine clearance) is measured in mL/min, age is expressed in years, weight in
kilograms (kg), and SCR (serum creatinine) in mg/dL;
•¿Or as measured by 24h urine assessment.

Adequate liver function, including:
a. Total serum bilirubin ¿1.5 × the upper limit of normal range (ULN);
b. Aspartate and Alanine aminotransferase (AST and ALT) ¿2.5 x ULN.

- Women of childbearing potential must have a negative blood pregnancy test at the baseline visit. For this trial, women of childbearing potential are defined as all women after puberty, unless they are postmenopausal for at least 12 months, are surgically sterile, or are sexually inactive;
- Subjects and their partners must be willing to avoid pregnancy during the trial and until 6 months after the last trial treatment. Male subjects with female partners of childbearing potential and female subjects of childbearing potential must, therefore, be willing to use adequate contraception as approved by the investigator, such as a two-barrier method or one-barrier method with spermicidal or intrauterine device. This requirement begins 2 weeks before receiving the first trial treatment and ends 6 months after receiving the last treatment;
- Signed informed consent obtained before any study specific procedures.
- KRAS/NRAS-wt status, tested on ctDNA, at the time of progression after first line treatment
- Life expectancy of at least 3 months;

• Diagnosi istologica di adenocarcinoma del colon-retto
• KRAS/NRAS mutato su biopsia tissutale (tumore primitivo /metastasi) al momento della diagnosi
• Evidenza radiologica di progressione di malattia dopo prima linea con chemioterapia e bevacizumab
• Malattia misurabile secondo criteri RECIST (RECIST criteria, vers.1.1);
• Uomo o donna, età > 18 anni
• ECOG Performance Status = 2;
• Adeguata funzionalità ematologica, epatica e renale valutata entro 14 giorni dall’inizio del trattamento in studio
Adequate bone marrow function (without hematopoietic growth factor or transfusion support within 14 days prior to study enrollment), including:
a. Absolute Neutrophil Count (ANC) ¿1,500/mm3 or ¿1.5 x 109/L.
b. Platelets ¿100,000/mm3 or ¿100 x 109/L.
c. Hemoglobin ¿9 g/dL (¿5.6 mmol/L).

Adequate renal function defined by an estimated creatinine clearance ¿30 mL/min
according to the Cockcroft-Gault formula as:
•¿CLCR={[(140–age) × weight)]/(72 x SCR)} × 0.85 (if female), where CLCR
(creatinine clearance) is measured in mL/min, age is expressed in years, weight in
kilograms (kg), and SCR (serum creatinine) in mg/dL;
•¿Or as measured by 24h urine assessment.

Adequate liver function, including:
a. Total serum bilirubin ¿1.5 × the upper limit of normal range (ULN);
b. Aspartate and Alanine aminotransferase (AST and ALT) ¿2.5 x ULN.
• Donne fertili devono avere test di gravidanza negativo alla visita basale. Vengono considerate donne fertili tutte le donne dopo la pubertà, ad eccezione di quelle in menopausa da almeno 12 mesi, quelle chirurgicamente sterili o sessualmente inattive
• I pazienti e i loro partner devono evitare gravidanze in corso di trattamento e fino a 6 mesi dopo l’ultima somministrazione. I soggetti di sesso maschile con partner fertili e I soggetti di sesso femminile fertili devono pertanto accettare l’uso di un metodo contraccettivo adeguato approvato dallo sperimentatore (es. doppia barriera o singola barriera con spermicida o dispositivo intrauterino. La contraccezione è richiesta 2 settimane prima dell’inizio del trattamento e fino a 6 mesi dopo l’ultima somministrazione.
• Consenso informato scritto nella fase di screening e nella fase di arruolamento
• KRAS/NRAS wild-type su plasma (DNA tumorale circolante) al momento della progressione da prima linea di trattamento
• Aspettativa di vita di almeno 3 mesi

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;
- Women who are pregnant or are breastfeeding.
- Severe, acute, or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration
- BRAF mutant tumors
- Known hypersensitivity to drugs used in this study or to any of the ingredients of these drugs
- eligeble potential patients must not be enrolled in clinicl trials which administered study drugs whithin 4 weeks prior to be enrolled in this trial

• Infezioni in atto non controllate o coagulazione intravascolare disseminate in atto
• Storia passata o corrente di altri tumori oltre a quello del colon-retto, ad eccezione di basaliomi o carcinomi squamocellulari della cute o carcinoma in situ della cervice uterine
• Donne fertili (<12 mesi dall’ultima mestruazione) e uomini in età fertile che non utilizzino adeguati metodi contraccettivi;
• Donne in gravidanza o allattamento
• Comorbidità severe sia acute che croniche sia mediche che psichiatriche o anomalie di laboratorio che possano aumentare il rischio associate alla partecipazione allo studio o al trattamento.
• Nota reazione allergica ai farmaci previsti nello studio
• Pazienti con tumori BRAF mutati
. i pazienti eleggibili non possono partecipare a trials clinici che prevedono utilizzo e somministrazione di farmaci nelle 4 settimane precedenti all’arruolamento
.

E.5 End points

E.5.1

Primary end point(s)

Verificare il tasso di risposta secondo criteri RECIST v1.1 alla chemioterapia di II linea in combinazione con cetuximab in pazienti con tumori del colon-retto metastatici RAS mutati su biopsia tissutale alla diagnosi, con assenza di mutazioni di RAS su plasma alla progressione da prima linea, misurata con il tasso di risposta al trattamento

E.5.1.1

Timepoint(s) of evaluation of this end point

2 months

2 mesi

E.5.2

Secondary end point(s)

-The duration of progression free survival (PFS)
-PFS: measured as the time from the start of study treatment (second line therapy) until the first observation of disease progression or death due to any cause; The duration of overall survival (OS)
OS: calculated as the time from the start of the study treatment (second line therapy) until death from any cause; The safety profile
Adverse events graded according to NCI CTCAE v5.0
Laboratory parameters

Malattia libera da progressione; la sopravvivenza; Profilo di sicurezza
Tossicità del trattamento secondo NCI CTCAE v5.0
Parametri di laboratorio

E.5.2.1

Timepoint(s) of evaluation of this end point

2 months; from the start of the study treatment until the death; 2 months

2 mesi; dall'inizio del trattamento sperimentale fino alla morte; 2 mesi

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

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

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

Yes

E.8.1.7.1

Other trial design description

Singolo braccio

single arm

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

Information not present in EudraCT

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. 26 months from last enrolled patient

LVLS. 26 mesi dall'ultimo paziente arruolato

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

112

F.4.2

For a multinational trial

F.4.2.1

In the EEA

112

F.4.2.2

In the whole clinical trial

112

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)

patients will be trated as per standard of care

Normale pratica clinica al termine del trattamento sperimentale

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

2020-03-09

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-04-22

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

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