Clinical Trials Register

Summary
EudraCT Number:	2015-003275-30
Sponsor's Protocol Code Number:	011-IRCC-10IIS-15
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2021-01-27
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

2015-003275-30

A.3

Full title of the trial

Open-label, phase ii study of trastuzumab emtansine in patients with HER2-positive metastatic colorectal cancer progressing after trastuzumab and lapatinib: (HER2 Amplification for Colo-rectaL cancer Enhanced Stratification ¿ REchallenge with her2 Selective Cytotoxic Uptake of Emtansine). The HERACLES-RESCUE trial

Studio in aperto, di fase II, di trastuzumab emtansine in pazienti con carcinoma del colon retto metastatico positivo per HER-2 refrattario al trattamento con lapatinib e trastuzumab: STUDIO HERACLES-RESCUE (HER2 Amplification for Colo-rectaL Cancer Enhanced Stratification ¿ REchallenge with HER2 Selective Cytotoxic Uptake of Emtansine)

A.3.1

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

Rechallenge with trastuzumab emtansine of patient with metastatic colorectal cancer progressing after treatment with lapatinib and trastuzumab

Trastuzumab-emtansine in pazienti con tumore del colon con amplificazione di HER2 dopo progressione al trattamento con lapatinib o trastuzumab

A.3.2

Name or abbreviated title of the trial where available

HERACLES-RESCUE

A.4.1

Sponsor's protocol code number

011-IRCC-10IIS-15

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	FONDAZIONE DEL PIEMONTE PER L'ONCOLOGIA IRCCS
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	Roche S.p.A.
B.4.2	Country	Italy
B.4.1	Name of organisation providing support	AIRC
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	Fondazione del Piemonte per l'Oncologia
B.5.2	Functional name of contact point	Clinical Trial Coordination Unit
B.5.3	Address:
B.5.3.1	Street Address	Strada Provinciale 142 Km 3,95
B.5.3.2	Town/ city	Candiolo
B.5.3.3	Post code	10060
B.5.3.4	Country	Italy
B.5.4	Telephone number	0119933926
B.5.5	Fax number	0119933318
B.5.6	E-mail	silvia.marsoni@ircc.it

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	KADCYLA - 100 MG - POLVERE PER CONCENTRATO PER SOLUZIONE PER INFUSIONE - USO ENDOVENOSO - FLACONCINO (VETRO) - 1 FLACONCINO
D.2.1.1.2	Name of the Marketing Authorisation holder	ROCHE REGISTRATION LIMITED
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	KADCYLA
D.3.4	Pharmaceutical form	Powder for 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	TRASTUZUMAB EMTANSINE
D.3.9.1	CAS number	1018448-65-1
D.3.9.2	Current sponsor code	n.a.
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
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)	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.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	KADCYLA - 100 MG - POLVERE PER CONCENTRATO PER SOLUZIONE PER INFUSIONE - USO ENDOVENOSO - FLACONCINO (VETRO) - 1 FLACONCINO
D.2.1.1.2	Name of the Marketing Authorisation holder	ROCHE REGISTRATION LIMITED
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	KADCYLA
D.3.4	Pharmaceutical form	Powder for 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	Yes
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

metatastatic colorectal carcinoma

carcinoma metastatico del colon retto

E.1.1.1

Medical condition in easily understood language

advanced cancer of colon

tumore avanzato del colon retto

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	21.0
E.1.2	Level	LLT
E.1.2	Classification code	10001172
E.1.2	Term	Adenocarcinoma of colon stage IV
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

Define the efficacy of trastuzumab-emtansine in HER2 amplified metastatic CRC patients with advanced disease refractory to chemotherapy, anti EGFR monoclonals, antiangiogenics and lapatinib plus trastuzumab combination (i.e. patients progressing within the HERACLES trial).

Definire l'efficacia di trastuzumab-emtansine in pazienti mCRC HER2 amplificati in stato di malattia avanzata, refrattari alla chemioterapia, ai anti-EGFR monoclonali, anti angiogenici e alla combinazione lapatinib pi¿ trastuzumab (cio¿ pazienti in progressione gi¿ arruolati nel trial HERACLES).

E.2.2

Secondary objectives of the trial

Define the safety profile of T-DM1 in patients pre-treated with trastuzumab-lapatinib.
Define the response duration to T-DM1
Define the time to progression to T-DM1

Definire il profilo di sicurezza di T-DM1 in pazienti trattati in precedenza con trastuzumab-lapatinib.
Definire la durata della risposta di T-DM1.
Definire il tempo alla progressione di T-DM1.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Histological/confirmed adenocarcinoma of the colon or rectum with metastatic disease not amenable to salvage surgery.
2. Progression (PD) after therapy with lapatinib plus trastuzumab combination within the HERACLES - A trial.
3. ECOG PS < 2
4. Measurable disease as defined by RECIST 1.1 criteria
5. Adequate haematological function as defined by: ANC ¿ 1.5 x 109/L, platelet count ¿100 x 109/L, haemoglobin ¿ 10 g/dL.
6. Adequate renal function, as defined by: creatinine ¿ 1.5 x UNL
7. Adequate hepatobiliary function, as defined by the following baseline liver function tests:
a. total serum bilirubin ¿1.5 upper normal limit (UNL) (unless documented Gilbert’s syndrome )
b. alanine aminotransferase (ALT), aspartate aminotransferase (AST) ¿ 2.5xUNL
c. alkaline phosphatase (AP) ¿ 2.5xUNL; if total alkaline phosphatase (AP) > 2.5xUNL, alkaline phosphatase liver fraction must be ¿ 2.5xUNL
8. Adequate contraception for all fertile patients
9. Negative pregnancy test.
Non mandatory pre-treatment biopsy is strongly encouraged.

1. Conferma istologica di adenocarcinoma del colon-retto metastatico non chirurgicamente trattabile.
2. Progressione (PD) dopo terapia con la combinazione lapatinib+trastuzumab prevista dallo studio HERACLES.
3. ECOG PS <2.
4. malattia misurabile come definito dai Criteri RECIST 1.1.
5. Funzione ematologica adeguata secondo i valori di: ANC = 1,5 x 10/L, conta piastrinica =100 x 10/L, emoglobina =10g/dl.
6. Funzione renale adeguata : creatinina =1,5 x UNL.
7. Funzionalità epatobiliare adeguata, come definito dai seguenti test di funzionalità epatica basale:
1. bilirubina sierica totale =1.5 superiore al limite della norma (UNL) (a meno che si sia la sindrome di Gilbert non documentata);
2. alanina aminotransferasi (ALT), aspartato aminotransferasi (AST) =2.5xUNL;
3. fosfatasi alcalina (AP) =2.5xUNL; se la fosfatasi alcalina totale (AP) > 2.5xUNL, fosfatasi alcalina della frazione del fegato deve essere =2.5xUNL.
8. Metodi di contraccezione adeguati per tutti i pazienti fertili.
9. Test di gravidanza negativo.
Biopsia pre-trattamento non obbligatoria ma fortemente consigliata.

E.4

Principal exclusion criteria

1. Symptomatic brain metastases
2. Active infection
3. Interval from last anti HER2 therapy < 2 weeks. Patients in treatment with T-DM1 (provided by third-parties) may be eligible for immediate treatment if not in progression at the time of protocol entry.
4. Prior chemotherapy <4 weeks.
5. Impaired cardiac function including any of the following: uncontrolled hypertension (systolic >150 mmHg and/or diastolic > 100 mmHg) or clinically significant (i.e. active) cardiovascular disease: cerebrovascular accident/stroke or myocardial infarction within 6 months prior to first study medication; unstable angina; chronic heart failure (CHF) of New York Heart Association (NYHA) Grade II or higher; or serious cardiac arrhythmia requiring medication, baseline Left Ventricular Ejection Fraction (LVEF) = 55% measured by echocardiography (ECHO)
6. Major surgery in the two weeks prior to entering the clinical trial
7. Concurrent treatment with any other anti-cancer therapy
8. Patient unable to comply with the study protocol owing to psychological, social or geographical reasons
9. Pregnant and lactating women
10. Men and women of childbearing potential who are not using an effective method of contraception
11. Participation in another clinical trial
12. Subjects who have current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment).

1. Metastasi cerebrali sintomatiche.
2. Infezione attiva.
3. Intervallo dall’ultima terapia anti HER2 <2 settimane. I pazienti in trattamento con T-DM1 (fornito da terzi) possono essere immediatamente eleggibili se non in progressione al momento dell’arruolamento nel protocollo.
4. Chemioterapia precedente <4 settimane.
5. Funzionalità cardiaca compromessa secondo uno dei seguenti criteri: i) ipertensione incontrollata (sistolica >150mmHg e/o diastolica >100mmHg) ii) malattie cardiovascolari clinicamente significative (attive) iii) eventi cerebrovascolari/ictus o infarto del miocardio nei 6 mesi precedenti alla prima medicazione iv) angina instabile v) insufficienza cardiaca cronica (CHF) secondo New York Heart Association (NYHA) di II grado o superiore v) aritmia cardiaca che richieda farmaci vi) Left Ventricular Ejection Fraction (LVEF) =55% misurata mediante ecocardiografia (ECHO).
6. Chirurgia nelle due settimane precedenti all’entrata nello studio.
7. Concomitante altro trattamento antineoplastico
8. Paziente non in grado di rispettare il protocollo di studio a causa di motivi psicologici, sociali o geografici.
9. Donne in gravidanza e in allattamento.
10. Uomini e donne in età fertile che non utilizzano metodi contraccettivi efficaci.
11. Partecipazione ad un altro studio clinico interventistico
12. Soggetti con altre malattie epatiche o delle vie biliari in corso (ad eccezione dei pazienti con sindrome di Gilbert, calcoli biliari asintomatici, metastasi epatiche o malattia epatica cronica stabile).

E.5 End points

E.5.1

Primary end point(s)

Objective Response Rate according to RECIST 1.1 criteria

E.5.1.1

Timepoint(s) of evaluation of this end point

first assessment after 6 weeks, then every 9 weeks

E.5.2

Secondary end point(s)

Description of the frequency and severity of Adverse Events based on the NCI ¿CTCAE V4.0; DCR; TTP

E.5.2.1

Timepoint(s) of evaluation of this end point

thoughtout the study; thoughtout the study; thoughtout 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

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

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.8.5.1

Number of sites anticipated in the EEA

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

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.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

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)

as per clinical practice

come da pratica clinica

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

2015-11-06

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

P. End of Trial
P.	End of Trial Status	Completed

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