Clinical Trials Register

Summary
EudraCT Number:	2014-000722-38
Sponsor's Protocol Code Number:	1203-GITCG
National Competent Authority:	Portugal - INFARMED
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-03-24
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

Portugal - INFARMED

A.2

EudraCT number

2014-000722-38

A.3

Full title of the trial

INtegratioN of trastuzumab, with or without pertuzumab, into periOperatiVe chemotherApy of HER-2 posiTIve stOmach caNcer: the INNOVATION-TRIAL

A.3.1

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

INtegratioN of trastuzumab, with or without pertuzumab, into periOperatiVe chemotherApy of HER-2 posiTIve stOmach caNcer: the INNOVATION-TRIAL

A.3.2

Name or abbreviated title of the trial where available

INNOVATION

A.4.1

Sponsor's protocol code number

1203-GITCG

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02205047

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	European Organisation for Research and Treatment of Cancer
B.1.3.4	Country	Belgium
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	European Organisation for Research and Treatment of Cancer (EORTC)
B.4.2	Country	Belgium
B.4.1	Name of organisation providing support	F. Hoffmann-La Roche
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	European Organisation for Research and Treatment of Cancer (EORTC)
B.5.2	Functional name of contact point	Regulatory Affairs Department
B.5.3	Address:
B.5.3.1	Street Address	Av E. Mounier 83/11
B.5.3.2	Town/ city	Brussels
B.5.3.3	Post code	1200
B.5.3.4	Country	Belgium
B.5.4	Telephone number	+3227741023
B.5.5	Fax number	+3227727063
B.5.6	E-mail	regulatory@eortc.org

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	Perjeta
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Pertuzumab
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	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	PERTUZUMAB
D.3.9.1	CAS number	380610-27-5
D.3.9.3	Other descriptive name	PERTUZUMAB
D.3.9.4	EV Substance Code	SUB16455MIG
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	30
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	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	Herceptin
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Trastuzumab
D.3.4	Pharmaceutical form	Powder for concentrate 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
D.3.9.1	CAS number	180288-69-1
D.3.9.4	EV Substance Code	SUB12612MIG
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	150
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	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

HER-2 positive, resectable gastric cancer

E.1.1.1

Medical condition in easily understood language

Her-2 positive, resectable gastric 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	23.0
E.1.2	Level	PT
E.1.2	Classification code	10066896
E.1.2	Term	HER2 positive gastric 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 increase the major pathological response rate (< 10% vital tumor cells) to neoadjuvant treatment by integrating both trastuzumab and pertuzumab into perioperative chemotherapy for HER-2 positive, resectable gastric cancer.

E.2.2

Secondary objectives of the trial

Not applicable

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1) Registration
For the determination of the HER-2 status, European sites will have the
choice, patient by patient, between the two following options:
a) Assessment of the HER-2 status of the potentially eligible patient in the
central lab
or
b) Assessment of the HER-2 status by IHC only in the local lab and
mandatory confirmation of the HER-2 positive result in the central lab.
Important note:
Despite excellent pathologists and quality-controlled testing in local
pathology laboratories, potential discrepancies between the peripheral
and central lab in the interpretation of IHC results are well known. In
order not to lose potentially eligible patients for the trial it is mandatory
that the material from all patients with any HER-2 positivity (IHC 1+ or
more) in the local lab should be sent to the central pathology laboratory
as specified below:
♦ All patients (HER-2 positive and negative) should be registered in the trial asap after written informed consent for screening according to ICH/GCP & national/local regulations
♦ Histologically proven, gastric or GE-junction adenocarcinoma (Siewert I-III)
♦ Absence of distant metastases on CT scan of thorax & abdomen
♦ Patient medically fit for gastrectomy/oesophagectomy as decided by investigator
♦ Age ≥ 18 years
♦ WHO performance status 0 – 1
2) RANDOMIZATION
♦ HER-2 overexpression, as determined by central testing using immunohistochemistry (IHC 3+) or the combination of IHC 2+ & HER-2 FISH positive (please see pathology guidelines)
♦ Amenable to gastrectomy/oesophagectomy with curative intent confirmed by multidisciplinary team discussion
♦ UICC tumor stage Ib to III, as defined by CT scan and/or MRI Endosonography (EUS) is recommended but not mandatory. EUS should especially be considered to distinguish T1&T2 tumors
&to evaluate local resectability. (In case of conflicting results of CT scan and/or MRI and endoscopic ultrasound, the final decision on which finding the staging is based should be taken by the multidisciplinary team
♦ The cardiac ejection fraction (LVEF) as determined by echocardiography,MUGA or cardiac MRI should be at least 55%
♦ Adequate organ function:
♦ White blood cell count (WBC) > 3 x 109/L
♦ Absolute neutrophil count (ANC) > 1.5 x 109/L
♦ Platelets ≥ 100 x 109/L
♦ Hemoglobin ≥ 9 g/dL (transfusions are permitted to reach this value)
♦ Estimated glomerular filtration rate (eGFR) according to MDRD should be > 50 ml/min (for patients treated with oxaliplatin-based regimens upfront)
NOTE: For patients that will receive CISPLATIN upfront a GFR > 60 ml/min is required
♦ Total bilirubin within normal limits (if the patient has documented Gilbert’s disease ≤ 1.5 × ULN or direct bilirubin ≤ ULN)
♦ Aspartate transaminase (AST) & alanine transaminase (ALT) ≤ 2.5 × ULN
♦ Absence of preexisting neuropathy > grade I
♦ Investigator and patient have to agree to replace any oral anticoagulations by subcutaneous administration of low-molecular weight heparin (LMWH) in equivalent doses before treatment start, or if on oral anticoagulations &unwilling to switch to LMWH, patients have to be treated with mandatory 5-FU i.v. instead of capecitabine
♦ Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with study protocol & follow-up schedule; those conditions should be discussed with the patient before registration in trial
♦ For women who are not postmenopausal (> 12 months of non- therapy induced amenorrhea)or surgically sterile(absence of ovaries and/or uterus):
♦ agreement to remain abstinent or use single or combined contraceptive methods that result in a failure rate of < 1% per year during treatment period &for at least 7 months after last
treatment dose
♦ Negative serum pregnancy test (β-human chorionic gonadotropin [β-hCG]) result should be available before randomization &within 7 days from treatment start should be performed
♦ For men:agreement to remain abstinent or use a condom plus additional contraceptive method that together result in a failure rate
of < 1% per year during the treatment period &for at least 7
months after last dose of study treatment. Abstinence is only acceptable if in line with preferred & usual lifestyle of the patient. Periodic abstinence (e.g. calendar, ovulation, symptothermal, or postovulation methods) & withdrawal are not acceptable methods for contraception

E.4

Principal exclusion criteria

2) Randomization
♦Prior chemo- or antibody therapy
♦History of significant cardiac disease defined as:
-Symptomatic CHF (NYHA classes II-IV, see Appendix D)
-High-risk uncontrolled arrhythmias, i.e. atrial tachycardia with a heart rate > 100/min at rest, significant ventricular arrhythmia (ventricular tachycardia) or higher-grade AV-block (second degree AV-block Type 2 [Mobitz 2] or third degree AV-block)
-History of myocardial infarction within 6 months prior to randomization
-Clinically significant valvular heart disease
♦Central nervous system metastasis or leptomeningeal tumor spread. For patients without any neurological symptoms, a brain MRI is recommended, but not obligatory. For patients with any clinical symptoms, which may be attributed to brain metastases, a brain MRI is compulsory to rule out cerebral metastases.
♦Known hypersensitivity to the components of trastuzumab, pertuzumab, oxaliplatin, docetaxel, 5-FU or capecitabine
♦Patients with interstitial lung disease
♦Known dihydropyrimidine dehydrogenase (DPD) deficiency (testing not required). In case of specific recommendations due to institutional and/or national guidelines please proceed accordingly
♦Ongoing or concomitant use of the antiviral drug sorivudine or its chemically related analogs, such as brivudine
♦Chronic treatment with high-dose intravenous corticosteroids (> 10 mg/day prednisone equivalents)
♦Previous malignancy within the last 5 years, with the exception of adequately treated cervical carcinoma in situ, localized non-melanoma skin cancer, or other curatively treated cancer without impact on the patient’s overall prognosis according to the judgment of the investigator.
♦ Female patients should NOT be breast feeding

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint of the phase II study is the major pathological response rate (< 10% vital tumor cells).

E.5.1.1

Timepoint(s) of evaluation of this end point

Post surgery.
The analysis of the primary endpoint will occur:
1. 30 days after all patients have undergone surgery
2. the trial is mature for the analysis of the primary endpoint as defined in the protocol
3. the database has been fully cleaned and frozen for the analysis

E.5.2

Secondary end point(s)

1 - R0 resection rate
2 -Pathological complete response
3 - Locoregional failure
4 - Distant failure
5 - Progression-free survival (according to Recist v1.1)
6 - Recurrence-free-survival (from surgery)
7 - Overall survival
8 - Adverse event assessment according to CTCAE v 4.0

E.5.2.1

Timepoint(s) of evaluation of this end point

1 & 2 - Post Surgery
3, 4, 5 & 6 - Disease evaluation will be performed with contrast-enhanced CT-scan and/or MRI of thorax and abdomen every 6 months since the date of surgery for the first 2 years, and every 12 months for the subsequent 4 years (thus for at least 6 years).
7 - Patients will be followed up for at least 6 years following end of treatment or until death.
8 - AEs will be collected until 30 days after end of treatment and during follow-up (as specified in protocol)

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

Yes

E.6.13.1

Other scope of the trial description

Elderly Minimal Dataset Comprehensive Geriatric Assessment for patients ≥ 70 years of age at 28 days after end of treatment.

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

Yes

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

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

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

Yes

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Belgium

Estonia

France

Germany

Israel

Italy

Korea, Republic of

Netherlands

Norway

Portugal

Singapore

Spain

Switzerland

United Kingdom

E.8.7

Trial has a data monitoring committee

Yes

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

Each patient will be followed until death for a minimum of 6 years from surgery
1. Thirty days after all patients have stopped protocol treatment
2. All patients have been followed up for at least 6 years from randomization
3. The database has been fully cleaned and frozen for the analysis of secondary endpoints.

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:

140

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

F.3.3.1

Women of childbearing potential not using contraception

Information not present in EudraCT

F.3.3.2

Women of child-bearing potential using contraception

Information not present in EudraCT

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

108

F.4.2.2

In the whole clinical trial

215

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)

According to the discretion of the treating physician.

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

2015-03-26

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-09-12

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

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