Clinical Trials Register

Summary
EudraCT Number:	2011-005328-17
Sponsor's Protocol Code Number:	MO28048
National Competent Authority:	Slovakia - SIDC (Slovak)
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-06-11
Trial results	View 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

Slovakia - SIDC (Slovak)

A.2

EudraCT number

2011-005328-17

A.3

Full title of the trial

A phase III prospective, two-cohort non-randomized, multi-centre, multinational, open label study to assess the safety of assisted- and self-administered subcutaneous trastuzumab as therapy in patients with operable Her2-positive early breast cancer [SafeHer study]

Prospektívne, nerandomizované, multicentrické, medzinárodné, otvorené skúšanie fázy III s dvoma kohortami pre posúdenie bezpečnosti asistovaného podania a samopodania trastuzumabu na subkutánne použitie ako liečby u pacientov s operovateľným her2 pozitívnym karcinómom prsníka vo včasnom štádiu

A.3.1

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

A study to assess the safety of assisted- and self-administered subcutaneous trastuzumab as therapy in patients with operable Her2-positive early breast cancer

A.3.2

Name or abbreviated title of the trial where available

SafeHer Study

A.4.1

Sponsor's protocol code number

MO28048

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	F. Hoffmann-La Roche Ltd
B.1.3.4	Country	Switzerland
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	F.Hoffmann-La Roche Ltd
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	F. Hoffmann-La Roche Ltd
B.5.2	Functional name of contact point	Trial Information Support Line-TISL
B.5.3	Address:
B.5.3.1	Street Address	Grenzacherstrasse 124
B.5.3.2	Town/ city	Basel
B.5.3.3	Post code	4070
B.5.3.4	Country	Switzerland
B.5.4	Telephone number	+41616881111
B.5.5	Fax number	+41616919319
B.5.6	E-mail	global.rochegenentechtrials@roche.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	No
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	Herceptin for SC injection
D.3.2	Product code	Ro 045-2317/F07
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	TRASTUZUMAB SC
D.3.9.1	CAS number	180288-69-1
D.3.9.2	Current sponsor code	RO0452317
D.3.9.3	Other descriptive name	rhuMAb HER2, Anti-HER
D.3.9.4	EV Substance Code	SUB12612MIG
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	120
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	Comparator
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	No
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	Herceptin SC
D.3.2	Product code	Ro 045-2317/F06
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	TRASTUZUMAB SC
D.3.9.1	CAS number	180288-69-1
D.3.9.2	Current sponsor code	RO0452317
D.3.9.3	Other descriptive name	rhuMAb HER2, Anti-HER
D.3.9.4	EV Substance Code	SUB12612MIG
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	120
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.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

HER2-positive primary breast cancer

E.1.1.1

Medical condition in easily understood language

Breast 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	20.0
E.1.2	Level	SOC
E.1.2	Classification code	10029104
E.1.2	Term	Neoplasms benign, malignant and unspecified (incl cysts and polyps)
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 assess the overall safety and tolerability of subcutaneous (SC) trastuzumab in HER2-positive early breast cancer (EBC) patients with assisted administration using a conventional syringe and needle (vial formulation) and with assisted administration with or without self-administration using a single-use injection device (SID).

E.2.2

Secondary objectives of the trial

• Efficacy (both cohorts):
- disease-free survival (DFS)
- overall survival (OS)
• Patient satisfaction with trastuzumab SC administration using the SID (patients in Cohort B who went on to self-administration of the study drug).

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

In some countries and sites, Medical Care Utilization (MCU, e.g. Time and Motion) and/or pharmacoeconomic sub-studies will be conducted.

E.3

Principal inclusion criteria

1. Signed written informed consent approved by the reviewing independent Ethics Committee
2. Female or male aged 18 years or above
3. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
4. Histologically confirmed early invasive HER2-positive carcinoma of the breast with no evidence of residual, locally recurrent or metastatic disease and defined as clinical stage I (T1, N0, M0) to IIIC (any T, N3, M0) that is eligible for treatment with trastuzumab.
Note: Patients treated without neoadjuvant or adjuvant chemotherapy, such as patients with low risk node negative tumours ≤ 1.0 cm, elderly patients (>65 years of age) or patients with HER2-positive EBC but denying chemotherapy, will also be eligible to participate in the study, but their enrolment will be limited to approximately 10% of the total study population.
5. HER2-positive EBC, defined as IHC 3+, or a positive in situ hybridization (ISH testing) by validate and approved methods within a certified laboratory.
6. Screening left ventricular ejection fraction (LVEF) ≥ 55% as measured by echocardiography, Multi Gated Acquisition (MUGA) scan or Magnetic Resonance Imaging (MRI) per local practice.
7. Agreement to use an adequate, non-hormonal means of contraception by women of childbearing potential (defined as pre-menopausal and not surgically sterilized or < 1 year after the onset of menopause) and by male participants with partners of childbearing potential only. Examples of adequate contraceptive measures are an intra-uterine device, a barrier method (condoms, diaphragm) in conjunction with spermicidal jelly, or total abstinence. Oral, injectable, or implant hormonal contraceptives are not acceptable for females participating in the study.
8. Intact skin at site of SC injection on the thigh.

E.4

Principal exclusion criteria

Cancer Related Criteria
1. Previous neoadjuvant or adjuvant breast cancer treatment with an approved or investigational anti-HER2 agent
2. History of other malignancy which could affect compliance with the protocol or interpretation of results (including previous invasive ipsilateral or contralateral breast cancer). Patients with curatively treated carcinoma in situ of the cervix or basal cell carcinoma, and patients with other curatively-treated malignancies, other than breast cancer, who have been disease-free for at least 5 years, are eligible.
3. Past history of ductal carcinoma in situ (DCIS) within the last 5 years that has been treated with any systemic therapy OR with radiation therapy to the ipsilateral breast where invasive cancer subsequently develops. Patients who had their DCIS treated with surgery only are allowed to enter the study.
4. Metastatic disease
Haematological, Biochemical and Organ Function Related Criteria
5. Inadequate bone marrow function (as indicated by any of the following):
• Total white blood cell count < 2,500 / mm3 (<2.5 x 10e9/L)
• Neutrophil count < 1,500 / mm3 (< 1.5 x 10e9/L)
• Platelets < 100,000 / mm3 (< 100 x 10e9/L)
• Haemoglobin < 10 g/dL
6. Impaired hepatic function (as indicated by any of the following):
• Serum total bilirubin > 1.5 x upper limit of normal (ULN)
• Alanine amino transferase > 2.5 x ULN
• Aspartate amino transferase > 2.5 x ULN
• Alkaline phosphatase > 2.5 x ULN
7. Impaired renal function: serum creatinine > 1.5 x ULN
Other Study Drug Related Exclusion Criteria
8. Serious cardiac illness or medical conditions including but not confined to:
• History of documented heart failure or systolic dysfunction (LVEF < 50%)
• High-risk uncontrolled arrhythmias such as atrial tachycardia with a heart rate > 100/min at rest, significant ventricular arrhythmia (ventricular tachycardia) or higher-grade atrioventricular (AV) block (second degree AV-block Type 2 [Mobitz 2] or third degree AV-block)
• Angina pectoris requiring anti-anginal medication
• Clinically significant valvular heart disease
• Evidence of transmural infarction on electrocardiogram (ECG)
• Poorly controlled or uncontrolled hypertension (blood pressure consistently over 140/90 mmHg, despite treatment), or history of hypertensive crisis or hypertensive encephalopathy
9. Other concurrent serious diseases that may interfere with planned treatment including severe pulmonary conditions/illness
10. Prior maximum cumulative dose of doxorubicin >360 mg/m2 or maximum cumulative dose of epirubicin >720 mg/m2 or equivalent
11. Known hypersensitivity to trastuzumab, murine proteins, or a general hypersensitivity to adhesives (Cohort B only)
12. History of severe allergic or immunological reactions, e.g. difficult to control asthma
General Exclusion Criteria
13. Pregnancy or lactation
14. Unable or unwilling to comply with the requirements of the protocol as assessed by the investigator
15. Concurrent enrolment in another clinical trial using an investigational anti-cancer treatment, including hormonal therapy, bisphosphonate therapy and immunotherapy, within 28 days prior to the first dose of study treatment
16. Major surgical procedure or significant traumatic injury within 14 days prior to the first dose of study treatment or anticipated need for major surgery during the course of study treatment except for breast cancer surgery for patient receiving study drug in the neoadjuvant setting. Patients must be free of any clinically significant sequalae of prior surgery before they can receive their first dose of study treatment.
17. More than 12 weeks between the end of the last chemotherapy cycle and the first dose of study treatment, in case these treatments are initiated sequentially. This criterion does not apply to patients who are starting trastuzumab SC without previous or concurrent chemotherapy or concurrently with chemotherapy.
18. Current peripheral neuropathy of grade 3 or greater per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0.

E.5 End points

E.5.1

Primary end point(s)

Safety endpoints are the primary objectives in this study and will include: all AEs, Grade ≥3 AEs, SAEs, AEs leading to premature discontinuation of study treatment, AEs causing interruption of trastuzumab SC, cardiac AEs, CHF-related SAEs, premature withdrawals from study and study medication, exposure to treatment, laboratory parameters, LVEF, vital signs, ECG, weight, and ECOG performance status.

E.5.1.1

Timepoint(s) of evaluation of this end point

The primary analysis of the safety endpoints will take place when all patients have received 18 cycles of trastuzumab SC and have completed the Safety Follow-up assessments (4 weeks after their last dose of study treatment).

E.5.2

Secondary end point(s)

Secondary efficacy endpoints include DFS, OS (both cohorts) and patients’ satisfaction with trastuzumab SC administration using the SID (Cohort B patients who went on to self administration only).

E.5.2.1

Timepoint(s) of evaluation of this end point

A preliminary analysis of DFS and OS will be undertaken at the time of the primary safety analysis, i.e. when all patients have received 18 cycles of trastuzumab SC and have completed the Safety Follow-up assessments (4 weeks after their last dose of study treatment). The final analysis of OS and DFS will take place when the last patient has been followed up for approximately 5 years after her/his last study treatment, or earlier, if one of the following is documented for all treated patients: withdrawal of consent, loss to follow-up or 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

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

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

Yes

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Immunogenicity, Patient satisfaction and Medical Care Utilization

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

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

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

337

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

Albania

Algeria

Argentina

Australia

Bosnia and Herzegovina

Brazil

Canada

Chile

Colombia

Croatia

Dominican Republic

Ecuador

Egypt

El Salvador

European Union

Guatemala

Hong Kong

India

Indonesia

Korea, Republic of

Malaysia

Mexico

Morocco

New Zealand

Pakistan

Panama

Peru

Philippines

Russian Federation

Saudi Arabia

Serbia

Singapore

South Africa

Switzerland

Taiwan

Thailand

Turkey

Ukraine

United Arab Emirates

Vietnam

Venezuela, Bolivarian Republic of

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

End of study is defined as the last patient last visit in the follow-up period. The study will end when all patients have been followed for at least 5 years after their last study treatment, or earlier, if one of the following is documented for all treated patients: withdrawal from the study, loss to follow up or death.

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:

2200

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

300

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

1447

F.4.2.2

In the whole clinical trial

2500

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 who discontinue study treatment prematurely due to lack of tolerability will be clinically managed as per local practice and followed as outlined in the Schedule of Assessments, Appendix 1.
All prematurely withdrawn patients, who have received at least one dose of trastuzumab, should continue to be monitored for cardiac function as described in the Herceptin SmPC, within or outside the study, as appropriate.

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2012-06-06

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-05-22

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2020-02-19

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