Clinical Trials Register

Summary
EudraCT Number:	2016-004019-11
Sponsor's Protocol Code Number:	Troka-1
National Competent Authority:	Bulgarian Drug Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2018-01-29
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

Bulgarian Drug Agency

A.2

EudraCT number

2016-004019-11

A.3

Full title of the trial

A randomised, double-blind, parallel group, equivalence, multicentre phase
III trial to compare the efficacy, safety and pharmacokinetics of HD201 to
Herceptin® in patients with HER2+ early breast cancer

A.3.1

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

A randomised, double-blind, parallel group, equivalence, multicentre phase
III trial to compare the efficacy, safety and pharmakokinetics of HD201 to
Herceptin® in patients with HER2+ early breast cancer

A.3.2

Name or abbreviated title of the trial where available

TROIKA

A.4.1

Sponsor's protocol code number

Troka-1

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	Prestige BioPharma Pte Ltd
B.1.3.4	Country	Singapore
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	Prestige BioPharma Pte Ltd
B.4.2	Country	Singapore
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Prestige BioPharma Pte Ltd
B.5.2	Functional name of contact point	Clinical
B.5.3	Address:
B.5.3.1	Street Address	2 Science Park Drive, Ascent Tower B, #04-13/14
B.5.3.2	Town/ city	Singapore
B.5.3.3	Post code	118222
B.5.3.4	Country	Singapore
B.5.4	Telephone number	6569246536
B.5.5	Fax number	6569242053
B.5.6	E-mail	info@pbpsg.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	Trastuzumab
D.3.2	Product code	HD201
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 drip use (Noncurrent)
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.3.9.2	Current sponsor code	HD201
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)	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

Non-metastatic, unilateral, newly diagnosed, operable early breast
cancer (EBC) of clinical stage II and III including inflammatory breast
cancer

E.1.1.1

Medical condition in easily understood language

HER2+ early breast cancer. HER2+ signals the cells to grow and
multiply, and thus promote growth and spread of more cancer cells

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective of this study is to show equivalence of the total
pathological complete response rate (tpCR) in patients treated with
HD201 plus chemotherapy to that in patients treated with Herceptin®
plus chemotherapy. tpCR will be assessed at the time of surgery after
neoadjuvant treatment completion after 24 weeks.

E.2.2

Secondary objectives of the trial

• To compare total breast pathological complete response rate (bpCR)
between the two arms at the time of surgery.
•To compare overall response rate (ORR) between the two treatment
arms at the time of surgery.
•To compare event-free survival (EFS) between the two treatment arms
two years after end of treatment.
•To compare overall survival (OS) between the two treatment arms two
years after end of treatment.
•To compare immunogenicity of HD201 and Herceptin®.
•To compare safety and tolerability between the two treatment arms.
•To compare the PK trough values of HD201 and Herceptin®.

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

Pharmacokinetics (and Ctrough):
Sampling will be performed in all patients. At Cycle 5 (Week 12) and Cycle 8 (Week 21), samples will be taken before administration of treatment (Ctrough).

E.3

Principal inclusion criteria

1. Able and willing to give written informed consent .
2. Females ≥ 18 years of age.
3. Eastern Cooperative Oncology Group (ECOG) performance status (PS) < 2.
4. Known hormone receptor (oestrogen receptor and progesterone
receptor) status.
5. HER2 overexpressed as assessed by
o Immunhistochemistry (IHC) or
o Fluorescent in site hybridisation (FISH); FISH positive is defined as
FISH amplification ratio ≥ 2.0 / number of HER2 gene copies per cell > 2
o Chromogenic in situ hybridisation (CISH positive)
o Patients with IHC score 3+ or positive FISH/CISH test
o Patients with IHC score 2+ must also have a positive FISH/CISH test.
6. LVEF ≥ 50% or within the normal level of the institution, as assessed
by echocardiography or MUGA scan.
7. Life expectancy > 12 weeks.
8. Adequate bone marrow function as evidenced by the following:
o Absolute neutrophils count ≥ 1,500/µL
o Haemoglobin ≥ 9 g/dL
o Platelet count ≥ 100,000/µL
Up to 5% deviation is acceptable.
9. Adequate hepatic and renal function as evidenced by the following:
o Creatinine clearance ≥ 60 mL/min
o Total bilirubin ≤ 1.5 x upper limit of normal (ULN)
o AST (SGOT) and ALT (SGPT) ≤ 2.5 x ULN
Up to 10% deviation is acceptable.
10. Ability to comply with the study protocol.
11. Female patients of childbearing potential must have a negative
serum pregnancy test within 7 days prior to first dose of study treatment
and agree to use effective contraception (intrauterine device,
diaphragm, diaphragm with spermicide or a reliable barrier method, e.g.
condom, or condom with spermicide) throughout the study period and 7
months after discontinuation of study drug.
12. Non-metastatic, unilateral, newly diagnosed, operable early breast
cancer (EBC) of clinical stage II and III including inflammatory breast
cancer.
o Histologically confirmed primary invasive carcinoma of the breast

E.4

Principal exclusion criteria

1. Metastatic (stage IV) with exception of supraclavicular nodes.
2. Bilateral Breast Cancer
3. Multicentric breast cancer
4. History of any prior invasive breast carcinoma, except for subjects
with a history of ductal carcinoma in situ (DCIS) treated with surgery.
5. History of malignant neoplasms within 5 years prior to randomisation,
except for curatively treated carcinoma in situ of uterine cervix, basal
cell carcinoma of the skin or squamous cell carcinoma of the skin
(malignant neoplasms occurring more than 5 years prior to
randomisation are permitted if curatively treated with surgery only).
6. Previous history of radiation therapy, anti-neoplastic immunotherapy,
chemotherapy or anti-neoplastic biotherapy (including prior HER2
directed therapy).
7. Major surgery within 2 weeks prior to randomisation
8. Serious cardiac illness that would preclude the use of trastuzumab
such as:
o history of documented congestive heart failure(CHF) (New York Heart
Association, NYHA, class III or greater heart disease)
o LVEF < 50% by echocardiography or MUGA scan
o angina pectoris requiring anti-anginal medication
o evidence of transmural infarction on electrocardiogram (ECG)
o uncontrolled hypertension (systolic > 180 mmHg and/or diastolic > 100 mmHg)
o clinically significant valvular heart disease
o high-risk uncontrolled arrhythmias.
9. Serious pulmonary illness enough to cause dyspnoea at rest or
requiring supplementary oxygen therapy.
10. Known history of active hepatitis B virus (HBV) and active hepatitis C
virus (HCV) infection.
11. Known HIV infection by patient declaration.
12. Other severe acute or chronic medical or psychiatric condition, or
laboratory abnormality that may increase the risk associated with study
participation or study drug administration, or may interfere with the
interpretation of study results, and in the judgment of the investigator
would make the patient inappropriate for entry into this study.
13. Known hypersensitivity to the IMPs, non-IMPs or any of the
ingredients or excipients of the IMPs or non-IMPs.
14. Known hypersensitivity to murine proteins.
15. Pre-existing peripheral sensory or motor neuropathy ≥ grade 2 (as
defined by NCI-CTCAE v4.03).
16. Lactating or pregnant woman. A pregnancy test is required for all
women of childbearing potential including women who had menopause
onset within 2 years prior to randomisation. Women of childbearing
potential must agree to use contraceptive methods during the study and
for 7 months after the last dose of IMP.
17. Participation in any clinical study or having taken any investigational
therapy during the 1-month period immediately preceding
administration of the first dose.
18. Patients unwilling to follow the study requirements.

E.5 End points

E.5.1

Primary end point(s)

tpCR defined as complete absence of cancer cells in the breast and in the axillary lymph nodes (ypT0/is, ypN0) assessed in specimen obtained during surgery.

E.5.1.1

Timepoint(s) of evaluation of this end point

at the time of surgery after neoadjuvant treatment completion after 24 weeks

E.5.2

Secondary end point(s)

Efficacy:
• bpCR defined as complete disappearance of cancer cells in the breast
(ypT0/is) at the time of surgery.
• Overall response rate (ORR) defined as proportion of patients whose
best overall response is either complete response (CR) or partial
response (PR) as assessed by ultrasound and mammography and clinical
examination prior to surgery.
• Overall survival (OS) defined as the time from randomisation until
death from any cause.
• Event-free survival (EFS) defined as the time from randomisation until
progression of disease or death from any cause.
Safety and tolerability:
• Safety and tolerability will be assessed using the National Cancer
Institute Common Terminology Criteria for Adverse Events and CTC
v4.03
• Cardiac dysfunction will be monitored by 12-lead ECG and
measurement of the LVEF by echocardiography or MUGA scan
• Vital signs
• Clinical laboratory parameters
Immunogenicity:
Incidence of human trastuzumab antibodies at baseline, before surgery, at end of treatment and one year after completion of trastuzumab therapy.
Pharmacokinetics (and Ctrough):
Sampling will be performed in all patients. At Cycle 5 (Week 12) and Cycle 8 (Week 21), samples will be taken before administration of treatment (Ctrough).

E.5.2.1

Timepoint(s) of evaluation of this end point

at the time of surgery

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

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

Yes

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)

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

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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

Yes

E.8.2.3.1

Comparator description

Herceptin

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

Belarus

Belgium

Croatia

Czechia

Denmark

France

Georgia

Germany

Hungary

Malaysia

Netherlands

Philippines

Russian Federation

Spain

Taiwan

Ukraine

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

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

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:

250

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

250

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

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

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

200

F.4.2.2

In the whole clinical trial

500

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)

None

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

2018-05-29

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-05-08

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2022-01-13

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IMP with orphan designation in the indication
Orphan Designation Number:
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