Clinical Trials Register

Summary
EudraCT Number:	2011-005002-30
Sponsor's Protocol Code Number:	ICORG09-13
National Competent Authority:	Ireland - HPRA
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2011-11-03
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

Ireland - HPRA

A.2

EudraCT number

2011-005002-30

A.3

Full title of the trial

Phase II Lap/Epi: Phase II evaluation of the combination of epirubicin and lapatinib in Her-2 positive, Topoisomerase II alpha positive, metastatic breast cancer.

A.3.1

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

This is a trial for women with metastatic breast cancer that test positive for a biological protein called Her 2 and a biological enzyme called Topoisomerase II alpha.
Patients will receive Epirubicin and Lapatinib.

A.3.2

Name or abbreviated title of the trial where available

Phase II Lap/Epi, ICORG 09-13

A.4.1

Sponsor's protocol code number

ICORG09-13

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	ICORG-the All Ireland co-operative Oncology Research group
B.1.3.4	Country	Ireland
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	GSK
B.4.2	Country	Ireland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	ICORG-the All Ireland co-operative Oncology Research group
B.5.2	Functional name of contact point	Tanya O' Shea
B.5.3	Address:
B.5.3.1	Street Address	60 Fitzwilliam Square
B.5.3.2	Town/ city	Dublin
B.5.3.3	Post code	2
B.5.3.4	Country	Ireland
B.5.4	Telephone number	353016677211
B.5.5	Fax number	353016697869
B.5.6	E-mail	Tanya.OShea@icorg.ie

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	Tyverb
D.2.1.1.2	Name of the Marketing Authorisation holder	Glaxo Group Ltd
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	Tyverb
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	LAPATINIB
D.3.9.1	CAS number	231277-92-2
D.3.9.4	EV Substance Code	SUB25379
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	1250
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)	No
	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	No
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	Yes
D.2.1.1.1	Trade name	Epirubicin
D.2.1.1.2	Name of the Marketing Authorisation holder	Actavis Group hf
D.2.1.2	Country which granted the Marketing Authorisation	Iceland
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.3.4	Pharmaceutical form	Solution for injection
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	EPIRUBICIN
D.3.9.1	CAS number	56420-45-2
D.3.9.4	EV Substance Code	SUB06571MIG
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	75
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)	No
	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	No
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

Metastatic breast cancer in patients who are HER-2-positive and Topoisomerase II alpha positive.

E.1.1.1

Medical condition in easily understood language

Breast cancer that has spread beyond the original origin to other parts of the body.

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	14.0
E.1.2	Level	LLT
E.1.2	Classification code	10027475
E.1.2	Term	Metastatic breast 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 evaluate the clinical efficacy (Overall Response Rate) of the combination of epirubicin and lapatinib in HER2+, TopoII alpha positive metastatic breast cancer.

E.2.2

Secondary objectives of the trial

• Provide further toxicological data on the combination of epirubicin with lapatinib.
• To evaluate the study population with respect to the following: overall survival (from treatment start until death from any cause), progression free survival (from treatment start until progression or death from any cause), clinical benefit (CR, PR and stable disease for at least 6 months).
• To carry out translational research in order to determine biomarkers that correlate with clinical benefit/response to epirubicin-lapatinib therapy.
• To carry out translational research to examine trough levels of lapatinib prior to anthracycline therapy and monitor patient compliance on lapatinib therapy.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Ability to understand and has signed a written informed consent document prior to any study related procedures.
2. Female patients age≥ 18 years
3. ECOG Performance Status of ≤ 2
4. Histologically or cytologically-confirmed invasive breast cancer with Stage IV disease (metastatic breast cancer)
5. Patients must have measurable disease according to RECIST 1.1 criteria, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >20 mm with conventional techniques or as >10 mm with spiral CT scan.
6. HER2-positivity defined as IHC score of 3+ or ratio of HER2 gene signals to centromere 17 (Cep17) signals ≥2.0 by fluorescent in situ hybridization (FISH).
7. TopoII alpha amplification defined as a ratio of TopoIIα gene signals to centromere 17 signals ≥1.5 by in situ hybridisation.
8. Cardiac ejection fraction within the institutional range of normal as measured by MUGA or ECHO.
9. Adequate haematological, hepatic, and renal function.
• Haemoglobin ≥ 9g/dL.
• Absolute granulocyte count ≥1.5 x 10^9/L.
• Platelets ≥ 100 x 10^9/L.
• Total bilirubin ≤ULN of the treating institution, unless the patient has a documented history of congenital hyperbilirubinemia (Gilbert's syndrome).
• Both ALT and AST ≤ 3 x ULN with or without liver metastases.
• Alkaline phosphatase ≤ 2.5 x ULN.
• Calculated creatinine clearance (CrCl) ≥ 40mL/min according to the formula of Cockcroft and Gault
10. women of child-bearing potential must agree to use adequate contraception prior to study entry and for the duration of study participation. Acceptable methods of birth control:
• Complete abstinence from intercourse from the time of the screening pregnancy test until 28 days after the final dose of lapatinib; or
• Consistent and correct use of one of the following acceptable methods of birth control:
• Male partner who is sterile prior to the female patient’s entry into the study and is the sole sexual partner for that female patient; or
• Any intrauterine device (IUD) with a documented failure rate of less than 1% per year; or
• Barrier methods (e.g. condoms, diaphragms, caps) only if used in combination with one of the above acceptable methods.
11. Life expectancy greater than 12 weeks
12. Patients may receive bisphosphonates where they are clinically indicated if started prior to first study treatment administration.
13. Patients with a history of any of the following cancers are eligible if diagnosed and treated longer than 5 years: cervical carcinoma in situ, melanoma in situ, and basal cell or squamous cell carcinoma of the skin;
14. Are able to swallow and retain oral medication.

E.4

Principal exclusion criteria

1. Untreated and uncontrolled central nervous system (CNS) metastases. Patients with known CNS metastases are eligible if metastases are treated and proven stable for at least 3 months (asymptomatic and not receiving steroids). CNS metastases cannot be used as target lesions to assess objective response
2. Prior anthracycline or anthracenedione therapy (Prior- non-anthracycline adjuvant therapy is NOT an exclusion criterion)
3. No prior chemotherapy and/or trastuzumab for metastatic breast cancer. Prior adjuvant trastuzumab is allowed (provided at least 3 months has elapsed from the most recent trastuzumab infusion). No prior other therapy with ErbB inhibitors is allowed. Subjects who have acute or currently active /requiring anti-viral therapy hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment)
4. Uncontrolled or symptomatic angina, arrhythmias, congestive heart failure or other cardiac disorders.
5. Evidence of or history of QT (QTc) interval above 470msec
6. Patients with elevated troponin I (TNI)
7. Immediate or delayed hypersensitivity or untoward reaction to lapatinib, epirubicin or other related compounds, or to drugs chemically related to lapatinib (including other anilinoquinazolines, e.g. gefitinib (Iressa) and erlotinib (Tarceva), or other chemically-related compounds).
8. Pregnant women are excluded from this study. (breastfeeding should be discontinued if the mother is treated with lapatinib).
9. Have unresolved or unstable grade ≥ 2 toxicity from administration of prior cancer treatment
10. Prior lapatinib treatment. Patients who received lapatinib in the adjuvant or neo-adjuvant setting as part of a clinical trial are NOT eligible,
11. Prior investigational drugs within the past 30 days
12. Concurrent treatment with prohibited medications (refer to Section 7.5 for details on prohibited medications)
13. Patients with GI tract disease resulting in an inability to take oral medication, malabsorption syndrome, a requirement for IV alimentation, prior surgical procedures affecting absorption, uncontrolled inflammatory GI disease (e.g., Crohn’s, ulcerative colitis).
14. Have a concurrent disease or condition that would make the patient inappropriate for study participation, or any serious medical disorder that would interfere with the patient safety;
15. Have an active or uncontrolled infection;
16. Have dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent;
17. HIV-positive patients receiving combination anti-retroviral therapy are excluded from the study because of possible pharmacokinetic interactions with lapatinib.

E.5 End points

E.5.1

Primary end point(s)

Overall Response Rate (ORR) (defined as the percentage of patients with a confirmed CR or PR as per RECIST 1.1 criteria).

E.5.1.1

Timepoint(s) of evaluation of this end point

The number of patients deemed to have shown a response will be expressed as a proportion of those taking part in the study (15 if only one stage, 46 if both stages are completed). Response will be assessed six months after the last patient is enrolled.

E.5.2

Secondary end point(s)

• Progression Free Survival (PFS).
• Overall survival (OS).
• Clinical benefit Rate .
• Provide further toxicological data on the combination of an anthracycline with lapatinib.
• Determine biomarkers that correlate with clinical benefit/response to epirubicin-lapatinib therapy.

E.5.2.1

Timepoint(s) of evaluation of this end point

Progression free survival will be analysed 12 months after the last patient is enrolled on the study. Overall survival will be analysed 24 months after the last patient is enrolled on the study. Progression-free and overall survival probabilities over time will be estimated at 12 months and 24 months for PFS and overall survival respectively.
The number of patients deemed to have shown clinical benefit will be expressed as a proportion of those taking part in the study (15 if only one stage, 46 if both stages are completed). Clinical benefit will be assessed six months after the last patient is enrolled.

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

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

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

E.8.6.2

Trial being conducted completely outside of the EEA

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

Patients will be followed up every 6 months for survival from the time of completing protocol treatment.

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)

F.1.3

Elderly (>=65 years)

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

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)

Patients will be followed up every 6 months for survival once treatment per protocol has ended.

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

2011-12-05

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-01-05

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2012-12-14

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