Clinical Trials Register

Summary
EudraCT Number:	2009-011217-24
Sponsor's Protocol Code Number:	E7389-E044-203
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2009-08-21
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

UK - MHRA

A.2

EudraCT number

2009-011217-24

A.3

Full title of the trial

A Phase 1b/2, Multicenter, Open-label, Dose-escalation and Confirmation Study of Eribulin in Combination with Capecitabine

A.3.1

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

A clinical trial to determine the most suitable dose of a combination of eribulin and capecitabine for use in late stage breast cancer patients

A.4.1

Sponsor's protocol code number

E7389-E044-203

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	Eisai Ltd
B.1.3.4	Country	United Kingdom
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	Eisai Ltd
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Eisai Europe Ltd
B.5.2	Functional name of contact point	Medical Information
B.5.3	Address:
B.5.3.1	Street Address	Mosquito Way
B.5.3.2	Town/ city	Hatfield
B.5.3.3	Post code	AL10 9SN
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	004408456761400
B.5.5	Fax number	004408456761401
B.5.6	E-mail	EUMedInfo@eisai.net

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	Halaven
D.2.1.1.2	Name of the Marketing Authorisation holder	Eisai Europe 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	Eribulin mesylate
D.3.2	Product code	E7389
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
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)	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	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	Xeloda
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration 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.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
D.3.7	Routes of administration for this IMP	Oral 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)	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

Phase 1 - Advanced and/or metastatic cancer
Phase 2 - Advanced and/or metastatic breast cancer

E.1.1.1

Medical condition in easily understood language

Advanced 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	17.0
E.1.2	Level	LLT
E.1.2	Classification code	10027477
E.1.2	Term	Metastatic carcinoma
E.1.2	System Organ Class	100000004864

E.1.2 Medical condition or disease under investigation

E.1.2	Version	17.0
E.1.2	Level	LLT
E.1.2	Classification code	10027475
E.1.2	Term	Metastatic breast cancer
E.1.2	System Organ Class	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

Dose-escalation cohorts (Phase 1b)
• To determine the maximum tolerated dose (MTD) and dose-limiting
toxicities (DLTs) of eribulin when administered in combination with
capecitabine in two different schedules in subjects with advanced and/or
metastatic cancer
Dose-confirmation cohort (Phase 2)
• To evaluate the efficacy of the combination of eribulin and capecitabine
when administered at the MTD (determined during Dose-escalation) in
the chosen dosing schedule from Phase Ib in female subjects with advanced
and/or metastatic breast cancer

E.2.2

Secondary objectives of the trial

Secondary objectives
• To evaluate the safety, tolerability and toxicity profile of eribulin when given in combination with capecitabine
• To explore the pharmacokinetic (PK) profiles, including evaluating the potential for drug-drug interaction, of eribulin, capecitabine and capecitabine metabolites when eribulin and capecitabine are given in combination
Exploratory objectives
• To explore the pharmacokinetic/pharmacodynamic (PK/PD) relationship
between the combination of eribulin and capecitabine with neutropenia

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Subjects in Dose-escalation cohorts (Phase 1b):
1) Histologically or cytologically confirmed cancer that is advanced and/or
metastatic
2) Resistant/refractory to approved therapies (defined as progressive
disease during or within 6 months after the last anti-cancer therapy) or
for whom single agent capecitabine at this dose level and schedule
would be a reasonable treatment option in the opinion of the investigator
3) Eastern Cooperative Oncology Group (ECOG) performance status (PS)
≤ 2
4) For subjects that previously received capecitabine all capecitabine
related toxicities must have completely resolved.

Subjects in Dose-confirmation cohorts (Phase 2):
1) Histologically or cytologically confirmed carcinoma of the breast that is
advanced and/or metastatic
2) Received up to three prior chemotherapy regimens in any setting
(sequential neo-adjuvant/adjuvant treatment counting as one regimen)
3) Chemotherapy regimens must have included an anthracycline (unless
anthracycline containing chemotherapy is inappropriate) and a taxane,
either in combination or in separate regimens
4) No prior treatment with capecitabine in any setting
5) At least one lesion of ≥ 1.5cm in longest diameter for non-lymph nodes
and ≥1.5cm in shortest diameter for lymph nodes which is serially
measurable according to the Response Evaluation Criteria in Solid
Tumors (RECIST) version 1.1
6) ECOG-PS 0 or 1

General inclusion criteria:
1) Adequate bone marrow function:
absolute neutrophil count (ANC) ≥ 1.5 x 109/L, hemoglobin ≥ 10.0 g/dL
(this may have been corrected by growth factor or transfusion), and
platelet count ≥ 100 x 109/L
2) Adequate liver function as evidenced by bilirubin ≤ 1.5 times the upper
limits of normal (ULN) and alkaline phosphatase, alanine
aminotransferase (ALT), and aspartate aminotransferase (AST)
≤ 3 x ULN (in the case of liver metastases ≤ 5 x ULN)
3) Adequate renal function as evidenced by calculated creatinine clearance
≥ 50 mL/min as per the Cockcroft-Gault formula or radioisotope
measurement

E.4

Principal exclusion criteria

1) Suspected dihydropyrimidine dehydrogenase (DPD) deficiency
2) Prior participation in an eribulin clinical study, even if not assigned to
eribulin treatment
3) Pre-existing neuropathy > Grade 2
4) Subjects with brain or subdural metastases are not eligible, unless they
have completed local therapy and have discontinued the use of
corticosteroids for this indication for at least 4 weeks before starting
study treatment. Any symptoms attributed to brain metastases must be
stable for at least 4 weeks before starting study treatment; radiographic
stability should be determined by comparing contrast-enhanced
computed tomography (CT) or magnetic resonance imaging (MRI) brain
scan performed during screening to a prior scan performed at least 4
weeks earlier.
5) Electrocardiogram (ECG) with QTc interval > 470 msec

E.5 End points

E.5.1

Primary end point(s)

Primary endpoint Dose-Escalation:
A dose limiting toxicity (DLT) is defined as any of the following toxicities considered to be
related to study treatment:
• Neutropenia Grade 4 that lasts ≥ 7 days
• Neutropenia Grade 3 or 4 complicated by fever and/or infection
(ANC < 1.0 x 109/L, fever ≥ 38.5°C)
• Thrombocytopenia Grade 4
• Thrombocytopenia Grade 3 complicated by bleeding and/or requiring
platelet or blood transfusion
• Non-hematological toxicity Grade 3 or higher (excluding Grade 3
nausea, and Grade 3 or 4 vomiting or diarrhea in subjects who have not
received optimal treatment with anti-emetic and/or anti-diarrheal
medication; also excluding any laboratory abnormalities without clinical
symptoms)
• Delayed recovery from treatment-related toxicity resulting in a dose
delay > 14 days
• Failure to administer ≥ 75% of the planned study drugs during Cycle 1
as a result of ≥ Grade 2 treatment-related toxicity that constitutes an
increase of ≥ 2 grades from baseline
The maximum tolerated dose (MTD) is defined as the highest dose level at which no more than one out
of six subjects experience DLT.
Efficacy:
Tumor response as assessed by the investigator will be based on RECIST
version 1.1 in all subjects. Tumor assessments (CT/MRI scans, photographs)
will be performed within 28 days prior to the start of study treatment and
every 6 weeks (within week 6) from first study drug dose. Bone scans will be
performed at baseline and every 18 weeks (within week 18) and at the time
of confirmation of response for breast cancer subjects in the Doseconfirmation
part of the study.

E.5.1.1

Timepoint(s) of evaluation of this end point

The maximum tolerated dose (MTD) is defined as the highest dose level at which no more than one out
of six subjects experience DLT.

E.5.2

Secondary end point(s)

To evaluate the safety, tolerability and toxicity profile of eribulin when given in combination with capecitabine
To explore the pharmacokinetic (PK) profiles, including evaluating the
potential for drug-drug interaction, of eribulin, capecitabine and
capecitabine metabolites when eribulin and capecitabine are given in combination

E.5.2.1

Timepoint(s) of evaluation of this end point

At end of trial

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

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

Dose escalation study (phase 1b)

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

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)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Different dosage schedule

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

Bulgaria

Russian Federation

United Kingdom

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 the Trial is the date of the last visit of the last subject undergoing the trial.

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)

After a subject has ended participation in the trial, the subject's doctor will advise what the most appropriate subsequent treatment is based on the subject's type and stage of cancer.

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

2009-10-05

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2009-12-03

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2015-10-13

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