Clinical Trials Register

Summary
EudraCT Number:	2010-019526-14
Sponsor's Protocol Code Number:	E7080-G000-206
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2010-09-29
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

Germany - BfArM

A.2

EudraCT number

2010-019526-14

A.3

Full title of the trial

An Open-Label, 2-Cohort, Multicenter, Phase 2 Study of E7080 in Previously Treated Subjects With Unresectable Stage III or Stage IV Melanoma

A.3.1

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

A study conducted in many hospitals, carried out in two groups of patients with advanced skin cancer who know that they are receiving the study medication and have previously received treatment for their advanced skin cancer and the disease has progressed since that treatment

A.4.1

Sponsor's protocol code number

E7080-G000-206

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 Inc
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Eisai Limited
B.5.2	Functional name of contact point	Medical Information
B.5.3	Address:
B.5.3.1	Street Address	European Knowledge Centre, 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	+440800001 4612
B.5.5	Fax number	+440845676 1388
B.5.6	E-mail	lmedinfo@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	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	E7080
D.3.2	Product code	E7080
D.3.4	Pharmaceutical form	Capsule, hard
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.3.9.2	Current sponsor code	E7080
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	4
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	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	E7080
D.3.2	Product code	E7080
D.3.4	Pharmaceutical form	Capsule, hard
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.3.9.2	Current sponsor code	E7080
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	10
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

American Joint Committee on Cancer unresectable stage III or stage IV melanima and disease progression with subjects not harboring the V600E-BRAF mutation with disease progression following first line standard of care (cohort 1) or subjects harboring the V600E-BRAF mutation with disease progression following BRAF-V600E-targeted therapy (cohort 2).

E.1.1.1

Medical condition in easily understood language

Advanced skin 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	18.1
E.1.2	Level	PT
E.1.2	Classification code	10025650
E.1.2	Term	Malignant melanoma
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

The primary objectives of this study are:
• To assess the ORR (complete response + partial response [CR + PR]) of E7080 in subjects with unresectable stage III or stage IV melanoma not harboring the V600E BRAF mutation and disease progression following first-line standard of care therapy (Cohort 1).
• To assess the ORR of E7080 in subjects with unresectable stage III or stage IV melanoma harboring the V600E BRAF mutation and disease progression following BRAF-V600E-targeted therapy (Cohort 2).

E.2.2

Secondary objectives of the trial

Secondary objectives:
• To assess progression-free survival and overall survival of subjects in this study population treated with E7080 (Cohorts 1 and 2).
• To assess the disease control rate (DCR; CR + PR + stable disease >=7 weeks); clinical benefit rate (CBR; CR + PR + durable SD rate); and durable SD rate >=23 weeks for subjects treated with E7080 (Cohorts 1 and 2).
• To assess the safety and tolerability of E7080 (Cohorts 1 and 2).
• To assess the pharmacokinetic profile and pharmacodynamics of E7080 in subjects with unresectable stage III or stage IV melanoma (Cohorts 1 and 2).

Exploratory objectives:
• To identify and evaluate blood and tumor biomarkers (including those based on mRNA and microRNA expression, DNA sequence, and proteomic signatures) which correlate with the efficacy-related endpoints of this study.
• To identify and evaluate DNA-sequence variants in genes influencing E7080 ADME.
• To compare the ORR between Cohort 1 and Cohort 2.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Histologically confirmed diagnosis of melanoma.
2. AJCC unresectable stage III or stage IV melanoma (Appendix 1).
3. Melanoma not harboring the V600E BRAF mutation (Cohort 1) and melanoma harboring the V600E BRAF mutation (Cohort 2).
4. Radiographic/photographic evidence of disease progression according to modified RECIST 1.1 (Appendix 2) following first-line standard of care therapy (Cohort 1) or BRAF-V600E-targeted therapy (Cohort 2) for unresectable stage III or stage IV disease.
5. Measurable disease meeting the following criteria:
– At least 1 lesion of >=1.5 cm in the longest diameter for a non-lymph node or >=1.5 cm in the short-axis diameter for a lymph node which is serially measurable according to modified RECIST 1.1 using computerized tomography/magnetic resonance imaging (CT/MRI) (see Section 8.5.1.3 Tumor Response Assessments and Appendix 2).
– Lesions that have had external beam radiotherapy (EBRT) or loco-regional therapies such as radiofrequency (RF) ablation must show evidence of progressive disease based on modified RECIST 1.1 to be deemed a target lesion.
6. ECOG performance status of 0 or 1 (Appendix 3).
7. Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP <=150/90 mmHg at screening and no change in antihypertensive medications within 1 week prior to the Screening Visit.
8. Adequate renal function defined as calculated creatinine clearance ≥30 mL/min per the Cockcroft and Gault formula (Appendix 4).
9. Adequate bone marrow function:
- Absolute neutrophil count (ANC) ≥1000/mm3 (≥1.0 x 103/micro/L);
- Platelets ≥100,000/mm3 (≥100 x 109/L);
- Hemoglobin ≥9.0 g/dL.
10. Adequate blood coagulation function as evidenced by an International Normalized Ratio (INR) <=1.5.
11. Adequate liver function:
- Bilirubin <=1.5 x the upper limit of normal (ULN) except for unconjugated hyperbilirubinaemia of Gilbert’s syndrome;
- Alkaline phosphatase, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) <=3 x ULN (<=5 x ULN if subject has liver metastases).
12. Males or females age ≥18 years at the time of informed consent.
13. All females must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of beta-human chorionic gonadotropin [β hCG]) at the Screening Visit (and/or within 72 hours of the first dose of study drug). Females of child-bearing potential must agree to use a medically acceptable method of contraception (e.g., abstinence, an intrauterine device [IUD], a double-barrier method such as condom + spermicide or condom + diaphragm with spermicide, a contraceptive implant, an oral contraceptive or have a vasectomised partner with confirmed azoospermia) throughout the entire study period and for 30 days after study drug discontinuation. The only subjects who will be exempt from this requirement are postmenopausal women (defined as women who have been amenorrheic for at least 12 consecutive months, in the appropriate age group, without other known or suspected primary cause) or subjects who have been sterilized surgically or who are otherwise proven sterile (i.e., bilateral tubal ligation with surgery at least 1 month prior to dosing, hysterectomy, or bilateral oophorectomy with surgery at least 1 month prior to dosing). All women who are of reproductive potential and who are using hormonal contraceptives must have been on a stable dose of the same hormonal contraceptive product for at least 4 weeks prior to dosing and must continue to use the same contraceptive during the study and for 30 days after study drug discontinuation.
14. Male subjects who are partners of women of childbearing potential must use or their partners must use a highly effective method of contraception (e.g., condom + spermicide, condom + diaphragm with spermicide, an IUD) beginning at least 1 menstrual cycle prior to starting study drug(s), throughout the entire study period, and for 30 days after the last dose of study drug, unless they are sexually abstinent or have undergone a successful vasectomy. Those with partners using hormonal contraceptives must also be using an additional approved method of contraception, as described previously.
15. Voluntary agreement to provide written informed consent and the willingness and ability to comply with all aspects of the protocol.

E.4

Principal exclusion criteria

1. Melanoma of intraocular origin.
2. Brain or leptomeningeal metastases.
3. More than 1 prior systemic chemotherapy regimen for unresectable stage III or stage IV disease or any treatment targeting vascular endothelial growth factor (VEGF)-directed angiogenesis. There is no restriction regarding prior adjuvant treatment (Cohort 1).
4. Subjects not previously treated with BRAF-V600E-targeted therapy for unresectable stage III or stage IV disease or subjects receiving any prior treatment targeting vascular endothelial growth factor (VEGF)-directed angiogenesis. There is no restriction regarding prior adjuvant treatment (Cohort 2).
5. Subjects who have received any anti-cancer treatment within 21 days or any investigational agent within 30 days prior to the first dose of study drug or who have not recovered from any acute toxicity related to previous anti-cancer treatment. The exception to this exclusion will be that subjects with rapid disease progression while receiving BRAF targeted therapy may begin E7080 treatment as soon as 14 days following the last dose of the BRAF targeted therapy.
6. Subjects with >1+ proteinuria on urinalysis will undergo 24-hour urine collection for quantitative assessment of proteinuria. Subjects with 24-hour urine protein ≥1 gm will be ineligible.
7. Inability to take oral medication, gastrointestinal malabsorption, or any other condition that might affect the absorption of E7080.
8. Major surgery within 3 weeks prior to the first dose of study drug.
9. Significant cardiovascular impairment: history or congestive heart failure greater than New York Heart Association (NYHA) Class II (Appendix 5); unstable angina; myocardial infarction or stroke within 6 months of the first dose of study drug; or cardiac arrhythmia requiring medical treatment.
10. Prolongation of QTc interval to >480 msec.
11. Bleeding disorder or a thrombotic disorder requiring anticoagulant therapy such as warfarin, or similar agents requiring therapeutic INR monitoring (treatment with low molecular weight heparin [LMWH] is allowed).
12. Active hemoptysis (bright red blood of at least ½ teaspoon) within 3 weeks prior to the first dose of study drug.
13. Active malignancy (except for melanoma, basal or squamous cell carcinoma of the skin, or carcinoma in-situ of the cervix) within the past 24 months.
14. Females who are pregnant or breastfeeding.
15. Know intolerance to the study drug (or any of the excipients).
16. Any medical or other condition which, in the opinion of the investigator, would preclude participation in a clinical trial.

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy endpoint is the objective response rate defined as the proportion of subjects in each cohort who have a best overall response of CR or PR based on modified RECIST 1.1 as determined by IRR.

E.5.1.1

Timepoint(s) of evaluation of this end point

End of the treatment phase for each cohort when all enrolled subjects complete a minimum of 6 cycles of treatment (or discontinue treatment prior to completing 6 cycles). The primary analysis for the 2 cohorts will be performed separately

E.5.2

Secondary end point(s)

Secondary endpoint is to assess the pfs and os of subjects, assess the disease control rate, clinical benefit rate and durable SD rate, assess safety and tolerability and assess the PK and PD of E7080 in subjects with unresectable stage III or stage IV melanoma

E.5.2.1

Timepoint(s) of evaluation of this end point

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

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

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)

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

E.8.1.1

Randomised

E.8.1.2

Open

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)

E.8.2.2

Placebo

E.8.2.3

Other

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

Information not present in EudraCT

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

Australia

Germany

United Kingdom

United States

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

The end of trial is when the last patient has completed treatement and had the final visit.

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:

160

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

180

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)

Treatment will continue until disease progression, development of unacceptable toxicity, withdrawal of consent or discontinuation of E7080 development by the Sponsor

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

2011-02-10

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-04-11

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2014-12-01

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