Clinical Trials Register

Summary
EudraCT Number:	2011-002347-10
Sponsor's Protocol Code Number:	E7080-703
National Competent Authority:	Hungary - National Institute of Pharmacy
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2011-08-29
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

Hungary - National Institute of Pharmacy

A.2

EudraCT number

2011-002347-10

A.3

Full title of the trial

A Phase II, Randomized, Double-Blind, Placebo-Controlled Study of Oral E7080 in Addition to Best Supportive Care (BSC) versus BSC Alone in Patients with Locally Advanced or Metastatic Non-Squamous Non-Small Cell Lung Cancer Who Have Failed at Least Two Systemic Anticancer Regimens

A.3.1

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

A study comparing the combination of the best supportive care plus E7080 versus best supportive care alone, in patients with advanced lung cancer or lung cancer that has spread, who have been previously treated, unsuccessfully, with at least 2 different treatments

A.4.1

Sponsor's protocol code number

E7080-703

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 Inc.
B.1.3.4	Country	United States
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.4.1	Name of organisation providing support	Pharmabio Development 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 Ltd
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	+4408000014612
B.5.5	Fax number	+4408456761388
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
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	lenvatinib
D.3.9.1	CAS number	857890-39-2
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
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	lenvatinib
D.3.9.1	CAS number	857890-39-2
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC)

E.1.1.1

Medical condition in easily understood language

Advanced lung 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	15.0
E.1.2	Level	PT
E.1.2	Classification code	10029522
E.1.2	Term	Non-small cell lung cancer stage IV
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	15.0
E.1.2	Level	PT
E.1.2	Classification code	10029521
E.1.2	Term	Non-small cell lung cancer stage IIIB
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	15.0
E.1.2	Level	PT
E.1.2	Classification code	10059515
E.1.2	Term	Non-small cell lung cancer metastatic
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

Compare the overall survival (OS) of patients receiving E7080 + BSC with those receiving placebo + best supportive care (BSC)

E.2.2

Secondary objectives of the trial

- Assess the safety and tolerability of E7080 administered as an oral 24 mg dose once daily on Days 1 to 28 of a 28-day cycle;
- Compare 6 month and 1-year survival rates of patients on E7080 + BSC with those on placebo + BSC;
- Compare the progression-free survival (PFS) of patients on E7080 + BSC with those on placebo + BSC;
- Compare the overall response rate (ORR; proportion of patients with complete response [CR] or partial response [PR]), response duration, and disease control rate (defined as the proportion of patients with CR, PR, or stable disease [SD] for ≥12 weeks) in patients on E7080 + BSC with those on placebo + BSC;
- To assess the pharmacokinetic (PK) profile of E7080 in patients with NSCLC

Exploratory objectives are:
- To assess blood pressure as a biomarker for response;
- To explore the PK/pharmacodynamic relationship between exposure to E7080 and response in patients with NSCLC.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Age ≥18 years;
2. Patients with histologically or cytologically confirmed non-squamous NSCLC with locally advanced or metastatic disease based on Tumor, Node, Metastasis (TNM) staging according to the American Joint Committee on Cancer (AJCC) Cancer Staging Manual, Seventh Edition, who have failed at least 2 lines of systemic anticancer therapy for advanced or metastatic NSCLC (does not include adjuvant chemotherapy);
In countries where erlotinib is approved and marketed for the treatment of NSCLC, patients must have received erlotinib (or
gefitinib for patients outside of the US) for their NSCLC if they have known EGFR activating mutations. Patients of unknown EGFR status who have not received prior erlotinib (or gefitinib) should be tested for EGFR activating mutations prior to study entry. In countries where crizotinib is approved and marketed, patients must have received crizotinib treatment for NSCLC that is anaplastic lymphoma kinase (ALK)-positive. Patients with ALK-positive NCSLC or patients with KRAS mutations are not required to have prior treatment with erlotinib or gefitinib;
3. Patients must have at least 1 site of measurable disease by the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v.1.1);
4. ECOG PS of 0 to 2;
5. Patients must have adequate renal function as evidenced by serum creatinine ≤1.5 X upper limit of normal (ULN) or calculated creatinine clearance ≥30 mL/min per the Cockcroft and Gault formula;
6. Blood pressure must be well-controlled (<140/90 mm Hg at Screening) with or without antihypertensive medication. Patients must have no history of hypertensive crisis or hypertensive encephalopathy;
7. Patients must have adequate bone marrow function as evidenced by absolute neutrophil count (ANC) ≥1.5 X 109/L, hemoglobin ≥9.0 g/dL, and platelet count ≥100 X 109/L;
8. Patients must have adequate liver function as evidenced by bilirubin ≤1.5 times the ULN, and alkaline phosphatase, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤3 X ULN (in the case of liver metastases, ≤5 X ULN). If there are bone metastases, liver-specific alkaline phosphatase may be separated from the total and used to assess liver function instead of total alkaline phosphatase;
9. Patients must have adequate coagulation system function as defined by prothrombin time/International normalized ratio (INR) ≤1.5 X ULN. Patients requiring INR monitoring are excluded. Low molecular weight heparin is allowed;
10. Male or female patients of child-producing potential must agree to use double barrier contraception, oral contraceptives, or avoidance of pregnancy measures during the study and for 90 days after the last day of treatment;
11. Females of childbearing potential must have a negative serum pregnancy test;
12. Females may not be breastfeeding;
13. Ability to understand and willingness to sign a written informed consent.

E.4

Principal exclusion criteria

1. Prior therapy with E7080 or other small molecule vascular endothelial growth factor inhibitors;
2. Presence of brain metastases, unless the patient has received adequate treatment at least 4 weeks prior to randomization, and is stable, asymptomatic, and off steroids for at least 4 weeks prior to randomization;
3. Meningeal carcinomatosis;
4. Received chemotherapy, targeted therapy, radiotherapy, surgery, or immunotherapy within the 21 days prior to commencing study treatment or have not recovered from all treatment-related toxicities to Grade ≤2, except for alopecia;
5. Received treatment with another investigational agent within the 30 days prior to commencing study treatment or patients who have not recovered from side effects of an investigational drug to Grade ≤2, except for alopecia;
6. Patients with proteinuria >1+ on urine dipstick testing will undergo 24-hour urine collection for quantitative assessment of proteinuria. Patients with 24-hour urine protein ≥1 g/24 hours will be ineligible;
7. Serious non-healing wound, ulcer, bone fracture, or have undergone a major surgical procedure, open biopsy, or significant traumatic injury within the 28 days prior to commencing study treatment. Minor surgery such as Portacath placement or skin biopsy is permitted if ≥7 days have passed;
8. Major surgery scheduled during the projected course of the study;
9. History of bleeding diathesis or coagulopathy;
10. Active hemoptysis (defined as bright red blood of a half teaspoon or more) within the 30 days prior to study entry;
11. Refractory nausea and vomiting, malabsorption, significant bowel resection, or any other medical condition that would preclude adequate absorption or result in the inability to take oral medication;
12. Other malignancy within 3 years of randomization, with the exception of adequately treated carcinoma in situ of the cervix or non-melanoma skin cancer, with no subsequent evidence of recurrence and/or malignancies diagnosed at a stage where definitive therapy results in near certain cures. The Medical Monitor must be consulted in such cases;
13. Significant cardiovascular impairment (history of congestive heart failure New York Heart Association [NYHA] Class >II, unstable angina or myocardial infarction within the past 6 months, or serious cardiac arrhythmia);
14. Any history of cerebral vascular accident (CVA), transient ischemic attack (TIA), or Grade ≥2 peripheral vascular disease unless they have had no evidence of active disease for at least 6 months prior to randomization;
15. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the 6 months prior to enrollment;
16. Patients with organ allografts requiring immunosuppression;
17. Known positive human immunodeficiency virus (HIV), known hepatitis B surface antigen, or hepatitis C positive;
18. Hypersensitivity to E7080 or any of the excipients;
19. Any history of or concomitant medical condition that, in the opinion of the Investigator, would compromise the patient’s ability to safely complete the study.

E.5 End points

E.5.1

Primary end point(s)

The primary end point is overall survival (OS).

E.5.1.1

Timepoint(s) of evaluation of this end point

90 deaths

E.5.2

Secondary end point(s)

6 month and 1-year survival rates
progression-free survival (PFS)
overall response rate (ORR; proportion of patients with complete response [CR] or partial response [PR]), response duration, and disease control rate (defined as the proportion of patients with CR, PR, or stable disease [SD] for ≥12 weeks)

E.5.2.1

Timepoint(s) of evaluation of this end point

PFS every 8 weeks
6 months, I year survival
ORR every 8 weeks

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

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)

E.8.2.2

Placebo

Yes

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

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

Belgium

Czech Republic

Hungary

India

Italy

Korea, Republic of

Netherlands

United Kingdom

United States

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

as per protocol

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

135

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)

usual care for the condition

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

2011-10-14

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-10-04

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2015-06-27

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