Clinical Trials Register

Summary
EudraCT Number:	2010-021082-74
Sponsor's Protocol Code Number:	U31287-A-U201
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:	2011-06-09
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

Bulgarian Drug Agency

A.2

EudraCT number

2010-021082-74

A.3

Full title of the trial

RANDOMIZED, PLACEBO-CONTROLLED, DOUBLE-BLIND PHASE 1B/2 STUDY OF U3-1287 (AMG 888) IN COMBINATION WITH ERLOTINIB IN EGFR TREATMENT NAÏVE SUBJECTS WITH ADVANCED NON-SMALL CELL LUNG CANCER (NSCLC) WHO HAVE PROGRESSED ON AT LEAST ONE PRIOR CHEMOTHERAPY

A.3.1

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

A Randomized Study comparing placebo and U3-1287 (AMG888) in
combination with erlotinib in treatment of subjects with advanced nonsmall cell lung cancer who have progressed on at least one prior
chemotherapy

A.4.1

Sponsor's protocol code number

U31287-A-U201

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01211483

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	DAIICHI SANKYO DEVELOPMENT 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	Daiichi Sankyo Pharma Development
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	Daiichi Sankyo Development Limited
B.5.2	Functional name of contact point	Clinical Trial Information
B.5.3	Address:
B.5.3.1	Street Address	Chiltern Place, Chalfont Park
B.5.3.2	Town/ city	Gerrards Cross, Buckinghamshire
B.5.3.3	Post code	SL9 0BG
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	+44 1753 482800
B.5.5	Fax number	+44 1753 899107
B.5.6	E-mail	info@dsd-eu.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	U3-1287 (AMG 888)
D.3.2	Product code	U3-1287 (AMG 888)
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 use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.1	CAS number	1262787-83-6
D.3.9.2	Current sponsor code	U3-1287
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	70
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Treatment for advanced or metastatic NSCLC in combination with erlotinib in subjects who are epidermal growth factor receptor (EGFR) treatment naïve after failure of at least one prior chemotherapy regimen

E.1.1.1

Medical condition in easily understood language

Non-small cell lung cancer (NSCLC) is a general term for the most
common form of solid cancer which affects the lungs.

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	14.1
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.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
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	14.1
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.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Phase 1b Portion
- To evaluate the safety and tolerability of the
combination of U3-1287 (AMG 888) and erlotinib in subjects with advanced or metastatic NSCLC.
- To determine the recommended dose of U3-1287 (AMG 888) for Phase 2 study (RP2D)in combination with erlotinib.

Phase II Portion
- To evaluate progression-free survival (PFS) among all randomized subjects treated with erlotinib in combination with high and low doses of U3-1287 (AMG 888) compared to erlotinib plus placebo.
- To evaluate the safety profile of the combination of U3-1287 (AMG 888) and erlotinib.

E.2.2

Secondary objectives of the trial

Phase Ib Portion
- To assess tumor response of U3-1287 (AMG 888) when combined with erlotinib.
- To assess the pharmacokinetic (PK) parameters of U3-1287 (AMG 888) when combined with erlotinib.
Phase II Portion
- To evaluate overall survival, objective response rate (ORR), duration of response, time to response, time to disease progression, duration of stable disease, and disease control rate (complete response [CR] + partial response [PR] + stable disease [SD]) among all randomized subjects treated with erlotinib in combination with high and low doses of U3-1287 (AMG 888) compared to erlotinib plus placebo.
- To assess the PK parameters of U3-1287 (AMG 888) when combined with erlotinib.
- To assess the PK parameters of erlotinib when combined with U3-1287 (AMG 888).
- To evaluate the incidence of HAHA formation (anti-U3-1287 [AMG 888] antibodies).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Men or women ≥ 18 years old.

2. Histologically or cytologically confirmed NSCLC
with either:
− Metastatic disease (Stage IV) OR
− Stage IIIB disease not amenable to surgery or curative intent.

3. Disease progression or recurrence following treatment after last chemotherapy or chemoradiation regimen (completed within the previous 12 months) documented by radiographic assessment.

4. Measurable disease per RECIST guidelines Version 1.1.

5. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.

6. Hematological function, as follows:
− Absolute neutrophil count (ANC) ≥ 1.5 × 10e9/L
− Platelet count ≥ 100 × 10e9/L
− Hemoglobin ≥ 9 g/dL.

7. Renal function, as follows:
− Calculated creatinine clearance ≥ 60 mL/min using the modified Cockroft-Gault equation or serum creatinine ≤ 1.5 x ULN.

8. Hepatic function, as follows:
− Aspartate aminotransferase (AST) ≤ 2.5 ×upper limit of normal (ULN) (if liver
metastases are present, < 5 × ULN)
− Alanine aminotransferase (ALT) ≤ 2.5 ×ULN (if liver metastases are present,
< 5 × ULN)
− Alkaline phosphatase ≤ 2.5 × ULN (if bone or liver metastases are present, < 5 × ULN)
− Bilirubin ≤ 1.5 × ULN.

9. Prothrombin time (PT) and partial thromboplastin time (PTT) ≤ 1.5 × ULN.

10. Availability of recent (before treatment start) or archival (does not have to be provided by treatment start) tumor specimen (Phase 2 subjects only).

11. For female subjects, must be postmenopausal (no menstrual period for a minimum of 12 months) or surgically sterile, or must use maximally effective birth control during the period of therapy, and be willing to use contraception for 6 months following the last investigational drug dose and have a negative urine or serum pregnancy test upon entry into this study if female subjects of childbearing
potential.

12. For male subjects, must be surgically sterile or willing to use a double barrier contraception method upon enrollment, during the course of the study, and for 6 months following the last investigational drug dose.

13. Subjects must be competent and able to comprehend, sign, and date an Independent Ethics Committee- or Institutional Review Board-approved
Informed Consent Form (including Health Insurance Portability and Accountability Act
authorization, if applicable) before performance of any study-specific procedures or tests.

E.4

Principal exclusion criteria

1. Left ventricular ejection fraction (LVEF) < 45%.

2. Prior EGFR-targeted regimen, anti-HER2, anti-HER3, or anti-HER4 therapy.

3. More than 2 prior chemotherapy regimens for this indication (Phase 2 subjects only).

4. History of other malignancies, except adequately treated non-melanoma skin cancer, curatively treated in-situ disease, or other solid tumors curatively treated with no evidence of disease for ≥ 5 years.

5. History of corneal disease.

6. History of interstitial lung disease.

7. Clinically active brain metastases, defined as untreated symptomatic, or requiring therapy with steroids or anticonvulsants to control associated symptoms. Subjects with treated brain metastases that are no longer symptomatic and require no reatment with steroids may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 4 weeks (2 weeks for subjects with a solitary brain lesion amenable to stereotactic radiosurgery) must have elapsed etween the end of radiotherapy and study enrollment.

8. Uncontrolled hypertension (diastolic > 100 mmHg or systolic > 140 mmHg). It is permissible for the subject to receive treatment with antihypertensive medication to maintain blood pressure within required parameters.

9. Clinically significant electrocardiogram (ECG) changes that obscure the ability to assess the RR, PR, QT, QTc, and QRS intervals.

10. Ascites or pleural effusion requiring chronic medical intervention.

11. Myocardial infarction within 1 year before enrollment, symptomatic congestive heart failure (New York Heart Association >Class II), unstable angina, or unstable cardiac arrhythmia requiring medication.

12. Treatment with anticancer therapy, antibody-based therapy, retinoid therapy, or hormonal therapy within 4 weeks before study drug treatment or treatment with nitrosoureas or mitomycin C within 6 weeks before study drug treatment or treatment with small molecule tyrosine kinase inhibitors (TKIs) within 2 weeks before study drug treatment. Prior and concurrent use of hormone replacement therapy is permitted.

13. Therapeutic radiation therapy or major surgery within 4 weeks before study drug treatment or palliative radiation therapy within 2 weeks before study drug reatment. Radiation treatment to all sites of measureable disease unless progression is
documented after radiation. No target lesion should be selected within the reviously irradiated field unless there was progression at that lesion following radiation.

14. Participated in clinical drug trials within 4 weeks (2 weeks for small molecule TKIs) before study drug treatment. Current participation in other investigational procedures.

15. Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals, known human immunodeficiency virus (HIV) infection, or active hepatitis B or C infection.

16. History of hypersensitivity to any of the study drugs or to any excipients.

17. Concurrent use of CYP3A4 inducers or inhibitors.

18. Any known pre-existing condition including substance abuse that could interfere with subject’s participation in and completion of the protocol.

E.5 End points

E.5.1

Primary end point(s)

• Treatment-emergent AEs
• Clinically significant or ≥ grade 3 events according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 in safety laboratory tests, physical examinations, ECGs, echocardiograms, or vital signs
• Incidence of DLTs (used to identify RP2D, if applicable) - Phase 1b
• PFS - Phase 2

E.5.1.1

Timepoint(s) of evaluation of this end point

12 months

E.5.2

Secondary end point(s)

For both Phase 1b and Phase 2
· PK parameters (Cmin, Cmax and AUC) of U3-1287 (AMG 888) when
combined with erlotinib
· PK parameters (Cmin, Cmax and AUC) of erlotinib when combined with
U3-1287(AMG 888)
· HAHA profile for U3-1287 (AMG 888)
· Best overall tumor response
For Phase 2 only
· Overall survival (OS)
· ORR
· Duration of response
· Time to response
· Duration of stable disease (SD)
· Time to disease progression (TTP)
· Disease control rate (CR+PR+SD)

E.5.2.1

Timepoint(s) of evaluation of this end point

12 months

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

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

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

biomarker

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

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

Belgium

Bulgaria

Germany

Hungary

Israel

Italy

Lithuania

Romania

Slovenia

Ukraine

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

Refer to 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	No
F.1.1.1	In Utero	No
F.1.1.2	Preterm newborn infants (up to gestational age < 37 weeks)	No
F.1.1.3	Newborns (0-27 days)	No
F.1.1.4	Infants and toddlers (28 days-23 months)	No
F.1.1.5	Children (2-11years)	No
F.1.1.6	Adolescents (12-17 years)	No
F.1.2	Adults (18-64 years)	Yes
F.1.3	Elderly (>=65 years)	Yes
F.2 Gender
F.2.1	Female	Yes
F.2.2	Male	Yes
F.3 Group of trial subjects
F.3.1	Healthy volunteers	No
F.3.2	Patients	Yes
F.3.3	Specific vulnerable populations	Yes
F.3.3.1	Women of childbearing potential not using contraception	No
F.3.3.2	Women of child-bearing potential using contraception	Yes
F.3.3.3	Pregnant women	No
F.3.3.4	Nursing women	No
F.3.3.5	Emergency situation	No
F.3.3.6	Subjects incapable of giving consent personally	No
F.3.3.7	Others	No
F.4 Planned number of subjects to be included
F.4.1	In the member state	20
F.4.2	For a multinational trial
F.4.2.1	In the EEA	195
F.4.2.2	In the whole clinical trial	210

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

2011-07-28

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-07-21

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2013-12-06

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