Clinical Trials Register

Summary
EudraCT Number:	2008-006212-38
Sponsor's Protocol Code Number:	20080580
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:	2009-04-14
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

2008-006212-38

A.3

Full title of the trial

Phase 2, Open-label Single-Arm, Multi-Center Study to Evaluate the Efficacy and Safety of AMG 386 and Sorafenib as First Line Therapy for Subjects with Advanced or Inoperable Hepatocellular Carcinoma.

A.3.1

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

A Study of the Effectiveness and Safety of AMG 386 and Sorafenib to Treat Advanced or Inoperable Hepatocellular Cancer

A.3.2

Name or abbreviated title of the trial where available

Not applicable

A.4.1

Sponsor's protocol code number

20080580

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT00872014

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	Amgen 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	Amgen 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	Amgen (EUROPE) GmbH
B.5.2	Functional name of contact point	IHQ Medical Info - Clinical Trials
B.5.3	Address:
B.5.3.1	Street Address	Dammstrasse 23, P.o. Box 1557
B.5.3.2	Town/ city	Zug
B.5.3.3	Post code	(CH-)6300
B.5.3.4	Country	Switzerland
B.5.6	E-mail	MedinfoInternational@amgen.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	AMG 386
D.3.2	Product code	AMG 386
D.3.4	Pharmaceutical form	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.3.8	INN - Proposed INN	N/A
D.3.9.1	CAS number	N/A
D.3.9.2	Current sponsor code	AMG 386
D.3.9.3	Other descriptive name	N/A
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	30
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.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	AMG 386
D.3.2	Product code	AMG 386
D.3.4	Pharmaceutical form	Powder 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.3.8	INN - Proposed INN	N/A
D.3.9.1	CAS number	N/A
D.3.9.2	Current sponsor code	AMG 386
D.3.9.3	Other descriptive name	N/A
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	240
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

advanced or inoperable hepatocellular carcinoma

E.1.1.1

Medical condition in easily understood language

advanced or inoperable hepatocellular carcinoma (a cancer of the liver)

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	17.1
E.1.2	Level	LLT
E.1.2	Classification code	10019828
E.1.2	Term	Hepatocellular carcinoma non-resectable
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

The primary objective is to evaluate the efficacy of AMG 386 in combination with sorafenib as measured by the progression-free survival rate (PFS) at 4 months in subjects with advanced or inoperable hepatocellular carcinoma (HCC).

E.2.2

Secondary objectives of the trial

• To evaluate the safety and tolerability of AMG 386 in combination with sorafenib in subjects with advanced or inoperable hepatocellular carcinoma and Child Pugh A liver function score
• To estimate the efficacy (as measured by objective response rate [ORR], disease control rate [DCR], time to progression [TTP], progression free survival [PFS], and overall survival [OS]) of AMG 386 10 mg/kg or 15 mg/kg IV QW in combination with sorafenib 400 mg PO BID in subjects with advanced or inoperable hepatocellular carcinoma
• To evaluate the pharmacokinetics (PK) of AMG 386 and sorafenib when used in combination (only in a sub-group of subjects at selected sites outside of Europe for sorafenib)
• To determine the incidence of occurrence of anti-AMG386 antibody formation

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Disease Related
• Subjects must have histologically confirmed advanced or inoperable HCC. Biopsy by fine needle aspirate (FNA) is not preferred over a core biopsy but acceptable
• Child-Pugh liver function class A (see Appendix G)
• Measurable disease with at least one unidimensionally measurable lesion per RECIST criteria 1.0 with modifications (see Appendix E).
Demographic
• Men or women ≥ 18 years old
• Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less
• Subjects of child-bearing potential and sexually active must consent to the use of an accepted and effective non-hormonal method of contraception (ie, double barrier method [eg, condom plus diaphragm]) from signing the informed consent through 6 months following last administration of study drug
Laboratory
Adequate organ and hematological function as evidenced by the following laboratory studies within 14 days prior to enrollment:
o Hematological function, as follows:
• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
• Platelet count ≥ 60 x 109/L
• Hemoglobin ≥ 8.5 g/dL
o Renal function, as follows:
• Creatinine clearance > 40 mL/min per 24-hour urine collection or
calculated according to the Cockcroft-Gault formula

(140-age) x actual body weight (kg) ( x 0.85 for
CrCl (mL/min) 72 x serum creatinine (mg/dL) females)

Or

CrCl (140-age) x actual body weight (kg) ( x 0.85 for
(mL/min) 0.8136 x serum creatinine (umol/L) females)

Urinary protein quantitative value of ≤ 30 mg/dL in urinalysis or
≤1+ on dipstick, unless quantitative protein is < 1000 mg in a
24 hour urine sample
o Hepatic function, as follows:
• Total bilirubin ≤ 2.0 mg/dL
o Hemostatic function, as follows:
• International Normalized Ratio (INR) ≤ 2.2
General
• Able to tolerate infusions and self-administer oral medications
• Competent to comprehend, sign, and date an institutional review board (IRB)/Independent Ethics Committee (IEC) -approved informed consent form
• Life expectancy ≥ 3 months (per investigator opinion)
• Subject plans to begin protocol directed therapy within 7 days of enrollment

E.4

Principal exclusion criteria

Disease Related
• Subject is eligible for liver transplant per investigator’s discretion
• Any previous systemic chemotherapy for HCC (chemotherapy or targeted therapies)
• Previous surgical resections are allowed if ≥ 30 days elapsed prior to enrollment
• Locoregional therapies (eg, TACE) are allowed if ≥ 30 days elapsed prior to enrollment provided that subjects either have a target lesion which has not been subjected to local therapy and/or the target lesions(s) within the field of the local therapy has shown an increase of ≥ 20% in size
• History of arterial or venous thromboembolism within 12 months prior to enrollment
o Subjects with portal vein thrombosis are eligible for this study
except those with main portal vein thrombosis defined as the part of
the portal vein between the inferior vena cava and the first
bifurcation into the left and right vein
• History of clinically significant bleeding within 6 months prior to enrollment (including pulmonary hemorrhage, gastroesophageal varices or gross hemoptysis (≥ 1/2 teaspoon or 2.5 mL of bright red blood)
• Known history of central nervous system metastases. An MRI or CT scan of the brain or head will be performed within 28 days prior to enrollment.
• Patients with fibrolamellar hepatocellular carcinoma
• Radiation therapy ≤ 14 days prior to enrollment. Subjects who received radiation therapy must have recovered from all radiation induced toxicities prior to enrollment
Medications
• Currently or previously treated with sorafenib or other small molecule inhibitors of VEGF including, but not limited to AMG 706 (motesanib), SU11248 (sunitinib), PTK787 (vatalanib), AZD 2171 (cediranib), AEE-788
• Currently or previously treated with AMG 386, or other molecules that inhibit the angiopoietins or Tie2 receptor
• Concomitant or use within 30 days prior to enrollment of any strong inducer of CYP3A4 including, but not limited to, rifampin, St. John’s wort, phenytoin, carbamazepine, phenobarbital and dexamethasone. Dexamethasone as bolus injection or premedication is allowed.
• Concomitant anti-viral therapy is allowed with the exception of interferon alfa or pegylated interferon alfa therapy
• Current or within 30 days prior to enrollment treatment with immune modulators such as systemic cyclosporine and tacrolimus
• Enrolled in or has not yet completed at least 30 days since ending other investigational device or drug trials, or currently receiving other investigational treatments
General Medical
• Known ongoing pancreatitis
• Clinically significant cardiovascular disease within 12 months prior to enrollment, including myocardial infarction, unstable angina, grade 2 or greater peripheral vascular disease, cerebrovascular accident, transient ischemic attack, congestive heart failure, or arrhythmias not controlled by outpatient medication, percutaneous transluminal coronary angioplasty/stent
• Major surgery within 4 weeks before enrollment or still recovering from prior surgery
• History of allergic reactions to bacterially produced proteins
• Pregnant (ie, positive beta-human chorionic gonadotropin test) or is breast feeding
• Exclude subjects with a history of prior malignancy (see protocol)
• Minor surgical procedures, except placement of tunneled central venous access device (except PICC or peripherally inserted central catheter), or fine needle aspiration within 7 days prior to enrollment
• Uncontrolled hypertension as defined as diastolic > 90 mmHg OR systolic > 150 mmHg. The use of anti-hypertensive medications to control hypertension is permitted.
• Known active or ongoing infection (except uncomplicated urinary tract infection [UTI]) within 14 days before enrollment
• Subject known positive test(s) for human immunodeficiency virus (HIV) infection,
• Anticoagulation therapy must be stopped 1 week prior to enrollment except:
- aspirin and anti-platelet agents
- low dose warfarin or derivatives (e.g. coumarin) (ie. ≤ 1mg daily)
• Non-healing wound, ulcer (including gastrointestinal) or fracture
Other
• Any condition which in the investigator’s opinion makes the subject unsuitable for study participation
• Other investigational procedures are excluded.
• Subject will not be available for follow-up assessment
• Subject has any kind of disorder that compromises the ability of the subject to give written informed consent and/or to comply with study procedures

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is progression-free survival (PFS) rate at 4 months.

E.5.1.1

Timepoint(s) of evaluation of this end point

The primary analysis of efficacy and safety will occur after the last subject enrolled has been followed for at least 4 months. The primary analysis of efficacy may occur at different times in cohorts A and B and will be performed separately for the 2 cohorts. The final analysis will occur after all the subjects have completed the long-term follow-up.

E.5.2

Secondary end point(s)

• Incidence of adverse events and significant laboratory abnormalities
• Objective response rate (ORR)
• Disease Control Rate (DCR)
• Progression Free Survival (PFS)
• Overall Survival (OS)
• Time to progression (TTP)
• Pharmacokinetic (PK) parameters (Cmax and Cmin) for AMG 386 when used in combination with sorafenib
• Pharmacokinetic (PK) parameter (Cmin) for sorafenib when used in combination with AMG 386 in a sub-group of subjects at selected sites outside of Europe
• Incidence of the occurrence of anti-AMG 386 antibody formation

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

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

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

Yes

E.8.2.3.1

Comparator description

Historical comparator data

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

Australia

France

Germany

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 study is when all subjects have completed the treatment period or safety follow-up or long-term follow-up (maximum 48 months from the date the last subject was enrolled), whichever is later.

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.1.2.1	Number of subjects for this age range:	29
F.1.3	Elderly (>=65 years)	Yes
F.1.3.1	Number of subjects for this age range:	31
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	8
F.4.2	For a multinational trial
F.4.2.1	In the EEA	16
F.4.2.2	In the whole clinical trial	60

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

2009-07-13

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2009-09-22

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2015-06-21

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