Clinical Trials Register

Summary
EudraCT Number:	2010-019318-26
Sponsor's Protocol Code Number:	IMCL_CP12-0919_(I4T-IE-JVBF)
National Competent Authority:	Sweden - MPA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2011-03-03
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

Sweden - MPA

A.2

EudraCT number

2010-019318-26

A.3

Full title of the trial

A Multicenter, Randomized, Double-Blind, Phase 3 Study of Ramucirumab (IMC-1121B) Drug Product and Best Supportive Care (BSC) Versus Placebo and BSC as Second-Line Treatment in Patients With Hepatocellular Carcinoma Following First-Line Therapy With Sorafenib

A.3.1

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

A Study of Ramucirumab and Best Supportive Care versus Placebo and Best Supportive care in patients with second line treatment advanced liver cancer after treatment with Sorafenib.

A.3.2

Name or abbreviated title of the trial where available

REACH

A.4.1

Sponsor's protocol code number

IMCL_CP12-0919_(I4T-IE-JVBF)

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01140347

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	ImClone LLC
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	ImClone Systems Corporation, a wholly-owned subsidiary
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	Eli Lilly and Company
B.5.2	Functional name of contact point	Clinical Trials Information
B.5.3	Address:
B.5.3.1	Street Address	Erl Wood Manor, Sunninghill Road
B.5.3.2	Town/ city	Windlesham, Surrey
B.5.3.4	Country	United Kingdom
B.5.6	E-mail	EU_Lilly_Clinical_Trials@lilly.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	ramucirumab
D.3.2	Product code	IMC-1121B, LY3009806
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	Ramucirumab
D.3.9.1	CAS number	947 687-13-0
D.3.9.2	Current sponsor code	IMC-1121B, LY3009806
D.3.9.3	Other descriptive name	recombinant human IgG1 monoclonal antibody
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	10
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

Hepatocellular Carcinoma

E.1.1.1

Medical condition in easily understood language

Advanced liver 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	16.0
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 compare the overall survival (OS; time from
randomization to death) in patients with hepatocellular carcinoma (HCC)
who had disease progression during or following sorafenib therapy, or
were intolerant to this agent.

E.2.2

Secondary objectives of the trial

Secondary objectives are to evaluate:
- Progression-free survival (PFS)
- Objective response rate (ORR)
- Time to radiographic progression
- Patient-reported outcome (PRO) measures of disease-specific symptoms and health-related quality of life
- Safety profile of ramucirumab DP
- Ramucirumab pharmacokinetics
- Immunogenicity of ramucirumab.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

* ECOG PS of 0 or 1.
* Child-Pugh score of < 7 (Child-Pugh Class A only).
* BCLC stage C or BCLC stage B not amenable to locoregional therapy or refractory to locoregional therapy.
* diagnosis of HCC (excluding fibrolamellar carcinoma) in the absence of histologic or cytologic confirmation
* There are either clinical, laboratory, or radiographic findings consistent with a diagnosis of liver cirrhosis.
* The patient has a liver mass measuring at least 2 cm with characteristic vascularization seen on either triphasic computed tomography (CT) scan or magnetic resonance imaging (MRI) with gadolinium.
* The patient has a serum alpha-fetoprotein (AFP) concentration greater than the institutional upper limit of normal (ULN).
* At least 1 measurable or evaluable lesion that is viable (ie, is vascularized), and has not been previously treated with
locoregional therapy. A lesion that has been previously treated will qualify as a measurable or evaluable lesion if there was demonstrable
progression following locoregional therapy.
* Previously treated with sorafenib and has discontinued sorafenib treatment at least 14 days prior to randomization. Patients may have experienced:
* Radiographically documented disease progression during sorafenib therapy or after discontinuation of sorafenib therapy, or
* Discontinuation of sorafenib due to an adverse drug reaction, despite dose reduction by 1 level and BSC.
* The patient has received sorafenib as the only systemic therapeutic intervention for advanced HCC. Any hepatic locoregional therapy that has been
administered prior to sorafenib is allowed, but not following sorafenib. Radiation to metastatic sites (eg, bone) following sorafenib therapy is permitted.
* Except where otherwise noted in the eligibility criteria, the patient has a resolution to grade ≤ 1 by the NCI-CTCAE v. 4.0 of all clinically significant toxic effects of prior locoregional therapy, surgery, chemoembolization or sorafenib.
Adequate organ function defined as:
* Total bilirubin < 3.0 mg/dL (51.3 μmol/L), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 5 × ULN;
* Serum creatinine ≤ 1.2 × ULN or calculated creatinine clearance > 50 mL/minute;
* Absolute neutrophil count (ANC) ≥ 1.0 × 10exp3/μL (1.0 × 10exp9/L), hemoglobin ≥ 9 g/dL (5.58 mmol/L), and platelets ≥ 75 × 10exp3/μL (75 × 10exp9/L);
* International Normalized Ratio (INR) ≤ 1.5. Patients receiving prophylactic low dose anticoagulant therapy are eligible provided that INR ≤ 1.5.
* The patient's urinary protein is ≤ 1+ on dipstick or routine urinalysis.
If urine dipstick or routine analysis indicates ≥ 2+ proteinuria, then a 24-hour urine must be collected and must demonstrate < 1000 mg of protein in 24 hours to allow participation in the study.

E.4

Principal exclusion criteria

* Major surgery within 28 days prior to randomization, or central venous access device placement within 7 days prior to randomization.
* Hepatic locoregional therapy within 28 days prior to randomization.
* Radiation to any nonhepatic (eg, bone) site within 14 days prior to randomization.
* Sorafenib within 14 days prior to randomization.
* Received any investigational therapy or non-approved drug within 28 days prior to randomization or is concurrently enrolled in any other type of medical research judged not to
be scientifically or medically compatible with this study.
* Received any previous systemic therapy with vascular endothelial growth factor (VEGF) inhibitors or vascular endothelial growth factor receptor (VEGFR) inhibitors (including investigational agents) other than sorafenib for treatment of HCC.
* Fibrolamellar carcinoma.
* Received any transfusion, blood component preparation, erythropoietin, albumin preparation, or granulocyte colony-stimulating factors (G-CSF) within 14 days prior to randomization.
* Therapeutic anticoagulation with warfarin, low-molecular-weight heparin, or similar agents. Patients receiving prophylactic, low-dose anticoagulation therapy are eligible provided that the coagulation parameters defined in the inclusion criteria (INR ≤ 1.5) are met.
* Receiving ongoing therapy with nonsteroidal anti-inflammatory agents (NSAIDs, eg, indomethacin, ibuprofen, naproxen, nimesulide, celecoxib, etoricoxib, or similar agents) or other antiplatelet agents (eg, clopidogrel, ticlopidine, prasugrel, dipyridamole, picotamide, indobufen, anagrelide, triflusal).Aspirin (ASA) at doses up to 100 mg/day is permitted.
* Symptomatic congestive heart failure, unstable angina pectoris, or symptomatic or poorly controlled cardiac arrhythmia.
* Any arterial thrombotic event, including myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack, within 6 months prior to randomization.
* Uncontrolled arterial hypertension ≥ 150 / ≥ 90 mm Hg despite standard medical management.
* Grade 3-4 gastrointestinal bleeding or any variceal bleeding episode in the 3 months prior to randomization requiring transfusion, endoscopic or operative intervention (patients with any bleeding episode considered life-threatening during the 3 months prior to randomization are excluded, regardless of transfusion or intervention status).
* Esophageal or gastric varices that require immediate intervention (eg, banding, sclerotherapy) or represent a high bleeding risk. Patients with evidence of portal hypertension (including splenomegaly) or any prior history of variceal bleeding must have had endoscopic evaluation within the 3 months immediately prior to randomization. Patients with evidence of portal hypertension are eligible for study participation if endoscopic evaluation does not indicate esophageal or gastric varices that require immediate intervention or represent a high bleeding risk; however, these eligible patients must receive supportive therapy (eg, beta blocker therapy) according to institutional standards and clinical guidelines during study participation.
* Central nervous system (CNS) metastases or carcinomatous meningitis.
* History of or current hepatic encephalopathy or current clinically meaningful ascites. Clinically meaningful ascites is defined as ascites resulting from cirrhosis and requiring ongoing treatment with diuretics and/or paracentesis.

E.5 End points

E.5.1

Primary end point(s)

Primary Efficacy Endpoint: Overall Survival
Overall survival is defined as the time from the date of randomization to the date of death from any cause.

E.5.1.1

Timepoint(s) of evaluation of this end point

• The first interim analysis will occur when 25% (109) deaths have been observed.
• The second interim analysis will be conducted when 50% (219) deaths have been observed.
• The third interim analysis will be conducted when 75% (328) deaths have been observed.
• The final OS analysis will be conducted when 100% (438) deaths have been observed. It will be a 1-sided test with a nominal significance level of 0.0241 to preserve the planned 0.025 overall significance level. Based on the assumptions, the expected time to observe this many events is 43 months from the enrollment of the first patient.

E.5.2

Secondary end point(s)

The secondary efficacy endpoints to be analyzed are:
• Progression-free survival
• ORR
• Time to radiographic progression
• Patient-reported outcomes
The analyses of the secondary endpoints will be adjusted by the stratification factors. An additional unstratified analysis will also be performed. The sequential order of the confirmatory testing after
OS will be: PFS, ORR, and TTP. Tests will continue in this order so long as the previous test is significant.

E.5.2.1

Timepoint(s) of evaluation of this end point

Secondary endpoints will be analyzed at the same time as OS and at the same level of significance. If the difference in OS is statistically significant at the 1-sided 0.005 level at the interim efficacy analysis, the secondary efficacy endpoints will be analyzed at that time also with a 1-sided significance level of 0.005. However, if statistical significance at the 0.005 level is not observed for OS at the interim analysis, the secondary efficacy endpoints will be analyzed at the end of the study with the same level of significance as OS ( 1-sided 0.0241), provided that OS is significant.
There may be additional exploratory efficacy analyses regarding response data, if deemed necessary.

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

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

immunogenicity

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

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

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

101

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

Austria

Belgium

Brazil

Bulgaria

Canada

China

Czech Republic

Finland

France

Germany

Hong Kong

Hungary

Indonesia

Israel

Italy

Japan

Korea, Republic of

Malaysia

Netherlands

New Zealand

Norway

Philippines

Portugal

Romania

Spain

Sweden

Switzerland

Taiwan

Thailand

Turkey

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

Study completion when 438 events observed and analysis of OS performed and fully interpreted as determined by Sponsor. End of trial occurs when Study completion occured and last patient discontinued study treatment and completed the 30-day safety followup visit (and any AE serious or considered related to study treatment or that caused discontinuation of treatment followed until the event has resolved, stabilized, returned to baseline, been deemed irreversible or otherwise explained).

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:

416

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

208

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

314

F.4.2.2

In the whole clinical trial

624

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)

Patients will be assigned to further treatments after discontinuation from the study at the discretion of the investigator.

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

2011-03-31

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-03-30

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2015-03-17

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