Clinical Trials Register

Summary
EudraCT Number:	2008-001727-65
Sponsor's Protocol Code Number:	IMCLCP12-0606/TRIO-012
National Competent Authority:	Poland - Office for Medicinal Products
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2009-02-12
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

Poland - Office for Medicinal Products

A.2

EudraCT number

2008-001727-65

A.3

Full title of the trial

A Multicenter, Multinational, Randomized, Double-Blind, Phase III Study of IMC-1121B Plus Docetaxel Versus Placebo Plus Docetaxel in Previously Untreated Patients with HER2-Negative, Unresectable, Locally-Recurrent or Metastatic Breast Cancer

A.3.1

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

Study investigating new drug, IMC-1121B, in patients with advanced breast cancer who have not yet been treated with drugs for breast cancer that has returned or is growing again and can not be removed by surgery, or that has spread to different parts of the body. Study has two groups: All patients will be treated with docetaxel. In addition, one group will receive IMC-1121B, the other group an inactive substance. Neither the patient nor the doctor will know the treatment group.

A.4.1

Sponsor's protocol code number

IMCLCP12-0606/TRIO-012

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT00703326

A.5.4

Other Identifiers

Name:

Lilly Number

Number:

I4T-IE-JVBC

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 of Eli Lilly and Company
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 Info
B.5.3.4	Country	United Kingdom
B.5.6	E-mail	Eli_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	IMC-1121B
D.3.2	Product code	IMC-1121B
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
D.3.9.3	Other descriptive name	recombinant human IgG1 monoclonal antibody (MAb) targeted to VEGFR-2
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

HER2-Negative, Unresectable, Locally-Recurrent or Metastatic Breast Cancer

E.1.1.1

Medical condition in easily understood language

Breast cancer returned or growing again locally and surgery not possible or that has spread to different parts of the body. The protein, HER2, cannot be detected or detected at very low concentrations

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	19.0
E.1.2	Level	LLT
E.1.2	Classification code	10027475
E.1.2	Term	Metastatic breast cancer
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

To compare the PFS of the drug combination IMC -1121B plus docetaxel to placebo plus docetaxel in previously untreated patients with HER2-negative, unresectable, locally-recurrent or metastatic breast cancer.

E.2.2

Secondary objectives of the trial

· to compare the overall survival of the drug combination IMC -1121B plus docetaxel to placebo plus docetaxel in previously untreated patients with HER2-negative, unresectable, locally-recurrent or metastatic breast cancer
· to compare the TTP, ORR, and duration of response between the two treatment arms
· to compare the safety of the two treatment arms
· to compare the quality of life of the two treatment arms
· to assess the immunogenicity of IMC-1121B

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Each patient must meet the following criteria to be randomized in this study:
1. The patient is able to provide signed informed consent.
2. The patient is female and ≥ 18 years of age or older if required by local laws or regulations.
3. The patient has histologically or cytologically confirmed adenocarcinoma of the breast that is now metastatic or locally-recurrent and inoperable with curative intent. Every effort should be made to make paraffin-embedded tissue or slides from the diagnostic biopsy or surgical specimen available for confirmation of diagnosis.
4. The patient has measurable and/or non-measurable disease.
5. The patients’ primary and/or metastatic tumor is HER2-negative by fluorescence in situ hybridization (FISH) or chromogenic in-situ hybridization (CISH) or 0, 1+ overexpression by immunohistochemistry (IHC).
6. The patient has not received prior chemotherapy for metastatic or locally recurrent and inoperable breast cancer.
7. The patient completed (neo) adjuvant taxane therapy at least 6 months prior to randomization.
8. The patient completed (neo) adjuvant biologic therapy at least 6 weeks prior to randomization.
9. The patient completed all prior radiotherapy with curative intent ≥ 3 weeks prior to randomization.
10. The patient may have received prior hormonal therapy for breast cancer in the (neo) adjuvant and/or the metastatic setting provided it was discontinued ≥ 2 weeks prior to randomization.
11. The patient’s left ventricular ejection fraction is within normal institutional ranges.
12. The patient has resolution to grade ≤ 1 by the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3 (NCI-CTCAE v 3.0) of all clinically significant toxic effects of prior chemotherapy, surgery, radiotherapy, or hormonal therapy with the exception of peripheral neuropathy which must have resolved to grade ≤ 2.
13. The patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
14. The patient is amenable to compliance with protocol schedules and testing.
15. The patient has adequate hematological functions (absolute neutrophil count [ANC] ≥ 1500 cells/mL, hemoglobin ≥ 9 g/dL, and platelets ≥ 100,000 cells/mL and
≤ 850,000 cells/mL).
16. The patient has adequate hepatic function (bilirubin within normal limits [WNL], or below the upper limit of normal [ULN], aspartate transaminase [AST] and alanine transaminase [ALT] ≤ 2.5 times the upper limit of normal [ULN], or ≤ 5.0 times the ULN if the transaminase elevation is due to liver metastases, and alkaline phosphatase ≤ 5.0 times the ULN).
17. The patient has serum creatinine ≤ 1.5 x ULN. If serum creatinine > 1.5 x ULN the
calculated creatinine clearance should be > 40 mL/min).
18. The patient’s urinary protein is ≤ 1+ on dipstick or routine urinalysis (UA); if urine
protein ≥ 2+, a 24-hour urine collection must demonstrate < 1000 mg of protein in 24 hours to allow participation in the study.
19. The patient must have adequate coagulation function as defined by international
normalized ratio (INR) ≤ 1.5 and a partial thromboplastin time (PTT) ≤ 1.5 X ULN if not receiving anticoagulation therapy. Patients on full-dose anticoagulation must be on a stable dose of oral anticoagulant or low molecular weight heparin and if on warfarin must have a INR between 2 and 3 and have no active bleeding (defined as within 14 days of randomization) or pathological condition that carries a high risk of bleeding (eg, tumor involving major vessels or known varices).
20. Women of childbearing potential must implement adequate contraception in the opinion of the investigator.
21. The patient has not received prior biologic therapy for metastatic or locally recurrent and inoperable breast cancer.

E.4

Principal exclusion criteria

A patient who has any of the following criteria will be excluded from the study:
1. The patient has a concurrent active malignancy other than breast adenocarcinoma,
adequately treated non-melanomatous skin cancer, or other non-invasive carcinoma or in situ neoplasm. A patient with previous history of malignancy is eligible, provided that she has been disease free for > 3 years.
2. The patient has a known sensitivity to docetaxel or other drugs formulated with polysorbate 80.
3. The patient has a known sensitivity to agents of similar biologic composition as IMC-1121B or other agents that specifically target VEGF.
4. The patient has a history of chronic diarrheal disease within 6 months prior to randomization.
5. The patient has received irradiation to a major bone marrow area as defined as > 25% of bone marrow (eg, pelvic or abdominal radiation) within 30 days prior to randomization.
6. The patient has participated in clinical trials of experimental agents within 4 weeks prior to randomization.
7. The patient has a history of uncontrolled hereditary or acquired bleeding or thrombotic disorders.
8. The patient has active, high risk bleeding (eg, via gastric ulcers or gastric varices) within 14 days prior to randomization.
9. The patient has an ongoing or active infection requiring parenteral antibiotic, antifungal, or antiviral therapy.
10. The patient has uncontrolled hypertension, symptomatic congestive heart failure, unstable angina pectoris, symptomatic or poorly controlled cardiac arrhythmia, psychiatric illness/social situations, or any other serious uncontrolled medical disorders in the opinion of the investigator.
11. The patient has brain metastases, uncontrolled spinal cord compression, or carcinomatous meningitis, or new evidence of brain or leptomeningeal disease.
12. The patient has known human immunodeficiency virus infection or acquired immunodeficiency syndrome-related illness.
13. The patient has pulmonary lymphangitic involvement that results in pulmonary dysfunction requiring active treatment, including the use of oxygen.
14. The patient is pregnant or lactating.

E.5 End points

E.5.1

Primary end point(s)

Progression-Free Survival (PFS)

Progression-free survival (PFS) is measured from the date of randomization to the first documented date of disease progression or death from any cause.

E.5.1.1

Timepoint(s) of evaluation of this end point

Time point defined by first documented date of disease progression.

E.5.2

Secondary end point(s)

- Overall Survival (OS)
Overall survival is measured as the interval from randomization to the date of death from any cause.

- Time to Progression (TTP)
Time to progression is the interval from the date of randomization to the first documented date of disease progression.

- Percentage of Participants with Objective Response (Objective Response Rate - ORR)
The percentage of participants with a confirmed best overall response of complete response (CR) or partial response (PR).

- Duration of Response
Duration of response is the interval from date of initial documented response (complete response or partial response) to the first documented date of disease progression or death.

- Total Functional Assessment of Cancer Therapy-Breast (FACT-B): Change From Baseline to End of Therapy
FACT-B measures the following domains of health-related quality of life (HR-QL): physical well-being (PWB), social/family well-being (SFWB), emotional well-being (EWB), functional well-being (FWB), & additional concerns of breast cancer (BCS). Total FACT-B scores range from 0-144, with higher scores representing better HR-QOL.

E.5.2.1

Timepoint(s) of evaluation of this end point

OS, TTP, ORR, duration of response will be captured as defined by definition per patient.
All patients will be followed for survival at regularly scheduled intervals (every 6 weeks until progressive disease and every 6 months thereafter) until death or for at least 36 months after discontinuing study therapy.

FACT-B: baseline, every 4 cycles and at the end of therapy

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

Yes

E.6.13.1

Other scope of the trial description

immunogenicity and circulating tumor cells testing

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

Yes

E.8.1.7.1

Other trial design description

Extension Lead Period and Extension Perios: unblinded

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

Australia

Belgium

Brazil

Canada

Croatia

Czech Republic

Egypt

Germany

Ireland

Israel

Korea, Republic of

Lebanon

New Zealand

Peru

Poland

Russian Federation

Serbia

Slovakia

South Africa

Spain

Taiwan

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

• A sufficient number of events have been observed for final analysis
of the secondary endpoint overall survival (792 OS events) and
• The last patient has discontinued study treatment and completed the
30-Day Safety Follow-up visit or
• The Steering Committee terminates the study

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