Clinical Trials Register

Summary
EudraCT Number:	2011-003399-36
Sponsor's Protocol Code Number:	MK-4214-008
National Competent Authority:	Latvia - SAM
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2011-08-25
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

Latvia - SAM

A.2

EudraCT number

2011-003399-36

A.3

Full title of the trial

A Phase III Randomized, Double-Blind, Active-Controlled Clinical Trial to Study the Efficacy and Safety of MK-4214 (filgrastim) and Neupogen™ as an Adjunct to Combination Chemotherapy with Doxorubicin and Docetaxel in Breast Cancer Patients

A.4.1

Sponsor's protocol code number

MK-4214-008

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	Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., 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	Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., 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	MSD Regional Business Support Center GmbH
B.5.2	Functional name of contact point	Steven Hildemann
B.5.3	Address:
B.5.3.1	Street Address	Richard-Reitzner-Allee 1
B.5.3.2	Town/ city	Haar
B.5.3.3	Post code	85540
B.5.3.4	Country	Germany
B.5.4	Telephone number	+498962731350
B.5.5	Fax number	+4989456655222
B.5.6	E-mail	steven.hildemann@essex.de

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	Filgrastim
D.3.2	Product code	MK-4214
D.3.4	Pharmaceutical form	Solution for injection in pre-filled syringe
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Filgrastim
D.3.9.2	Current sponsor code	MK-4214
D.3.9.3	Other descriptive name	Recombinant human granulocyte colony-stimulating factor
D.3.10	Strength
D.3.10.1	Concentration unit	µg/kg microgram(s)/kilogram
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	5
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	Comparator
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	Yes
D.2.1.1.1	Trade name	Neupogen™
D.2.1.1.2	Name of the Marketing Authorisation holder	Amgen Inc.
D.2.1.2	Country which granted the Marketing Authorisation	United States
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	Neupogen™
D.3.4	Pharmaceutical form	Solution for injection in pre-filled syringe
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Filgrastim
D.3.9.1	CAS number	143011-72-7
D.3.9.3	Other descriptive name	Neupogen™
D.3.9.4	EV Substance Code	SUB14018MIG
D.3.10	Strength
D.3.10.1	Concentration unit	µg/kg microgram(s)/kilogram
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	5
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

Breast Cancer

E.1.1.1

Medical condition in easily understood language

Breast 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	14.0
E.1.2	Level	PT
E.1.2	Classification code	10006201
E.1.2	Term	Breast cancer stage III
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	14.0
E.1.2	Level	PT
E.1.2	Classification code	10006202
E.1.2	Term	Breast 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	14.0
E.1.2	Level	PT
E.1.2	Classification code	10006200
E.1.2	Term	Breast cancer stage II
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

1) To compare DSN, defined as the number of days with ANC < 0.5 x 109/L, during Cycle 1, in patients with breast cancer receiving MK-4214 or Neupogen™ as adjunct to chemotherapy with doxorubicin in combination with docetaxel.

E.2.2

Secondary objectives of the trial

1. To evaluate the incidence of FN, defined as an oral temperature of ≥ 38.3ºC, persisting for at least one hour, concurrent with an ANC < 0.5 x 109/L within 24 hours of the fever, by cycle and across all cycles of chemotherapy in patients treated
with MK-4214 or Neupogen™ .
2. To evaluate the incidence of hospitalization due to infection by cycle and across all cycles of chemotherapy in patients treated with MK-4214 or Neupogen™
3. To evaluate the usage (incidence) of IV anti-infective agents by cycle and across all
cycles of chemotherapy in patients treated with MK-4214 or Neupogen™
4. To assess the safety and tolerability of MK-4214 and Neupogen™
5. To evaluate the incidence of anti-rG-CSF antibodies in patients treated with
MK-4214 or Neupogen™

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Patient understands the study procedures, alternative treatments available, the risks involved with the study, and agrees to participate by giving written informed consent.
2. Female who is ≥ 18 years of age on the day of signing informed consent.
3. Female who is not free from menses for > 1 year, or posthysterectomy/oophorectomy, or surgically sterilized, is willing to use 2 adequate barrier methods of contraception to prevent pregnancy or agrees to abstain from heterosexual activity throughout the study, starting with Visit 1 through 6 Months after the last dose of chemotherapy in the Randomized Blinded Trial or Open-Label Extension. Adequate contraceptive methods include for example, intrauterine device, diaphragm with spermicide, cervical cap with spermicide, or female condom with spermicide. Spermicides alone are not an acceptable method of contraception.
4. Patient has been diagnosed with Stage II, III, or IV breast cancer, classification according to American Joint Committee on Cancer, 7th Edition (See Appendix 6.6), and based on clinical disease characteristics is considered by the investigator to be an appropriate candidate for treatment with the combination of doxorubicin and docetaxel at the protocol-specified full doses. NOTE: Patient must receive full dose of chemotherapy in Cycle 1 in order to be eligible for randomization.
5. Patients with Stage II or III disease who have not received prior chemotherapy. Patients with Stage IV disease who have not received prior chemotherapy for metastatic disease (prior neo-adjuvant and/or adjuvant chemotherapy for early stage breast cancer is allowed, provided time since last dose of chemotherapy is > 1 year).
Prior or concomitant hormonal breast cancer therapy is allowed.
6. Patient satisfies the Eastern Cooperative Oncology Group performance status (ECOG) of ≤ 2 (Appendix 6.4).
7. In those cases of prior neo-adjuvant or adjuvant use of an anthracycline, patient will be able to receive a full course of doxorubicin-docetaxel chemotherapy at the protocol-specified doses for 4-6 cycles (duration of therapy in accordance with institutional standards of care) without exceeding a total cumulative anthracycline dose of 550 mg/m2. The calculation should include doxorubicin received on the current study as well as anthracyclines and/or anthracenediones received in prior adjuvant chemotherapy.
8. Patient has adequate cardiac, bone marrow, liver, kidney and other organ function for chemotherapy with doxorubicin in combination with docetaxel at the protocolspecified dosing, according to general treatment guidelines and institutional standards of care.

E.4

Principal exclusion criteria

1. Patient is currently participating or has participated in a study with an investigational compound or device within 30 days of receiving study therapy.
2. Patient is pregnant or breastfeeding, or expecting to conceive within the projected duration of the study or within 6 months after the last dose of chemotherapy.
3. Patient has known sickle cell disorder.
4. Patient has received a systemic anti-infective agent within 72 hours of randomization.
5. Patient has received filgrastim, pegfilgrastim or any granulocyte-colony-stimulating factors (G-CSF) or recombinant granulocyte–macrophage colony-stimulating factors (GM-CSF) or is expected to receive erythropoietin, darbepoetin, or another colonystimulating
factor other than study drug for the duration of the study. NOTE: Prior
erythropoietin or darbepoetin use > 6 weeks prior to randomization is permissible.
6. Patient is expected to take lithium during the course of the trial (lithium may potentiate the release of neutrophils).
7. Patient has a hypersensitivity to filgrastim or pegfilgrastim or any of the excipients of MK-4214 or Neupogen.
8. Patient has received biologics as targeted therapy (e.g. Herceptin within 4 weeks of randomization into the study.
9. Patient has undergone radiation therapy within 4 weeks of randomization with the exception of spot radiation (irradiation to ≤ 25% of total marrow) for the treatment of bone metastases.
10. Patient has had prior bone marrow or stem cell transplant.
11. Patient has hypersensitivity or intolerance to filgrastim or any of the excipients of MK-4214.
12. Patient is allergic or intolerant to latex (latex is a component of the pre-filled syringes of MK-4214 and Neupogen
13. Patient has known central nervous system (CNS) metastases and/or carcinomatous meningitis.
14. Patient has undergone a major surgical procedure within 4 weeks prior to study start.
15. Patient with a history of a prior malignancy, other than breast cancer, with the exception of cervical intraepithelial neoplasia; basal cell carcinoma of the skin; or
who has undergone potentially curative therapy with no evidence of that disease for five years, or who is deemed at low risk for recurrence by her treating physician.
16. Patient is taking anticoagulation therapy (with exception of low dose aspirin), or has a known bleeding disorder, or a history of increased bleeding tendencies, spontaneously or subsequent to minor traumas.
17. Patient has a history or current evidence of any condition, therapy, or lab abnormality that might confound the results of the study, interfere with the patient’s participation for the full duration

E.5 End points

E.5.1

Primary end point(s)

Duration of severe neutropenia in Cycle 1 as defined as the number of days with ANC < 0.5 x 109/L, during Cycle 1.

E.5.1.1

Timepoint(s) of evaluation of this end point

Planned analysis is after the last patient has their last visit

E.5.2

Secondary end point(s)

- Febrile Neutropenia, defined as an oral temperature of ≥ 38.3°C persisting for at least an hour, concurrent with an ANC < 0.5 109/L within 24 hours of the fever, by cycle, and across all cycles of chemotherapy

- Hospitalization for infection by cycle and across all cycles of chemotherapy

- Hospitalization for IV anti-infectives by cycle and across all cycles of chemotherapy

- Depth of ANC nadir in Cycle 1

-Time to ANC recovery in Cycle 1. This time begins at the start of chemotherapy and is defined as the number of days required for the ANC to reach ANC ≥ 2 x 109/L.

- Immunogenicity testing to assess the potential development of antibodies directed against G-CSF

E.5.2.1

Timepoint(s) of evaluation of this end point

Planned analysis is after the last patient has her last visit, with the exception of immunogenicity testing, which will be completed after patients have their 6-month follow up visit (about 2 years after last patient enrolls).

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)

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

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

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

Argentina

Belarus

Brazil

Chile

Croatia

Georgia

Germany

India

Italy

Latvia

Lithuania

Macedonia, the former Yugoslav Republic of

Mexico

Peru

Philippines

Romania

Russian Federation

Serbia

South Africa

Ukraine

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

Last patient, Last visit

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:	175
F.1.3	Elderly (>=65 years)	Yes
F.1.3.1	Number of subjects for this age range:	175
F.2 Gender
F.2.1	Female	Yes
F.2.2	Male	No
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	32
F.4.2	For a multinational trial
F.4.2.1	In the EEA	60
F.4.2.2	In the whole clinical trial	350

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

2011-10-28

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-08-31

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2012-01-26

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