Clinical Trials Register

Summary
EudraCT Number:	2008-007345-31
Sponsor's Protocol Code Number:	3144A2-3004-WW
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2009-06-30
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2008-007345-31

A.3

Full title of the trial

A Randomized Double-blind Placebo-Controlled Trial of Neratinib (HKI-272) After Trastuzumab in Women With Early-Stage HER-2/neu Overexpressed/Amplified Breast Cancer

A.3.2

Name or abbreviated title of the trial where available

A.4.1

Sponsor's protocol code number

3144A2-3004-WW

A.5.1

ISRCTN (International Standard Randomised Controlled Trial) Number

NCT00878709

A.7

Trial is part of a Paediatric Investigation Plan

Information not present in EudraCT

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Wyeth Research, Division of Wyeth Pharmaceuticals, 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
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation
B.5.2	Functional name of contact point

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	neratinib
D.3.2	Product code	HKI-272
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	neratinib
D.3.9.1	CAS number	698387-09-06
D.3.9.2	Current sponsor code	HKI-272
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	40
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Information not present in EudraCT
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	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
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	Information not present in EudraCT
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	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Her2 overexpressed, early stage breast cancer (adjuvant treatmente stage).

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	12.0
E.1.2	Level	LLT
E.1.2	Classification code	10006173
E.1.2	Term	Breast adenocarcinoma

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 of this study is to compare disease free survival (DFS) of women with early stage erbB-2 overexpressed/amplified breast cancer following trastuzumab in the adjuvant setting, receiving neratinib against that of women receiving placebo. DFS is defined as the time from randomization to the first occurrence of the following DFS events: invasive ipsilateral breast tumor recurrence, local/regional invasive recurrence, distant recurrence, death from any cause, and invasive contralateral breast cancer.

E.2.2

Secondary objectives of the trial

Secondary objectives are to compare additional endpoints of subjects receiving neratinib against those of subjects receiving placebo: o Disease free survival including ductal carcinoma in situ (DFS-DCIS), defined as the time from randomization to the first occurrence of any DFS event or DCIS. o Time to distant recurrence (TTDR), defined as the time between randomization and the date of the first distant recurrence,or death from breast cancer. o Distant disease free survival (DDFS), defined as the time from randomization to the first distant recurrence or death from any cause. o Incidence of central nervous system (CNS) recurrence. o Overall survival (OS). o Short- and long-term safety (including incidence of grade 3 or higher diarrhea).

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

FARMACOGENETICA: Versione:Originale Data:2009/04/29 Titolo:N.A. Obiettivi:Dopo aver raccolto un consenso informato separato, il campione bioptico tumorale originale sara` studiato per: EGFR, amplificazione di erbB-2, erbB-3, ed erbB-4, mutazioni di PIK3CA nei punti caldi (ie, exoni 9,20 mediante sequenziamento genico), amplificazione di PIK3CA (q-PCR o FISH), perdita di PTEN, amplificazione di c-Myc (q-PCR o FISH). Quando la ricaduta della malattia sara` stata documentata patologicamente, saranno richiesti campioni prelevati dalle sedi di ricaduta per le analisi dei biomarker. Il campione bioptico in paraffina fissato in formalina (tumore originale e/o recidiva) potra` essere inviato per le analisi (blocco o serie di sezioni da 5 �m su un numero totale di 14 vetrini per microscopio).

E.3

Principal inclusion criteria

1.Subjects must have histologically confirmed primary adenocarcinoma of the breast that is erbB-2 positive by one of the following assays, performed locally: o Fluorescence in situ hybridization (FISH) or silver in situ hybridization (SISH) must show gene amplification (defined as >2.2), OR o Chromogenic in situ hybridization (CISH) show gene amplification according to the manufacturer`s kit instructions, OR o Immunohistochemistry (IHC) assay must show strong positive (ie, 3+ = >30% of invasive tumor cells) staining score. 2. Primary tumor ER/PgR status must be known before study entry. 3. Subjects must have completed a course of prior adjuvant trastuzumab. If less than 12 months of trastuzumab have been given, at least 8 prior doses of weekly trastuzumab, or at least 3 prior doses of trastuzumab given every 3 weeks, must have been administered and it must be specified that the subject is either not eligible or unable to receive further adjuvant trastuzumab. The last dose of trastuzumab must have been given >2 weeks and <2 years from randomization. 4. Have a diagnosis of stage 1 through stage 3c primary breast cancer according to the American Joint Committee on Cancer (sixth edition) staging criteria for breast cancer and meet one of the following criteria: o Axillary node-positive disease OR node-negative disease with a primary tumor greater than or equal to 1.0 cm in greatest diameter. (For clarification, isolated tumor cells are considered pN0 and micrometastases are considered pN1.) o Node-negative disease is defined as negative sentinel node biopsy OR no positive lymph nodes found among 6 ancillary nodes examined on axillary node dissection OR status after axillary radiotherapy for sterilization if clinically evaluated as cN0. 5. Adequately treated primary breast cancer with surgery, as defined by prior mastectomy OR lumpectomy, with margins clear of invasive carcinoma and DCIS. Subjects with positive sentinel node biopsies must have subsequent axillary dissection to be eligible; negative sentinel node biopsies require no more axillary surgery for eligibility. 6. Completed treatment with a neoadjuvant or adjuvant chemotherapy regimen containing either an anthracycline or a taxane or any cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) regimen. 7. Clinical and radiologic assessments that are negative for local or regional recurrence of disease or metastatic disease at the time of study entry, including: o Bone scan; required only if alkaline phosphatase (ALP) is &#8805;2 x upper limit of normal (ULN) and/or there are symptoms of metastatic bone disease. A confirmatory imaging study is required if the results from the bone scan are questionable. o Computed tomography (CT) or ultrasound scan of the abdomen; required only if aspartate transaminase (AST)/alanine transaminase (ALT) or ALP is &#8805;2 x ULN, unless the elevation is in the bone fraction. o Chest radiograph. 8. Negative bilateral mammogram (or unilateral mammogram of the remaining breast if unilateral total mastectomy was performed) within 12 months before study entry. Mammogram not indicated in case of bilateral total mastectomy. 9. Subjects with bilateral breast cancers are eligible only if their primary cancers occurred synchronously (ie, diagnosed at the same time [occurring within 6 months of each other]). One or both tumors need to be erbB-2 positive. One could be negative. 10. Female subjects aged 18 years or older. 11. Subjects must have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1. 12. Adequate organ function as defined by: o Absolute neutrophil count (ANC): &#8805;1.5 � 109/L (1500/mm3) o Platelet count: &#8805;100 � 109/L (100,000/mm3) o Hemoglobin: &#8805;9.0 g/dL (90 g/L) o Serum creatinine: &#8804;1.5 x ULN o Total bilirubin: &#8804;1.5 � ULN (in case of known Gilbert�s syndrome, <2 x ULN is allowed) o AST and ALT: ...

E.4

Principal exclusion criteria

1. Clinical or radiologic evidence of local or regional recurrence of disease or metastatic disease at the time of study entry. 2. Currently receiving chemotherapy, radiation therapy, immunotherapy, or biotherapy for breast cancer. 3. Any prior mediastinal irradiation except internal mammary node irradiation for the present breast cancer. 4. Metachronous invasive or DCIS breast cancer (ie, primary breast cancers diagnosed at different times [diagnosed greater than 6 months apart from each other]). 5. Prior therapy with an erbB-1 and/or erbB-2 inhibitor other than trastuzumab. 6. Received any investigational agent within 14 days or 5 half-lives, whichever is longer, before administration of the first dose of investigational product. 7. Pregnant or breastfeeding women. 8. Subjects with a concurrently active second malignancy, other than adequately treated nonmelanoma skin cancers, in situ melanoma, or in situ cervical cancer. Subjects with other nonmammary malignancies must have been disease free for at least 5 years. 9. Subjects with unstable angina, congestive heart failure (New York Heart Association class II, III, or IV) (including individuals who currently use digitalis, beta-blockers, or calcium channel blockers specifically for congestive heart failure), ventricular arrhythmia requiring medical therapy, or with a history of myocardial infarction within 12 months. 10. Subjects with active unresolved infections. 11. Inability or unwillingness to swallow tablets. 12. Significant chronic gastrointestinal disorder with diarrhea as a major symptom (eg, Crohn�s disease, ulcerative colitis, malabsorption, or grade &#8805;2 diarrhea of any etiology at baseline). 13. QTc interval >0.45 seconds or known history of QTc prolongation or torsades de pointes. 14. History of idiopathic ventricular tachycardia or ventricular fibrillation. 15. Subjects with a psychiatric illness that would prevent them from understanding the nature of the investigational therapy and complying with protocol requirements. 16. Any major concurrent illness or medical condition that, in the investigator�s judgment, will substantially increase the risk associated with the subject�s participation in and completion of the study. 17. Known or suspected allergy to neratinib or other compounds related to these classes of medication.

E.5 End points

E.5.1

Primary end point(s)

Disease Free Survival (DFS): Time from randomization to the first occurrence of the following DFS events: invasive ipsilateral breast tumor recurrence, local/regional invasive recurrence, distant recurrence, death from any cause, and invasive contralateral breast cancer. For any subject for whom a DFS event has not been observed by the cutoff date of an analysis, DFS will be censored at the date of the last physical examination (including targeted physical examination), either scheduled or unscheduled.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

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

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

Yes

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)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

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

280

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

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

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

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	No
F.3.3.1	Women of childbearing potential not using contraception	No
F.3.3.2	Women of child-bearing potential using contraception	No
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	600
F.4.2	For a multinational trial
F.4.2.1	In the EEA	1900
F.4.2.2	In the whole clinical trial	3850

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

2009-10-30

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2009-06-23

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2019-10-04

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