Clinical Trials Register

Summary
EudraCT Number:	2008-007345-31
Sponsor's Protocol Code Number:	3144A2-3004-WW
National Competent Authority:	Bulgarian Drug Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2010-02-18
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

Bulgarian Drug 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.

Рандомизирано, двойно сляпо, плацебо-контролирано изпитване с Нератиниб (HKI-272) след Трастузумаб при жени с ранен стадий рак на гърдата със свръхекспресия / усилена експресия на HER-2/ /new (човешки епидермален растежен фактор рецептор 2)

A.3.1

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

Neratinib adjuvant study

A.3.2

Name or abbreviated title of the trial where available

ExteNET®

A.4.1

Sponsor's protocol code number

3144A2-3004-WW

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT00878709

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	Puma Biotechnology, 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	Puma Biotechnology, 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	Puma Biotechnology, Inc
B.5.2	Functional name of contact point	Personal
B.5.3	Address:
B.5.3.1	Street Address	10880 Wilshire Blvd, Suite 2150
B.5.3.2	Town/ city	Los Angeles
B.5.3.3	Post code	CA 90024
B.5.3.4	Country	United States
B.5.4	Telephone number	0018002486550
B.5.5	Fax number	0013032486501
B.5.6	E-mail	rphilips@pumabiotechnology.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	Neratinib
D.3.2	Product code	HKI-272
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
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,WAY-179272-B
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)	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	No
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	Yes
D.3.11.13.1	Other medicinal product type	targeted therapy

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 treatment stage)

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	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10006173
E.1.2	Term	Breast adenocarcinoma
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 Disease Free Survival (DFS) of women with early-stage erbB-2 overexpressed/amplified node positive 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

To compare the following endpoints of subjects receiving neratinib against those of subjects receiving placebo:

- 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.

- Time to Distant Recurrence (TTDR), defined as the time between randomization and the date of the first distant recurrence, or death from breast cancer.

- Distant Disease-free Survival (DDFS), defined as the time from randomization to the first occurence of distant recurrence or death from any cause.

- Incidence of central nervous system (CNS) recurrence, defined as the cumulative incidence of CNS recurrence at a site of first recurrence.

- Overall Survival (OS), defined as the time from randomization until the date of death.

- Short- and long-term safety (including incidence of grade 3/4 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

A pharmacogenetic sub-study is conducted under this protocol.
Upon separate consent, the original tumor biopsy sample will also be studied for: EGFR, erbB-2, erbB-3, and erbB-4 amplification, PIK3CA mutations in hotspots (ie, exons 9,20 via gene sequencing), PIK3CA amplification (q-PCR or FISH), PTEN loss, c-Myc amplification (q-PCR or FISH). Other assays will be explored.
When disease recurrence is documented pathologically, specimens will be requested for biomarker analyses.

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: Fluorescence in Situ Hybridization (FISH) or Silver in Situ Hybridization (SISH), or Chromogenic in Situ Hybridization (CISH), or Immunohistochemistry assay.
2. Archived diagnostic tumor sample must be available, and subject must agree to submission of sample for central erbB-2 testing.
3. Primary tumor ER/PgR status known before study entry.
4. 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. Also, it must be specified that the subject is either not eligible or unable to receive further adjuvant trastuzumab, since the patient either completed the intended treatment course of adjuvant trastuzumab based on published data or experienced side effects that resulted in early discontinuation of trastuzumab that have since resolved.
5. If subjects had prior neoadjuvant therapy (chemotherapy with or without neoadjuvant trastuzumab, regardless of nodal status at initial diagnosis), they are eligible provided they had residual invasive cancer in the breast and/or axilla after completing neoadjuvant therapy. Subjects will be excluded if they achieved a pathologic complete response (pCR) in breast and axilla, or if they have only residual in situ disease in breast (DCIS) and pCR in axilla (if axillary status is known).
6. The last dose of trastuzumab must have been given > 2 weeks and ≤1 year (365 days) from randomization.
7. Have a diagnosis of stage 2 through stage 3c primary breast cancer with axillary node-positive disease according to the American Joint Committee on Cancer (sixth edition) staging criteria for breast cancer. Note that subjects who completed neoadjuvant therapy and have residual invasive disease only in the breast, with negative or unknown nodal status, are eligible.
8. Adequately treated primary breast cancer with surgery, as defined by prior mastectomy OR lumpectomy, with margins clear of invasive carcinoma and ductal carcinoma in situ. Subjects with positive sentinel node biopsies must have subsequent axillary dissection to be eligible.
9. Completed treatment with a neoadjuvant or adjuvant chemotherapy regimen containing an anthracycline and/or a taxane or any cyclophosphamide, methotrexate and 5 fluorouracil (CMF) regimen.
10. Clinical and radiologic assessments that are negative for local or regional recurrence of disease or metastatic disease at the time of study entry, including
- Bone scan; required only if alkaline phosphatase (ALP) is ≥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.
- Computed tomography, MRI or ultrasound of the abdomen and chest; required only if aspartate transaminase (AST)/alanine transaminase (ALT) or ALP is ≥2 x ULN.
- Chest radiograph.
11. Negative bilateral mammogram (or unilateral mammogram of the remaining breast if unilateral total mastectomy was performed) within 12 months (≤ 365 days) before randomisation. Mammogram is not indicated in case of bilateral total mastectomy.
12. Subjects with bilateral breast cancers are eligible only if their cancers are synchronous (ie, diagnosed at the same time [within 6 months of each other]). One or both tumors need to be erbB-2 positive. One could be negative.
13. Female subjects aged 18 years or older (For Japan 20 years or older).
14. Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
15. QTc interval must be ≤0.450 seconds.
16. Adequate organ function as defined by:
- Absolute neutrophil count: ≥1.5 × 109/L (1500/mm3).
- Platelet count: ≥100 × 109/L (100,000/mm3).
- Hemoglobin: ≥9.0 g/dL (90 g/L).
- Serum creatinine: ≤1.5 x ULN.
-Total bilirubin: ≤1.5 × ULN (in case of known Gilbert’s syndrome, <2 x ULN is allowed).
- AST and ALT: ≤2.5 × ULN.
- ALP: ≤2.5 x ULN.
17. Left ventricular ejection fraction (LVEF) within institutional range of normal; performed by multigated acquisition (MUGA) or echocardiogram (ECHO).
18. Negative β-HCG pregnancy test (serum) for premenopausal women of reproductive capacity and for women less than 12 months after the menopause. All female subjects who are biologically capable of having children must agree and commit to the use of a reliable method of birth control from 2 weeks before administration of the first dose of investigational product until 28 days after the last dose of investigational product.
19. Recovery (ie, to grade 1 or baseline) from all clinically significant AEs related to prior therapies (excluding alopecia, neuropathy and nail changes).

E.4

Principal exclusion criteria

1. Clinical or radiologic evidence of local or regional recurrence of disease or metastatic disease prior to or 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 metachronous DCIS breast cancer (ie, primary breast cancers diagnosed at different times [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 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 ≥2 diarrhea of any etiology at baseline).

13. QTc interval >0.450 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. On treatment or in follow-up of any other neoadjuvant or adjuvant breast cancer trial with DFS as an endpoint.

E.5 End points

E.5.1

Primary end point(s)

Comparison of Disease free survival (DFS) of women with early-stage erbB-2 overexpressed 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.5.1.1

Timepoint(s) of evaluation of this end point

during treatment, brief symptom guided physical exam will be done at months 0,3.6.9, full physical exam on month 12.targeted physical examinations during follow up every 4 months for 2 years from randomization until distance recurrence and with a mammogram every 12 months.

E.5.2

Secondary end point(s)

DFS-DCIS, incidence of CNS recurrence, OS, long and short term safety

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

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

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

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

200

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

Argentina

Australia

Bahamas

Belgium

Brazil

Bulgaria

Canada

Chile

China

Colombia

Croatia

Czech Republic

Denmark

France

Germany

Greece

Hong Kong

Hungary

Israel

Italy

Japan

Korea, Republic of

Lebanon

Lithuania

Macedonia, the former Yugoslav Republic of

Malaysia

Malta

Mexico

Netherlands

New Zealand

Peru

Poland

Portugal

Romania

Saudi Arabia

Serbia

Singapore

Slovakia

Spain

Sweden

Switzerland

Taiwan

Turkey

United Kingdom

United States

Jordan

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

The study will be completed when the last subject randomized has been followed up for survival to death.

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