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The European Union Clinical Trials Register allows you to search for protocol and results information on:
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    The EU Clinical Trials Register currently displays   39192   clinical trials with a EudraCT protocol, of which   6421   are clinical trials conducted with subjects less than 18 years old.
    The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).
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    EudraCT Number:2008-007345-31
    Sponsor's Protocol Code Number:3144A2-3004-WW
    National Competent Authority:Slovakia - SIDC (Slovak)
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2009-07-09
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedSlovakia - SIDC (Slovak)
    A.2EudraCT number2008-007345-31
    A.3Full 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.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Neratinib adjuvant study
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code number3144A2-3004-WW
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT00878709
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorPuma Biotechnology, Inc
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportPuma Biotechnology, Inc
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPuma Biotechnology, Inc
    B.5.2Functional name of contact pointPersonal
    B.5.3 Address:
    B.5.3.1Street Address10880 Wilshire Blvd, Suite 2150
    B.5.3.2Town/ cityLos Angeles
    B.5.3.3Post codeCA 90024
    B.5.3.4CountryUnited States
    B.5.4Telephone number0018002486550
    B.5.5Fax number0013032486501
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameNeratinib
    D.3.2Product code HKI-272
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNeratinib
    D.3.9.1CAS number 698387-09-06
    D.3.9.2Current sponsor codeHKI-272,WAY-179272-B
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product Yes
    D. medicinal product typetargeted therapy
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Her2 overexpressed, early stage breast cancer (adjuvant treatment stage)
    E.1.1.1Medical condition in easily understood language
    Breast Cancer
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level LLT
    E.1.2Classification code 10006173
    E.1.2Term Breast adenocarcinoma
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main 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.2.2Secondary 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.2.3Trial contains a sub-study Yes
    E.2.3.1Full 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.3Principal inclusion criteria
    1. Female subjects aged 18 years or older

    2. 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.

    3. Archived diagnostic tumor sample must be available, and subject must agree to submission of sample for central erbB-2 testing.

    4. Primary tumor ER/PgR status known before study entry.

    5. 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.

    6. 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).

    7. The last dose of trastuzumab must have been given > 2 weeks and ≤1 year (365 days) from randomization.

    8. 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.

    9. 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.

    10. 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.

    11. 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.

    12. 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.

    13. 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.

    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
    - 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.4Principal 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.5.1Primary 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.5.1.1Timepoint(s) of evaluation of this end point
    During treatment, brief symptom-guided physical examinations will be done at months 0, 1, 3, 6, and 9, full
    physical exam on month 12. Targeted physical examinations during follow-up every 4 months for 2 years from
    randomization until distant recurrence and with a mammogram every 12 months.
    E.5.2Secondary end point(s)
    DFS-DCIS, incidence of CNS recurrence, OS, long and short term safety.
    E.5.2.1Timepoint(s) of evaluation of this end point
    During treatment, brief symptom-guided physical examinations will be done at months 0, 1, 3, 6, and 9, full
    physical exam on month 12. Targeted physical examinations during follow-up every 4 months for 2 years from
    randomization until distant recurrence and with a mammogram every 12 months.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic Yes
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E. trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA200
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Czech Republic
    Hong Kong
    Korea, Republic of
    Macedonia, the former Yugoslav Republic of
    New Zealand
    Saudi Arabia
    United Kingdom
    United States
    E.8.7Trial 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.8.9.1In the Member State concerned years8
    E.8.9.1In the Member State concerned months2
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years8
    E.8.9.2In all countries concerned by the trial months2
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F. of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F. of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F. of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F. of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F. of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F. of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 2132
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 710
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male No
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 1342
    F.4.2.2In the whole clinical trial 2842
    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)
    After completion of the follow-up period or withdrawal, subjects will be treated/followed-up as per local clinical guidelines.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2009-09-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2009-09-08
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-10-04
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
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