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    Summary
    EudraCT Number:2007-007885-39
    Sponsor's Protocol Code Number:3144A1-2204-WW/B1891015
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2008-09-02
    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
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2007-007885-39
    A.3Full title of the trial
    A Phase I/II Study of HKI-272 in Combination With Vinorelbine in Subjects With Solid Tumors and Metastatic Breast Cancer.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Neratinib in combination with vinorelbine in metastatic breast cancer patients
    A.4.1Sponsor's protocol code number3144A1-2204-WW/B1891015
    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 pointRichard B. Phillips
    B.5.3 Address:
    B.5.3.1Street Address10880 Wilshire Blvd, Suite 2150
    B.5.3.2Town/ cityLos Angeles
    B.5.3.3Post codeCA 91320
    B.5.3.4CountryUnited States
    B.5.4Telephone number0014242486550
    B.5.5Fax number0014242486501
    B.5.6E-mailrphillips@pumabiotechnology.com
    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 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.3.9.2Current sponsor codeWAY-179272-B
    D.3.9.3Other descriptive nameHKI-272 Maleate
    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.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee 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 No
    D.IMP: 2
    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 Yes
    D.2.1.1.1Trade name Navelbine 10mg/ml Concentrate for Solution for Infusion
    D.2.1.1.2Name of the Marketing Authorisation holderPierre Fabre Ltd
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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 nameVINORELBINE 10MG/ML CONCENTRATE FOR SOLUTION FOR INFUSION
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.1CAS number 125317-39-7
    D.3.9.3Other descriptive nameVINORELBINE TARTRATE
    D.3.9.4EV Substance CodeSUB20777
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee 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 No
    D.IMP: 3
    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 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.3.9.2Current sponsor codeWAY-179272-B
    D.3.9.3Other descriptive nameHKI-272 Maleate
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number240
    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.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee 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 No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Solid tumors (part 1) and metastatic breast cancer (part 2).
    E.1.1.1Medical condition in easily understood language
    Metastatic 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 14.1
    E.1.2Level LLT
    E.1.2Classification code 10027475
    E.1.2Term Metastatic breast cancer
    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
    Part 1: The primary objectives of part 1 of the study are to assess the safety and tolerability and to define the maximum tolerated dose (MTD) of HKI-272 in combination with vinorelbine in subjects with advanced solid tumors.

    Part 2: The primary objective of part 2 of the study is to estimate the ORR for subjects with ErbB-2-positive breast cancer treated at the MTD of HKI-272 in combination with vinorelbine.
    E.2.2Secondary objectives of the trial
    Part 1: The secondary objectives of part 1 are to obtain preliminary data describing antitumor activity for the combination of HKI-272 with vinorelbine.

    Part 2: The secondary objectives of part 2 are to confirm the MTD identified in part 1 of the study, to obtain safety and PK information, and to assess additional efficacy parameters including clinical benefit (complete response [CR]+partial response [PR]+stable disease [SD] >=24 weeks), PFS rate, and duration of response to HKI-272 in combination with vinorelbine.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Aged ≥18 years.

    2. Confirmed pathologic diagnosis of a solid tumor that is not curable with available therapies for which HKI-272 plus vinorelbine is a reasonable treatment option (part 1 only).

    3. Confirmed pathologic diagnosis of ErbB-2-positive breast cancer (current stage IV) in female subjects for which vinorelbine plus HKI-272 is a reasonable treatment option (part 2 only).

    4. At least 1 prior antineoplasic chemotherapy treatment regimen for metastatic disease or subject relapsing under adjuvant treatment (part 2 only).

    5. At least 1 prior treatment with a trastuzumab-containing regimen for at least 6 weeks [receiving no more than 6 weeks (weekly or tri weekly schedule equivalents) for economical reason is acceptable] , for metastatic disease or subject relapsing under adjuvant treatment (part 2 only) [“relapsing under adjuvant treatment” should be understood as patients still taking trastuzumab treatment or being off trastruzumab treatment for a maximal period of 6 months after the last dose of trastuzumab at the time of disease recurrence].

    6. erbB-2 gene amplified tumor detected by fluorescence in situ hybridization (FISH) or chromogenic in situ hybridization (CISH) (part 2 only). Documentation of erbB-2 status by FISH or CISH performed by a local laboratory is accepted. Otherwise, tumor tissue must be available and adequate for centralised FISH testing prior to study day 1. In case of more than 1 result, the status retrieved on the most recent biopsy should be used.

    7. At least 1 measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST).

    8. Eastern Cooperative Oncology Group (ECOG) status of 0 to 2 (not declining within 2 weeks before signing the informed consent form (ICF)).

    9. Recovery from all clinically significant AEs related to prior therapies (excluding alopecia).

    10. Left ventricular ejection fraction (LVEF) within the study site’s limits of normal.

    11. Screening laboratory values within the following parameters:
    Absolute neutrophil count (ANC): >=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×upper limit of normal (ULN)
    Total bilirubin: ≤1.5×ULN
    Aspartate aminotransferase (AST) and alanine aminotransferase (ALT): ≤2.5 ×
    ULN (≤5×ULN if liver metastases are present)

    12. For women of childbearing potential, a negative urine or serum pregnancy test result before study entry.

    13. All subjects who are not surgically sterile or postmenopausal must agree and commit to the use of a reliable method of birth control for the duration of the study and for 28 days after the last dose of test article.
    E.4Principal exclusion criteria
    1. More than 2 prior antineoplasic treatment regimens ( excluding hormonotherapy) for metastatic disease. Subjects who relapsed under adjuvant therapy should not have received more than one line of antineoplasic treatment for metastatic disease (part 2 only).

    2. Prior treatment with vinorelbine for metastatic setting, or prior treatment with any ErbB-2 targeted agents except trastuzumab (part 2 only). Up to 20 subjects with ErbB-2-overexpressing metastatic breast cancer who have been previously exposed to lapatinib but are not refractory to lapatinib may be enrolled in part 2.

    3. Prior treatment with anthracyclines with a cumulative dose of doxorubicin of >400 mg/m2, or of epirubicin dose of >800 mg/m2, or the equivalent dose for other anthracyclines or derivatives (part 2 only).

    4. Major surgery, chemotherapy, radical (curative intent) radiotherapy, investigational agents, or other cancer therapy within at least 2 weeks before treatment day 1.

    5. Subjects with bone only disease or skin lesions that are not measurable by CT or MRI as the only site of disease.

    6. Subject with history of inflammatory breast cancer

    7. Active central nervous system (CNS) metastases, as indicated by clinical symptoms, cerebral edema, and/or progressive growth.

    8. QT (QTc) interval >0.47 second or known history of QTc prolongation or torsades de pointes (TdP).

    9. Presence of clinically significant or uncontrolled cardiac disease, including congestive heart failure (New York Heart Association [NYHA] functional classification of ≥2), angina requiring treatment, myocardial infarction within the past 12 months, or any clinically significant supraventricular arrhythmia or ventricular arrhythmia requiring treatment or intervention.

    10. Pregnant or breastfeeding women.

    11. Significant chronic or recent acute gastrointestinal disorder with diarrhea as a major symptom (eg, Crohn disease, malabsorption, or grade >=2 diarrhea of any etiology at baseline).

    12. Inability or unwillingness to swallow tablets (HKI-272).

    13. Preexisting grade 2 or greater motor or sensory neuropathy.

    14. Subject known to be human immunodeficiency virus (HIV) seropositive and/or acute chronic hepatitis B (HBsAg positive) or hepatitis C (anti-HCV positive).

    15. History of known hypersensitivity to vinorelbine and any of its components.

    16. Any other cancer within 5 years prior to screening with the exception of contralateral breast carcinoma, adequately treated cervical carcinoma in situ, or adequately treated basal or squamous cell carcinoma of the skin.

    17. Clinically significant ongoing or recent infection within 2 weeks before treatment day 1.

    18. Evidence of significant medical illness or abnormal laboratory finding that would, in the investigator’s judgment, make the subject inappropriate for this study.
    E.5 End points
    E.5.1Primary end point(s)
    The primary end-point of this study is to assess the safety and define the maximum tolerated dose of the combination of HKI-272 with vinorelbine in subjects with solid tumors, and to assess the efficacy of the optimal safe dose for the drug combination in subjects with metastatic breast cancer
    E.5.1.1Timepoint(s) of evaluation of this end point
    Every 6 weeks
    E.5.2Secondary end point(s)
    Safety data collection
    E.5.2.1Timepoint(s) of evaluation of this end point
    Every 6 weeks
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    First use in human for HKI 272 + Vinorelbine
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised Information not present in EudraCT
    E.8.1.2Open Information not present in EudraCT
    E.8.1.3Single blind Information not present in EudraCT
    E.8.1.4Double blind Information not present in EudraCT
    E.8.1.5Parallel group Information not present in EudraCT
    E.8.1.6Cross over Information not present in EudraCT
    E.8.1.7Other Information not present in EudraCT
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    E.8.2.4Number of treatment arms in the trial1
    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.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA25
    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
    Belgium
    China
    France
    Hong Kong
    Netherlands
    Spain
    Sweden
    Taiwan
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee No
    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 visit of the last subject.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months9
    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.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 20
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 30
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    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 state
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 50
    F.4.2.2In the whole clinical trial 95
    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)
    As applicable under country-specific standard of care
    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 Decision2008-09-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2009-02-09
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-06-07
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