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    The EU Clinical Trials Register currently displays   43871   clinical trials with a EudraCT protocol, of which   7290   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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    Summary
    EudraCT Number:2013-002872-42
    Sponsor's Protocol Code Number:PUMA-NER-5201
    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:2014-02-07
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2013-002872-42
    A.3Full title of the trial
    An Open-Label, Phase 2 Study of Neratinib in Patients With Solid Tumors With Somatic Human Epidermal Growth Factor Receptor (EGFR, HER2, HER3) Mutations or EGFR gene amplification
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study of Neratinib in patients with solid tumours that have specific genetic mutations
    A.3.2Name or abbreviated title of the trial where available
    BASKET
    A.4.1Sponsor's protocol code numberPUMA-NER-5201
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01953926
    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 pointClinical Trials Information Desk
    B.5.3 Address:
    B.5.3.1Street Address10880 Wilshire Boulevard, Suite 2150
    B.5.3.2Town/ cityLos Angeles
    B.5.3.3Post codeCA 90024
    B.5.3.4CountryUnited States
    B.5.4Telephone number+14242486500
    B.5.5Fax number+14242486501
    B.5.6E-mailClinicalTrials@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 PB-272; 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 698387-09-6
    D.3.9.3Other descriptive nameNERATINIB
    D.3.9.4EV Substance CodeSUB32232
    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.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
    Cancer tumor with somatic human epidermal growth factor receptor mutation (EGFR, ERBB2 (HER2), ERBB3 (HER3) or EGFR gene amplification
    E.1.1.1Medical condition in easily understood language
    Solid cancer tumours with specific genetic mutations
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.1
    E.1.2Level LLT
    E.1.2Classification code 10065143
    E.1.2Term Malignant solid tumour
    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 determine the objective response rate at 8 weeks (ORR8) following treatment with neratinib in patients with solid tumors that test positive for somatic human epidermal growth factor receptor mutations in the ERBB gene family (EGFR, HER2, and/or HER3) or EGFR gene amplification.
    E.2.2Secondary objectives of the trial
    To determine:
    - the best confirmed overall response rate (ORR) with neratinib in patients with tumors with somatic human epidermal growth factor receptor mutation (EGFR, HER2, HER3) or EGFR gene amplification;
    - the clinical benefit rate (CBR) of neratinib therapy, defined as the percentage of patients with complete response (CR) + partial response (PR) + stable disease (SD) ≥ 16 weeks from the Cycle 1 Day 1 (C1D1);
    - progression-free survival (PFS), defined as the time from C1D1 to first date of recurrence, progression, or death due to any cause;
    - duration of response (DOR) of neratinib therapy, defined as time from which measurement criteria are met for CR or PR until the first date of documented disease progression;
    - overall survival (OS) for each cohort;
    - assess the safety profile and tolerability of neratinib therapy in patients with ERBB mutation-positive solid tumors.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Men and women who are ≥18 years old at signing of informed consent.
    2. Histologically confirmed cancers for which no curative therapy exists.
    3. Documented human epidermal growth factor receptor (EGFR, HER2, or HER3) mutation identified through mutation analysis assays as routinely performed at each participating site according to their local laboratory procedures:
    i. HER2 mutation or
    ii. EGFR mutation or EGFR amplification primary brain tumor (see additional criteria for this cohort only) or
    iii. HER3 mutation
    4. Patients must have at least one measurable or evaluable lesion, preferably as defined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Patients without RECIST-measurable disease will be eligible for enrollment to the EGFR-mutation primary brain tumor cohort or the solid tumor NOS cohorts, regardless of tumor type, provided their disease can be evaluated using another accepted response criteria (eg, Gynecologic Cancer InterGroup [GCIG] CA125 Response Criteria, Pediatric Cancer Working Group 2 (PCWG2) Criteria; PET Response Criteria in Solid Tumors PERCIST).
    5. Left ventricular ejection fraction (LVEF) ≥50% measured by multiple-gated acquisition scan (MUGA) or echocardiogram (ECHO).
    6. Eastern Cooperative Oncology Group (ECOG) status of 0 to 2.
    7. Negative β-human chorionic gonadotropin (hCG) pregnancy test for premenopausal women of reproductive capacity (those who are biologically capable of having children) and for women less than 12 months after menopause.
    8. Women of child-bearing potential must agree and commit to the use of a highly effective method of contraception, as determined to be acceptable by the investigator, from the time of informed consent until 28 days after the last dose of the investigational product. Men must agree and commit to use a barrier method of contraception while on treatment and for 3 months after the last dose of the investigational product.
    9. Provide written, informed consent to participate in the study and follow the study procedures.

    Additional inclusion criteria for patients with Primary Brain Tumors that harbor EGFR Mutations (Cohort 2a):
    10. Glioblastoma multiforme (GBM), gliosarcoma, and/or Grade III glioma.
    11. Has received prior treatment including radiation and/or chemotherapy.
    12. Documentation of EGFR gene amplification or EGFR mutation from most recent tumor sample.
    13. Able to undergo repeated magnetic resonance imaging (MRI) scans.
    14. Subjects with recurrent disease (confirmed by MRI and evaluable by Macdonald criteria) at the time of first or second recurrence or progression following initial definitive therapy(s) such as surgery with or without adjuvant radiation therapy and/or chemotherapy.
    15. Have ≥ 1 site of bi-dimensionally measurable disease:
    i. The size of at least one of the measurable lesions should ≥ 1 cm in each dimension and noted on more than one imaging slice.
    ii. Measured using contrast-enhanced MRI clearly limited residual lesion (re-growth within the surgical or irradiated field is acceptable).
    iii. Imaging study performed within 28 days before enrollment while on stable dose steroid medication for at least 5 days immediately before and during the imaging study.
    E.4Principal exclusion criteria
    1. Prior treatment with any HER2 directed TKI (eg, lapatinib, afatinib, dacomitinib, neratinib).
    2. Not recovered to at least Grade 1 or baseline (CTCAE v4.0) from all clinically significant AEs related to prior therapies (excluding alopecia).
    3. Received chemotherapy or biologic therapy ≤ 2 weeks or 5 half-lives (t½) of the agent used, whichever is shorter, prior to the start of neratinib.
    4. Received radiation therapy ≤14 days prior to initiation of the investigational product, except primary brain tumor patients.
    5. Patients who are receiving any other anticancer agents with the exception of patients on 1) a stable dose of bisphosphonates or denosumab or 2) a gonadotropin-releasing agonist/antagonist in the case of prostate cancer.
    6. Received prior therapy resulting in a cumulative epirubicin dose >900 mg/m2 or cumulative doxorubicin dose ≥350 mg/m2 or equivalent dose of other anthracyclines.
    7. Symptomatic or unstable brain metastases. (Note: Asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days are eligible to participate in the study.) Patients with primary central nervous system tumors are eligible.
    8. Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of ≥2), unstable angina, myocardial infarction within 12 months of enrollment, or ventricular arrhythmia.
    9. QTc interval > 450 ms for men or > 470 ms for women, or known history of congenital QT prolongation or Torsade de pointes (TdP).
    10. Inadequate bone marrow, renal or hepatic function as defined on screening laboratory assessments outside the following limits:
    - Absolute neutrophil count (ANC): <1,000/µL (1.0 x 10e9 /L);
    - Platelet count <100,000/µL (<100 x 10e9/L);
    - Hemoglobin: <8 g/dL (transfusion allowed to treat low hemoglobin-transfusion must be at least 7 days prior to baseline);
    - Total bilirubin: >1.5 x institutional upper limit of normal (ULN) (in case of known Gilbert's syndrome, >2× ULN);
    - Aspartate aminotransferase (AST) and/or Alanine aminotransferase (ALT): >3 x institutional ULN (>5 × ULN if liver metastases are present);
    - Creatinine: >1.5 × ULN or calculated Creatinine Clearance <50 mL/min (as calculated by Cockroft-Gault formula or Modification of Diet in Renal Disease [MDRD] formula).
    11. Active infection or unexplained fever >38.5°C (101.3°F).
    12. Uncontrolled concurrent malignancy (early stage or chronic disease is allowed if not requiring active therapy or intervention and is under control).
    13. Women who are pregnant or breast-feeding.
    14. Significant chronic gastrointestinal disorder with diarrhea as a major symptom (eg, Crohn's disease, malabsorption, or Grade ≥2 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events Version 4.0 [CTCAE v.4.0] diarrhea of any etiology at baseline).
    15. Clinically active infection with a hepatitis virus.
    16. Evidence of significant medical illness, abnormal laboratory finding, or psychiatric illness/social situations that could, in the Investigator's judgment, make the patient inappropriate for this study.
    17. Known hypersensitivity to any component of the investigational product.
    18. Unable or unwilling to swallow tablets.

    Additional exclusion criteria for patients with Primary Brain Tumors that harbor EGFR Mutations (Cohort 2a):
    19. Prior or scheduled Gliadel® wafer implant unless area of assessment is outside the region previously implanted.
    20. Prior interstitial brachytherapy or stereotactic radiosurgery unless area of assessment is outside the region previously treated.
    21. Has received enzyme-inducing anti-epileptic drugs (EIAED) such as carbamazepine, phenytoin, phenobarbital, or primidone within 14 days before C1D1.
    22. Received treatment with bevacizumab or any other anti-EGFR therapy (eg, erlotinib, gefitinib, cetuximab, CDX-110).
    23. Received radiation therapy ≤ 12 weeks prior to initiation of the investigational product.
    E.5 End points
    E.5.1Primary end point(s)
    To determine the objective response rate at 8 weeks (ORR8) following treatment with neratinib in patients with solid tumors that test positive for somatic human epidermal growth factor receptor mutations in the ERBB gene family (EGFR, HER2, and/or HER3) or EGFR gene amplification.
    E.5.1.1Timepoint(s) of evaluation of this end point
    After 8 weeks of treatment with neratinib.
    E.5.2Secondary end point(s)
    To determine the best confirmed overall response rate (ORR) with neratinib in patients with tumors with somatic human epidermal growth factor receptor mutation (EGFR, HER2, HER3) or EGFR gene amplification.
    To determine the clinical benefit rate (CBR) of neratinib therapy, defined as the percentage of patients with complete response (CR) + partial response (PR) + stable disease (SD) ? 16 weeks from the C1D1.
    To determine progression-free survival (PFS), defined as the time from C1D1 to the first date of recurrence, progression, or death due to any cause, whichever comes first.
    To determine the duration of response (DOR) of neratinib therapy, defined as the time from which measurement criteria are met for CR or PR (whichever status is recorded first) until the first date of documented disease progression.
    To determine overall survival (OS) for each cohort.
    To assess the safety profile and tolerability of neratinib therapy in patients with ERBB mutation-positive solid tumors
    E.5.2.1Timepoint(s) of evaluation of this end point
    Tumor assessments will be performed after every 8 weeks of treatment with neratinib.
    Follow-up visits will occur every 8 weeks for patients discontinuing treatment for any reason other than disease progression.
    Patients with disease progression will be followed up every 12 weeks for survival.
    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 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 No
    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.7.1.3.1Other trial type description
    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 No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    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 No
    E.8.2.3Other No
    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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA11
    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 No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    France
    Italy
    Finland
    Spain
    Israel
    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
    LVLS
    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 months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months0
    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: 90
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 90
    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 state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 110
    F.4.2.2In the whole clinical trial 180
    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)
    None
    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 Decision2014-04-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-02-28
    P. End of Trial
    P.End of Trial StatusCompleted
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