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    Summary
    EudraCT Number:2012-005037-37
    Sponsor's Protocol Code Number:10-005
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-10-15
    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 ConcernedDenmark - DHMA
    A.2EudraCT number2012-005037-37
    A.3Full title of the trial
    A Phase I/II Trial of Temsirolimus Plus Neratinib for Patients with Metastatic HER2-Amplified or Triple-Negative Breast Cancer
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical study of Temsirolimus and Neratinib in patients with breast cancer who have a specific genetic make up.

    A.4.1Sponsor's protocol code number10-005
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01111825
    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 Blvd, Suite 2150
    B.5.3.2Town/ cityLos Angeles
    B.5.3.3Post codeCA 90024
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1424248 6500
    B.5.5Fax number+1424248 6501
    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.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 Torisel®
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Inc
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    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.3.4Pharmaceutical form Concentrate and solvent 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.3.8INN - Proposed INNTEMSIROLIMUS
    D.3.9.1CAS number 162635-04-3
    D.3.9.4EV Substance CodeSUB21308
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    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.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
    Advanced breast carcinoma in patients with trastuzumab-refractory HER2-amplified disease
    E.1.1.1Medical condition in easily understood language
    Breast cancer which has grown in spite of standard treatment
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.0
    E.1.2Level PT
    E.1.2Classification code 10065430
    E.1.2Term HER-2 positive breast cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.0
    E.1.2Level LLT
    E.1.2Classification code 10072737
    E.1.2Term Advanced breast cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.0
    E.1.2Level LLT
    E.1.2Classification code 10027475
    E.1.2Term Metastatic breast cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Phase 1
    To determine the maximum tolerated dose (MTD) of weekly intravenous (IV) temsirolimus when administered in combination with a fixed dose of daily oral neratinib therapy.

    Phase 2
    • To estimate the efficacy [overall response rate (ORR) = complete response (CR) and partial response (PR)] by RECIST (v 1.1) of temsirolimus when administered in combination with neratinib at the established maximum tolerated dose (MTD) for both HER2-amplified trastuzumab-refractory and triple-negative patients.
    • To estimate the ORR for patients with dose escalation to 240 mg neratinib plus 15 mg temsirolimus with a revised prophylactic diarrhea management regimen in pretreated HER2+ MBC patients.
    E.2.2Secondary objectives of the trial
    Phase 1:
    • To determine if the addition of neratinib affects the exposure and half-life of temsirolimus and its active metabolite, sirolimus.

    Phase 2 :
    • To determine the safety and tolerability of temsirolimus when administered in combination with neratinib.
    • To determine progression-free survival (PFS), duration of response (DoR), clinical benefit rate (CBR, i.e., CR + PR + SD ≥24) weeks for the combination at the MDT, and overall survival (OS).
    • To assess the safety of dose escalation to 240 mg neratinib plus 15 mg temsirolimus with a revised prophylactic diarrhea management regimen in pretreated HER2+ MBC patients.

    Exploratory:
    • Exploratory end points are detailed in the protocol.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Phase 1 HER2-Amplified (HER2-Positive) Cohort – Closed to accrual

    Phase 2 HER2-Amplified (HER2-Positive) Cohort - US only (Not EU)

    Phase 1 Triple-Negative Cohort – Closed to accrual

    Phase 2 Triple-Negative Cohort – Closed to accrual

    Phase 2 HER2-Positive Cohort with dose escalation
    • HER2 overexpression and/or amplification as determined by IHC (3+) or FISH (≥2.0).
    • Previously received trastuzumab as part of a regimen in the adjuvant or metastatic setting with evidence of progression. Washout period for trastuzumab of 14 days.
    • May have previously received lapatinib as part of a regimen in the adjuvant or metastatic setting with evidence of progression of disease. Washout period for lapatinib of 14 days.
    • Radiographic progression of disease while on treatment with trastuzumab as defined by RECIST 1.1 criteria.
    • Prior therapy inclusion:
    o No restriction on prior chemotherapy regimens for advanced stage disease. No restriction for prior hormonal therapy. No concurrent use of endocrine therapy is permitted.

    Inclusion Criteria for ALL patients
    • Patients with a diagnosis of invasive adenocarcinoma of the breast confirmed by histology or cytology.
    • Metastatic disease that is or has been pathologically documented.
    • At least one measurable metastatic lesion according to RECIST 1.1 criteria. Ascites, pleural effusions, and bone metastases are not considered measurable. Minimum indicator lesion size ≥10 mm by helical computerized tomography (CT) or ≥20 mm by conventional techniques.
    o Pathological nodes must be ≥15 mm by the short axis to be considered measurable.
    • Age ≥18, as no dosing or adverse event data are currently available on the use of neratinib or temsirolimus in patients <18 years of age.
    • Patients must be willing to discontinue sex hormonal therapy, e.g., birth control pills, hormonal replacement therapy, prior to enrollment. Women of childbearing potential must consent to use effective contraception while on treatment and for 28 days thereafter. Men must consent to use a barrier method of contraception while on treatment and for 3 months thereafter.
    • Negative serum human chorionic gonadotropin (HCG) pregnancy test for premenopausal women of reproductive capacity and for women less than 12 months after menopause.
    • Asymptomatic, central nervous system metastases are permitted if patients remain clinically stable after discontinuation of steroids and anticonvulsants for 3 months.
    • Eastern Cooperative Oncology Group (ECOG) performance status score of ≤2.
    • Patients must have normal organ and marrow function: AST/ALT ≤2.5x institutional upper limit of normal except for patients with liver metastases. For patients with liver metastases, AST/ALT/alkaline phosphatase ≤5.0 x institutional upper limit of normal. Total bilirubin within institutional limits except for patients with liver metastases. For patients with liver metastases, total bilirubin ≤1.5x institutional upper limit of normal. Creatinine clearance within normal limits or ≥60 mL/min, prothrombin time (PT) and partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) ≤1.5x institutional upper limit of normal except for patients on Coumadin or low molecular weight heparin, leukocytes ≥3,000/µL, absolute neutrophil count ≥1,000/µL, and platelets ≥75,000/µL.
    • Able to swallow and retain oral medication.
    E.4Principal exclusion criteria
    • Patients receiving any concurrent anticancer therapy or investigational agents with the intention of treating breast cancer.
    • Previous treatment with any strong inhibitor and/or inducer of CYP3A4 enzyme or sensitive P glycoprotein (P gp) substrates ≤30 days prior to initiation of investigational products.
    • History of allergic reactions attributed to compounds of similar chemical or biologic composition to neratinib or temsirolimus.
    • Women who are pregnant or breast feeding.
    • Life expectancy <3 months.
    • Completion of previous chemotherapy regimen <3 weeks prior to the start of study treatment. Prior hormonal therapy must be discontinued prior to treatment start. Biologic therapy with bevacizumab for the treatment of metastatic disease must be discontinued ≥3 weeks from the start of protocol treatment.
    • Concurrent radiotherapy is not permitted for disease progression on treatment on protocol, but might be allowed for pre-existing non-target lesions with approval from the Sponsor.
    • Concurrent medical conditions which may increase the risk of toxicity, including ongoing or active infection, history of significant bleeding disorder unrelated to cancer (congenital bleeding disorders, acquired bleeding disorders within one year), human immunodeficiency virus (HIV)-positive or active hepatitis.
    • History of clinically significant or uncontrolled cardiac disease, including congestive heart failure, angina, myocardial infarction, arrhythmia, and left ventricular ejection fraction less than 50% measured by a multigated acquisition imaging (MUGA scan) of the heart or an echocardiogram (ECHO).
    • QTc interval >0.47 seconds.
    • Patients with GI tract disease resulting in an inability to take oral medication, malabsorption syndrome, a requirement for IV alimentation, prior surgical procedures affecting absorption, or uncontrolled inflammatory GI disease.
    • History of an invasive second primary malignancy diagnosed within the previous 3 years, except for stage I endometrial or cervical carcinoma or prostate carcinoma treated surgically, and non-melanoma skin cancer.
    • History of uncontrolled seizures, central nervous system disorders or psychiatric disability judged by the investigator to be clinically significant, precluding informed consent, or interfering with compliance of oral drug intake.
    • Unwillingness to give written informed consent, unwillingness to participate, or inability to comply with the protocol for the duration of the study. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests and other study procedures are necessary to participation in this clinical trial.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint in the Phase 2 portion of the trial is the ORR (CR + PR) by RECIST 1.1.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Patients are evaluable for response if they complete at least one week of treatment.
    Baseline extent of disease evaluation will usually be measured including CT scan of chest, abdomen, and pelvis with oral and intravenous contrast (if not contraindicated) and a bone or positron emission tomography (PET) scan. Target lesions will be identified at this time according to RECIST 1.1. Radiographic tumor assessments will be performed after every 8 weeks of treatment for the first 6 cycles and subsequently every 12 weeks after 6 cycles of treatment.
    E.5.2Secondary end point(s)
    The secondary efficacy endpoints include:
    • PFS
    • DoR
    • CBR (CR + PR + SD ≥24 weeks)
    • OS
    E.5.2.1Timepoint(s) of evaluation of this end point
    Baseline extent of disease evaluation will usually be measured including CT scan of chest, abdomen, and pelvis with oral and intravenous contrast (if not contraindicated) and a bone or positron emission tomography (PET) scan. Target lesions will be identified at this time according to RECIST 1.1. Radiographic tumor assessments will be performed after every 8 weeks of treatment for the first 6 cycles and subsequently every 12 weeks after 6 cycles of treatment.
    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 Yes
    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
    to identify a maximum tolerated dose
    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 No
    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 Yes
    E.8.1.7.1Other trial design description
    open-label, single arm, adaptive design, dose-escalation Phase 1/2 study
    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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA7
    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
    Hong Kong
    Spain
    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
    The end of study (EOS) is defined as the last visit of the last patient or the completion of any/all follow-up monitoring and data collection described in the protocol (ie, survival). In the event that the EOS is declared earlier patients who continue to receive clinical benefit from neratinib plus temsirolimus will be offered the opportunity to continue to receive this combination via a treatment extension study or expanded access protocol.
    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 months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years6
    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: 100
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 81
    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 state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 70
    F.4.2.2In the whole clinical trial 181
    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)
    The end of study (EOS) is defined as the last visit of the last patient or the completion of any/all follow-up monitoring and data collection described in the protocol (ie, survival). In the event that the EOS is declared earlier patients who continue to receive clinical benefit from neratinib plus temsirolimus will be offered the opportunity to continue to receive this combination via a treatment extension study or expanded access protocol.
    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 Decision2013-10-11
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-07-28
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2016-07-04
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