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    Summary
    EudraCT Number:2017-000419-17
    Sponsor's Protocol Code Number:AFT-38
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2017-10-23
    Trial 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 ConcernedGermany - BfArM
    A.2EudraCT number2017-000419-17
    A.3Full title of the trial
    A Randomized, Open Label, Phase III Trial to Evaluate the Efficacy and Safety of Palbociclib + Anti-HER2 Therapy + Endocrine Therapy vs. Anti-HER2 Therapy + Endocrine Therapy after Induction Treatment for Hormone Receptor Positive (HR+)/HER2-Positive Metastatic Breast Cancer
    Eine randomisierte, offene, Phase III Studie zur Evaluierung der Effektivität und Sicherheit von Palbociclib in Kombination mit einer Anti-HER-2-Therapie plus Endokrinen Therapie im Vergleich zu einer alleinigen Anti-Her-2-Therapie plus Endokrinen Therapie nach Induktionstherapie gegen Hormonrezeptor-positiven / Her-2-positiven, metastasierten Brustkrebs
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Randomized, Open Label, Clinical Study of the Targeted Therapy, Palbociclib, to treat Metastatic Breast Cancer (PATINA)
    Eine randomisierte, offene Klinische Studie mit dem Präparat Palbociclib zur Behandlung von metastasiertem Brustkrebs
    A.3.2Name or abbreviated title of the trial where available
    PATINA
    PATINA
    A.4.1Sponsor's protocol code numberAFT-38
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02947685
    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 SponsorAlliance Foundation Trials, LLC
    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 supportPfizer, Inc
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAlliance Foundation Trials, LLC
    B.5.2Functional name of contact pointSenior Project Manager
    B.5.3 Address:
    B.5.3.1Street Address221 Longwood Avenue; Room 108
    B.5.3.2Town/ cityBoston
    B.5.3.3Post code02215
    B.5.3.4CountryUnited States
    B.5.4Telephone number+16175257522
    B.5.5Fax number+16177328576
    B.5.6E-mailjlanzilotti@alliancefoundationtrials.org
    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 Yes
    D.2.1.1.1Trade name IBRANCE 125mg
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Labs, Division of Pfizer, Inc, NY, NY 10017
    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.3.1Product nameIBRANCE
    D.3.4Pharmaceutical form Capsule, hard
    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 INNPALBOCICLIB
    D.3.9.1CAS number 571190-30-2
    D.3.9.4EV Substance CodeSUB177204
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number125
    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 IBRANCE 100mg
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Labs, Division of Pfizer, Inc, NY, NY 10017
    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.3.1Product nameIBRANCE
    D.3.4Pharmaceutical form Capsule, hard
    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 INNPALBOCICLIB
    D.3.9.1CAS number 571190-30-2
    D.3.9.4EV Substance CodeSUB177204
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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 Yes
    D.2.1.1.1Trade name IBRANCE 75mg
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Labs, Division of Pfizer, Inc. NY, NY 10017
    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.3.1Product nameIBRANCE
    D.3.4Pharmaceutical form Capsule, hard
    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 INNPALBOCICLIB
    D.3.9.1CAS number 571190-30-2
    D.3.9.4EV Substance CodeSUB177204
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number75
    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
    HR+/HER2+ metastatic breast cancer
    HR+/HER2+ metastasierter Brustkrebs
    E.1.1.1Medical condition in easily understood language
    metastatic breast cancer
    metastasierter Brustkrebs
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 23.0
    E.1.2Level PT
    E.1.2Classification code 10065430
    E.1.2Term HER2 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 20.0
    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.1.2 Medical condition or disease under investigation
    E.1.2Version 23.0
    E.1.2Level LLT
    E.1.2Classification code 10070575
    E.1.2Term Estrogen receptor positive 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
    The primary objective of this study is to demonstrate that the combination of palbociclib with anti-HER2 therapy plus endocrine therapy is superior to anti-HER2-based therapy plus endocrine therapy in prolonging PFS in participants with hormone receptor-positive, HER2+ metastatic breast cancer who have not received any prior treatment beyond induction treatment in this setting.
    Das primäre Ziel der Studie ist es zu zeigen, dass die Kombination von Palbociclib mit Anti-HER2-Therapie plus endokriner Therapie der alleinigen Anti-HER2-Therapie plus endokrinen Therapie im Hinblick auf die Verlängerung des progressionsfreien Überlebens (PFS) von Patienten/Patientinnen mit HR+, HER2+, metastasierten Brustkrebs, die außer einer vorangegangenen Induktionstherapie bisher noch keine weitere Therapie erhalten haben, überlegen ist.
    E.2.2Secondary objectives of the trial
    1. To compare measures of tumor control (including PFS, OR, CBR, DOR) between the treatment arms
    2. To compare median overall survival and overall survival probabilities at 3-years and 5-years between the treatment groups
    3. To compare safety and tolerability between the treatment arms
    4. To compare the incidence of CNS metastasis between the treatment arms
    5. To compare patient reported time to symptom progression as assessed by the FACT-B TOI-PFB
    6. To compare patient reported breast cancer specific health related quality of life (HRQOL) and general health status.
    1. Vergleich des Tumoransprechens (einschließlich PFS, OR, CBR, DOR) zwischen den Behandlungsarmen.
    2. Vergleich des medianen Gesamtüberlebens (OS) und der Gesamtüberlebenswahrscheinlichkeit nach 3 Jahren und 5 Jahren zwischen den Behandlungsarmen.
    3. Vergleich der Sicherheit und Verträglichkeit zwischen den beiden Behandlungsarmen.
    4. Vergleich der Inzidenz von ZNS- Metastasen zwischen den beiden Behandlungsarmen.
    5. Vergleich der vom Patienten/von der Patientin berichteten Dauer bis zur Verschlechterung der Symptome der Erkrankung ermittelt mittels FACT-B, TOI-PFB
    6. Vergleich der vom Patienten/der Patientin berichteten brustkrebs- und gesundheitsspezifischen Lebensqualität (HRQOL) und des allgemeinen Gesundheitszustandes.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Inclusion Criteria Screening
    1. Signed informed consent obtained prior to any study specific assessments and procedures
    2. Age ≥18 years (or per national guidelines)
    3. Participants must have histologically confirmed invasive breast cancer that is metastatic or not amenable for resection or radiation therapy with curative intent. Histological documentation of metastatic/recurrent breast cancer is not required if there is unequivocal evidence for recurrence of the breast cancer.
    4. Patients must have histologically confirmed HER2+ and hormone receptor positive (ER+ and/or PR+), metastatic breast cancer. ER, PR and HER2 measurements should be performed according to institutional guidelines, in a CLIA-approved setting in the US or certified laboratories for Non-US regions. Cut-off values for positive/negative staining should be in accordance with current ASCO/CAP (American Society of Clinical Oncology/College of American Pathologists) guidelines.
    5. Sites must be able to submit a representative formalin-fixed paraffin-embedded (FFPE) tumor tissue block (preferred) from primary breast or metastatic site (archival) OR at least 15 freshly cut unstained slides from such a block, along with a pathology report documenting HER2 positivity and hormone receptor positivity.
    6. Sites should be willing to provide a representative tumor specimen obtained from recently biopsied metastatic disease if clinically feasible. This is recommended but optional tissue

    Inclusion Criteria (Randomization)
    7. Signed informed consent obtained prior to any study specific assessments and procedures
    8. Age ≥ 18 years (or per national guidelines)
    9. ECOG performance status 0-1
    10. Patients must be able and willing to swallow and retain oral medication without a condition that would interfere with enteric absorption.
    11. Serum or urine pregnancy test must be negative within 7 days of randomization in women of childbearing potential. Pregnancy testing does not need to be pursued in patients who are judged as postmenopausal before randomization, as determined by local practice, or who have undergone bilateral oophorectomy, total hysterectomy, or bilateral tubal ligation. Women of childbearing potential and male patients randomized into the study must use adequate contraception for the duration of protocol treatment and for 6 months after the last treatment with palbociclib if they are in Arm A. Adequate contraception is defined as one highly effective form (i.e. abstinence, (fe)male sterilization OR two effective forms (e.g. non-hormonal IUD and condom / occlusive cap with spermicidal foam / gel / film / cream / suppository).
    12. Resolution of all acute toxic effects of prior induction anti-HER2-based chemotherapy regimen to NCI CTCAE version 4.0 Grade ≤1 (except alopecia or other toxicities not considered a safety risk for the patient at investigator's discretion) 3-6 weeks between last dose of chemotherapy–anti-HER2therapy and randomization are allowed. Endocrine therapy could start before study randomization.
    13. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures
    14. Evidence of (a) personally signed and dated informed consent document indicating that the patient (or a legal representative) has been informed of all pertinent aspects of the study before any study specific activity is performed

    Inclusion Criteria 15-24: Please see full protocol
    Einschusskriterien (Screening)
    1. Schriftliches Einverständnis vor Beginn jeglicher studienspezifischer Erhebungen und Untersuchungen.
    2. Alter ≥18 Jahre (oder je nach nationalen Leitlinien).
    3. Histologisch gesicherter, invasiver Brustkrebs, der metastasiert oder nicht für eine Resektion oder Bestrahlung mit kurativen Ansatz geeignet ist. Eine histologische Bestätigung des metastasierten/ wiederaufgetretenen Brustkrebs ist nicht erforderlich, sofern es sich zweifelsfrei um ein Wiederauftreten von Brustkrebs handelt.
    4. Histologisch gesicherter HER2+ , HR+ (ER+ und/oder PR+), metastasierter Brustkrebs. Die ER-, PR- und HER2- Messung sollte anhand lokaler Richtlinien durchgeführt werden (mit einem durch die CLIA-zugelassenen Verfahren in den US oder zertifizierten Laboren für die nicht-US Regionen). Die Cut-off Werte für eine positive/negative Färbung sollten mit der aktuellen ASCO/CAP (American Society of Clinical Oncology/College of American Pathologists) Leitlinie korrelieren.
    5. Das Zentrum muss fähig sein einen repräsentativen, in Formalin fixierten und in Paraffin eingebetteten Tumorblock (FFPE) vom Primärtumor der Brust (bevorzugt) oder von einer Metastase (archiviert) ODER mindestens 15 frisch geschnittene, ungefärbte Objektträger von einem solchen Tumorblock gemeinsam mit den Pathologiebericht (auf dem die HER- und HR- Positivität dokumentiert ist) zu versenden.
    6. Sofern eine Biopsie klinisch durchführbar ist, sollte das Zentrum bereit sein geeignetes Tumormaterial von einer Metastase bereitzustellen. Die Biopsie ist eine empfohlene aber optionale Biopsie, die Forschungszwecken dient.

    Einschlusskriterien (bei Randomisation)
    7. Schriftliches Einverständnis vor Beginn jeglicher studienspezifischer Erhebungen und Untersuchungen.
    8. Alter ≥18 Jahre (oder je nach nationalen Leitlinien).
    9. ECOG Performance Status 0-1.
    10. Der Patient/die Patientin muss fähig und bereit sein eine orale Medikation zu schlucken und bei sich zu behalten und die enterale Aufnahme darf nicht beeinflusst sein.
    11. Ein Schwangerschaftstest im Serum oder Urin muss innerhalb von 7 Tagen vor Randomisation bei gebärfähigen Frauen negativ sein. Ein Schwangerschaftstest ist nicht erforderlich bei Frauen, die vor Randomisation als postmenopausal eingestuft werden (anhand der lokalen Routine), bei Z. n. beidseitiger Eierstockentfernung, bei Z.n. totaler Hysterektomie oder beidseitiger Eileiterunterbindung. Sofern eine Behandlung in Arm A erfolgt, müssen gebärfähige Frauen und Männer, die in die Studie randomisiert werden, eine adäquate Verhütung für die Dauer der Studienbehandlung und 6 Monate nach der letzten Behandlung mit Palbociclib anwenden. Eine adäquate Verhütung ist durch die Benutzung einer hoch effektiven Methode (Abstinenz, Sterilisation) oder durch Benutzung von zwei effektiven Methoden (nicht-hormonelles IUD, Kondom oder Verhütungskappe in Kombination mit spermiziden Schaum/Gel/ Film/ Creme/Zäpfchen).
    12. Erholung von allen akuten Nebenwirkungen einer vorherigen HER2-basierten Chemotherapie auf Grade ≤1 NCI CTCAE Version 4.0 (Ausnahme Alopezie und andere Nebenwirkungen die vom Prüfarzt nicht als Risiko für die Sicherheit des Patienten/der Patientin angesehen werden). Es dürfen 3-6 Wochen zwischen der letzten Chemo- und HER2-Therapie und der Randomisation liegen. Die endokrine Therapie kann bereits vor Randomisation begonnen werden.
    13. Bereitschaft und Fähigkeit die geplanten Visiten, Behandlungen, Laboruntersuchungen und andere Studienprozeduren einzuhalten.
    14. Nachweis einer persönlich unterschriebenen und datierten Einwilligungserklärung die zeigt, dass der Patient/die Patientin (oder sein/ihr gesetzlicher Vertreter) über alle relevanten Aspekte der Studie informiert wurde, bevor irgendeine studienspezifische Aktivität erfolgte.

    Einschlusskriteria 15-24: siehe Protokoll
    E.4Principal exclusion criteria
    1. Concurrent therapy with other Investigational Products.
    2. Prior therapy with any CDK inhibitor.
    3. History of allergic reactions attributed to compounds of chemical or biologic composition similar to palbociclib.
    4. Patients receiving any medications or substances that are strong inhibitors or inducers of CYP3A isoenzymes within 7 days of randomization.
    5. Uncontrolled current illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, diabetes, or psychiatric illness/social situations that would limit compliance with study requirements. Ability to comply with study requirements is to be assessed by each investigator at the time of screening for study participation.
    6. Pregnant women, or women of childbearing potential without a negative pregnancy test (serum or urine) within 7 days prior to randomization, irrespective of the method of contraception used, are excluded from this study because the effect of palbociclib on a developing fetus is unknown. Breastfeeding must be discontinued prior to study entry.
    7. Patients on combination antiretroviral therapy, i.e. those who are HIV-positive, are ineligible because of the potential for pharmacokinetic interactions or increased immunosuppression with palbociclib.
    8. QTc interval >480 msec, Brugada syndrome or known history of QTc prolongation or Torsade de Pointes.
    9. Patients with clinically significant history of liver disease, including viral or other known hepatitis, current alcohol abuse, or cirrhosis
    1. Gleichzeitige Therapie mit einem anderen Prüfpräparat.
    2. Vorherige Therapie mit einem CDK-Inhibitor.
    3. Vorgeschichte einer allergischen Reaktion auf Bestandteile von chemischen oder biologischen Zusammensetzungen, die Palbociclib ähnlich sind.
    4. Patienten/Patientinnen, die innerhalb 7 Tage vor Randomisation mit einem Medikament (bzw. Substanz) behandelt werden, welches ein starker Inhibitor oder Induktor der CYP3A Isoenzyme ist.
    5. Unkontrollierte interkurrente Krankheit inklusive, aber nicht limitiert auf, andauernde oder aktive Infektion, Herzinsuffizienz, instabile Angina pectoris, Herzarrhythmien, Diabetes oder psychiatrische Erkrankungen und soziale Begebenheiten, die die Compliance bezüglich der Studienprozeduren verringern können. Die Fähigkeit des Patienten/der Patientin die Studienprozeduren zu befolgen muss jeweils vom Prüfarzt während des Screenings der Studie abgeschätzt werden.
    6. Schwangere Frauen oder gebärfähige Frauen ohne einen negativen Schwangerschaftstest (Serum oder Urin) innerhalb 7 Tagen vor Randomisation werden unabhängig von der benützten Verhütungsmethode von der Studie exkludiert, da Auswirkungen von Palbociclib auf den Fetus unbekannt sind. Stillende Patientinnen müssen vor Studieneintritt abstillen.
    7. Patienten/Patientinnen unter antiretroviraler Therapie, z.B. bei HIV-Positivität, können auf Grund der möglichen pharmakokinetischen Interaktionen und der erhöhten Immunsuppression unter Palbociclib nicht in die Studie eingeschlossen werden.
    8. QTc Interval >480 msec, Brugada Syndrom oder bekannte Vorgeschichte einer Verlängerung der QTc-Zeit oder Torsade de Pointes.
    9. Patienten/Patientinnen mit einer klinisch signifikanten Vorgeschichte einer Lebererkrankung einschließlich einer viralen oder anderen bekannten Hepatitis, derzeitigen Alkoholabusus oder einer Leberzirrhose.
    E.5 End points
    E.5.1Primary end point(s)
    Progression-free survival (PFS) as assessed by the Investigator
    Progressionsfreies Überleben (PFS) basierend auf der Erhebung durch den Prüfarzt
    E.5.1.1Timepoint(s) of evaluation of this end point
    Based on the expected recruitment and treatment duration, the primary endpoint analysis is expected to take place 18 month after randomization of the last Patient.
    Basierend auf der angenommenen Rekrutierungsgeschwindigkeit und der angenommenen Behandlungsdauer, wird die Analyse des primären Endpunktes 18 Monate nach Randomisierung der letzten Patientin/des letzten Patienten erfolgen.
    E.5.2Secondary end point(s)
    1. Overall Survival (OS)
    2. 3-year and 5-year survival probabilities
    3. Objective response (OR: CR or PR)
    4. Duration of response (DOR)
    5. Clinical Benefit Rate (CBR: CR or PR or SD ≥ 24 weeks)
    6. Safety: Type, incidence, severity (as graded by the NCI CTCAE v. 4.0), seriousness and attribution to the study medications of AEs and any laboratory abnormalities
    7. Patient Reported Outcomes: Time to symptom progression (FACT-B PFB-TOI), breast cancer specific health treatment related quality of life and general health status
    1. Gesamtüberleben (OS).
    2. 3-Jahres und 5-Jahres Gesamtüberlebenswahrscheinlichkeit.
    3. Objektives Tumoransprechen (OR: CR oder PR).
    4. Dauer des Ansprechenes (DOR).
    5. Klinische Benefit Rate (CBR: CR oder PR oder SD ≥ 24 Wochen)
    6. Sicherheit: Typ, Häufigkeit, Intensität (Severity) (Einstufung anhand NCI CTCAE v. 4.0), Schweregrad (Seriousness) und Zusammenhang mit der Studienmedikation von unerwünschten Ereignissen (AEs) und jeglichen Laboranomalien.
    7. Patient Reported Outcomes: Zeit bis zum Voranschreiten der Symptome (FACT-B PFB-TOI), brustkrebs- und gesundheitsspezifische Lebensqualität (HRQOL) und allgemeiner Gesundheitszustand.
    E.5.2.1Timepoint(s) of evaluation of this end point
    All secondary endpoints, will be assessed at the same timepoints as the Primary Criterion.
    Alle sekundären Zielkriterien werden zum selben Zeitpunkt wie das primäre Zielkriterium ausgewertet.
    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 No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    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) 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 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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Anti-HER2 Therapie mit Trastuzumab und Pertuzumab und Endokrine Therapie
    Anti-HER2 therapy with trastuzumab + pertuzumab and endocrice therapy
    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 concerned20
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA75
    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
    Australia
    Germany
    Italy
    New Zealand
    Portugal
    Spain
    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
    Study Duration will be for 5 years after the last patient is randomized, regardless of time to progression.
    Last follow-up for patients is expected to be May 2025 and study close out activities are expected to be completed by August 2025.
    Die Dauer der Studie ist festgelegt auf 5 Jahre nach Randomisierung des letzten Patienten, unabhängig von der Zeit bis zur Progression.
    Der Follow-up für den letzten Patienten wird für Mai 2025 erwartet. Es wird davon ausgegangen, dass die Study Close-Out Aktivitäten bis August 2025 beendet sein werden.
    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 months6
    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 months6
    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: 340
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 156
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Subjects incapable of giving consent personally may authorize an authorized representative to provide consent (see inclusion criterion number 14)
    Nicht einwilligungsfähige Patienten können teilnehmen, wenn sein/ihr gesetzlicher Vertreter die Einwilligungserklärung unterschreibt (siehe auch Einschluss-Kriterium Nummer 14)
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state120
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 300
    F.4.2.2In the whole clinical trial 496
    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
    keine
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation SOLTI
    G.4.3.4Network Country Spain
    G.4 Investigator Network to be involved in the Trial: 2
    G.4.1Name of Organisation Fondazione Michelangelo
    G.4.3.4Network Country Italy
    G.4 Investigator Network to be involved in the Trial: 3
    G.4.1Name of Organisation The Australian and New Zealand Breast Cancer Trials Group
    G.4.3.4Network Country Australia
    G.4 Investigator Network to be involved in the Trial: 4
    G.4.1Name of Organisation PrECOG, LLC
    G.4.3.4Network Country United States
    G.4 Investigator Network to be involved in the Trial: 5
    G.4.1Name of Organisation German Breast Group (GBG) Forschungs GmbH
    G.4.3.4Network Country Germany
    G.4 Investigator Network to be involved in the Trial: 6
    G.4.1Name of Organisation Unicancer
    G.4.3.4Network Country France
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-03-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-03-13
    P. End of Trial
    P.End of Trial StatusOngoing
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