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    Summary
    EudraCT Number:2015-003509-41
    Sponsor's Protocol Code Number:GBG90
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2016-05-31
    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 number2015-003509-41
    A.3Full title of the trial
    A randomized phase II trial to assess the efficacy of paclitaxel and olaparib in comparison to paclitaxel / carboplatin followed by epirubicin/cyclophosphamide as neoadjuvant chemotherapy in patients with HER2-negative early breast cancer and Homologous Recombination Deficiency (HRD patients with deleterious BRCA1/2 tumor or germline mutation and/or HRD score high) (GeparOLA)
    Eine randomisierte Phase II-Studie zum Vergleich von Paclitaxel/Olaparib versus Paclitaxel / Carboplatin gefolgt von Epirubicin / Cyclophosphamid als neoadjuvante Behandlung von Patienten mit HER2-negativem primären Brustkrebs mit homologen rekombinanten Mangel (HRD) [HRD Patienten mit abträglichen Tumor oder Keimbahn BRCA 1/2 Mutationen und / oder HRD-Score hoch] (GeparOLA)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A randomized phase II trial to assess the efficacy of paclitaxel and olaparib in comparison to paclitaxel / carboplatin followed by epirubicin/cyclophosphamide as neoadjuvant chemotherapy in patients with HER2-negative early breast cancer and Homologous Recombination Deficiency (HRD) (GeparOla)
    Eine randomisierte Phase II-Studie zum Vergleich von Paclitaxel/Olaparib versus Paclitaxel / Carboplatin gefolgt von Epirubicin / Cyclophosphamid als neoadjuvante Behandlung von Patienten mit HER2-negativem primären Brustkrebs mit homologen rekombinanten Mangel (HRD) (GeparOLA)
    A.4.1Sponsor's protocol code numberGBG90
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02789332
    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 SponsorGBG Forschungs GmbH
    B.1.3.4CountryGermany
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAstra Zeneca GmbH
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGBG Forschungs GmbH
    B.5.2Functional name of contact pointProjectmanagement GeparOla
    B.5.3 Address:
    B.5.3.1Street AddressMartin Behaim Str. 12
    B.5.3.2Town/ cityNeu-Isenburg
    B.5.3.3Post code63263
    B.5.3.4CountryGermany
    B.5.4Telephone number+4961027480337
    B.5.5Fax number+4961027480440
    B.5.6E-mailgeparola@gbg.de
    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 nameolaparib
    D.3.2Product code AZD2281
    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 INNolaparib
    D.3.9.1CAS number 763113-22-0
    D.3.9.2Current sponsor codeKU-0059436; AZD2281; CO-CE 42
    D.3.9.3Other descriptive nameOLAPARIB
    D.3.9.4EV Substance CodeSUB32234
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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: 2
    D.1.2 and D.1.3IMP RoleComparator
    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.2.5The 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 nameCARBOPLATIN
    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 INNCarboplatin
    D.3.9.1CAS number 41575-94-4
    D.3.9.3Other descriptive nameCARBOPLATIN
    D.3.9.4EV Substance CodeSUB06614MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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
    Patients with triple negative or HRpositive, early breast cancer
    E.1.1.1Medical condition in easily understood language
    Patients with an illness associated with a very aggressive form of breast cancer, however they are chemosensitive and the chromosomal instability might be a suitable target for Olaparib.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10006187
    E.1.2Term 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
    To assess the pathological complete response (pCR=ypT0/is ypN0) rate of neoadjuvant treatment of olaparib and paclitaxel followed by epirubicin and cyclophosphamide (PO→EC) inneoadjuvant breast cancer patients with early breast cancer and HR deficient tumors defined as either tBRCA1/2 mutation or HRD score high or known gBRCA mutation.
    E.2.2Secondary objectives of the trial
    • To assess the pCR rates of patients receiving PO→EC and the pCR rates of patients receiving paclitaxel and carboplatin followed by EC (PCb→EC)
    • To assess the pCR rates (ypT0/is, ypN0) in the stratified subgroups
    • To determine other pCR rates (ypT0 ypN0; ypT0 ypN0/+; ypT0/is ypN0/+; ypT(any) ypN0)
    • To assess the pCR rate in HRD high with vs without tBRCA mutation
    • To determine the response rates of the breast tumor and axillary nodes based on physical examination and imaging tests (sonography, mammography, or MRI)
    • To determine the breast conservation rate
    • To assess the toxicity and compliance
    • To correlate co-occurring mutations detected by next generation sequencing in lymphocytes or in tumors cells with pCR (exploratory)
    • Potential biomarkers predicting safety and compliance for breast cancer
    • Bestimmung der pCR-Raten von POEC und PCb EC
    • Bestimmung der pCR Raten (ypT0/is, ypN0) in den stratifizierten Subgruppen
    • Bestimmung der Raten von ypT0 ypN0; ypT0 ypN0/+; ypT0/is ypN0/+; ypT(jedes Stadium) ypN0; bei POEC und Vergleich mit PbEC.
    • Bestimmung der pCR Rate bei HRD high mit und ohne tBRCA Mutation
    • Bestimmung der Ansprechrate des Brusttumors und der axillären Lymphknoten anhand körperlicher Untersuchung und bildgebender Verfahren (Sonographie, Mammographie oder MRT) bei POEC und Vergleich mit PCbEC.
    • Bestimmung der Rate der brusterhaltenden Therapie bei POEC und Vergleich mit PCbEC.
    • Bestimmung von Toxizität und Compliance bei POEC und Vergleich mit PCbEC.
    • Evaluation genomweiter Single Nucleotide Polymorphismen (SNPs), stromaler TILs, PARP, 53BP1, REV7 und weiterer Biomarker zur Behandlung von Brustkrebs.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Genetic Markers from peripheral blood to predict tumor biology, treatment response and prognosis
    E.3Principal inclusion criteria
    1. Written informed consent for all study specific procedures according to local regulatory requirements prior to beginning specific protocol procedures.
    2. Complete baseline documentation must be sent to GBG Forschungs GmbH.
    3. Unilateral or bilateral primary carcinoma of the breast, confirmed histologically by core biopsy. Fine-needle aspiration alone is not sufficient. Incisional biopsy is not allowed. In case of bilateral cancer, the investigator has to decide prospectively which side will be evaluated for the primary endpoint.
    4. Centrally confirmed negative HER2-status. Centrally confirmed estrogen and progesterone receptor, and Ki-67 status detected on core biopsy. ER/PR positive is defined as ≥1% stained cells and HER2-positive is defined as IHC 3+ or in-situ hybridisation (ISH) ratio ≥2.0. Formalin-fixed, paraffin-embedded (FFPE) breast tissue from core biopsy has therefore to be sent to the Dept. of Pathology at the Charité, Berlin prior to randomization.
    5. Centrally confirmed tumor Homologous Recombinant Deficiency score (tBRCA positive/mutated and/or HRD high). Patients with known gBRCA and/or tBRCA status can be enrolled prior to the central test results available.
    6. Tumor lesion in the breast with a palpable size of ≥ 2 cm or a sonographical size of ≥ 1 cm in maximum diameter. If the tumor is not detectable with sonography mammography assessment can be considered. The lesion has to be measurable in two dimensions, preferably by sonography. In case of inflammatory disease, the extent of inflammation can be used as measurable lesion.
    7. Patients must be in the following stages of disease:
    - cT2 - cT4a-d or
    - cT1c and cN+ or cT1c and pNSLN+ or
    - cT1c and ER-neg and PR-neg or
    - cT1c and Ki67>20%
    In patients with multifocal or multicentric breast cancer, the largest lesion should be measured and at least one lesion has to meet the above criteria
    8. Age ≥ 18 years.
    9. Karnofsky Performance status index ≥ 80%.
    10. Normal cardiac function must be confirmed by ECG and cardiac ultrasound (LVEF or shortening fraction) within 3 months prior to randomization. Results must be above the normal limit of the institution.
    11. Laboratory requirements:
    Hematology
    - Absolute neutrophil count (ANC) ≥ 2.0 x 109 / L and - Platelets ≥ 100 x 109 / L and - Hemoglobin ≥ 10 g/dL (≥ 6.2 mmol/L)
    Hepatic function
    - Total bilirubin ≤ 1.5x UNL and - ASAT (SGOT) and ALAT (SGPT) ≤ 1.5x UNL and - Alkaline phosphatase ≤ 2.5x UNL.
    12. Negative pregnancy test (urine or serum) within 14 days prior to randomization for all women of childbearing potential.
    13. Complete staging work-up within 3 months prior to randomization. All patients must have bilateral mammography, breast ultrasound (≤ 21 days, and in no case exceed 6 weeks prior to randomization) (Note MRI/ CT scan may be used as an alternative imaging technique). In case of high risk according to guidelines: chest X-ray (PA and lateral) or as an alternative breast MRI/CT, abdominal ultrasound or CT scan or MRI, and bone scan in case of high risk for primary metastasis according to guidelines. In case of positive bone scan, bone X-ray or CT scan is mandatory. Other tests may be performed as clinically indicated.
    14.Male or female patients
    15. Patients must be available and compliant for central diagnostics, treatment and follow-up.
    E.4Principal exclusion criteria
    1. Prior chemotherapy for any malignancy within 5 years.
    2. Prior radiation therapy for breast cancer within 5 years.
    3. Pregnant or lactating patients. Patients of childbearing potential must implement adequate non-hormonal contraceptive measures (barrier methods, intrauterine contraceptive devices, sterilization) during study treatment.
    4. Inadequate general condition (not fit for anthracycline-taxane-targeted agents-based chemotherapy).
    5. Previous malignant disease without being disease-free for less than 5 years (except CIS of the cervix and non-melanomatous skin cancer).
    6. Known or suspected congestive heart failure (>NYHA I) and / or coronary heart disease, angina pectoris requiring antianginal medication, previous history of myocardial infarction, evidence of transmural infarction on ECG, uncontrolled or poorly controlled arterial hypertension (i.e. BP >140 / 90 mm Hg under treatment with two antihypertensive drugs), rhythm abnormalities requiring permanent treatment, clinically significant valvular heart disease.
    7. History of significant neurological or psychiatric disorders including psychotic disorders, dementia or seizures that would prohibit the understanding and giving of informed consent.
    8. Patients currently in an institution by order of jurisdictional or governmental grounds.
    9. Currently active infection.
    10. Definite contraindications for the use of corticosteroids.
    11. Known hypersensitivity reaction to one of the compounds or incorporated substances used in this protocol.
    12. Concurrent treatment with:
    • chronic corticosteroids unless initiated > 6 months prior to study entry and at low dose (10 mg or less methylprednisolone or equivalent).
    • sex hormones. Prior treatment must be stopped before study entry.
    • other experimental drugs or any other anti-cancer therapy.
    13. Participation in another clinical trial with any investigational, not marketed drug within 30 days prior to study entry.
    14. Prior use of a PARP-Inhibitor
    E.5 End points
    E.5.1Primary end point(s)
    Pathological complete response of breast and lymph nodes (ypT0/is ypN0) defined as no microscopic evidence of residual invasive viable tumor cells in all resected specimens of the breast and axilla.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Pathological response will be assessed considering all removed breast and lymphatic tissues from all surgeries after NACT. pCR rate will be assessed approximately 25 weeks after randomization.
    E.5.2Secondary end point(s)
    Other pCR definition
    ypT0 ypN0 is defined as no microscopic evidence of residual invasive and no non-invasive viable tumor cells in all resected specimens of the breast and axilla.
    ypT0 ypN0/+ is defined as no microscopic evidence of residual invasive or non-invasive viable tumor cells in all resected specimens of the breast;
    ypT0/is ypN0/+ is defined as no microscopic evidence of residual invasive viable tumor cells in all resected specimens of the breast; patients with a sentinel node biopsy prior to treatment start will be evaluated for ypT(any) ypN0 similarly to the description given for the primary endpoint.
    Breast conservation is defined as tumorectomy, segmentectomy or quadrantectomy as a most radical surgery.
    Clinical (c) and imaging (i) response will be assessed after EC and before surgery by physical examination and imaging tests. Sonography is the preferred examination, however, if sonography appears not to provide valid results or is not performed, other imaging tests will be considered with the following priority: MRI, mammography, computed tomogram. The same imaging method should be considered for the measurement before, during and after treatment.
    Tolerability and safety will be assessed on the basis of adverse events, serious adverse events, adverse events of special interest and treatment discontinuations. Safety by toxicity grades is defined by the NCI-CTCAE version 4.0.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Most secondary objectives will be assessed approximately 25 weeks after randomization. LRRFS, RRFS, LRFS, DDFS, IDFS and OS are defined as the time period between registration and first event
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis Yes
    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 No
    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 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 No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned35
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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
    last visit of the last subject, 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
    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: 102
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 102
    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 state102
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 102
    F.4.2.2In the whole clinical trial 102
    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 Decision2016-08-01
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-02-27
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