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    Summary
    EudraCT Number:2016-004424-38
    Sponsor's Protocol Code Number:011604QM
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2018-02-14
    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 - PEI
    A.2EudraCT number2016-004424-38
    A.3Full title of the trial
    A phase II study investigating preoperative combination strategies for immunotherapy in patients with untreated, operable ER+, HER2-negative primary breast cancer.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A phase II study investigating preoperative combination strategies for immunotherapy in patients with untreated, operable oestrogen receptor positive primary breast cancer
    A.3.2Name or abbreviated title of the trial where available
    ECLIPSE: Preoperative immunotherapy combinations in breast cancer
    A.4.1Sponsor's protocol code number011604QM
    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 SponsorQueen Mary University of London
    B.1.3.4CountryUnited Kingdom
    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 supportF. Hoffmann-La Roche Ltd
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationQueen Mary University of London
    B.5.2Functional name of contact pointKelly Mousa
    B.5.3 Address:
    B.5.3.1Street AddressBarts Cancer Institute
    B.5.3.2Town/ cityOld Anatomy Building
    B.5.3.3Post codeEC1M 6BQ
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number00442078828197
    B.5.6E-mailbci-eclipse@qmul.ac.uk
    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 Tecentriq
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Pharma AG
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameAtezolizumab
    D.3.4Pharmaceutical form 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 INNAtezolizumab
    D.3.9.1CAS number 1380723-44-3
    D.3.9.3Other descriptive nameRO5541267
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number60
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 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 nameIpatasertib
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNIpatasertib
    D.3.9.3Other descriptive nameRO5532961
    D.3.9.4EV Substance CodeAS3
    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 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 nameIpatasertib
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNIpatasertib
    D.3.9.3Other descriptive nameRO5532961
    D.3.9.4EV Substance CodeAS3
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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
    Untreated, operable ER+, HER2-negative primary breast cancer.
    E.1.1.1Medical condition in easily understood language
    Untreated, operable breast cancer.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10057654
    E.1.2Term Breast cancer female
    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 determine whether adding immune-modulatory agents to atezolizumab increases the probability of an immune response over atezolizumab alone in patients with operable ER+ breast cancer.
    E.2.2Secondary objectives of the trial
    • Status and changes of the biomarkers listed below in pre- and end-of treatment tumour and/or blood samples: Immunephenotyping, CD8, PD-L1, MHC-I,immune infiltrates (IFNg gene signature expression).

    • Percentage change in Ki67 expression and caspase-3 expression between pre- and end of study-treatment tumour biopsies.

    • Incidence, nature and severity of adverse events with severity determined according to CTCAE v4.03.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Willing and able to provide written informed consent prior to study entry
    2. Female ≥ 18 years of age
    3. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 1
    4. Histologically confirmed operable primary breast cancer
    5. Palpable breast tumour of any size, or tumour with an ultrasound / MRI size of ≥ 1 cm or mammogram
    6. ER+ tumours defined as tumours with ≥1% of tumour cells positive for ER on IHC staining or an IHC score (Allred) of ≥ 3
    7. HER2-negative tumours defined as 0, 1+ or 2+ intensity on IHC and no evidence of amplification of the HER2 gene on ISH.
    8. Patients with either: (a) Luminal B breast cancer defined as: high Ki67 defined as ≥20% and /or histological grade 3 and / or Luminal B according to PAM50 assay OR (b) Non-Luminal B breast cancer
    9. Adequate haematologic and end-organ function within 28 days prior to the first study treatment.
    10. Patients of childbearing potential are eligible provided they have a negative serum or urine pregnancy test within 14 days of Day 1 Cycle 1 of study treatment, preferably as close to the first dose as possible. Patients must agree to use adequate contraception, defined as those methods with a failure rate of < 1 % per year, beginning 14 days before the first dose of study drug and for 6 months after the last dose of study drug.
    11. Ability to comply with the protocol
    12. Representative formalin-fixed paraffin embedded (FFPE) breast tumour samples with an associated pathology report that are determined to be available and sufficient for central testing OR tumour accessible for biopsy.

    E.4Principal exclusion criteria
    1. Inflammatory breast cancer
    2. Concurrent use of HRT.
    3. Previous systemic or local treatment for the new primary breast cancer currently under investigation; prior treatment for previous breast cancer or other neoplasms is allowed as long as it was completed ≥1 year prior to Day 1 Cycle 1.
    4. Previous systemic treatment for other neoplasms within 1 year prior to randomisation.
    5.Patients with prior allogeneic stem cell or solid organ transplantation.
    6. Prior treatment with CD137 agonists, AKT inhibitors, anti-CTLA-4, anti− PD-1, or anti−PD-L1 therapeutic antibody or pathway-targeting agents.
    7.Patients must not have had oral or IV steroids for 14 days prior to study entry; the use of inhaled corticosteroids, physiologic replacement doses of glucocorticoids and mineralocorticoids is allowed.
    8. Received therapeutic oral or intravenous antibiotics <14 days prior to randomisation.
    9. Administration of a live, attenuated vaccine <28 days prior to randomisation, treatment, or within 5 months following the last dose of atezolizumab.
    10. Treatment with systemic immunostimulatory agents <28days or five half-lives of the drug, whichever is shorter, prior to enrolment.
    11. History of autoimmune disease. Patients with autoimmune-related hypothyroidism on a stable dose of thyroid replacement therapy may be eligible for the study following discussion with the medical monitor.
    12. History of idiopathic pulmonary fibrosis, drug-induced pneumonitis, organizing pneumonia, or evidence of active pneumonitis on screening chest CT scan.
    13. History of HIV infection
    14. Known active hepatitis infection or hepatitis C.
    15. Active tuberculosis
    16. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
    17. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab formulation.
    18. Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that, in the investigator’s opinion, gives reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, may affect the interpretation of the results, render the patient at high risk from treatment complications or interferes with obtaining informed consent.
    19. Psychological, familial, sociological or geographical conditions that do not permit compliance with the study protocol.
    20. Concurrent treatment with other experimental drugs or participation in another clinical trial with therapeutic intent < 28 days prior to randomisation.
    21. Pregnant and lactating female patients.
    22. Major surgical procedure < 4 weeks prior to randomisation or anticipation of need for a major surgical procedure during the course of the study other than for diagnosis.
    23. Malignancies other than breast cancer < 5 years prior to Cycle 1, Day 1, with the exception of those with a negligible risk of metastasis or death and treated with expected curative outcome
    24. Severe infections < 28 days prior to enrolment in the study including but not limited to hospitalization for complications of infection, bacteraemia, or severe pneumonia.
    25. Significant cardiovascular disease.
    26. Evidence of bleeding diathesis or coagulopathy.
    27. Inability to swallow medication or malabsorption condition that would alter the absorption of orally administered medications.
    28. Clinically significant abnormalities of glucose metabolism
    29. History of or active inflammatory bowel disease or active bowel inflammation.
    30. Treatment with strong CYP3A inhibitors or strong CYP3A inducers within 2 weeks or 5 drug-elimination half-lives, whichever is longer, prior to initiation of study drug.
    E.5 End points
    E.5.1Primary end point(s)
    2-fold increase in GzmB+ CD8+ T cell levels from baseline to end of treatment sample.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Samples collected pre-treatment and on completion of treatment.
    E.5.2Secondary end point(s)
    1. Status and changes of the biomarkers listed below in pre- and end-of treatment tumour and/or blood samples: Immunephenotyping, CD8, PD-L1, MHC-I, immune infiltrates (IFNg gene signature expression).

    2. Percentage change in Ki67 expression and caspase-3 expression between pre- and end of study-treatment tumour biopsies.

    3. Incidence, nature and severity of adverse events with severity determined according to CTCAE v4.03.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. Samples collected pre-treatment and on completion of treatment.

    2. Samples collected pre-treatment and on completion of treatment.

    3. Consent to 30 days after after the last dose of Atezolizumab.
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy No
    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 Yes
    E.6.13.1Other scope of the trial description
    Biomarker driven
    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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA12
    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
    Korea, Republic of
    Germany
    Spain
    United Kingdom
    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 is defined as last patient last data collection, which for the primary and secondary analysis is expected to occur within approximately 24 months after the last patient last visit to allow for the centralisation of tumour samples and T cell analysis. All translational research will be completed within 24 months of the LPLV.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days30
    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 days30
    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: 45
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 12
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male No
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state57
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 77
    F.4.2.2In the whole clinical trial 97
    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, this is a window of opportunity trial. On completion of the study subjects will either be considered for definitive surgery or primary medical treatment e.g. neoadjuvant chemotherapy, at the discretion of the treating physician and as per normal treatment.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-07-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-10-19
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2023-08-18
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