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    Summary
    EudraCT Number:2018-004121-80
    Sponsor's Protocol Code Number:
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2019-01-14
    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 ConcernedUK - MHRA
    A.2EudraCT number2018-004121-80
    A.3Full title of the trial
    A proof of concept, window trial of the IMmunological effects of AveLumab and Aspirin in Triple-Negative Breast Cancer.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Proof of concept window trial of the immunological effects of Avelumab and Aspirin
    A.3.2Name or abbreviated title of the trial where available
    IMpALA
    A.4.1Sponsor's protocol code number
    A.5.4Other Identifiers
    Name:Sponsor ReferenceNumber:CFTSp123
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorThe Christie Hospital NHS Foundation Trust
    B.1.3.4Country
    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 support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationManchester Clinical Trials Unit at University Of Manchester
    B.5.2Functional name of contact pointRachel Cox
    B.5.3 Address:
    B.5.3.1Street AddressOxford Road
    B.5.3.3Post codeM13 9PL
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number01613063199
    B.5.6E-mailrachel.cox@manchester.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 BAVENCIO
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Serono Europe Limited
    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 nameBAVENCIO
    D.3.2Product code L01XC32
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous drip use (Noncurrent)
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAvelumab
    D.3.9.1CAS number 1380723-44-3
    D.3.9.3Other descriptive nameAvelumab
    D.3.9.4EV Substance CodeAS1
    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) Yes
    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 Aspirin
    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 nameAspirin
    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 INNacetylsalicylic acid (ASA)
    D.3.9.1CAS number 50-78-2
    D.3.9.4EV Substance CodeAS2
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Breast Cancer
    E.1.1.1Medical condition in easily understood language
    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 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 examine whether aspirin, given in combination with avelumab, reduces tumour promoting inflammation and thereby shifts the profile towards an anti-cancer pathway when compared to avelumab alone in patients with newly diagnosed TNBC
    E.2.2Secondary objectives of the trial
    1. To determine if Aspirin 300mg given three times daily for 18 days (+3days) enhances the efficacy of single dose Avelumab 10mg/kg by increasing cancer cell infiltration

    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    *Female subjects, age 18 and over

    *Histologically confirmed triple negative invasive breast cancer as defined as oestrogen receptor (ER) negative, progesterone receptor (PgR) negative (if available, otherwise PgR unknown), (as defined by Allred score 0- 2 or <1% of tumour cells positive for stain) and HER2 negative (immunohistochemistry 0/1+ or negative by in situ hybridization) as determined by local laboratoryHave previously untreated, non-metastatic TNBC with a tumour amenable to multiple biopsies including a T stage of at least T2. Note multifocal primary tumours are allowed providing at least one tumour meets the criteria above. All biopsies should be obtained from the same tumour.

    *Have previously untreated, non-metastatic TNBC with a tumour amenable to multiple biopsies including a T stage of at least T2 T2T1c
    Note multifocal primary tumours are allowed providing at least one tumour meets the criteria above. All biopsies should be obtained from the same tumour.

    *ECOG performance status 0/1


    Full inclusion as per trial protocol eligibility section circa page 23
    E.4Principal exclusion criteria
    *Prior systemic anti-cancer treatment (immune therapy, targeted therapy, vaccine therapy, or investigational treatment) for triple negative breast cancer.

    *Malignancy within the last 5 years except: adequately treated non-melanoma skin cancer; curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS); stage 1, grade I endometrial carcinoma or other solid tumours that have been treated with curative intent with no evidence of disease for ≥ 5 years.

    Contraindications to aspirin dosing including hypersensitivity to aspirin (eg known aspirin sensitive asthma; history of peptic ulcer disease, gastric bleeding or cerebrovascular haemorrhages; haemorrhagic diathesis.

    *Evidence of distant metastases apparent prior to randomisation. Patients who are diagnosed with distant metastases during the course of the study can complete study procedures if willing to do so.

    *Subjects with active, known or suspected autoimmune disease. Subjects with type 1 diabetes mellitus, hypothyroidism only requiring hormone replacement, skin or rheumatological disorders (such as vitiligo, psoriasis, rheumatoid arthritis or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger will be permitted to enrol. Autoimmune conditions such as ulcerative colitis that have been definitively treated (e.g. with total colectomy) will be permitted to enrol but should be discussed with the CI.

    *Subjects with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement steroid doses > 10 mg daily prednisone equivalent are permitted in the absence of active autoimmune disease.

    *16. Current or previous regular use of aspirin (at any dose) or current use of another NSAID for any indication (see section 7.11 (II) prohibited medications for list of medications not permitted in the trial). Regular aspirin use is defined as taking aspirin more than twice in any given week for more than 4 consecutive weeks. Current NSAID use is defined as taking any NSAID for more than a week in the preceding month. If investigators feel that this definition may unfairly exclude a participant, this can be discussed with the CI/MCTU and a case by case decision will be made.

    Full exclusion as per trial protocol eligibility section circa page 24
    E.5 End points
    E.5.1Primary end point(s)
    Mean combined gene expression of COX-2 tumour-promoting genes (ILA, IL1B, IL6, IL8, CXCL1, CXCL2, VEGFA, CFSF3 and CCL2),in samples taken post treatment
    E.5.1.1Timepoint(s) of evaluation of this end point
    Derived from samples taken at Visit 4 and/or Visit 5
    E.5.2Secondary end point(s)
    1. Post treatment tumour infiltrating lymphocytes (TIL) assessed by IHC using standardised methodology (Salgado et al., 2015)
    2. Mean combined gene expression of the elements of the denominator of the COX-2 ratio (cancer-inhibitory genes: CXCL9, CXCL10, CXCL11, CCL5, TBX21, EOMES, CD8A, CD8B, PRF1, GZMB, GZMA, STAT1, IL12B, IL12B, IFNG) in samples taken post treatment.
    3. The post treatment COX-2 ratio (a ratio of mean expression of 9 tumour-promoting to 15 tumour-inhibitory genes)
    4. Safety and tolerability assessed by grade 3-4 AEs and SAEs. In addition, grade 2 renal toxicity AEs (creatinine rise) and grade 2 gastrointestinal toxicity AEs (duodenal perforation, dyspepsia, oesophageal haemorrhage, dysphagia, oesophageal pain, oesophageal perforation, oesophagitis).
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. Derived from Visit 4 biopsy
    2. Derived from Visit 4 and/or 5 samples
    3. Derived from Visit 4 and/or 5 samples
    4. Derived from throughout Visit 3 through to 5
    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 No
    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 No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open 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 No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned4
    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 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
    As the lab analysis needs to be complete in order to report on the outcomes, the end of trial will be defined as the point in which the laboratory analysis is completed.
    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 months8
    E.8.9.1In the Member State concerned days31
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months8
    E.8.9.2In all countries concerned by the trial days31
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 42
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 0
    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 state42
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 42
    F.4.2.2In the whole clinical trial 42
    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 treatment provided within this window of opportunity study will not be provided on an ongoing basis once the study treatment is complete. All post biopsy and/or study treatment will be at the discretion of the patient’s treating physician per local standard of care (SOC).
    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 Manchester Clinical Trials Unit at The University of Manchester
    G.4.3.4Network Country United Kingdom
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-02-05
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-01-23
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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