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    Summary
    EudraCT Number:2020-005792-12
    Sponsor's Protocol Code Number:GOIRC-06-2020
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-10-19
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2020-005792-12
    A.3Full title of the trial
    Pilot ‘Window of Opportunity’ Neoadjuvant Study of Abemaciclib in Low-Estrogen Receptor (ER) positive/Human Epidermal Growth Factor Receptor 2 (HER2)-negative Early Breast Cancer (BC)
    Studio Pilota con "Finestra di Opportunità Biologica" di Abemaciclib nel carcinoma mammario in fase precoce con bassa positività per i recettori estrogenici (ER)/negativo al recettore di tipo 2 per il fattore di crescita epidermico umano (HER2)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Abemaciclib as neoadjuvant, chemo-free treatment for patients with breast cancer with low expression of estrogen receptors. A clinical and biological study.
    Abemaciclib come trattamento prechirurgico, non chemioterapico, di pazienti affette da carcinoma mammario con bassa espressione del recettore per gli estrogeni. Studio clinico-biologico.
    A.3.2Name or abbreviated title of the trial where available
    AbNeo Trial
    Studio AbNeo
    A.4.1Sponsor's protocol code numberGOIRC-06-2020
    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 SponsorGRUPPO ONCOLOGICO ITALIANO DI RICERCA CLINICA (GOIRC)
    B.1.3.4CountryItaly
    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 supportEli Lilly Italia S.p.A.
    B.4.2CountryItaly
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGruppo Oncologico Italiano di Ricerca Clinica (GOIRC)
    B.5.2Functional name of contact pointOncologia Azienda Ospedaliero Unive
    B.5.3 Address:
    B.5.3.1Street AddressViale Gramsci, 14
    B.5.3.2Town/ cityParma
    B.5.3.3Post code43126
    B.5.3.4CountryItaly
    B.5.4Telephone number+390521702682
    B.5.5Fax number+390521995448
    B.5.6E-mailgoirc-abneo@goirc.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 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 nameAbemaciclib
    D.3.2Product code [LY2835219]
    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 INNAbemaciclib
    D.3.9.1CAS number 1231929-97-7
    D.3.9.2Current sponsor codeLY2835219
    D.3.9.3Other descriptive name2-Pyrimidinamine, N-[5-[(4-ethyl-1-piperazinyl)methyl]-2-pyridinyl]-5-fluoro-4-[4-fluoro-2-methyl-1-(1-methylethyl)-1Hbenzimidazol-6-yl] N-(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-amine N-[5-[(4-Ethyl-1-piperazinyl)methyl]-2-pyridinyl]-5-fluoro-4-[4-fluoro-2-methyl-1-(1-methylethyl)-1H-benzimidazol-6-yl]-2-pyrimidinamine [5-(4-Ethyl-piperazin-1-ylmethyl)-pyridin-2-yl]-[5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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
    Low-Estrogen Receptor (ER) positive/Human Epidermal Growth Factor Receptor 2 (HER2)-negative Early Breast Cancer (BC)
    Carcinoma mammario in fase precoce con bassa positività per i recettori estrogenici (ER)/negativo al recettore di tipo 2 per il fattore di crescita epidermico umano (HER2)
    E.1.1.1Medical condition in easily understood language
    Breast cancer with low ER / HER-2 negative expression without evidence of metastatic disease
    Tumore alla mammella con bassa espressione ER/HER-2 negativo senza evidenza di malattia metastatica
    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 10083232
    E.1.2Term HER2 negative 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 evaluate the antiproliferative effect of Abemaciclib in the neoadjuvant phase in terms of change in Ki67 values found before and after treatment in patients with low positivity for ER/HER2 negative.
    Valutare l'effetto antiproliferativo di Abemaciclib in fase neoadiuvante in termini di variazione dei valori di Ki67 riscontrati prima e dopo il trattamento in pazienti con bassa positività per ER/HER2 negativo.
    E.2.2Secondary objectives of the trial
    To evaluate the clinical activity of neoadjuvant therapy with Abemaciclib in terms of objective response rate (ORR) in patients with low positive ER / HER2 negative breast cancer.
    To assess the safety, feasibility, and survival outcomes of the study treatment.
    To evaluate the role of the tumor phenotype, determined by standard immunohistochemical approaches (IHC) and / or by the gene expression profile (GEP), in predicting the antiproliferative effect and clinical outcome of the study treatment.
    To explore the correlation of PI3CA / ESR1 / FGFR / p16 / CYCLIND mutations, RB and BRCA1 / 2 status with clinical outcome.
    To evaluate immune biomarkers that may be related to changes in the host's immune response and clinical outcome.
    To evaluate the role of organoid co-culture with autologous TIL in predicting response to the study regimen.
    (see protocol for space limit)
    Valutare l'attività clinica di una terapia neoadiuvante con Abemaciclib in termini di tasso di risposte obiettive (ORR) in pazienti con carcinoma mammario con bassa positività per ER/HER2 negativo.
    Valutare la sicurezza, la fattibilità e i risultati di sopravvivenza del trattamento in studio.
    Valutare il ruolo del fenotipo tumorale, determinato dagli approcci immunoistochimici standard (IHC) e/o dal profilo di espressione genica (GEP), nel predire l'effetto antiproliferativo e l'esito clinico del trattamento in studio.
    Esplorare la correlazione delle mutazioni PI3CA / ESR1 / FGFR / p16 / CYCLIND, lo stato di RB e BRCA1 / 2 con l'esito clinico.
    Valutare i biomarcatori immunitari che possono essere correlati alle variazioni della risposta immunitaria dell'ospite e all'esito clinico.
    Valutare il ruolo della co-coltura di organoidi con TIL autologo nel predire la risposta al regime in studio
    (vedere protocollo per limite di spazio)


    .
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Adult patients, male or female aged = o > 18 years at the time of informed consent.
    • T1cN0 - T3N0 infiltrating breast cancer without evidence of metastatic disease, not previously treated.
    • Histologically confirmed diagnosis of infiltrating breast cancer with low estrogen receptor positivity (1-10%).
    • HER2-negative breast cancer defined with a negative in situ hybridization test (ISH) or an immunohistochemical status (IHC) of 0, 1+, or 2+. If IHC is 2+, a negative in situ hybridization test (FISH, CISH or SISH) is required
    • Ki67 at the diagnostic biopsy, assessed by the local laboratory, with a value> 15%
    • Patients must have clinically and / or radiographically documented measurable disease according to RECIST 1.1 criteria.
    • All radiological examinations must be performed within 28 days prior to registration (35 days if negative).
    • Availability, at the time of registration, of a tumor sample of the primary tumor lesion fixed in formalin and embedded in paraffin (FFPE).
    • Previous (neo) adjuvant anticancer therapy is not allowed.
    • The patient must have an ECOG (Eastern Cooperative Oncology Group) performance status < o = 1 and no life-threatening disease.
    • The patient must not have had major surgery in the 14 days prior to study drug initiation or recovered from surgical outcomes.
    • The patient must not have had malignancy within 3 years of starting study drug, with the exception of adequately treated basal or squamous cell carcinoma, non-melanoma skin cancer, or curatively resected cervical cancer.
    • The patient must not have impaired gastrointestinal (GI) function or gastrointestinal disease that can significantly alter the absorption of study drugs (eg, ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or resection of the small intestine).
    • Patients with bleeding diathesis or on oral anti-vitamin K therapy (except low dose warfarin and acetylsalicylic acid or equivalent, provided the INR < o 2.0) are not eligible.
    • The patient must not have uncontrolled diabetes, defined by a fasting glucose> 1.5 × ULN.
    • Patients with respiratory insufficiency cannot be enrolled. If clinically indicated, lung function tests including measurements of predicted lung volumes, DLco, and resting ambient air oxygen saturation should be considered to rule out restrictive lung disease, pneumonia, or pulmonary infiltrates.
    • The patient should not have a known history of HIV infection (testing not mandatory).
    • Patients should not have a known history of hepatitis B or C (testing not mandatory).
    • Serum creatinine <1.5 mg / dl or creatinine clearance> 50 ml / min according to the Cockcroft-Gault formula.
    • Potassium, sodium, calcium corrected for serum albumin and magnesium within normal limits or corrected within normal limits with supplements before the first dose of study drug.
    • INR < o = 1.5.
    • The patient must not have other serious and / or uncontrolled concomitant medical conditions which, in the investigator's judgment, could cause unacceptable safety risks, contraindicate patient participation in the clinical trial, or compromise protocol compliance (eg. Chronic pancreatitis, chronic active hepatitis, untreated or uncontrolled active fungal, bacterial or viral infections, etc.).
    • Patients should not have any clinically significant, uncontrolled heart disease and / or cardiac repolarization abnormalities.

    Please refer to the protocol For the full list of inclusion criteria.
    • Pazienti adulti, maschio o femmina di età = o > 18 anni al momento del consenso informato.
    • Carcinoma mammario infiltrante T1cN0 - T3N0 senza evidenza di malattia metastatica, non precedentemente trattato.
    • Diagnosi istologicamente confermata di carcinoma mammario infiltrante con bassa positività al recettore degli estrogeni (1-10%).
    • Carcinoma mammario HER2-negativo definito con un test di ibridazione in situ (ISH) negativo o uno stato immunoistochimico (IHC) di 0, 1+ o 2+. Se IHC è 2+, è richiesto un test di ibridazione in situ negativo (FISH, CISH o SISH)
    • Ki67 alla biopsia diagnostica, valutato dal laboratorio locale, con valore > 15%
    • I pazienti devono avere una malattia misurabile documentata clinicamente e / o radiograficamente secondo I criteri RECIST 1.1.
    • Tutti gli esami radiologici devono essere eseguiti entro 28 giorni prima della registrazione (35 giorni se negativi).
    • Disponibilità, al momento della registrazione, di un campione tumorale della lesion tumorale primitiva fissato in formalina e incluso in paraffina (FFPE).
    • Non è consentita una precedente terapia antitumorale (neo) adiuvante.
    • Il paziente deve avere un performance status ECOG (Eastern Cooperative Oncology Group) < o = 1 e nessuna malattia potenzialmente letale.
    • Il paziente non deve aver subito un intervento chirurgico maggiore nei 14 giorni precedenti l'inizio del farmaco in studio o deve essersi ripreso dagli esiti chirurgici.
    • Il paziente non deve aver avuto un tumore maligno entro 3 anni dall'inizio del farmaco in studio, ad eccezione del carcinoma a cellule basali o squamose adeguatamente trattato, del cancro della pelle non melanomatoso o del cancro del collo dell'utero resecato curativamente.
    • Il paziente non deve avere una compromissione della funzione gastrointestinale (GI) o una malattia gastrointestinale che può alterare in modo significativo l'assorbimento dei farmaci in studio (ad esempio, malattie ulcerative, nausea incontrollata, vomito, diarrea, sindrome da malassorbimento o resezione dell'intestino tenue).
    • Non sono arruolabili pazienti con diatesi emorragiche o in terapia orale anti-vitamina K (eccetto warfarin a basso dosaggio e acido acetilsalicilico o equivalenti, purché l'INR sia < o = 2,0).
    • Il paziente non deve avere un diabete non controllato, definito dal riscontro di glicemia a digiuno> 1,5 × ULN.
    • Non sono arruolabili pazienti con insufficienza respitaria. Se clinicamente indicato, devono essere presi in considerazione test di funzionalità polmonare che includano misure dei volumi polmonari previsti, DLco e saturazione di O2 a riposo nell'aria ambiente per escludere malattie polmonari restrittive, polmonite o infiltrati polmonari.
    • Il paziente non deve avere una storia nota di infezione da HIV (test non obbligatorio).
    • I pazienti non devono avere una storia nota di epatite B o C (test non obbligatorio).
    • Creatinina sierica <1,5 mg / dl o clearance della creatinina> 50 ml / min secondo la formula di Cockcroft-Gault.
    • Potassio, sodio, calcio corretti per albumina sierica e magnesio entro limiti normali o corretti entro limiti normali con integratori prima della prima dose del farmaco in studio.
    • INR < o =1,5.
    • Il paziente non deve avere altre condizioni mediche concomitanti gravi e / o incontrollate che, a giudizio dello sperimentatore, potrebbero causare rischi per la sicurezza inaccettabili, controindicare la partecipazione del paziente allo studio clinico o compromettere il rispetto del protocollo (es. Pancreatite cronica, epatite cronica attiva, infezioni fungine, batteriche o virali attive non trattate o non controllate, ecc.).
    • I pazienti non devono avere alcuna malattia cardiaca clinicamente significativa, non controllata e / o anomalie della ripolarizzazione cardiaca.

    Per l'elenco completo dei criteri di inclusione fare riferimento al protocollo.
    E.4Principal exclusion criteria
    • Patient has been diagnosed with locally advanced or stage IV BC.
    • Ki67 expression in core biopsy specimen < o = 15% as evaluated by local laboratory.
    • Patient has been treated with Abemaciclib.
    • Patient has been treated with any other investigational agent or has participated in another clinical trial within 28 days prior to enrolment.
    • Patient has received breast radiotherapy prior to registration.
    • Patient has a known hypersensitivity to any of the excipients of Abemaciclib.
    • The patient has any disease, neurological or metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or puts the patient at high risk for treatment-related complications.
    • The patient has serious and/or uncontrolled preexisting medical condition(s) that, in the judgment of the investigator, would preclude participation in this study (for example, interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, severe renal impairment [e.g. estimated creatinine clearance <30ml/min], history of major surgical resection involving the stomach or small bowel, or preexisting Crohn’s disease or ulcerative colitis or a preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea).
    • The patient has any uncontrolled inter-current illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
    • The patient has active bacterial infection (requiring intravenous [IV] antibiotics at time of initiating study treatment), fungal infection, or detectable viral infection (such as known human immunodeficiency virus positivity or with known active hepatitis B or C [for example, hepatitis B surface antigen positive]. Screening is not required for enrollment.
    • The patient has a personal history of any of the following conditions: syncope of cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but not limited to, ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest.
    • Patient has a concurrent malignancy or malignancy within 3 years prior to starting study drug, with the exception of adequately treated, basal or squamous cell carcinoma, non-melanomatous skin cancer or curatively resected cervical cancer.
    • Females who are pregnant or lactating.
    • Patient of childbearing / reproductive potential do not want to use adequate birth control measures, as defined by the investigator, during the study treatment period and for at least 6 months after the last study treatment. A highly effective method of birth control is defined as those which result in low failure rate (i.e. less than 1% per year) when used consistently and correctly.
    • Patient with unwilling or unable to comply with the protocol.
    • Paziente con diagnosi di carcinoma mammario localmente avanzato o in stadio IV.
    • Ki67 alla biopsia diagnostica, valutato dal laboratorio locale, con valore < o = 15%.
    • Il paziente è stato trattato con Abemaciclib.
    • Il paziente è stato trattato con qualsiasi altro agente sperimentale o ha partecipato a un altro studio clinico entro 28 giorni prima dell'arruolamento.
    • La paziente ha ricevuto radioterapia al seno prima della registrazione.
    • Il paziente ha una nota ipersensibilità a uno qualsiasi degli eccipienti di Abemaciclib.
    • Il paziente ha una malattia, una disfunzione neurologica o metabolica, un esame fisico o un risultato di laboratorio che diano un ragionevole sospetto di una malattia o condizione che controindichi l'uso di un farmaco sperimentale o metta il paziente ad alto rischio di complicanze correlate al trattamento.
    • Il paziente presenta una o più condizioni mediche preesistenti gravi e / o incontrollate che, a giudizio dello sperimentatore, precluderebbero la partecipazione a questo studio (ad esempio, malattia polmonare interstiziale, dispnea grave a riposo o che richiedono ossigenoterapia, grave insufficienza renale [es. clearance stimata della creatinina <30 ml / min], anamnesi di resezione chirurgica maggiore che coinvolge lo stomaco o il piccolo intestino, o morbo di Crohn preesistente o colite ulcerosa o una condizione cronica preesistente con conseguente diarrea di grado 2 o superiore al basale).
    • Il paziente ha una malattia intercorrente incontrollata inclusa, ma non limitata a, infezione in corso o attiva, insufficienza cardiaca congestizia sintomatica, angina pectoris instabile, aritmia cardiaca o malattia psichiatrica / situazioni sociali che limiterebbero la conformità ai requisiti dello studio.
    • Il paziente ha un'infezione batterica attiva (che richiede antibiotici per via endovenosa [IV] al momento dell'inizio del trattamento in studio), infezione fungina o infezione virale rilevabile (come positività nota al virus dell'immunodeficienza umana o con epatite B o C attiva nota [ad esempio, epatite Antigene di superficie B positivo]. Lo screening non è richiesto per l'arruolamento.
    • Il paziente ha una storia personale di una delle seguenti condizioni: sincope di eziologia cardiovascolare, aritmia ventricolare di origine patologica (incluse, ma non limitate a, tachicardia ventricolare e fibrillazione ventricolare) o arresto cardiaco improvviso.
    • Il paziente ha un tumore maligno o tumore maligno concomitante entro 3 anni prima dell'inizio del farmaco in studio, ad eccezione del carcinoma a cellule basali o squamose adeguatamente trattato, del cancro della pelle non melanomatoso o del cancro cervicale resecato in modo curativo.
    • Donne in gravidanza o in allattamento.
    • Pazienti in età fertile / riproduttiva che non desiderano utilizzare adeguate misure di controllo di gravidanza, definite dallo sperimentatore, durante il periodo di trattamento in studio e per almeno 6 mesi dopo l'ultimo trattamento in studio. Metodi di controllo di gravidanze altamente efficacy sono definiti come quelli che si traducono in un basso tasso di fallimento (cioè meno dell'1% all'anno) se usati in modo coerente e corretto.
    • Pazienti con riluttanza o impossibilità a rispettare il protocollo.
    E.5 End points
    E.5.1Primary end point(s)
    Change in KI67 measured at baseline and at the end of treatment with Abemaciclib.
    Variazione del KI67 misurato al baseline e alla fine del trattamento con Abemaciclib.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The study will be carried out according to Optimal Simon’s two stage design.
    The first stage ends after 10 patients have been evaluated, and if none of them exhibited an objective response, the study will be terminated. Otherwise, enrolment will continue until a sample size of 29 individuals has been reached. If at least 4 objective responses will be observed by the end of stage two, then the study treatment will be considered successful.
    Lo studio sarà condotto secondo il disegno a due stadi (two-stage) di Simon.
    Il primo stadio (first stage) terminerà dopo che i primi 10 pazienti saranno stati valutati e se nessuno di loro avrà mostrato una risposta obiettiva, lo studio verrà interrotto. In caso contrario, l'arruolamento continuerà fino al raggiungimento di una dimensione del campione di 29 individui. Se si osserveranno almeno 4 risposte oggettive entro la fine del secondo stadio (second stage), il trattamento in studio sarà considerato di successo.
    E.5.2Secondary end point(s)
    Clinical endpoints:
    • Objective response rate (ORR), defined as the proportion of participants who have a complete response (CR) or partial response (PR), as determined by the local investigator using RECIST 1.1 criteria.
    • Toxicity (both predefined and not predefined side effects will be recorded, classified, graded and managed according to NCI Common Terminology Criteria for Adverse Events (CTCAE; version 5.0).
    • Disease-free survival (DFS), defined as the date of diagnosis of primary breast cancer to the date of local, regional, or distant invasive recurrence or death of any cause.; Translational endpoints:
    • Association of Ki-67 expression with ORR and DFS. The analysis will include evaluation of tumor samples at baseline and at the end of treatment for Ki-67 expression by IHC.
    • Association of HER2 status with Ki-67 variation, ORR and DFS. The analysis will include assessment of tumor samples at baseline and at the end of treatment for HER2 expression by IHC.
    • Association of GEP with variation of Ki-67, ORR and DFS. The analysis will include evaluation of tumor samples at baseline and at the end of treatment for GEP using PAM50 nanostring.
    • Association of TILs with Ki-67 variation, ORR and DFS. The analysis will include evaluation of basal and end-of-treatment tumor samples for TILs (sections stained with hematoxylin and eosin (H-E) and IHC [immunophenotype]).
    • Association of PI3CA, ESR1, FGFR, p16, CYCLIND, RB and BRCA1 / 2 mutations with variation of Ki-67, ORR and DFS. The analysis will include assessment of baseline and end-of-treatment samples for gene mutations (PI3CA / ESR1 / FGFR / p16 / CYCLIND / RB / BRCA).
    • Association of expression of PI3CA, ESR1, FGFR, p16, CYCLIND, RB and BRCA1 / 2 mRNA with variation of Ki-67, ORR and DFS. Analysis will include assessment of tumor samples at baseline and at the end of treatment for PI3CA / ESR1 / FGFR / p16 / CYCLIND / RB / BRCA mRNA expression.
    • Association of the expression of PI3CA, ESR1, FGFR, p16, CYCLIND, RB and BRCA1 / 2 proteins with variation of Ki-67, ORR and DFS. The analysis will include assessment of tumor samples at baseline and at the end of treatment for PI3CA / ESR1 / FGFR / p16 / CYCLIND / RB / BRCA protein expression by IHC.
    • Association of HER2 status and / or changes in HER2 status over time with PI3CA / ESR1 / FGFR / p16 / CYCLIND / RB / BRCA mutations.
    • Association of Ki 67 expression and / or changes in Ki67 status over time with PI3CA / ESR1 / FGFR / p16 / CYCLIND / RB / BRCA mutations.
    • Association of GEP and / or changes in GEP status over time with PI3CA / ESR1 / FGFR / p16 / CYCLIND / RB / BRCA mutations.
    • Association of TIL levels and / or changes in TIL rate over time with PI3CA / ESR1 / FGFR / p16 / CYCLIND / RB / BRCA mutations.
    • Association of TIL levels and / or changes over time of the TIL rate with the expression of Ki67 and / or changes over time of the state of Ki67.
    • Association of TIL levels and / or changes in TIL rate over time with HER2 status.
    • Association of TIL levels and / or variations over time of the TIL rate with GEP.
    • Association between co-cultured organoids with autologous TILs and in vivo response to the experimental regimen. The analysis will include the collection of fresh tumor biopsy material for the generation of co-cultured organoids with autologous TILs.; Exploratory endpoints:
    • Association of HRD by RAD51 Predict, measured as the percentage of geminin-positive cells with 5 or more RAD51 nuclear foci with change in Ki-67 and ORR.
    • Association of HRD by RAD51 Predict with GEP.
    • Association of HRD by RAD51 Predict with TILs.
    • Association of HRD by RAD51 Predict with PI3CA/ESR1/FGFR/p16/CYCLIND/BRCA1/2 mutations, RB status and Ki67 expression.
    Endpoint clinici:
    • Tasso di risposte obiettive (ORR), definito come la proporzione di partecipanti che hanno una risposta completa (CR) o risposta parziale (PR), come determinate dallo sperimentatore locale mediante i criteri RECIST 1.1.
    • Tossicità (gli effetti collaterali predefiniti e non predefiniti saranno registrati, classificati e gestiti secondo i criteri comuni di terminologia per gli eventi avversi dell'NCI (CTCAE; versione 5.0).
    • Sopravvivenza libera da malattia (DFS), definita come l'intervallo tra la data di diagnosi di carcinoma mammario e la data di recidiva invasiva locale, regionale o a distanza, o morte per qualsiasi causa.; Endpoint traslazionali:
    • Associazione dell'espressione del Ki-67 con ORR e DFS. L'analisi includerà la valutazione dei campioni di tumore al basale e alla fine del trattamento per l'espressione del Ki-67 mediante IHC.
    • Associazione dello stato di HER2 con variazione del Ki-67, ORR e DFS. L'analisi includerà la valutazione dei campioni di tumore al basale e alla fine del trattamento per l'espressione di HER2 mediante IHC.
    • Associazione di GEP con variazione del Ki-67, ORR e DFS. L'analisi includerà la valutazione dei campioni di tumore al basale e alla fine del trattamento per GEP mediante nanostring PAM50.
    • Associazione di TILs con variazione del Ki-67, ORR e DFS. L'analisi comprenderà la valutazione di campioni tumorali basali e di fine trattamento per TILs (sezioni colorate con ematossilina ed eosina (H-E) e IHC [immunofenotipo]).
    • Associazione delle mutazioni PI3CA, ESR1, FGFR, p16, CYCLIND, RB e BRCA1/2 con variazione del Ki-67, ORR e DFS. L'analisi includerà la valutazione dei campioni di base e di fine trattamento per le mutazioni geniche (PI3CA / ESR1 / FGFR / p16 / CYCLIND / RB / BRCA).
    • Associazione dell'espressione di PI3CA, ESR1, FGFR, p16, CYCLIND, RB e BRCA1 / 2 mRNA con variazione del Ki-67, ORR e DFS. L'analisi includerà la valutazione dei campioni di tumore al basale e alla fine del trattamento per l'espressione dell'mRNA di PI3CA / ESR1 / FGFR / p16 / CYCLIND / RB / BRCA.
    • Associazione dell'espressione delle proteine PI3CA, ESR1, FGFR, p16, CYCLIND, RB e BRCA1 / 2 con variazione del Ki-67, ORR e DFS. L'analisi includerà la valutazione dei campioni di tumore al basale e alla fine del trattamento per l'espressione della proteina PI3CA / ESR1 / FGFR / p16 / CYCLIND / RB / BRCA mediante IHC.
    • Associazione dello stato di HER2 e / o modifiche nel tempo dello stato di HER2 con le mutazioni PI3CA / ESR1 / FGFR / p16 / CYCLIND / RB / BRCA.
    • Associazione dell'espressione del Ki 67 e/o modifiche nel tempo dello stato di Ki67 con le mutazioni PI3CA / ESR1 / FGFR / p16 / CYCLIND / RB / BRCA.
    • Associazione di GEP e / o modifiche nel tempo dello stato GEP con le mutazioni PI3CA / ESR1 / FGFR / p16 / CYCLIND / RB / BRCA.
    • Associazione dei livelli di TIL e / o variazioni nel tempo del tasso di TIL con le mutazioni PI3CA / ESR1 / FGFR / p16 / CYCLIND / RB / BRCA.
    • Associazione dei livelli TIL e/o variazioni nel tempo del tasso di TIL con l'espressione di Ki67 e/o modifiche nel tempo dello stato di Ki67.
    • Associazione dei livelli TIL e / o modifiche nel tempo del tasso TIL con lo stato di HER2.
    • Associazione dei livelli TIL e / o variazioni nel tempo del tasso TIL con GEP.
    • Associazione tra organoidi in co-coltura con TIL autologhi e risposta in vivo al regime sperimentale. L'analisi includerà la raccolta di materiale da biopsia tumorale fresca per la generazione di organoidi in co-coltura con TIL autologhi.; Endpoint esplorativi:
    • Associazione di HRD (RAD51 Predict), misurata come percentuale di cellule positive per RAD51, con variazione di Ki67 e ORR.
    • Associazione di HRD (RAD51 Predict) con GEP.
    • Associazione di HRD (RAD51 Predict) con TILs.
    • Associazione di HRD (RAD51 Predict) con mutazioni PI3CA / ESR1 / FGFR / p16 / CYCLIND / BRCA1 / 2, stato RB ed espressione Ki67.
    E.5.2.1Timepoint(s) of evaluation of this end point
    • The pathological complete response rate (pCR) is defined at the time of surgery.
    • Disease-free survival (DFS): This is defined as the interval between the date of diagnosis of primary breast cancer to the date of local, regional, or distant invasive recurrence or death of any cause.; At baseline, on-treatment and at the end-of-treatment.; At baseline, on treatment and at the end-of-treatment.
    • Il tasso di risposta patologica completa (pCR) è definito al momento dell'intervento.
    • Sopravvivenza libera da malattia (DFS), definita come l'intervallo tra la data di diagnosi di carcinoma mammario e la data di recidiva invasiva locale, regionale o a distanza, o morte per qualsiasi causa.; Al basale, durante il trattamento e alla fine del trattamento.; Al basale, durante il trattamento e alla fine del trattamento.
    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 No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) 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 Yes
    E.8.1.7.1Other trial design description
    Studio pilota con "finestra di opportunità biologica"
    Pilot ‘Window of Opportunity’ Neoadjuvant Study
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    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 concerned10
    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 Information not present in EudraCT
    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
    Last Patient Last Visit
    Last Patient Last Visit
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 27
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 5
    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 state32
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 32
    F.4.2.2In the whole clinical trial 32
    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)
    At the end of treatment with Abema, patients will be managed as per local practice(LP). Post surgery, patients will receive radiotherapy according to LP and will receive hormone manipulation as per LP. They will be followed up until 5years since enrollment, or earlier, in case of withdrawal of consent, loss to FU, death, or study closure. Ipsilateral and/or contralateral mammography +/- ultrasound will be performed every year. Routine lab and/or imaging tests indicated physician’s discretion.
    Al termine del trattamento in studio, pazienti verranno trattati come da pratica clinica (PC) standard. Dopo l'intervento, i pazienti verranno sottoposti a radioterapia, come da PC e a terapia endocrina adiuvante. Saranno seguiti fino a 5anni dall'arruolamento, o prima, in caso di ritiro delconsenso, perdita del FU, morte o chiusura dello studio. La mammografia omolaterale e/o controlaterale +/- ecografia sarà eseguita ogni anno. Esami laboratorio e/o imaging indicati a discrezione del medico.
    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 Decision2022-03-02
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-04-05
    P. End of Trial
    P.End of Trial StatusOngoing
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