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    Summary
    EudraCT Number:2018-000345-39
    Sponsor's Protocol Code Number:B9991032
    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:2021-01-22
    Trial results View 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 number2018-000345-39
    A.3Full title of the trial
    A Phase 2 Study to Evaluate Safety and Anti-tumor Activity of Avelumab in Combination with Talazoparib In Patients with BRCA or ATM Mutant Tumors
    STUDIO DI FASE 2 PER VALUTARE LA SICUREZZA E L’ATTIVITÀ ANTITUMORALE DI AVELUMAB IN COMBINAZIONE CON TALAZOPARIB IN PAZIENTI CON TUMORI CON MUTAZIONI BRCA O ATM
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 2 Study to Evaluate Safety and Anti-tumor Activity of Avelumab in Combination with Talazoparib In Patients with BRCA or ATM Mutant Tumors
    STUDIO DI FASE 2 PER VALUTARE LA SICUREZZA E L’ATTIVITÀ ANTITUMORALE DI AVELUMAB IN COMBINAZIONE CON TALAZOPARIB IN PAZIENTI CON TUMORI CON MUTAZIONI BRCA O ATM
    A.3.2Name or abbreviated title of the trial where available
    JAVELIN BRCA/ATM
    JAVELIN BRCA/ATM
    A.4.1Sponsor's protocol code numberB9991032
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03565991
    A.5.4Other Identifiers
    Name:US INDNumber:133,902
    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 SponsorPFIZER INC
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportPfizer Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPfizer Inc.
    B.5.2Functional name of contact pointClinical Trials.gov Call Centre
    B.5.3 Address:
    B.5.3.1Street Address235 East 42nd Street
    B.5.3.2Town/ cityNew York
    B.5.3.3Post codeNY 10017
    B.5.3.4CountryUnited States
    B.5.4Telephone number+18007181021
    B.5.6E-mailClinicalTrials.gov_Inquiries@pfizer.com
    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.2.1.2Country 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 nameAvelumab
    D.3.2Product code [MSB0010718C]
    D.3.4Pharmaceutical form Concentrate 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 INNAvelumab
    D.3.9.1CAS number 319460-85-0
    D.3.9.2Current sponsor codeMSB0010718C
    D.3.9.3Other descriptive nameAnti PD-L1
    D.3.9.4EV Substance CodeSUB176547
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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 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 Yes
    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 nameTalazoparib
    D.3.2Product code [ PF-06944076 (MDV3800; BMN 673)]
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTalazoparib
    D.3.9.1CAS number 1373431-65-2
    D.3.9.2Current sponsor codePF-06944076
    D.3.9.3Other descriptive nameMDV3800; BMN 673
    D.3.9.4EV Substance CodeSUB122393
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number250
    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.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 nameTalazoparib
    D.3.2Product code [ PF-06944076 (MDV3800; BMN 673)]
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTalazoparib
    D.3.9.1CAS number 1373431-65-2
    D.3.9.2Current sponsor codePF-06944076
    D.3.9.3Other descriptive nameMDV3800; BMN 673
    D.3.9.4EV Substance CodeSUB122393
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    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
    locally advanced (primary or recurrent) or metastatic solid tumors with a pathogenic or likely pathogenic germline or loss-of-function somatic BRCA1, or BRCA2, or ATM gene defect
    tumori localmente avanzati (primari o ricorrenti) o tumori solidi metastatici, con una linea germinativa patogena o probabilmente patogena o gene di suscettibilità somatico “loss of fuction” BRCA1, o BRCA2, o difetto genetico ATM
    E.1.1.1Medical condition in easily understood language
    Solid tumors
    Tumori solidi
    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 LLT
    E.1.2Classification code 10065147
    E.1.2Term Malignant solid tumor
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10065252
    E.1.2Term Solid tumor
    E.1.2System Organ Class 100000004864
    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 ORR of avelumab in combination with talazoparib, in patients with locally advanced or metastatic solid tumors harboring BRCA1, BRCA2 or ATM defect.
    Valutare l’ORR di avelumab in combinazione con talazoparib, in pazienti con tumori solidi localmente avanzati o metastatici che presentano difetti di BRCA1, BRCA2 o ATM.
    E.2.2Secondary objectives of the trial
    - To assess the overall safety and tolerability of avelumab in combination with talazoparib.
    - To characterize the PK of avelumab and talazoparib when given in combination.
    - To evaluate the immunogenicity of avelumab when given in combination with talazoparib.
    - To assess other measures of the anti-tumor activity of avelumab in combination with talazoparib.
    - To assess the correlation of anti-tumor activity of avelumab in combination with talazoparib with PD-L1 expression in baseline tumor tissue.
    - To assess the correlation of anti-tumor activity and emergence of resistance with defects in a panel of key oncogenes, including BRCA 1/2 and ATM, and TMB in circulating tumor DNA (ctDNA) and tumor tissue at baseline, during treatment and at the end of treatment.
    • Valutare la sicurezza complessiva e la tollerabilità di avelumab in combinazione con talazoparib.
    • Caratterizzare la PK di avelumab e di talazoparib somministrati in combinazione.
    • Valutare l’immunogenicità di avelumab, somministrato in combinazione con talazoparib.
    • Valutare altre misure dell’attività antitumorale di avelumab in combinazione con talazoparib.
    • Valutare la correlazione tra l’attività antitumorale di avelumab in combinazione con talazoparib con espressione di PD-L1 nel tessuto tumorale al basale.
    • Valutare la correlazione tra l’attività antitumorale e la comparsa di resistenza con difetti in un pannello di oncogeni chiave, tra cui BRCA 1/2 e ATM, e TMB nel DNA tumorale circolante (ctDNA) e nel tessuto tumorale al basale, durante il trattamento e a fine trattamento.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Pathogenic or likely pathogenic germline or somatic gene defect as determined by local assessment and classification:
    - One or more BRCA1 or BRCA2 gene defect (Cohort 1);
    - ATM gene defect in the absence of concurrent BRCA 1/2 defect (Cohort 2).
    2. Histological diagnosis of locally advanced (primary or recurrent) or metastatic solid tumors that are not amenable for treatment with curative intent, as follows:
    a. Recurrent Epithelial Ovarian Cancer;
    b. TNBC (defined as ER- and PgR-negative [IHC nuclear staining <5%] and HER2-negative [IHC 0, 1+, or 2+ and/or ISH non-amplified with ratio less than 2.0]) or hormone-receptor-positive (HR+), HER2-negative breast cancer;
    c. Metastatic castration-resistant prostate cancer (mCRPC) without small cell features;
    d. Metastatic ductal adenocarcinoma of the pancreas;
    e. Any other advanced solid tumor.
    3. Availability of a fresh or recent tumor tissue sample from a diagnostic biopsy/surgery or a metastatic tumor biopsy; the sample must have been obtained within 24 months prior to study enrollment. When only bone disease is present, an archival tumor tissue sample obtained within 5 years prior to study enrollment may be accepted for non-prostate cancer patients and a fresh bone biopsy may be accepted for prostate cancer patients only).
    4. Have progressive disease at study enrollment as defined by RECIST v1.1 (except for mCRPC, who must meet criterion 2c above).
    5. Must have measurable disease by RECIST v1.1 with at least 1 measurable lesion that has not been previously irradiated (patients with mCRPC may have only non-measurable disease).
    6. Age =18 years (except in Japan, where patients must be = 20 years old).
    7. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1.
    8. Adequate bone marrow function (without hematopoietic growth factor or transfusion support within 14 days prior to study enrollment), including:
    a. Absolute Neutrophil Count (ANC) = 1,500/mm3 or = 1.5 x 109/L.
    b. Platelets = 100,000/mm3 or =100 x 109/L.
    c. Hemoglobin = 9 g/dL (= 5.6 mmol/L).
    9. Adequate renal function defined by an estimated creatinine clearance = 30 mL/min according to the Cockcroft-Gault formula as:
    - CLCR={[(140–age) × weight)]/(72 x SCR)} × 0.85 (if female), where CLCR (creatinine clearance) is measured in mL/min, age is expressed in years, weight inkilograms (kg), and SCR (serum creatinine) in mg/dL;
    - Or as measured by 24h urine assessment.
    10. Adequate liver function, including:
    a. Total serum bilirubin = 1.5 × the upper limit of normal range (ULN);
    b. Aspartate and Alanine aminotransferase (AST and ALT) = 2.5 x ULN.
    for criteria 11-12-13 please refer to Protocol. Cirterion 11 has been updated by Protocol Amend 1.
    1. Mutazione genetica germinale o somatica patogena o probabilmente patogena come determinato dalla valutazione e dalla classificazione locali:
    - una o più mutazioni nel gene BRCA1 o BRCA2 (Coorte 1);
    - mutazione del gene ATM in assenza di mutazione BRCA 1/2 concomitante (Coorte 2).
    2. Diagnosi istologica di uno tra i seguenti tumori solidi localmente avanzati (primitivi o recidivanti) o metastatici non trattabili con intento curativo:
    a. carcinoma ovarico epiteliale ricorrente;
    b. TNBC (definito come ER- e PgR-negativo [colorazione nucleare IHC <5%] e HER2-negativo [IHC 0, 1+ o 2+ e/o ISH non amplificata con rapporto <2,0]) o carcinoma mammario positivo al recettore ormonale (HR+), HER2-negativo;
    c. carcinoma prostatico metastatico resistente alla castrazione (mCRPC) non a piccole cellule;
    d. adenocarcinoma duttale metastatico del pancreas;
    e. qualsiasi altro tumore solido in stadio avanzato.
    3. Disponibilità di un campione di tessuto tumorale fresco o recente ottenuto da una biopsia/un intervento chirurgico a fini diagnostici o da una biopsia del tessuto tumorale metastatico; il campione deve essere stato ottenuto nei 24 mesi precedenti l’arruolamento nello studio.
    (In presenza di malattia esclusivamente ossea, per i pazienti non interessati da carcinoma prostatico è accettabile un campione di tessuto tumorale conservato ottenuto nei 5 anni precedenti l’arruolamento nello studio mentre un campione bioptico di tessuto osseo fresco è accettabile solo per i pazienti con carcinoma prostatico).
    4. Malattia progressiva all’arruolamento nello studio come definita in base ai criteri RECIST v. 1.1 (tranne che per il mCRPC, che deve soddisfare il criterio 2c precedente).
    5. Malattia misurabile in base ai criteri RECIST v. 1.1 con almeno 1 lesione misurabile non precedentemente irradiata (i pazienti con mCRPC possono presentare solo malattia non misurabile).
    6. Età =18 anni (tranne che in Giappone, dove l’età dei pazienti deve essere =20 anni).
    7. Indice di performance(PS) ECOG (Eastern Cooperative Oncology Group) pari a 0 o 1
    8. Funzionalità del midollo osseo adeguata (senza supplementazione con fattore di crescita ematopoietico o terapia trasfusionale nei 14 giorni precedenti l’arruolamento nello studio), inclusi:
    a. conta assoluta dei neutrofili (ANC) =1.500/mm3 o =1,5 x 109/L;
    b. piastrine =100.000/mm3 o =100 x 109/L;
    c. emoglobina =9 g/dL (=5,6 mmol/L);
    9. Funzionalità renale adeguata, definita da una clearance della creatinina stimata =30 mL/min. in base alla formula di Cockcroft-Gault seguente:
    - CLCR={[(140–età) × peso)]/(72 x SCR)} × 0,85 (se di sesso femminile), dove la CLCR (clearance della creatinina) è misurata in mL/min., l’età è espressa in anni, il peso in chilogrammi (kg) e la SCR (creatinina sierica) in mg/dL;
    - o come misurato mediante un esame delle urine delle 24 ore.
    10. Funzionalità epatica adeguata, inclusi:
    a. bilirubina sierica totale =1,5 × il limite superiore della norma (ULN);
    b. aspartato e alanina aminotransferasi (AST e ALT) =2,5 x ULN.
    per i criteri 11-12-13 fare riferimento al protocollo. Il criterio 11 è stato modificato dall'Emend 1 al Protocollo per l'aggiunta del dettaglio sulla classificazione degli stati di fertilità correlata alla necessità dell'utilizzo della contraccezzione durnate la sperimentazione sia per pazienti di sesso femminile che maschile.
    E.4Principal exclusion criteria
    1. Prior treatment with a PARP inhibitor.
    2. Prior immunotherapy with anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibody.
    3. Prior anti-cancer therapy within 2 weeks prior to study enrollment or prior radiation therapy within 2 weeks prior to study enrollment. Prior palliative radiotherapy to metastatic lesion(s) is permitted, provided it has been completed at least 2 days prior to study enrollment and no clinically significant toxicities are expected (eg, mucositis, esophagitis).
    4. Major surgery within 4 weeks prior to study enrollment.
    5. Current use of immunosuppressive medication at the time of study enrollment, EXCEPT for the following permitted steroids: see Section 4.2.
    6. Known prior severe hypersensitivity to investigational products or any component in their formulations, including known severe hypersensitivity reactions to monoclonal antibodies ([NCI CTCAE] v4.03 Grade = 3).
    7. Known history of immune-mediated colitis, inflammatory bowel disease, pneumonitis, pulmonary fibrosis.
    8. Active or prior autoimmune disease that might deteriorate when receiving an immunostimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, or hypoor hyperthyroid disease not requiring immunosuppressive treatment are eligible.
    9. Prior organ transplantation including allogenic stem-cell transplantation.
    10. Administration of live attenuated vaccines within 4 weeks of study enrollment.
    11. Diagnosis of myelodysplastic syndrome (MDS).
    12. Known symptomatic brain metastases requiring steroids. Patients with previously diagnosed brain metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to study enrollment, have discontinued corticosteroid treatment for these metastases for at least 4 weeks, and are neurologically stable.
    13. Participation in other studies involving investigational drug(s) within 4 weeks prior to study entry and/or during study participation.
    14. Persisting toxicity related to prior therapy (NCI CTCAE v4.03 Grade >1); however, alopecia and sensory neuropathy Grade = 2, or other Grade = 2 AEs not constituting a safety risk, based on investigator's judgment, are acceptable.
    15. Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
    16. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive).
    17. Active infection requiring systemic therapy. Minor infections, eg, periodontal or urinary tract infection (UTI) infection, which may be treated with short term oral antibiotics are allowed.
    for criteria from 18 to 23 please refer to protocl
    1. Precedente trattamento con un PARP-inibitore.
    2. Precedente immunoterapia con anticorpi anti PD-1, anti PD-L1, anti PD-L2 o anti CTLA-4.
    3. Terapia oncologica o radioterapia nelle 2 settimane precedenti l’arruolamento nello studio. È consentita una precedente radioterapia palliativa diretta alla/e lesione/i metastatica/metastatiche, purché sia stata completata almeno 2 giorni prima dell’arruolamento nello studio e non si prevedano tossicità clinicamente significative (ad es. mucosite, esofagite).
    4. Intervento di chirurgia maggiore nelle 4 settimane precedenti l’arruolamento nello studio.
    5. Uso corrente di immunosoppressori al momento dell’arruolamento nello studio, TRANNE che per gli steroidi consentiti seguenti: vedere Sezione 4.2.
    6. Grave precedente ipersensibilità nota ai prodotti sperimentali o a qualsiasi componente presente nelle loro formulazioni, incluse reazioni note di grave ipersensibilità (di grado [NCI CTCAE v. 4.03] =3) agli anticorpi monoclonali.
    7. Storia nota di colite immunomediata, malattia infiammatoria intestinale, polmonite, fibrosi polmonare.
    8. Malattia autoimmune pregressa o in fase attiva che potrebbe peggiorare con la somministrazione di un immunostimolante. Possono essere inclusi pazienti con diabete di tipo I, vitiligine, psoriasi o ipo/ipertiroidismo che non necessitano di terapia immunosoppressiva.
    9. Precedente trapianto d’organo incluso il trapianto di cellule staminali allogeniche.
    10. Somministrazione di vaccini vivi attenuati nelle 4 settimane precedenti l’arruolamento nello studio.
    11. Diagnosi di sindrome mielodisplastica (SMD).
    12. Metastasi cerebrali sintomatiche note che richiedono il trattamento con steroidi. I pazienti con una diagnosi precedente di metastasi cerebrali possono essere inclusi se hanno completato il relativo trattamento e si sono ripresi dagli effetti acuti della radioterapia o dell’intervento chirurgico prima dell’arruolamento nello studio, hanno interrotto l’assunzione di corticosteroidi per queste metastasi da almeno 4 settimane e sono neurologicamente stabili.
    13. Partecipazione ad altri studi con farmaci sperimentali nelle 4 settimane precedenti l’ingresso nello studio e/o durante la partecipazione allo studio.
    14. Tossicità persistente (di grado NCI CTCAE v. 4.03 >1) correlata alla precedente terapia; sono tuttavia accettabili l’alopecia e la neuropatia sensoriale di grado =2 o altri AE di grado =2 che secondo il giudizio dello sperimentatore non costituiscono un rischio per la sicurezza.
    15. Storia nota di positività al virus dell’immunodeficienza umana (HIV) o sindrome da immunodeficienza acquisita (AIDS) nota.
    16. Infezione da virus dell’epatite B (HBV) o dell’epatite C (HCV) allo screening (positività all’antigene di superficie HBV o all’HCV RNA se il test degli anticorpi anti HCV effettuato allo screening è risultato positivo).
    17. Infezione in fase attiva che necessita di terapia sistemica. Sono permesse infezioni minori, ad es. infezione parodontale o delle vie urinarie (IVU), trattabili con terapia antibiotica orale di breve durata.
    Per i criteri da 18 a 23 fare riferimento al protocollo.
    E.5 End points
    E.5.1Primary end point(s)
    Confirmed OR in patients with locally advanced or metastatic solid tumors with BRCA 1/2 or ATM defect, as assessed by Blinded Independent Central Review (BICR), using RECIST v1.1 and, in patients with mCRPC, RECIST v1.1 and PCWG3 (bone).
    OR confermata nei pazienti con tumori solidi localmente avanzati o metastatici con difetto di BRCA 1/2 o di ATM, valutato dalla revisione centrale indipendente in cieco (Blinded Independent Central Review, BICR), utilizzando i criteri RECIST v1,1 e, in pazienti affetti da mCRPC, con i criteri RECIST v1,1 e PCWG3 (ossa).
    E.5.1.1Timepoint(s) of evaluation of this end point
    For patients with solid tumors, except mCRPC: Objective response (OR) is defined as a CR or PR per RECIST v1.1 from the first dose of study treatment until disease progression or death due to any cause. Both CR and PR must be confirmed by repeat assessments performed no less than 4 weeks after the criteria for response are first met.
    For patients with mCRPC: Objective response (OR) is defined as the proportion of patients with a best overall soft tissue response of CR or PR per RECIST v1.1 from the first dose of study treatment until disease progression or death due to any cause. Soft tissue responses will be confirmed by a follow-up radiographic assessment at least 4 weeks later with a repeated CT or MRI with no evidence of confirmed bone disease progression per PCWG3 criteria.
    Per pazienti con tumori solidi, eccetto mCRPC: Risposta obiettiva (OR) è definita come CR o PR come da RECIST v1.1 vautata dalla prima prima dose di farmaco finoa progressione di malattia o decesso per qualunque causa. Entrambe CR e PR devono essere confermate da valutazioni ripetute effettuate non meno di 4 settimane dopo che i criteri di risposta sono stai raggiunti.
    Per pazienti con mCRPC: Risposta obiettiva (OR) è definita come la proporzione dei pazienti con la migliore riposta generale di CR o PR nei tessuti molli secondo il RECIST v1.1 vautata dalla prima prima dose di farmaco finoa progressione di malattia o decesso per qualunque causa.
    E.5.2Secondary end point(s)
    - Adverse Events as characterized by type, severity (as graded by National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] v.4.03), timing, seriousness, and relationship to study therapy.
    - Laboratory abnormalities as characterized by type, severity (as graded by NCI CTCAE v.4.03) and timing.
    - PK parameters including: pre-dose/trough concentrations (Ctrough) for avelumab and talazoparib and post-dose concentrations (for talazoparib) and
    maximum concentrations (Cmax) for avelumab.
    - Avelumab Anti-drug antibody (ADA) levels and neutralizing antibodies (Nab) against avelumab.
    - Confirmed OR as assessed by the investigator, using RECIST v1.1 and, in patients with mCRPC, RECIST v1.1 and PCWG3.
    - Time to event endpoints: Endpoints as assessed by BICR and as assessed by the investigator, using RECIST v1.1 and in patients with mCRPC, RECIST v1.1 and PCWG3, including time to tumor response (TTR), duration of response (DR), and progression free survival (PFS). Additional time-to-event endpoints include overall survival (OS) for all patients and time to prostate-specific antigen (PSA) progression (= 25% increase) for mCRPC patients.
    - PSA response = 50% decrease and CTC count conversion for patients with mCRPC.
    - Cancer antigen (CA)-125 response = 50% decrease for patients with ovarian cancer.
    - PD-L1 expression level in baseline tumor tissue
    - Presence of defects in a panel of key oncogenes, including BRCA1/2 and ATM, and TMB in ctDNA and tumor tissue at baseline, during treatment, and at the end of treatment.; • Eventi avversi, caratterizzati per tipo, gravità (secondo la classificazione in base ai criteri comuni di terminologia per gli eventi avversi [Common terminology criteria, CTCAE] del National Cancer Institute [NCI] v. 4.03), tempistica, serietà e relazione con la terapia dello studio).
    • Anomalie di laboratorio, caratterizzate per tipo, gravità (secondo la classificazione in base ai CTCAE del NCI v.4.03) e tempistica.
    • Parametri PK tra cui: concentrazioni pre-dose/minime (Cdi valle) per avelumab e di talazoparib e concentrazioni post-dose (per talazoparib) e concentrazioni massime (Cmax) per avelumab.
    • Livelli dell’anticorpo anti-farmaco di avelumab (Anti-drug antibody, ADA) e degli anticorpi neutralizzanti (Neutralizing antibodies, Nab) contro avelumab.
    • OR confermata valutata dallo sperimentatore, utilizzando i criteri RECIST v1,1 e, in pazienti affetti da mCRPC, i criteri RECIST v1,1 e PCWG3.
    • Endpoint di tempo all’evento: Endpoint valutati mediante BICR e valutati dallo sperimentatore, utilizzando i criteri RECIST v1,1 e in pazienti affetti da mCRPC, i criteri RECIST v1,1 e PCWG3, compresi il tempo alla risposta tumorale (TTR), la durata della risposta (DR) e la sopravvivenza libera da progressione (PFS). Ulteriori endpoint di tempo all’evento includono la sopravvivenza complessiva (OS) per tutti i pazienti e il tempo alla progressione dell’antigene prostatico specifico (prostate-specific antigen, PSA) (¿aumento del 25%) per pazienti con mCRPC.
    • Risposta PSA diminuzione del ¿50% e conversione del conteggio CTC per i pazienti con mCRPC.
    • Risposta dell’antigene tumorale (Cancer antigen, CA)-125 diminuzione del ¿50% per pazienti con tumore ovarico.
    • Livello di espressione di PD-L1 nel tessuto tumorale al basale
    • Presenza di difetti in un pannello di oncogeni chiave, tra cui i geni BRCA1/2 e ATM, e TMB in ctDNA e nel tessuto tumorale al basale, durante il trattamento, e a fine trattamento.
    E.5.2.1Timepoint(s) of evaluation of this end point
    multiple timepoints as per protocol
    diversi tempi di rilevazione in accordo al protocollo
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Tolerability, Immunogenicity
    tollerabilità, immunigenicità
    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
    In aperto
    Open
    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 concerned9
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA40
    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 Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Israel
    United States
    Belgium
    Denmark
    France
    Italy
    Netherlands
    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
    End of trial in a Member State of the European Union (EU) is defined as the time at which it is deemed that a sufficient number of patients have been recruited and completed the study as stated in the regulatory application and ethics application in the Member State.
    End of trial in all other participating countries is defined as last subject last visit (LSLV).
    La conclusione della sperimentazione negli stati Membri EU è definita come il momento in cui il numero di pazienti arruolati e che hanno completato lo studio sarà ritenuto sufficiente come dichiarato nelle domande di autorizzazione alle AC e CE.
    La conclusione della sperimentazione negli altri Paesi partecipanti è definita come LSLV.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months5
    E.8.9.2In all countries concerned by the trial days10
    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: 216
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 325
    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 state28
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 196
    F.4.2.2In the whole clinical trial 541
    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
    nessuno
    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 Decision2018-11-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-09-19
    P. End of Trial
    P.End of Trial StatusOngoing
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