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    Summary
    EudraCT Number:2014-004848-36
    Sponsor's Protocol Code Number:BAY80-6946/17119
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-04-27
    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 number2014-004848-36
    A.3Full title of the trial
    An open-label, single-arm Phase II study in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) to evaluate efficacy and safety of treatment with single agent copanlisib and the impact of biomarkers thereupon.
    Studio in aperto, a braccio singolo, di Fase II, in pazienti affetti da linfoma diffuso a grandi cellule B (DLBCL) recidivato o refrattario, per valutare l’efficacia e la sicurezza del trattamento con copanlisib come unico farmaco ed il relativo impatto dei biomarcatori.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical study to investigate the efficacy and safety of copanlisib in
    patients with relapsed or refractory diffuse large B-cell lymphoma.
    Studio di Fase II con copanlisib nel DLBCL recidivato o refrattario
    A.3.2Name or abbreviated title of the trial where available
    Phase II copanlisib in relapsed/refractory DLBCL
    Studio di Fase II con copanlisib nel DLBCL recidivato o refrattario
    A.4.1Sponsor's protocol code numberBAY80-6946/17119
    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 SponsorBayer HealthCare AG
    B.1.3.4CountryGermany
    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 supportBayer HealthCare AG
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBayer HealthCare AG
    B.5.2Functional name of contact pointBayer Clin. Trials Contact CTP Team
    B.5.3 Address:
    B.5.3.1Street AddressBayer Pharma AG, S102, Level 2, Room 156
    B.5.3.2Town/ cityBerlin
    B.5.3.3Post code13342
    B.5.3.4CountryGermany
    B.5.6E-mailclinical-trials-contact@bayerhealthcare.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.2.5The 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 nameCopanlisib
    D.3.2Product code BAY84- 1236
    D.3.4Pharmaceutical form Lyophilisate 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 INNCopanlisib
    D.3.9.2Current sponsor codeBAY 84-1236
    D.3.9.3Other descriptive nameBAY 80-6946 (AS DIHYDROCHLORIDE BAY 84-1236)
    D.3.9.4EV Substance CodeSUB32033
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number60
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    patients with relapsed or refractory diffuse large B cell lymphoma
    DLBCL recidivato o refrattario
    E.1.1.1Medical condition in easily understood language
    patients with relapsed or refractory diffuse large B cell lymphoma
    Linfoma diffuso a grandi cellule B recidivato o refrattario
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of this study is to assess the potential efficacy (in terms of objective response) of single agent copanlisib in patients with relapsed or refractory DLBCL and assess the relationship between efficacy and a potentially predictive biomarker.
    L’obiettivo primario dello studio è:
    • Valutare la potenziale efficacia (in termini di risposta obiettiva) di copanlisib come unico farmaco in pazienti affetti da DLBCL recidivato o refrattario e valutare il rapporto tra l’efficacia e biomarcatori potenzialmente predittivi.
    E.2.2Secondary objectives of the trial
    Secondary objectives of this study are to assess:
    - Other radiological and survival indicators of treatment efficacy.
    - Safety and tolerability of copanlisib
    - Long-term effects of the treatment

    Further objectives of this study are to assess:
    -Pharmacokinetics of copanlisib
    - To explore additional biomarkers in predicting efficacy
    - Patient-reported outcomes
    Gli obiettivi secondari dello studio consistono nel valutare :
    • Altri indicatori di efficacia del trattamento (radiologici e di sopravvivenza).
    • La sicurezza e la tollerabilità di copanlisib
    • Gli effetti a lungo termine del trattamento
    Ulteriori obiettivi dello studio sono:
    • Valutare la farmacocinetica di copanlisib
    • Ricercare ulteriori biomarcatori predittivi dell’efficacia
    Valutare gli esiti riportati dal paziente
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Ability to understand and willingness to sign written informed consent. Signed informed consent (including consent to genetic analysis) must be obtained before any study specific procedure.

    2. Male or female patients age ≥ 18 years old

    3. Diagnosis of DLBCL (de novo or DLBCL transformed from follicular lymphoma on the basis of a tissue biopsy). Pathology and immunohistochemistry reports documenting the current histological diagnosis of DLBCL or DLBCL transformed from follicular lymphoma according to WHO classification must be reviewed by the sponsor or designee prior to enrollment. Patients whose NHL has transformed from follicular lymphoma must have had a complete or partial response to first-line therapy for NHL lasting at least 12 weeks.
    • DLBCL not otherwise specified (NOS)
    • T-cell/histiocyte-rich large B-cell lymphoma
    • Epstein-Barr virus (EBV) positive DLBCL of the elderly

    4. Received at least one prior therapy for aggressive NHL (DLBCL)
    Note: High dose myeloablative therapy with SCT used to consolidate a response and local consolidative radiation, corticosteroids as single agents, and maintenance therapy with rituximab or other agents are not considered independent regimens.

    5. Received CHOP + rituximab or equivalent regimen (addition of etoposide or substitution of idarubicin, epirubicin, or mitoxantrone for doxorubicin is allowed) for NHL

    6. At least 28 days from completion of last NHL therapy to first dose of study treatment.

    7. Patients must have measurable disease (at least one bidimensionally measurable site of disease that has not been previously irradiated: nodal disease >1.5 cm or an extranodal lesion > 1.0 cm in longest perpendicular diameter). Lesion must be PET-positive if a PET scan is obtained.

    8. Not eligible or not willing to receive the high-dose (myeloablative) chemotherapy (HDC) and SCT.

    9. A fresh tumor biopsy collected during screening and /or archival tumor tissue collected after the last relapse/disease progression (material which has been collected before the last line of treatment is not accepted). In addition, a sufficient amount of the material is required for acceptance of the archival material. If neither condition occurs a fresh tumor biopsy needs to be performed as stated above.

    10. ECOG performance status (PS) ≤ 2

    11. Life expectancy ≥ 12 weeks in investigator’s judgment

    12. Left ventricular ejection fraction (LVEF) ≥ the lower limit of normal (LLN) for the Institution (as per local standard of care) as measured by ECHO (echocardiogram) or Multiple gated acquisition (MUGA) scan

    13. Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements conducted within 7 days before start of study treatment:
    - Hemoglobin ≥ 8 g/dL
    - Platelet count ≥ 100 x 109L/; platelet count ≥ 75 x 109/L permitted if documented bone marrow involvement
    - Absolute neutrophil count (ANC) ≥ 1.5 x 109/L; ANC ≥ 1.0 x 109/L permitted if documented bone marrow involvement
    - Total bilirubin ≤ 1.5 x upper limit of normal (ULN); patients with proven Gilbert’s syndrome and total bilirubin ≤ 5 x ULN may be enrolled.
    - Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤ 2 x ULN, or ≤ 5 x ULN if elevation is due to hepatic involvement by lymphoma
    - Glomerular filtration rate (GFR) ≥ 30 mL/min/1.73 m2 according to the Modification of Diet in Renal Disease (MDRD) abbreviated formula (See Appendix 16.4).
    - International normalized ratio (INR) and partial thromboplastin time (PTT) ≤ 1.5 x ULN. Patients who are therapeutically treated with an agent such as warfarin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in coagulation parameters exists. Close monitoring is recommended according to the local standard of care.
    - Lipase < 1.5 x the ULN

    14. Willingness and ability to comply with the visit schedule and assessments required by the study protocol

    15. Women and men of reproductive potential must agree to use adequate contraception when sexually active. This applies for the time period between signing of the ICF and 3 months after the last administration of study drug. The investigator or a designated associate is requested to advise the patient how to achieve an adequate birth control. Adequate contraception is defined in the study as any medically recommend method (or combination of methods) as per standard of care.
    1. Capacità di comprendere e volontà di firmare il consenso informato scritto. Il consenso informato firmato (incluso il consenso all’analisi genetica) deve essere ottenuto prima di qualsiasi procedura studio-specifica.
    2. Pazienti di sesso maschile e femminile ≥ 18 anni.
    3. Diagnosi di DLBCL (ex novo o DLBCL trasformato da linfoma follicolare in base alla biopsia tissutale). I referti anatomo-patologico e immunoistochimico comprovanti la diagnosi istologica di DLBCL o DLBCL trasformato da linfoma follicolare in accordo alla classificazione WHO devono essere rivisti dallo sponsor o un suo designato prima dell’arruolamento. I pazienti con NHL trasformato da linfoma follicolare devono aver avuto una risposta completa o parziale al trattamento di prima linea per NHL di almeno 12 settimane.
    • DLBCL non altrimenti specificato (NOS)
    • Linfoma diffuso a grandi cellule B T-cell/histiocyte-rich
    • DLBCL dell'anziano Epstein-Barr virus (EBV) positivo
    4. I pazienti devono aver ricevuto almeno un precedente trattamento per NHL aggressivo(DLBCL) Nota: Non sono considerati trattamenti indipendenti la terapia mieloablativa ad alte dosi con SCT utilizzata per consolidare la risposta alla terapia e la radioterapia locale di consolidamento,i corticosteroidi come singolo trattamento e la terapia di mantenimento con rituximab o altri farmaci.
    5. I pazienti devono aver ricevuto un trattamento secondo schema CHOP + rituximab o trattamenti equivalenti per NHL (sono permessi l'aggiunta di etoposide o la sostituzione di doxorubicina con idarubicina, epirubicina o mitoxantrone)
    6. Devono essere intercorsi almeno 28 giorni tra la fine dell’ultimo trattamento per NHL e la prima dose del farmaco in studio.
    7. I pazienti devono presentare una malattia misurabile (deve essere presente almeno una lesione della malattia misurabile bi-dimensionalmente non precedentemente irradiata: diametro perpendicolare maggiore della malattia nodale >1.5 cm, di una lesione extranodale > 1.0 cm). Se è stata eseguita una indagine PET, la lesione deve essere PET-positiva.
    8. I pazienti non devono essere candidabili a, o devono rifiutare il, trattamento chemioterapico mieloablativo ad alte dosi (HDC) e successivo trapianto di cellule staminali (SCT).
    9. Biopsia di tessuto tumorale fresco effettuata durante lo screening, e /o tessuto tumorale archiviato raccolto dopo l’ultima recidiva/progressione di malattia (il materiale prelevato prima dell’ultima linea di trattamento non è accettato). Inoltre è richiesta una quantità sufficiente per poter accettare il materiale archiviato. Se neanche questa condizione è soddisfatta deve essere effettuata una biopsia di un campione di tessuto tumorale fresco.
    10. ECOG performance status (PS) ≤ 2
    11. Aspettativa di vita ≥ 12 secondo il giudizio clinico.
    12. Frazione di eiezione del ventricolo sinistro (LVEF) ≥ il limite inferiore di normalità (LLN) secondo lo standard di cura locale, misurata mediante ecocardiogramma (ECHO) o scintigrafia miocardica (MUGA- scan)
    13. Adeguata funzionalità del midollo ematopoietico, epatica e renale dimostrata dai seguenti esami di laboratorio eseguiti entro i 7 giorni precedenti l'inizio del trattamento in studio: - Emoglobina ≥ 8 g/dL - Piastrine ≥ 100 x 109L/; Piastrine ≥ 75 x 109/L è consentito se è comprovato l’interessamento del midollo osseo – Conta assoluta dei neutrofili (ANC) ≥ 1.5 x 109/L; ANC ≥ 1.0 x 109/L consentito se è comprovato l’interessamento del midollo osseo – Bilirubina totale ≤ 1.5 x limite superiore di normalità (ULN); pazienti con dimostrata sindrome di Gilbert e bilirubina totale ≤ 5 x ULN possono essere inclusi. - Aspartato aminotransferasi (AST) and Alanina aminotransferasi (ALT) ≤ 2 x ULN, or ≤ 5 x ULN se l’aumento è dovuto all’interessamento epatico del linfoma – Velocità di filtrazione glomerulare (GFR) ≥ 30 mL/min/1.73 m2 in accordo alla formula abbreviata Modification of Diet in Renal Disease (MDRD) (Rif. Appendice 16.4). - International normalized ratio (INR) e tempo di tromboplastina parziale (PTT) ≤ 1.5 x ULN. Pazienti in trattamento con farmaci come warfarina e eparina possono partecipare se non vi è evidenza di un peggioramento dei parametri della coagulazione. E’ raccomandato uno stretto monitoraggio secondo lo standard di cura locale. Lipasi < 1.5 x the ULN
    14. Disponibilità e possibilità di rispettare il programma delle visite e delle procedure richieste dal protocollo di studio
    15. Uomini e donne in età fertile devono accettare di utilizzare un adeguato metodo contraccettivo se sessualmente attivi. Questo è applicabile per tutto il periodo che intercorre dalla firma del consenso informato e fino a 3 mesi dopo l’ultima somministrazione di farmaco in studio. Lo sperimentatore,o un suo delegato, è tenuto a informare il paziente sull’adeguato metodo contraccettivo da utilizzare.
    E.4Principal exclusion criteria
    1. Previous assignment to treatment during this study. Patients permanently withdrawn from study participation will not be allowed to re-enter the study.

    2. Concurrent participation in other clinical studies. Patients must complete their participation in another clinical study with an investigational medicinal product 28 days before the start of treatment or 5 half-lives of the investigational treatment, whichever is longer.

    3. Patients who previously received therapy with copanlisib or other PI3K inhibitors are not eligible for enrollment.

    4. Close affiliation with the investigational site; e.g. a close relative of the investigator, dependent person (e.g. employee or student of the investigational site)

    Excluded medical conditions
    5. Any of the following as the only site(s) of disease: palpable lymph nodes not visible on imaging studies, skin lesions, or bone marrow involvement only.

    6. Active CTCAE Grade 3/4 infection

    7. Hepatitis B (HBV) or hepatitis C (HCV). All patients must be screened for HBV and HCV up to 28 days prior to study drug start using the routine hepatitis virus laboratorial panel. Patients positive for HBsAg or HBcAb will be eligible if they are negative for HBV-DNA; patients positive for anti-HCV will be eligible if they are negative for HCV-RNA

    8. Known history of human immunodeficiency virus (HIV) infection

    9. Current central nervous system (CNS) involvement by lymphoma
    - Any past history or evidence of current leptomeningeal involvement by lymphoma is prohibited.
    - Patients with prior localized CNS involvement who have been without recurrence for ≥ 12 mths and currently have a negative head MRI and negative cerebrospinal fluid (CSF) may be eligible.

    10. Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 mths). Myocardial infarction within the past 6 months before start of study treatment

    11. Uncontrolled arterial hypertension (systolic blood pressure > 150mmHg or diastolic blood pressure > 90mmHg despite optimal medical management).

    12. Type I or II diabetes mellitus with HbA1c > 8.5% or fasting plasma glucose > 160mg/dL at Screening.

    13. New York Heart Association (NYHA) class III or IV heart disease.

    14. Any other malignancy within last 3 yrs except for the following, which are permitted:
    a. curatively treated non-melanoma skin cancer
    b. carcinoma in situ of the cervix
    c. in situ ductal carcinoma of the breast after complete resection
    d. superficial bladder tumors (Ta [non-invasive tumor], Tis [carcinoma in situ] and T1 [tumor invades lamina propria])

    15. Any illness or conditions (substance abuse, medical, psychological or social) that may interfere with the patient’s participation in the study, evaluation of the study results, or could jeopardize the safety of the patient and his/her compliance in the study.

    16. Non-healing wound ulcer or bone fracture.

    17. Major surgical procedure or significant traumatic injury (as judged by the investigator) less than 28 days before start of study treatment.

    18. Patients with seizure disorder requiring medication.

    19. Patients with evidence or history of bleeding diathesis. Any hemorrhage or bleeding event with CTCAE Grade ≥ 3 within 4 weeks prior to screening.

    20. Proteinuria of CTCAE Grade 3 or higher (> 3.5 measured by urine protein to creatinine ratio on a random urine sample)

    21. History or concurrent condition of interstitial lung disease of any severity and/or severely impaired lung function (as judged by the investigator).

    22. Pregnant or breast-feeding patients. Women of childbearing potential must have a serum pregnancy test performed a maximum of 7 days before start of study treatment and a negative result must be documented before start of study treatment.

    23. Unresolved toxicity higher than CTCAE Grade 1 attributed to any prior therapy/procedure, excluding alopecia and ≤ CTCAE Grade 2 peripheral neuropathy. Patients with B symptoms are eligible for enrollment.

    Excluded previous therapies and medications:
    24. Radiotherapy or immuno-/chemotherapy less than 4 wks before start of study treatment

    25. Radioimmunotherapy or autologous transplant less than 3 mths before start of study treatment

    26. Myeloid growth factors less than 7 days before start of study treatment

    27. Blood or platelet transfusion less than 7 days before start of study treatment

    28. Ongoing systemic corticosteroid therapy at a daily dose higher than 15mg prednisone or equivalent. Previous corticosteroid therapy must be stopped or reduced to the allowed dose (≤15mg of prednisone or equivalent) at least 7 days before performing the screening CT/MRI or PET-CT whichever is performed first and again prior to the first study drug administration. If a patient is on chronic corticosteroid therapy, corticosteroids should be de-escalated to the maximum allowed dose before the Screening. Patients may be using topical or inhaled corticosteroids.
    1. Precedente trattamento nell’ambito dello stesso studio. I pazienti che hanno interrotto definitivamente la partecipazione allo studio non possono essere re-inseriti nello studio.
    2. Partecipazione contemporanea ad altri studi clinici. I pazienti devono sospendere la loro partecipazione ad un altro studio clinico con farmaco sperimentale 28 giorni prima di iniziare il trattamento, o 5 emivite del farmaco sperimentale prima , a seconda di quale periodo sia più lungo.
    3. Pazienti che sono stati precedentemente trattati con copanlisib o altri inibitori di PI3K non possono essere inclusi.
    4. Relazione stretta con il centro sperimentale; es. un parente stretto dello sperimentatore, una persona subordinata (es. dipendente o studente del centro sperimentale)
    5. Una qualsiasi tra le seguenti come unica sede(i) della malattia: linfonodi palpabili non visibili mediante diagnostica per immagini, lesioni cutanee o interessamento del solo midollo osseo
    6. Infezione in atto di Grado 3/4 secondo i CTCAE
    7. Epatite B (HBV) o epatite C (HCV). I pazienti devono effettuare l’esame diagnostico per HBV e HCV entro i 28 giorni precedenti all’inizio del farmaco in studio secondo la routine del laboratorio locale. I pazienti positivi per HBsAg o HBcAb saranno eleggibili se sono negativi per il DNA dell’HBV. I pazienti positivi per gli anticorpi anti-HCV saranno eleggibili se sono negativi per il RNA dell’HCV
    8. Infezione nota da parte del virus dell’immunodeficienza umana (HIV)
    9. Coinvolgimento del sistema nervoso centrale (CNS) da parte del linfoma. Non sono elegibili pazienti che presentino qualsiasi precedente storia o evidenza di coinvolgimento leptomeningeale da parte del linfoma. Posso essere inclusi pazienti con precedente coinvolgimento del SNC localizzato senza ricaduta per ≥ 12 mesi, con MRI del sistema nervoso centrale negativa ed esame del fluido cerebrospinale negativo (CSF).
    10. Angina instabile (sintomi di angina a riposo), nuova insorgenza di angina (iniziata entro gli ultimi 3 mesi). Iinfarto del miocardico entro gli ultimi 6 mesi prima dell’inizio del farmaco in studio.
    11. Ipertensione non controllata (pressione sistolica>150 mmHg o diastolica>90 mmHg nonostante trattamento medico ottimale).
    12. Diabete mellito di tipo 1 o 2 con valori di HbA1c > 8.5% oppure glicemia a digiuno > 160 mg/dL allo screening.
    13. Insufficienza cardiaca di Classe III o IV secondo la classificazione della New York Heart Association (NYHA).
    14. Qualsiasi altro tipo di tumore negli ultimi 3 anni, eccetto i seguenti che sono ammessi: a. tumore della cute non melanoma, trattato con scopi curativi b. carcinoma della cervice uterina in situ c. carcinoma della mammella duttale in situ dopo completa resezione chirurgica d. tumori superficiali della vescica (Ta [tumore non invasivo], Tis [carcinoma in situ] e T1 [tumore che invade la lamina propria])
    15. Qualsiasi malattia o condizione (abuso di sostanze, condizioni mediche, psicologiche o sociali) che possano interferire con la partecipazione allo studio, la valutazione dei risultati e che possano mettere a rischio la sicurezza del paziente e la sua compliance allo studio.
    16. Ferita aperta, ulcera o frattura ossea.
    17. Intervento di chirurgia maggiore o lesione traumatica significativa ( a giudizio dello sperimentatore) entro 28 giorni prima dell’inizio del farmaco in studio.
    18. Pazienti con disturbi epilettici che richiedano l’assunzione di farmaci.
    19. Pazienti con diatesi emorragica in atto o pregressa. Qualsiasi emorragia o sanguinamento con CTCAE Grade ≥ 3 nelle 4 settimane precedenti allo screening.
    20. Proteinuria di CTC di grado 3 o maggiore (> 3,5 g misurata secondo il rapporto tra proteina urinaria e creatinina urinaria su un campione di urina casuale).
    21 Malattia polmonare interstiziale in atto o pregressa di qualsiasi severità e/o che impatta gravemente sulla funzionalità polmonare (a giudizio dello sperimentatore)
    22. Pazienti in stato di gravidanza o allattamento. Le donne in età fertile devono effettuare un test di gravidanza al massimo 7 giorni prima di iniziare il farmaco in studio, ed il risultato negativo deve essere documentato.
    23. Tossicità non risolta di grado CTCAE maggiore a 1 attribuita ad una qualsiasi terapia/procedura precedente, ad esclusione di alopecia e neuropatia periferica di grado CTCAE ≤2. I pazienti con i sintomi B possono essere inclusi.
    24. Radioterapia o immuno/chemioterapia nelle 4 settimane antecedenti l’inizio del farmaco in studio
    25. Radioimmunoterapia o trapianto autologo nei 3 mesi antecedenti ll’inizio del farmaco in studio
    26. Fattori di crescita mieloidi nei 7 giorni antecedenti l’inizio del farmaco in studio
    27. Trasfusione di sangue o piastrine nei 7 giorni antecedenti l’inizio del farmaco in studio
    28. Trattamento concomitante con corticosteroidi sistemici alla dose giornaliera maggiore di 15 mg di prednisone o equivalente.
    E.5 End points
    E.5.1Primary end point(s)
    The primary variableis the objective Response Rate (ORR), defined as the proportion of patients who have at least once a post baseline overall response of CR (complete response) or PR (partial response) during study conduct; according to the criteria defined in The Lugano Classification.
    La variabile primaria è il tasso di risposta obiettiva (ORR), definito come la percentuale dei pazienti che durante lo studio presentino almeno una volta una risposta globale CR (risposta completa) o PR (risposta parziale) secondo i criteri definiti dalla Classificazione di Lugano
    E.5.1.1Timepoint(s) of evaluation of this end point
    It will be assessed 24 weeks after the last patient fully evaluable for the primary endpoint started treatment.
    Sarà valutato 24 settimane dopo che l’ultimo paziente valutabile per l’endpoint primario avrà iniziato il trattamento
    E.5.2Secondary end point(s)
    Duration of response (DOR);
    Progression-free survival (PFS);
    Overall survival (OS);
    Disease control rate (DCR);
    Duration of stable disease (DOSD).
    Durata della risposta; Sopravvivenza libera da progressione; Sopravvivenza globale; Tasso di controllo della malattia; Durata della stabilità di malattia.
    E.5.2.1Timepoint(s) of evaluation of this end point
    The final analyses of all secondary efficacy and safety variables and an
    additional exploratory analysis of the primary efficacy variable will be
    performed 2 years after the last patient's first treatment or the last
    patient dies, whichever occurs first.
    Le analisi finali di tutte le variabili di efficacia secondaria e di sicurezza e un' analisi esplorativa aggiuntiva della variabile di efficacia primaria verranno effettuate 2 anni dopo il primo trattamento dell’ultimo paziente o al decesso dell’ultimo paziente, a seconda di quale dei due eventi si verificherà prima.
    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 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 Yes
    E.6.13.1Other scope of the trial description
    Biomarker analysis
    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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) 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 concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA25
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Belgium
    Canada
    Denmark
    France
    Germany
    Italy
    Korea, Republic of
    Netherlands
    Poland
    Singapore
    Spain
    Sweden
    Switzerland
    Turkey
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of study as a whole will be reached as soon as the last survival contact of the last patient has occurred in all centers in all participating countries (EU and non-EU)
    La fine studio verrà raggiunta quando l’ultimo contatto relativo all’ultimo Paziente in vita verrà registrato nell’ultimo Centro dell’ultimo Paese
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days3
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months3
    E.8.9.2In all countries concerned by the trial days3
    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: 30
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 36
    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 state19
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 50
    F.4.2.2In the whole clinical trial 66
    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)
    After the end of study treatment, further therapy is at the discretion of the investigator.
    A discrezione dello Sperimentatore
    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 Decision2015-07-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-05-21
    P. End of Trial
    P.End of Trial StatusCompleted
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