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    Summary
    EudraCT Number:2019-000790-23
    Sponsor's Protocol Code Number:AN2025H0301
    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:2021-08-30
    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 number2019-000790-23
    A.3Full title of the trial
    The BURAN Study of Buparlisib (AN2025) In Combination with Paclitaxel Compared to Paclitaxel Alone, in Patients with Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma
    Studio clinico BURAN di Buparlisib (AN2025) in associazione con Paclitaxel rispetto al Paclitaxel solo, in pazienti con carcinoma a cellule squamose di testa e collo recidivante o metastatico
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    The BURAN Study of Buparlisib (AN2025) In Combination with Paclitaxel Compared to Paclitaxel Alone in patients with head and neck cancer
    Studio BURAN di Buparlisib (AN2025) in associazione con Paclitaxel rispetto al Paclitaxel solo, in pazienti con carcinoma testa e collo
    A.3.2Name or abbreviated title of the trial where available
    The BURAN Study
    Studio BURAN
    A.4.1Sponsor's protocol code numberAN2025H0301
    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 SponsorAdlai Nortye USA 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 supportAdlai Nortye USA Inc.,
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAdlai Nortye USA Inc.,
    B.5.2Functional name of contact pointKevin Dreyer
    B.5.3 Address:
    B.5.3.1Street Address685 US-1,
    B.5.3.2Town/ cityNorth Brunswick Township, NJ
    B.5.3.3Post code08902
    B.5.3.4CountryUnited States
    B.5.6E-mailKevin.Dreyer@adlainortye.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 nameBuparlisib
    D.3.2Product code [NA]
    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 INNbuparlisib
    D.3.9.1CAS number 944396-07-0
    D.3.9.2Current sponsor codeAN2925
    D.3.9.4EV Substance CodeSUB128477
    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.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Paclitaxel
    D.2.1.1.2Name of the Marketing Authorisation holderEbewe Pharma Ges.m.b.H. Nfg. KG
    D.2.1.2Country which granted the Marketing AuthorisationBulgaria
    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 namePaclitaxel
    D.3.2Product code [NA]
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPaclitaxel
    D.3.9.1CAS number 33069-62-4
    D.3.9.2Current sponsor codeNA
    D.3.9.4EV Substance CodeSUB09583MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product 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 nameBuparlisib
    D.3.2Product code [NA]
    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 INNBUPARLISIB
    D.3.9.1CAS number 944396-07-0
    D.3.9.2Current sponsor codeAN2925
    D.3.9.4EV Substance CodeSUB128477
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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
    Head and Neck Squamous Cell Carcinoma (HNSCC)
    carcinoma a cellule squamose di testa e collo
    E.1.1.1Medical condition in easily understood language
    Head and Neck Cancer
    tumore testa e collo
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level PT
    E.1.2Classification code 10060121
    E.1.2Term Squamous cell carcinoma of head and neck
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of the study is as follows:
    • To assess the overall survival (OS) of buparlisib in combination with
    paclitaxel compared to paclitaxel alone in patients with refractory,
    recurrent, or metastatic HNSCC.
    Obiettivo primario: L’obiettivo primario dello studio clinico è il seguente:
    • Valutare la sopravvivenza complessiva (OS) di buparlisib in associazione con paclitaxel rispetto a paclitaxel da solo in pazienti affetti da HNSCC refrattario, recidivante o metastatico.
    E.2.2Secondary objectives of the trial
    The secondary objectives of the study are as follows:
    • To evaluate additional efficacy parameters: progression free survival
    (PFS), ORR, and DoR, by the Investigator and Independent Radiological
    Review Committee (IRRC).
    • To evaluate efficacy parameters in subgroups of patients defined by
    the randomization strata.
    • To assess the effect of buparlisib in combination with paclitaxel on
    patient's symptoms and health-related quality of life (HRQoL).
    • To assess biomarkers of response to buparlisib in combination with
    paclitaxel.
    • To assess the pharmacokinetics (PK) of buparlisib in combination with
    paclitaxel.
    Obiettivi secondari: Gli obiettivi secondari dello studio clinico sono i seguenti:
    • Valutare ulteriori parametri di efficacia: sopravvivenza libera da progressione (PFS), ORR e DoR, da parte dello sperimentatore e del comitato indipendente di revisione radiologica (IRRC).
    • Valutare i parametri di efficacia in sottogruppi di pazienti definiti dagli strati di assegnazione per randomizzazione.
    • Valutare l’effetto di buparlisib in associazione con paclitaxel sui sintomi del paziente e sulla qualità della vita correlata alla salute (HRQoL).
    • Valutare i biomarcatori della risposta al buparlisib in associazione con paclitaxel.
    • Valutare la farmacocinetica (PK) di buparlisib in associazione con paclitaxel.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Aged =18yo.
    Able to provide ICFobtained before any study related activities.
    PT has histologically and/or cytologically-confirmed HNSCC.
    Patient has archival or new tumor tissue for the analysis of
    biomarkers. A tumor block (preferred) or a minimum of 12 (15
    recommended) unstained slides to be provided. Enrollment in the study
    is contingent on confirmation of an adequate amount of tumor tissue.
    Patients progressing following treatment with an anti PD 1/anti PD L1 therapy are encouraged to have a new tumor biopsy for biomarker analysis.
    PT has either progressive or recurrent disease after treatment with PDL1/PD1 based therapy for recurrent or metastatic disease:
    PDLl/PD1 therapy alone for metastatic (monotherapy) disease
    PDL1/PD1 in combination with chemotherapy for metastatic and
    recurrent disease PDL1/PD1 used for metastatic disease, after or prior to receiving a
    platinum agent for locally advanced or metastatic disease.
    PT has received no more than two prior lines of systemic
    treatment for HNSCC (single agent chemotherapy used as a
    radiosensitizer is not counted as a prior line of therapy).
    PT has measurable disease as determined per RECIST version 1.1.
    If the only site of measurable disease is a previously irradiated lesion,
    documented progression of disease and a four-week period since
    radiotherapy completion is required.
    PT has adequate bone marrow function and organ function as
    shown by the following:
    ANC=1.5x109/L.
    Hemoglobin=9g/dL (which may be reached by transfusion).
    Platelets=100x109/L (which may be reached by transfusion).
    International normalized ratio (INR) = 1.5.
    Ca(corrected for serum albumin) within normal limits (WNL) or
    = grade 1 severity according to NCI-CTCAE version 5.0 if judged
    clinically not significant by the Investigator. Patients concomitantly
    taking bisphosphonates or denosumab for calcium correction are
    eligible.
    AST and ALT=1.5 xULNor<3.0xULN if liver metastases
    are present.
    Total serum bilirubin = ULN or = 1.5 x ULN if liver metastases are
    present; or total bilirubin = 3.0 x ULN with direct bilirubin below or
    within normal range in patients with well documented Gilbert's
    Syndrome. Gilbert's syndrome is defined as presence of episodes of
    unconjugated hyperbilirubinemia with normal results from cells blood
    count (including normal reticulocyte count and blood smear), normal
    liver function test results, and absence of other contributing disease
    processes at the time of diagnosis.
    Serum creatinine = 1.5 x ULN or calculated or directly measured
    creatinine clearance (CrCL) > 30 mL/min.
    I. Haemoglobin A1c (glycosylated hemoglobin; HbA1c) =8%.
    Patient has Eastern Cooperative Oncology Group (ECOG) performance
    status =1.
    Patient is able to swallow and retain oral medication. Patients able to
    swallow oral medication but mostly self-nourished through gastric or
    jejunal feeding tube are eligible.
    Patients must apply highly effective contraception during and
    throughout the study, as well after the final dose of study treatment, as
    detailed below:
    Men should use an effective method of contraception and not father a
    child during the study and for the six-month period after treatment. Men
    are recommended to seek advice on conservation of sperm prior to
    treatment with paclitaxel as per product label.
    Women of child-bearing potential, defined as all women
    physiologically capable of becoming pregnant, must use a highly
    effective contraceptive during the study and for at least four weeks after
    the final dose of study treatment or as specified in the local prescription
    guidelines for paclitaxel
    Highly effective contraception is defined as either: o Total abstinence: When this is in line with the preferred and usual
    lifestyle of the patient.
    Female sterilization: surgical bilateral oophorectomy (with/o hysterectomy) or tubal ligation
    Male partner sterilization. Vasectomized should be the sole partner.
    Using a combination of the following
    Placement of an IUD or IUS, and barrier methods of contraception
    Età=18anni.
    In grado fornire ICF ottenuto prima di attività correlata studio
    PT ha HNSCC confermato istologicamente e/o citologicamente.
    ha tessuto tumorale archivio o nuovo per analisi biomarcatori. blocco tumorale o min12 vetrini non colorati fornire.Arruolamento studio condizionato conferma quantità adeguata.PT subiscono progressione dopo trattamento terapia antiPD1/antiPDL1 incoraggiati nuova biopsia.
    PT ha malattia progressione o recidivante dopo trattamento a base PDL1/PD1 permalattia recidivante o metastatica:
    Terapia PDL1/PD1 da sola per malattia metastatica;
    PDL1/PD1 combinazione chemioterapia malattia;
    PDL1/PD1 utilizzato per malattia metastatica, dopo o prima ricezione agente platino.
    PT non ricevuto più 2linee precedenti trattamento sistemico per HNSCC (la chemioterapia ad agente singolo utilizzata come radiosensibilizzante non è considerata come una linea di terapia precedente).
    Il paziente ha una malattia misurabile come determinato in base alla versione RECIST 1.1. Se l’unico sito di malattia misurabile è una lesione precedentemente irradiata, la progressione documentata della malattia e un periodo di quattro settimane dal completamento della radioterapia sono necessari.
    Il paziente ha funzione del midollo osseo e una funzione organica adeguate come mostrato di seguito:
    Conta assoluta dei neutrofili (ANC) = 1,5 x 109/L.
    Emoglobina = 9 g/dL (valore che può essere raggiunto mediante trasfusione).
    Piastrine = 100 x 109/L (valore che può essere raggiunto mediante trasfusione).
    Rapporto internazionale normalizzato (INR) = 1,5.
    Ca (corretto per l’albumina sierica) entro limiti normali (WNL) o gravità di grado=1 secondo NCI-CTCAE v5.0 se giudicata clinicamente non significativa dallo sperimentatore. I pazienti che assumono contemporaneamente bifosfonati o denosumab per la correzione del calcio sono idonei.
    Alanina aminotransferasi (AST) e aspartato aminotransferasi (ALT) = 1,5 x limite superiore della norma (ULN) o < 3,0 x ULN se sono presenti metastasi epatiche.
    Bilirubina sierica totale = ULN o = 1,5 x ULN se sono presenti metastasi epatiche; o bilirubina totale = 3,0 x ULN con bilirubina diretta sotto o entro l’intervallo normale in pazienti con sindrome di Gilbert ben documentata. La sindrome di Gilbert è definita come presenza di episodi di iperbilirubinemia non coniugata con risultati normali da conte di cellule ematiche (incluse la conta reticolocitaria normale e lo striscio a sbavatura di sangue), i risultati del test della funzionalità epatica normale e l’assenza di altri processi di malattia che contribuiscono al momento della diagnosi.
    Creatinina sierica=1,5xULN o CrCL>30 mL/min.
    Emoglobina glicosilata;HbA1c=8%.
    PT con stato di performance ECOG=1.
    PT è in grado ingerire/trattenere farmaco orale. PT in grado ingerire farmaci orali ma autoalimentati alimentazione gastrica o digiunale.
    I pazienti devono applicare una contraccezione altamente efficace durante tutto lo studio clinico, anche dopo la dose finale del trattamento dello studio clinico, come descritto di seguito:
    Gli uomini devono utilizzare un metodo contraccettivo efficace e non generare figli durante lo studio clinico e per un periodo di sei mesi dopo il trattamento. Si raccomanda agli uomini di chiedere consiglio sulla conservazione dello sperma prima del trattamento con paclitaxel come da etichetta del prodotto.
    Donne età fertile devono utilizzare contraccettivo altamente efficace durante studio e 4 settimane dopo dose finale o prescrizione locale paclitaxel.
    Una contraccezione altamente efficace è definita come:
    Astinenza totale.Sterilizzazione femminile: ovariectomia bilaterale chirurgica (con/senza isterectomia) legatura delle tube
    Sterilizzazione partner maschio, Vasectomia,deve essere l’unico partner della paziente.
    Utilizzando una combinazione:Posizionamento IUD o IUS, Metodi di contraccezione a barriera con schiuma/gel/film/crema/supposta vaginale spermicidi.Met contraccettivi ormonali non sono ammessi,buparlisib riduce efficacia pratica
    E.4Principal exclusion criteria
    Pt has received previous treatment with any PKB/AKT, mammalian target of rapamycin (mTOR) inhibitors, or PI3K pathway inhibitors.Pt received treatment with taxane as part prior treatment for
    metastatic disease.
    Pt has symptomatic CNS metastases.Pts with asymptomatic CNS metastases may participate in study. Pt must have
    completed any prior local treat for CNS metastases=28 d prior to start study treatment (including radiotherapy) and must be on a stable low dose corticosteroid therapy. Radiosurgery must have been completed at least 14 d prior to start study treatment.
    Pt has received wide field radiotherapy=4w or limited field
    radiation for palliation=2 w prior to starting study treatment or
    who have AE which have not recovered to grade1 or better
    from previous chemotherapy treat.
    Pt has grade=2 neuropathy, colitis, pneumonitis, elevated
    HbA1C, and uncontrolled endocrinopathies from previous treatment.
    Pt has had major surgery within 14 d prior to starting treatment or has not recovered from major side effects.
    Pt is currently receiving increasing or chronic treatment (>5d) with corticosteroids or immunosuppressive agent. following uses of corticosteroids are permitted: single doses; standard premedication for paclitaxel, topical applications, inhaled
    sprays, eye drops,local injections,or<10mg prednisolone or equivalent.
    Pt is being treated start of study treatment with any of the following drugs:
    Drugs known to be strong/moderate inhibitors or inducers of
    isoenzyme cytochrome P4503A4(CYP3A4) including herbal
    medications.Drugs with known risk inducing Torsades de Pointes.
    Pt is currently receiving warfarin or coumarin-derived anticoagulant,prophylaxis, or otherwise. Therapy with heparin,LMWH,fondaparinux or NOACs is allowed.
    Pt has a known hypersensitivity and/or contraindication to
    paclitaxel, standard premedication for paclitaxel, or other products
    containing Cremophor®.Pt has other concurrent severe and/or uncontrolled medical
    conditions that would, in the Dr's judgment, contraindicatept participation
    Pt has a known history of HIV infection.
    Pt has any following cardiac abnormalities: Symptomatic congestive heart failure within 12 months
    screening period ,History of documented congestive heart failure or
    documented cardiomyopathy and LVEF<50% as determined by multiple gated acquisition (MUGA) scan orECHO, Myocardial infarction=6m prior to enrollment, Unstable
    angina pectoris, Serious uncontrolled cardiac arrhythmia, Symptomatic
    pericarditis, QT interval corrected according to the formula of Fridericia
    (QTcF)>450 msec for males and 470 msec for females, on the
    screening ECG, Currently receiving treatment with medication that has a
    known risk to prolong the QT interval or inducing Torsades de Pointes,
    and the treatment cannot be discontinued or switched to a different
    medication prior to starting study treatment.
    Pt has impairment of GI function or GI disease that may
    significantly alter the absorption of study treatment.
    Patient has a medically documented history of or active major
    depressive episode, bipolar disorder (I or II), obsessive-compulsive
    disorder, schizophrenia, a history of suicidal attempt or ideation, or
    homicidal ideation or active severe personality disorders are not eligible.
    Pt has other prior or concurrent malignancy except for the
    following: adequately treated basal cell or squamous cell skin cancer, or
    other adequately treated in situ cancer, early gastric or GI cancer
    resected completely by endoscopy procedures or any other cancer from
    which the patient has been disease free for=3y.
    Pt has a history of non-compliance to any medical regimen or
    inability to grant consent.
    Pt is concurrently using or has used another approved or
    investigational cancer agent within 4 weeks of the screening period.
    Patient is pregnant or nursing (lactating). Patients with elevated
    hCG baseline that is judged to be
    related to the tumor are eligible if hCG levels do not show the expected
    doubling when repeated five to seven
    Pt ha ricevuto un tratt precedente qualsiasi PKB/AKT, bersaglio rapamicina in mammiferi (mTOR) o inibitori via PI3K.
    Pt ha ricevuto tratt con taxano come parte tratt precedente per malattia
    Pt ha metastasi sintomatiche SNC. Pt affetti da metastasi SNC possono partecipare studio Pt deve aver completato tratt locale precedente metastasi del SNC=28 gg prima inizio tratt studio (inclusa la radioterapia) e deve essere sottoposto bassa dose stabile terapia con corticosteroidi. radiochirurgia deve essere completata almeno 14g prima inizio tratt. studio.
    Pt ha ricevuto una radioterapia campo ampio=4w o radiazione campo limitata per cure palliative=2w prima tratt studio o che hanno EA che non hanno recuperato grado 1 o migliore tratt precedente chemioterapia Pt ha neuropatia di grado=2, colite, polmonite, HbA1C elevato ed endocrinopatie non controllate dal tratt precedente.
    Pt ha subito intervento chirurgico>14g precedenti inizio tratt studio o non è guarito importanti effetti collaterali.
    Pt sta attualmente ricevendo un tratt crescente o cronico (>5g) con corticosteroidi o un altro agente immunosoppressivo. Sono consentiti i seguenti usi corticosteroidi: singole dosi; premedicazione standard per paclitaxel, applicazioni topiche, spray inalati, gocce oculari,iniezioni locali,prednisolone o equivalente<10mg.
    Pt viene trattato inizio del tratt studio con qualsiasi dei seguenti farmaci:
    Farmaci noti come inibitori forti o moderati o induttori di isoenzima citocromo P4503A4, inclusi i farmaci di erbe.
    Farmaci con rischio noto di indurre torsioni di punta.
    Pt deve aver interrotto forti induttori per almeno una settimana e deve aver interrotto inibitori forti prima dell’inizio del tratt. È consentito passare a un farmaco diverso prima di iniziare il tratt studio.
    Pt sta attualmente ricevendo warfarin o altro anticoagulante derivato da cumarina, per il tratt, la profilassi o altro. È consentita la terapia con eparina, eparina LMWH, fondaparinux o NOAC.Pt presenta un’ipersensibilità nota e/o una controindicazione al paclitaxel, alla premedicazione standard per paclitaxel o ad altri prodotti Cremophor.Pt presenta altre condizioni mediche contemporanee severe e/o non controllate che, a giudizio Dr, controindicano la partecipazione pt studio.Pt ha un’anamnesi nota infezione daHIV.Pt presenta:Insufficienza cardiaca congestizia sintomatica entro 12m dal periodo di screening.Anamnesi di insufficienza cardiaca congestizia documentata (class funzionale III-IV della NYHA),cardiomiopatia documentata e LVEF<50% come determinato esame MUGA o ECHO.Infarto miocardico=6m prima arruolamento.Angina pectoris instabile.Aritmia cardiaca grave non controllata.Pericardite sintomatica.Intervallo QT corretto secondo la formula di Fridericia (QTcF)>450ms per i maschi e>470ms per le femmine, ECG.Attualmente riceve tratt con farmaci che hanno rischio noto prolungare intervallo QT o indurre torsioni di punta, e tratt non può essere interrotto o commutato altro farmaco prima iniziare tratt studio.Pt ha compromissione della funzione GI o una malattia GI che potrebbe alterare significativamente assorbimento tratt studio.Pt con anamnesi clinicamente documentata o ep depressivo maggiore attivo, disturbo bipolare (I/II), disturbo ossessivo-compulsivo, schizofrenia, anamnesi tentativo/ideazione suicida/omicida o severi disturbi attivi personalità non sono idonei.Pt presenta tumori maligni precedenti/concomitanti, eccetto i seguenti: carcinoma della pelle a cellule squamose o basali con tratt adeguato, o altro cancro in situ adeguatamente trattato, cancro gastrico o GI stadio in resecato completamente con procedure endoscopiche/qualsiasi altro cancro per cui Pt è in remissione=3y.Pt ha anamnesi nonconformità a qualsiasi regime medico o incapacità fornire ICF.Pt sta utilizzando contemporaneamente o ha utilizzato altro agente approvato o sperimentale per cura entro 4w periodo screening.Donne gravid/allattamento. Pt con elevata hCG basale giudicata correlata al tumore sono idonei
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint of this study is OS for the entire (Intent-to-Treat
    [ITT]) population of patients. The interim endpoint of the study is ORR
    on a subset of patients with at least six months follow up at the time the
    last patient is enrolled
    Endpoint primario: l’endpoint primario di questo studio clinico è OS per l’intera popolazione di pazienti (Intent-to-treat [ITT]). L’endpoint ad interim dello studio clinico è ORR su un sottogruppo di pazienti con almeno sei mesi di follow-up al momento dell’arruolamento dell’ultimo paziente.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary statistical analysis of the study will be based on OS data
    from all patients once 383 events (deaths) have occurred. This analysis
    is expected to occur when all patients have either discontinued from the
    study or been followed for a minimum of 12 months
    L'analisi statistica primaria dello studio si baserà sui dati di OS
    da tutti i pazienti una volta che si sono verificati 383 eventi (decessi). Questa analisi
    si prevede che si verifichi quando tutti i pazienti hanno interrotto il trattamento con
    studiare o essere stato seguito per un minimo di 12 mesi
    E.5.2Secondary end point(s)
    The secondary endpoints of this study are as follows:
    Efficacy:
    • PFS
    • Overall response rate (ORR)
    • Duration of response (DoR)
    • Change from baseline in the global health status/Quality of life (QOL)
    and pain scale scores of the EORTC QLQ-C30, respectively.
    • Time to definitive 10% deterioration in the global health status/QOL
    and pain scale scores of the EORTC QLQ-C30, respectively.
    • EQ-5D-5L
    • Biomarkers; Safety:
    • AEs
    • Clinical laboratory tests
    • PHQ-9
    • GAD-7
    Efficacia:
    • PFS.
    • Tasso di risposta globale (ORR).
    • Durata della risposta (DoR).
    • Variazione rispetto al basale nei punteggi di stato di salute globale/qualità della vita (QOL) e della scala del dolore EORTC QLQ-C30, rispettivamente.
    • Tempo di deterioramento definitivo del 10% nei punteggi di stato di salute globale/QOL e scala del dolore del EORTC QLQ-C30, rispettivamente.
    • EQ-5D-5L.
    • Biomarcatori.; Sicurezza:
    • AE;
    • Test clinici di laboratorio;
    • PHQ-9;
    • GAD-7.
    E.5.2.1Timepoint(s) of evaluation of this end point
    All secondary analyses will be reported by treatment arm and analyses
    will be based on the ITT Population. PFS and DoR will be analyzed using
    the same methods as for the primary endpoint of OS. ORR will be
    analyzed using a Cochran-Mantel-Haenszel chi-square test with
    randomization factors as the strata.
    Safety summaries and analyses will be performed on the Safety
    population. Descriptive statistics will be presented to summarize the
    safety data.; All secondary analyses will be reported by treatment arm and analyses
    will be based on the ITT Population. PFS and DoR will be analyzed using
    the same methods as for the primary endpoint of OS. ORR will be
    analyzed using a Cochran-Mantel-Haenszel chi-square test with
    randomization factors as the strata.
    Safety summaries and analyses will be perfor
    Tutte le analisi secondarie verranno riportate per braccio di trattamento e analisi
    sarà basato sulla popolazione ITT. PFS e DoR verranno analizzati utilizzando
    gli stessi metodi dell'endpoint primario del sistema operativo. ORR sarà
    analizzato utilizzando un test chi quadrato di Cochran-Mantel-Haenszel con
    fattori di randomizzazione come gli strati.
    Verranno eseguite sintesi e analisi sulla sicurezza
    popolazione. Saranno presentate statistiche descrittive per riassumere il
    dati di sicurezza.; Tutte le analisi secondarie verranno riportate per braccio di trattamento e analisi
    sarà basato sulla popolazione ITT. PFS e DoR verranno analizzati utilizzando
    gli stessi metodi dell'endpoint primario del sistema operativo. ORR sarà
    analizzato utilizzando un test chi quadrato di Cochran-Mantel-Haens
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety No
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned16
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA75
    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
    Australia
    Canada
    Japan
    Korea, Republic of
    Russian Federation
    Taiwan
    United States
    Belgium
    France
    Germany
    Hungary
    Italy
    Poland
    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
    Last visit of last subject
    ultima visita ultimo paziente
    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: 276
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 206
    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 state40
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 249
    F.4.2.2In the whole clinical trial 489
    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)
    Patients will revert to their normal standard of care
    I pazienti torneranno alla loro cura standard
    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 Decision2021-09-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-09-28
    P. End of Trial
    P.End of Trial StatusOngoing
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