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    Summary
    EudraCT Number:2013-000075-33
    Sponsor's Protocol Code Number:SINTART1
    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:2013-03-12
    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 number2013-000075-33
    A.3Full title of the trial
    Multidisciplinary approach for poor prognosis sinonasal tumors: Phase II study of chemotherapy, surgery, photon and heavy ion radiotherapy integration for more effective and less toxic treatment in operable patients.
    Approccio multidisciplinare per la cura dei tumori dei seni paranasali operabili a prognosi sfavorevole: studio di fase II di trattamento integrato chemioterapico, chirurgico e radioterapico (con protoni e/o ioni pesanti) allo scopo di identificare un approccio terapeutico più efficace e con minor tossicità.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Multidisciplinary approach for sinonasal tumors: chemotherapy, surgery, photon and heavy ion radiotherapy integration for more effective and less toxic treatment in operable patients.
    Approccio multidisciplinare per i tumori dei seni paranasali operabili: trattamento integrato chemioterapico, chirurgico e radioterapico (con protoni e/o ioni pesanti) per una terapia più efficace e con minor tossicità.
    A.4.1Sponsor's protocol code numberSINTART1
    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 SponsorFondazione IRCCS Istituto Nazionale Tumori
    B.1.3.4CountryItaly
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportRegione Lombardia
    B.4.2CountryItaly
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationFondazione IRCCS Istituto Nazionale Tumori
    B.5.2Functional name of contact pointPaolo Bossi
    B.5.3 Address:
    B.5.3.1Street AddressVia Giacomo Venezian, 1
    B.5.3.2Town/ cityMilano
    B.5.3.3Post code20133
    B.5.3.4CountryItaly
    B.5.4Telephone number+390223902150
    B.5.5Fax number+390223903769
    B.5.6E-mailPaolo.Bossi@istitutotumori.mi.it
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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.3.4Pharmaceutical 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 INNDOCETAXEL TRIHYDRATE
    D.3.9.1CAS number 148408-66-6
    D.3.9.4EV Substance CodeSUB21602
    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 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.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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.3.4Pharmaceutical 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 INNCISPLATIN
    D.3.9.1CAS number 15663-27-1
    D.3.9.4EV Substance CodeSUB07483MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    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 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.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 Yes
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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.3.4Pharmaceutical form Solution for injection
    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 INN5-FLOUROURACIL
    D.3.9.1CAS number 51-21-8
    D.3.9.3Other descriptive name5-FU
    D.3.9.4EV Substance CodeSUB27520
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    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 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.IMP: 4
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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.3.4Pharmaceutical 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 INNETOPOSIDE
    D.3.9.1CAS number 33419-42-0
    D.3.9.4EV Substance CodeSUB07337MIG
    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 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.IMP: 5
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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.3.4Pharmaceutical form Powder for solution for injection
    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 INNDOXORUBICIN HYDROCHLORIDE
    D.3.9.1CAS number 25316-40-9
    D.3.9.4EV Substance CodeSUB01827MIG
    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 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.IMP: 6
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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.3.4Pharmaceutical form Powder 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 INNIFOSFAMIDE
    D.3.9.1CAS number 3778-73-2
    D.3.9.4EV Substance CodeSUB08125MIG
    D.3.10 Strength
    D.3.10.1Concentration unit g gram(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 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.IMP: 7
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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.3.4Pharmaceutical form Powder 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 INNCALCIUM LEVOFOLINATE PENTAHYDRATE
    D.3.9.1CAS number 80433-71-2
    D.3.9.4EV Substance CodeSUB11775MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number127.08
    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
    Poor prognosis sinonasal tumors in operable patients.
    Tumori dei seni paranasali operabili a prognosi sfavorevole.
    E.1.1.1Medical condition in easily understood language
    Malignant tumors of the nasal cavity in operable patients.
    Tumori della cavità nasale operabili a prognosi sfavorevole.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 15.1
    E.1.2Level PT
    E.1.2Classification code 10060768
    E.1.2Term Nasal neoplasm
    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
    To assess the efficacy of the multimodality treatment in terms of progression-free survival (PFS) at 5 years, in patients with poor prognosis operable sinonasal tumors.
    Definire l’efficacia del trattamento multimodale in termini di sopravvivenza libera da progressione (PFS) a 5 anni, in pazienti con tumore dei seni paranasali operabili a prognosi sfavorevole.
    E.2.2Secondary objectives of the trial
    •To assess additional efficacy measure of the multimodality treatment in term of Overall Survival (OS).
    •To evaluate visual functionality preservation after multimodality treatment in term of ocular preservation (organ preservation) in case surgical approach at diagnosis should consist of exenteratio orbitae and visual preservation (function preservation).
    •To evaluate hearing function preservation.
    •To evaluate the safety of the multimodality treatment.
    •To assess the efficacy of the induction chemotherapy in term of Overall Response Rate (ORR) by RECIST criteria version 1.1.
    •To correlate radiological response after induction chemotherapy (by RECIST criteria version 1.1) and pathological response in patients undergoing surgery.
    •To evaluate late toxicities related to radiotherapy (both photon radiotherapy [RT] and heavy ion RT).

    Exploratory Objective:
    To explore the prognostic/predictive value of biological markers.
    •Definire ulteriori misure di efficacia del trattamento multimodale come sopravvivenza completa.
    •Valutare la conservazione della funzionalità visiva dopo il trattamento multimodale come funzionalità visiva e conservazione del bulbo oculare quando l’approccio chirurgico alla diagnosi consista nell’exenteratio orbitae.
    •Valutare la conservazione della funzionalità uditiva.
    •Definire il profilo di tollerabilità del trattamento multimodale.
    •Definire l’efficacia della chemioterapia di induzione come risposte parziali e risposte complete (ORR) secondo i criteri RECIST (versione 1.1).
    •Mettere in correlazione le risposte radiologiche dopo la chemioterapia di induzione (secondo i criteri RECIST versione 1.1) e le risposte patologiche nei pazienti sottoposti a chirurgia.
    •Valutare le tossicità tardive correlate alla radioterapia (sia per radioterapia con protoni che con ioni pesanti).

    Obiettivi esplorativi:
    Esplorare i valori prognostici e predittivi dei biomarcatori tumorali.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Signed and dated IEC-approved Informed Consent.
    2.Diagnosis of sinonasal tumor with the following histotypes: Squamous Cell Carcinoma (SCC); Sinonasal Undifferentiated Carcinoma (SNUC); Small Cell Carcinoma Neuroendocrine Type (SmCCNET); Pure Sinonasal Neuroendocrine Carcinoma (SNEC); Intestinal Type Adenocarcinoma (ITAC) with a functional p53 gene; Esthesioneuroblastoma with differentiation grade III-IV by Hyams. The inclusion of the maxillary sinus carcinomas is reserved only in cases requiring exenteratio orbitae for a radical surgery.
    3.AJCC stage II-III-IVa with the exception of Esthesioneuroblastoma and Intestinal Type Ethmoid Adenocarcinoma where stage III-IV only will be included.
    4.Resectable disease.
    5.ECOG performance status 0-2.
    6.Adequate bone marrow, renal and hepatic functionality, defined as haemoglobin >10 g/dL, neutrophils >1500/mmc, platelets > 100.000/mmc, creatinine value ≤ 1.5 x ULN or calculated creatinine clearance (by Cockcroft and Gault’s formula) > 60 mL/min, transaminases values < 1.5 times over the upper normal limit (ULN).
    7.Polychemiotherapy treatment clinical feasibility as per Investigator’s Judgment.
    8.Male or female patients ≥ 18 years of age.
    9.Negative pregnancy test (if female in reproductive years).
    10.Agreement upon the use of effective contraceptive methods (hormonal or barrier method of birth control, or abstinence) prior to study entry and for the duration of study participation, if men and women of child producing potential.
    1.Modulo di consenso informato approvato dal Comitato Etico firmato e datato.
    2.Diagnosi dei tumori dei seni paranasali con i seguenti tipi istologici: Carcinoma squamocellulare (SCC); Carcinoma indifferenziato dei seni paranasali (SNUC); Carcinoma Neuroendocrino a piccole cellule (SmCCNET); Carcinoma neuroendocrino (SNEC); Adenocarcinoma di tipo intestinale dell’etmoide (ITAC) con p53 funzionale; Estesioneuroblastoma o neuroblastoma olfattivo con grado III-IV differenziato by Hyams. L’inclusione dei carcinomi dei seni mascellari è riservato solo nei casi che richiedono exenteratio orbitae per una chirurgia radicale.
    3.Una classificazione di grado II-III-IV secondo l’AJCC ad eccezione del neuroblastoma olfattivo e dell’adenocarcinoma di tipo intestinale dell’etmoide dove sono compresi solo gli stadi III-IV.
    4.Tumore operabile.
    5.Performance status 0-2, secondo la scala ECOG.
    6.Adeguata funzionalità midollare, renale ed epatica definita come emoglobina > 10 g/dL, conta assoluta dei neutrofili (ANC) > 1,500 cellule/mm3, piastrine > 100,000 cellule/mm3, valori di creatinina serica ≤ 1.5 ULN (Limite Superiore di Normalità) o creatinina clearance calcolata (tramite la formula Cockcroft and Gault) > 60 mL/min, valori delle transaminasi epatiche < 1.5 volte sopra il limite superiore di normalità (ULN).
    7.Possibilità di un trattamento clinico chemioterapico a giudizio dell’Investigatore.
    8.Pazienti maschi e femmine adulti (età ≥ 18 anni).
    9.Test di gravidanza negativo (se donne in età riproduttiva).
    10.Accettazione dell’utilizzo di efficaci metodi contraccettivi prima dell’entrata nello studio e per la durata della partecipazione allo studio, per donne potenzialmente fertili e uomini con potenziale riproduttivo.
    E.4Principal exclusion criteria
    1.Previous radiotherapy or chemotherapy for head and neck district tumors (surgical treatment relapses are admitted).
    2.Metastatic disease.
    3.Cardiac, pulmonary, infective, neurological disease or any other medical condition that could interfere with treatment.
    4.Unable and unwilling to comply with scheduled visits, therapy plans, and laboratory tests required in this protocol.
    5.Previous diagnosis of other malignant neoplasm in the last 3 years (in situ cervical cancer or completely excised basocellular/squamocellular skin cancer are always admitted).
    6.Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient inappropriate for entry into this study or could compromise protocol objectives in the opinion of the Investigator and/or the Sponsor.
    1.Precedente radioterapia o chemioterapia per i tumori del distretto testa-collo (sono ammessi trattamenti chirurgici per recidiva).
    2.Tumore metastatico.
    3.Malattie cardiache, polmonari, infettive o neurologiche o qualsiasi altra condizione medica che potrebbe interferire con il trattamento.
    4.Incapacità e non disponibilità a partecipare alle visite programmate richieste dal protocollo, di aderire allo schema di trattamento, di effettuare i tests di laboratorio e di seguire le indicazioni o procedure richieste dal protocollo di studio.
    5.Diagnosi precedenti di altre neoplasie maligne negli ultimi 3 anni (sono sempre ammessi tumori cervicali in situ o tumori della pelle squamocellulari e basocellulari completamente asportati).
    6.Altre condizioni mediche severe acute o croniche o condizioni psichiatriche o anormalità di laboratorio che possono aumentare il rischio associato alla partecipazione allo studio, alla somministrazione del farmaco, che possano interferire con l’interpretazione dei risultati e, che a giudizio dello Sperimentatore, possano rendere il paziente inappropriato per l’entrata nello studio compromettendo il raggiungimento degli obiettivi del protocollo.
    E.5 End points
    E.5.1Primary end point(s)
    Progression Free Survival (PFS) at 5 years, defined as the time from enrollment to progression of disease or death for any cause.
    Sopravvivenza libera da progressione (PFS) a 5 anni, calcolata come il tempo trascorso dall’arruolamento fino al tempo di progressione o di decesso.
    E.5.1.1Timepoint(s) of evaluation of this end point
    At five years, at progression or patient's death.
    A cinque anni, alla progressione o decesso del paziente
    E.5.2Secondary end point(s)
    1.Overall Survival (OS) defined as the time from enrollment (ITT population) or treatment start (PP population) to the date of death for any cause.
    2.Organ preservation and function preservation by visual field tests.
    3.Hearing preservation performed by audiogram test.
    4.Overall safety profile of the whole treatment characterized by type, severity (graded using the National Cancer Institute Common Terminology Criteria for Adverse Events NCI CTCAE Version 4.03), timing and relationship to study therapy of adverse events and laboratory abnormalities collected.
    5.Objective Response Rate (CR and PR by RECIST criteria version 1.1).
    6.Radiological response as per RECIST criteria (version 1.1) after last cycle of induction CT; pathological response defined as obtaining or not a pathologic complete response (i.e., absence of any residual viable tumor cell).
    7.Adverse events (characterized by type, severity, timing) and laboratories abnormalities (graded using the National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] Version 4.03), induced by radiotherapy (both photon RT and heavy ion RT).

    Exploratory Endpoint.
    Analysis of predictive/prognostic biomarkers.
    1.Sopravvivenza (OS) definita come il tempo trascorso dall’arruolamento (popolazione ITT) o dall’inizio del trattamento (popolazione PP) fino al decesso.
    2.Conservazione del bulbo oculare e della funzionalità visiva, valutata tramite l’eseme del campo visivo.
    3.Conservazione della funzionalità uditiva valutata tramite il test audiometrico.
    4.Profilo di tollerabilità generale di tutto il trattamento, valutato sulla base del tipo, classificazione della severità (saranno usati i National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), versione 4.3), tempo e relazione tra la terapia di trattamento e le anomalie raccolte tramite gli eventi avversi e i laboratori.
    5.Frequenza di risposte obiettive confermate (CR + PR) in base ai criteri RECIST versione 1.1.
    6.Risposta radiologica secondo i criteri RECIST (versione 1.1) dopo l’ultimo ciclo di chemioterapia; risposta patologica definita come il raggiungimento o meno di risposta completa (intesa come assenza di qualsiasi cellula tumorale residua).
    7.Eventi avversi (caratterizzati per tipo, severità e tempo) e anormalità di laboratorio (saranno usati i National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), versione 4.3) indotti dalla radioterapia (sia da radioterapia con protoni che con ioni pesanti).

    Endpoint esplorativi:
    Analisi dei valori prognostici e predittivi dei biomarcatori tumorali.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. At patient's death or at last follw up visit.
    2, 3. At pretreatment and during follow up until 8 years' follow up
    4, 5, 6, 7. All study period including follow up

    1. Al decesso del paziente o all'ultima visita di follow up.
    2, 3. Al pretrasttamento e durante il follow up di 8 anni
    4, 5, 6, 7. Lungo tutta la durata dello studio, follow up compreso

    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned7
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    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
    Date of last visit of last patient, including follow up
    Data dell'ultima visita dell'ultimo paziente, follow up incluso
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years10
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned 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: 20
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 20
    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.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)
    Standard Medical Care for that condition.
    Terapie per la patologia secondo la pratica clinica.
    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 Decision2013-05-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-03-26
    P. End of Trial
    P.End of Trial StatusOngoing
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