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    Summary
    EudraCT Number:2015-001048-12
    Sponsor's Protocol Code Number:GEIS40
    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:2020-11-25
    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 number2015-001048-12
    A.3Full title of the trial
    Phase II, single arm, non-randomized and multicenter clinical trial of regorafenib as a single agent in the first-line setting for patients with metastatic and/or unresectable KIT/PDGFR Wild Type GIST
    Studio di fase II, multicentrico, non randomizzato, a braccio singolo sull’utilizzo di regorafenib in monoterapia in prima linea, per il trattamento di pazienti con GIST KIT/PDGFR Wild Type metastatico o non candidabili a chirurgia
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Clinical trial of regorafenib as the treatment for patients with KIT/PDGFR wild type GIST that have not received any treatment for the metastatic disease
    Studio di fase II con regorafenib per il trattamento di GIST wild type metastatico o nel quale vi è controindicazione alla chirugia
    A.3.2Name or abbreviated title of the trial where available
    REGISTRI
    REGISTRI
    A.4.1Sponsor's protocol code numberGEIS40
    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 SponsorGRUPO ESPAñOL DE INVESTIGACIóN EN SARCOMAS
    B.1.3.4CountrySpain
    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 supportBayer
    B.4.2CountrySpain
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationItalian Sarcoma Group
    B.5.2Functional name of contact pointClinical Trial Unit
    B.5.3 Address:
    B.5.3.1Street AddressVia di Barbiano 1/10
    B.5.3.2Town/ cityBologna
    B.5.3.3Post code40136
    B.5.3.4CountryItaly
    B.5.4Telephone number0516366470
    B.5.5Fax number0516366627
    B.5.6E-mailemanuela.marchesi@ior.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.2.1.1.1Trade name Stivarga
    D.2.1.1.2Name of the Marketing Authorisation holderBayer Pharma AG
    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.3.1Product nameregorafenib
    D.3.2Product code [regorafenib]
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNREGORAFENIB
    D.3.9.2Current sponsor codeREGORAFENIB
    D.3.9.3Other descriptive nameREGORAFENIB
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    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
    KIT/PDGFR wild type GastroIntestinal Stromal Tumor (GIST)
    Tumore Stromale Gastrointestinale (GIST) wild type
    E.1.1.1Medical condition in easily understood language
    Gastrointestinal Stromal tumor with no mutations on KIT/PDGFR (wild type)
    GIST privo di mutazioni al gene KIT/PDGFR
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level HLGT
    E.1.2Classification code 10017991
    E.1.2Term Gastrointestinal neoplasms malignant and unspecified
    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
    Disease Control Rate (DCR)
    Tasso di controllo della malattia
    E.2.2Secondary objectives of the trial
    Progression Free Survival (PFS)
    Overall Survival (OS)
    Responses determined by CHOI
    Correlation with Translational Research
    Safety (Adverse events CTCAE v4.03)
    Early metabolic response by PET scan
    Quality of Life: EQ-ED-5L and QLQ-C30
    Sopravvivenza libera da progressione
    Sopravvienza globale
    Risposta alla trattamento secondo criteri CHOI
    Correlazione con la ricerca traslazionale
    Sicurezza
    Risposta metabolica precoce alla PET
    Qualità della vita valutata con EQ-ED-5L e QLQ-C30
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives

    Other types of substudies
    Specify title, date and version of each substudy with relative objectives: Optional translational biological study for the evaluation of potential predictive response biomarker in the regorafenib GIST wilde type treatment

    Altre tipologie di sottostudi
    specificare il titolo, la data e la versione di ogni sottostudio con i relativi obiettivi: Sottostudio biologico opzionale di ricerca traslazionale per l'individuazione di eventuali marker predittivi di risposta al trattamento con regorafenib del GIST wild type
    E.3Principal inclusion criteria
    - Male or female subjects =18 years of age
    - Histologically confirmed GIST KIT/PDGFR wild-type, unresectable or metastatic GIST (confirmed by central laboratory). Paraffin-embedded tumor block must be provided by all subjects during screening period.
    - Screening of mutations done in exon 11, 9, 13 and 17 in KIT gene and in 12 and 18 exons of PDGFR gene
    - Subjects must have at least one measurable lesion according to RECIST v1.1 criteria. A lesion in a previously irradiated area is eligible to be considered as measurable disease as long as there is objective evidence of progression of the lesion prior to study enrolment.
    - Adequate bone marrow, liver, and renal function as assessed by the following laboratory requirements conducted within 7 days of starting study treatment:
    ­ Total Bilirubin = 1.5 x the upper normal limit (UNL). Documented Gilbert Syndrome is allowed if total bilirubin is mildly elevated (=6mg/dl).
    ­ Alanine Aminotransferase (ALT) and aspartate aminotransferase (AST) = 3.0 x UNL (=5xUNL for subjects with liver involvement of GIST)
    ­ Lipase =1.5 x UNL
    ­ Serum Creatinine = 1.5 x UNL
    ­ Glomerular filtration rate (GFR) = 30ml/mn/1.73 m2 according to the Modified Diet in Renal Disease (MDRD) abbreviated formula.
    ­ International Normalized Ratio (INR) =1.5xUNL and partial thromboplastin time (PTT) or activated partial thromboplastine time (aPTT) =1.5xUNL.
    Subjects who are being treated with an anti-coagulant, such as warfarin or heparin, will be allowed to participate provided that no prior evidence of an underlying abnormality in these parameters exists. Close monitoring of at least weekly evaluations will be performed until INR and PTT are stable based on a pre-dose measurement as defined by the local standards of care.
    ­ Platelet count =100000mm3, hemoglobin (Hb) = 9.0 g/dl, absolute neutrophil count (ANC) =1500/mm3. Blood transfusions to meet the inclusion criteria will not be allowed.
    ­ Alkaline phosphatase limit = 2.5 x UNL (= 5x UNL for subjects with disease involving the liver)
    - Women of childbearing potential and men must agree to use adequate contraception from the moment of signing the Informed Consent Form until at least 3 months after the last study drug administration. The investigator or a designated associate is requested to advise the subject on how to achieve an adequate birth control. Adequate contraception is defined in the study as any medically recommended method (or combination of methods) as per standard of care.
    - Women of childbearing potential must have a blood or urine 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
    - Consenso informato scritto
    - Pazienti = 18 anni, maschi e femmine
    -Diagnosi di GIST KIT/PDGFR wild-type, non operabile o metastatico
    -Precedente Analisi di mutazione negli esoni 11, 9, 13 e 17 del gene KIT e negli esoni 12 e 18 del gene PDGFR.
    -Malattia misurabile secondoRECIST.
    - ECOG 0-1
    -Adeguata funzionalità midollare, epatica e renale
    - Donne potenzialmente fertili e pazienti di sesso maschile devono acconsentire all’utilizzo di un adeguato metodo contraccettivo dal momento della firma del consenso informato fino almeno a 3 mesi dopo l’ultima assunzione di farmaco sperimentale.
    - Donne potenzialmente fertili debbono avere test di gravidanza negativo sul sangue o urine effettuato entro al massimo 7 giorni prima dell’inizio della terapia.
    E.4Principal exclusion criteria
    1. Prior systemic treatment for GIST. However, patients that have relapsed after receiving imatinib during adjuvant setting are eligible
    .
    2. Cancer other than GIST within 5 years prior to randomization EXCEPT for curatively treated cervical cancer in situ, non-melanoma skin cancer, and superficial bladder tumors (Ta (Non Invasive tumor), and Tis (Carcinoma In situ)).
    3. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before the start of study medication.
    4. Congestive Heart Failure New York Heart Association (NYHA) = class 2.
    5. Unstable angina (angina symptoms at rest, new-onset angina, ie, within the lasts 3 months prior to entering study) or myocardial infarction (MI) within the past 6 months before the start of study medication.
    6. Cardiac arrhythmias requiring anti-arrhytmic therapy (beta blockers or digoxin are permitted).
    7. Uncontrolled hypertension (Systolic blood pressure > 140 mmHg or diastolic pressure > 90mmHg despite optimal medical management).
    8. Subjects with pheochromocytoma.
    9. Arterial thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), or pulmonary embolism within 6 months from start of study treatment.
    10. Venous thrombotic events such as deep vein thrombosis within the 3 months before the start of study treatment.
    11. Ongoing infection > grade 2 National Cancer Institute- Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03
    12. Known history of human immunodeficiency virus (HIV) infection.
    13. Subjects with seizure disorder requiring medication
    14. Symptomatic metastasis in brain or meningeal tumors.
    15. History of organ allograft.
    16. Subjects with evidence or history of bleeding diathesis. Any hemorrhage or bleeding event = NCI-CTCAE version 4.03 grade 3 or higher within 4 weeks prior to start of study treatment.
    17. Non-healing wound, ulcer, or bone fracture.
    18. Renal failure requiring hemo- or peritoneal dialysis.
    19. Dehydration NCI-CTCAE version 4.03 grade = 1
    20. Substance abuse or medical, psychological, or social conditions that may interfere with the subject´s participation in the study or evaluation of the study results.
    21. Known hypersensitivity to the study drug, study drug class, or excipients in the formulation.
    22. Any illness or medical conditions that are unstable or could jeopardize the safety of the subject and his/her compliance in the study
    23. Interstitial lung disease with ongoing signs and symptoms at the time of screening.
    24. Subjects unable to swallow oral medication
    25. Persistent proteinuria of NCI-CTCAE version 4.03 grade 3 or higher (>3.5g/24hrs), measured by urine protein creatinine ratio on a random urine sample)
    26. Any malabsorption condition.
    27. Left Ventricular Ejection Fraction (LVEF) < 50% or below the LLN for the institution (whichever is higher).
    28. Pleural effusion or ascites that causes respiratory compromise (= NCI-CTCAE version 4.03 grade 2 dyspnea)
    - Precedente trattamento per la malattia in fase avanzata. Tuttavia i pazienti che sono ricaduti dopo avere rcevuto imatinib in regime adiuvante sono eleggibili.
    - Altro i tumore, ad eccezione del GIST, nei 5 anni precedenti al ingresso in studio
    - Procedure chirurgiche maggiori nei 28 giorni precedenti l’inizio del trattamento
    - Insufficienza cardiaca congestizia di classe NYHA = 2
    - Angina instabile, infarto del miocardio (IM) nei 6 mesi precedenti l’inizio del trattamento in studio.
    - Aritmia cardiaca che richiede una terapia antiaritmica
    - Ipertensione non controllata
    -Feocromocitoma.
    - Eventi trombotici o embolici arteriosi o embolia polmonare nei 6 mesi precedenti l’inizio dello studio.
    - Eventi di trombosi venosa, quali trombosi venosa profonda nei 3 mesi precedenti l’inizio dello studio.
    - Infezione in corso di grado > 2 NCI-CTCAE 4.03
    - Storia di infezione da HIV
    - Crisi convulsive che richiedono trattamento
    - Metastasi cerebrali sintomatiche o tumori ad interessamento meningeale.
    -Storia di trapianto allogenico.
    -Anamnesi o evidente diastesi emorragica.
    - Ferite non rimarginate, ulcere o fratture ossee.
    -Emodialisi o dialisi peritoneale
    -Disidratazione di grado = 1 CTCAE 4.03
    - Abuso di sostanze, o qualsiasi condizione medica, psicologica o sociale che possa interferire con lo studio
    - ipersensibilità al farmaco in studio
    - Qualsiasi malattia o condizione medica instabili che possa mettere a repentaglio la sicurezza del soggetto - Malattia polmonare interstiziale con segni e sintomi presenti al momento dello screening.
    - Persistente proteinuria di >=G3 secondo NCI-
    -Condizione di malassorbimento.
    -LVEF < 50%
    - Versamento pleurico o ascite che causa una compromissione respiratoria (Dispnea di grado = 2 CTCAE 4.03)
    E.5 End points
    E.5.1Primary end point(s)
    Disease Control Rate (DCR)
    Controllo della malattia in termine di numero di pazienti che non hanno progressione di malattia
    E.5.1.1Timepoint(s) of evaluation of this end point
    Imaging assessment will be performed every 8 cycles during study.
    al tempo di progressione della malattia
    E.5.2Secondary end point(s)
    Time that patients remains free of disease progression; Disease evalutaion by CHOI measured in terms of tumor size and density; Evaluation of metabolic response by PET; Safety evaluation
    Sopravvivenza libera da progressione; Valutazione di malattia secondo CHOI in termini di misura e densità delle lesioni tumorali; Valutazione della risposta metabolica mediante PET; Valutazione di sicurezza del trattamento
    E.5.2.1Timepoint(s) of evaluation of this end point
    Tumor imaging assessment will be performed every 8 weeks; Every 8 weeks from start of regorafenib treatment; After 1 month of treatment; Every 28 days, up to 30 days from last regorafenib administration
    Ogni 8 settimane; Ogni 8 settimane a partire dall'inizio della terapia; Dopo il primo mese di trattamento; Ogni 28 giorni e fino a 30 giorni dopo l'ultima assunzione di regorafenib
    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 Yes
    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.8.2.4Number 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 concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA18
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned 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: 15
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 18
    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 39
    F.4.2.2In the whole clinical trial 39
    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)
    Pts will be treated according to the disease guidelines
    Al termine della terapia in studio i pazienti verranno trattati secondo le linee guida specifiche per i GIST
    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 Decision2016-08-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-08-16
    P. End of Trial
    P.End of Trial StatusCompleted
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