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    Summary
    EudraCT Number:2015-003582-28
    Sponsor's Protocol Code Number:LOXO-TRK-15002
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-01-27
    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 number2015-003582-28
    A.3Full title of the trial
    A Phase 2 Basket Study of the Oral TRK Inhibitor larotrectinib in Subjects with NTRK Fusion-Positive Tumors

    P/0401/2019
    Studio basket di fase 2 sull’inibitore orale di TRK, larotrectinib, in soggetti con tumori positivi per fusioni NTRK
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 2 Basket Study of the Oral TRK Inhibitor larotrectinib in Subjects with NTRK Fusion-Positive Tumors
    Studio basket di fase 2 sull’inibitore orale di TRK, larotrectinib, in soggetti con tumori positivi per fusioni NTRK
    A.3.2Name or abbreviated title of the trial where available
    NAVIGATE
    NAVIGATE
    A.4.1Sponsor's protocol code numberLOXO-TRK-15002
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02576431
    A.5.4Other Identifiers
    Name:Bayer Compound Number / Study NumberNumber:BAY 2757556 / 20289
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/179/2017
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorBayer Consumer Care AG
    B.1.3.4CountrySwitzerland
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportBayer Consumer Care AG
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBayer AG
    B.5.2Functional name of contact pointBayer Clinical Trials Contact
    B.5.3 Address:
    B.5.3.1Street AddressNA
    B.5.3.2Town/ cityBerlin
    B.5.3.3Post code13342
    B.5.3.4CountryGermany
    B.5.6E-mailclinical-trials-contact@bayer.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 nameLarotrectinib
    D.3.2Product code [LOXO-101; BAY 2757556]
    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 INNLarotrectinib
    D.3.9.2Current sponsor codeLOXO-101; BAY 2757556
    D.3.9.4EV Substance CodeSUB179762
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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 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 nameLarotrectinib
    D.3.2Product code [Loxo-101; BAY 2757556]
    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 INNLarotrectinib
    D.3.9.2Current sponsor codeLOXO-101; BAY 2757556
    D.3.9.4EV Substance CodeSUB179762
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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 nameLarotrectinib
    D.3.2Product code [LOXO-101; BAY 2757556]
    D.3.4Pharmaceutical form Oral solution
    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 INNLarotrectinib
    D.3.9.2Current sponsor codeLOXO-101; BAY 2757556
    D.3.9.4EV Substance CodeSUB179762
    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 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: 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 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 nameLarotrectinib
    D.3.2Product code [LOXO-101; BAY 2757556]
    D.3.4Pharmaceutical form Oral solution
    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 INNLarotrectinib
    D.3.9.2Current sponsor codeLOXO-101; BAY 2757556
    D.3.9.4EV Substance CodeSUB179762
    D.3.10 Strength
    D.3.10.1Concentration unit % percent
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    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
    Solid Tumors
    Tumori solidi
    E.1.1.1Medical condition in easily understood language
    Cancer
    Cancro
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10065252
    E.1.2Term Solid tumor
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine the overall response rate (ORR) as determined by an independant radiology review committee and measured by the proportion of subjects with best overall confirmed response of complete response (CR) or partial response (PR) by the Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) or Response Assessment in Neuro-Oncology (RANO) criteria, as appropriate, following treatment with larotrectinib in subjects with an advanced cancer harboring a fusion involving NTRK1, NTRK2, or NTRK3 (collective referred to as NTRK fusions).
    Determinare il tasso di risposta globale (ORR) definito da un comitato di revisione radiologica indipendente e misurato sulla base della percentuale di soggetti con migliore risposta globale confermata di risposta completa (CR) o risposta parziale (PR) secondo i Criteri di valutazione della risposta nei tumori solidi, versione 1.1 (RECIST v1.1) oppure i Criteri di valutazione della risposta in neuro-oncologia (RANO), a seconda del caso, dopo trattamento con larotrectinib in soggetti affetti da carcinoma in stadio avanzato portatore di fusioni a carico del gene umano codificante per il recettore della tirosin-chinasi neurotrofica (NTRK)1, NTRK2 o NTRK3 (nell’insieme indicate come fusioni NTRK).
    E.2.2Secondary objectives of the trial
    • To determine the ORR using RECIST1.1 or RANO criteria
    • To evaluate the DOR in subjects with best overall response of CR or PR
    • To estimate the proportion of subjects that has any tumor regression as a best response
    • To evaluate the duration of progression-free survival (PFS) following initiation of Larotrectinib
    • To evaluate the duration of OS following initiation of Larotrectinib
    • To assess the safety profile and tolerability of Larotrectinib
    • To compare the duration of PFS following initiation of Larotrectinib to that following the line of therapy immediately preceding Larotrectinib in subjects who have received prior therapy
    • To evaluate the CBR based on the proportion of subjects with best overall response of CR, PR, or stable disease lasting 16 or more weeks following initiation of Larotrectinib
    • To evaluate the concordance of prior molecular profiling that detected an NTRK fusion within the subject’s tumor with the diagnostic test being evaluated by the Sponsor
    • Determinare ORR secondo RECIST v1.1 o RANO
    • Valutare la durata della risposta in soggetti con migliore risposta globale di CR o PR
    • Stimare la percentuale di soggetti che presentano una regressione del tumore come migliore risposta
    • Stabilire la durata della sopravvivenza libera da progressione (PFS) dopo terapia con larotrectinib
    • Stabilire la durata della sopravvivenza complessiva dopo terapia con larotrectinib
    • Valutare il profilo di sicurezza e la tollerabilità di larotrectinib
    • Confrontare la durata della PFS dopo terapia con larotrectinib rispetto a quella ottenuta dopo la linea di terapia somministrata prima di larotrectinib nei soggetti con una precedente terapia
    • Valutare il tasso di beneficio clinico sulla base della percentuale di soggetti con migliore risposta globale di CR, PR o malattia stabile persistente per 16 o più settimane dopo terapia con larotrectinib
    • Valutare la conformità tra il precedente test molecolare con quello fatto dallo sponsor
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Locally-advanced or metastatic malignancy with an NTRK1, NTRK2 or NTRK3 gene fusion, identified through molecular assays as routinely performed at CLIA or other similarly-certified laboratories. Subjects who have an NTRK gene fusion identified in a lab where certification of the lab cannot be confirmed by the Sponsor at the time of consent may have been enrolled in Cohort 9 as per protocol versions 1.0 - 8.0. From protocol version 9.0: CLIA or similar certification of the lab performing the fusion assay is required. However, patients may be included after discussion with the sponsor if CLIA or similar certification of the lab performing the fusion assay is not confirmed at the time of consent.
    2. Subjects must have received prior standard therapy appropriate for their tumor type and stage of disease, or in the opinion of the Investigator, would be unlikely to tolerate or derive clinically meaningful benefit from appropriate standard of care therapy.
    3. Subjects must have at least one measurable lesion as defined by RECIST v1.1 (Eisenhauer 2009). Subjects with solid tumors without RECIST measurable disease (e.g., evaluable disease only) had been eligible for enrollment to Cohort 8 as per protocol versions 1.0 - 8.0, regardless of tumor type. Subjects with primary CNS tumors should meet the following criteria:
    a. Have received prior treatment including radiation and/or chemotherapy, with radiation completed >12 weeks prior to C1D1 of therapy, as recommended or appropriate for that CNS tumor type.
    b. Have =1 site of bi-dimensionally measurable disease (confirmed by magnetic resonance imaging [MRI] and evaluable by RANO criteria), with the size of at least one of the measurable lesions =1 cm in each dimension and noted on more than one imaging slice.
    c. Imaging study performed within 28 days before enrollment. If on steroid therapy, the dose must be stable for at least 7 days immediately before and during the imaging study.
    d. Must be neurologically stable based on stable neurologic exam for 7 days prior to enrollment.
    4. At least 18 years of age.
    5. Performance Status: Eastern Cooperative Oncology Group (ECOG) score of =3. If enrolled with primary CNS tumor to be assessed by RANO, Karnofsky Performance Score (KPS) = 50%.
    6. Tumor tissue before treatment (mandatory). If neither fresh tissue can be obtained nor archival tissue is available patients might be enrolled after consultation with the sponsor.
    7. Adequate organ function as defined by the following criteria:
    a. Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) <2.5 × upper limit of normal (ULN), or AST and ALT <5 × ULN if liver function abnormalities are due to underlying malignancy.
    b. Total bilirubin <2.5 × ULN, except in the setting of biliary obstruction. Subjects with a known history of Gilberts Disease and an isolated elevation of indirect bilirubin are eligible.
    c. Serum creatinine <2.0 × ULN OR an estimated glomerular filtration rate =30 mL/minute using the Cockroft-Gault formula:
    (140 – age) x body weight (kg) × 0.85 (if female) / serum creatinine (mg/dL) × 72. with either result acceptable for enrollment.
    8. Ability to comply (or for guardian to ensure compliance) with outpatient treatment, laboratory monitoring, and required clinic visits for the duration of study participation.
    9. Willingness of men and women of reproductive potential to use double effective birth control methods, defined as one used by the subject and another by his/her partner, for the duration of treatment and for 1 month following study completion.
    1. Carcinoma localmente avanzato o metastatico con fusioni geniche NTRK1, NTRK2 o NTRK3 identificate mediante saggi molecolari svolti di routine presso laboratori certificati CLIA o con analoga certificazione. I soggetti che presentano una fusione genica NTRK identificata in un laboratorio la cui certificazione di laboratorio non possa essere confermata dallo sponsor al momento del consenso potrebbero essere stati arruolati nella Coorte 9 come da protocollo versioni 1.0-8.0. A partire dalla versione 9.0 del protocollo: è richiesta la certificazione CLIA o una certificazione analoga da parte del laboratorio che esegue il test di fusione. Tuttavia, previa discussione con lo sponsor, i pazienti possono essere inclusi anche se la certificazione CLIA o una certificazione simile del laboratorio che esegue il test di fusione non viene confermata al momento del consenso.
    2. I soggetti devono aver ricevuto una precedente terapia standard appropriata per il tipo e lo stadio del tumore oppure, secondo lo sperimentatore, è improbabile che tollerino o traggano un beneficio clinico significativo dalla terapia standard appropriata.
    3. I soggetti devono avere almeno una lesione misurabile secondo RECIST v1.1. I soggetti con tumori solidi privi di malattia misurabile secondo RECIST v1.1 (ad es. solo malattia valutabile) erano risultati idonei per essere arruolati nella Coorte 8 conformemente alle versioni 1.0-8.0 del protocollo, indipendentemente dal tipo di tumore. I soggetti con tumori primitivi dell’SNC devono soddisfare i seguenti criteri:
    a. Aver ricevuto un trattamento precedente, comprese radioterapia e/o chemioterapia, con la radioterapia completata >12 settimane prima del Ciclo 1 Giorno 1 della terapia, come raccomandato o appropriato per quel tipo di tumore dell’SNC.
    b. Avere =1 sito di malattia misurabile bidimensionalmente (confermata alla risonanza magnetica e valutabile secondo i criteri RANO), con almeno una delle lesioni misurabili =1 cm in ciascuna dimensione e rilevata in più di una sezione di scansione.
    c. Studio di diagnostica per immagini eseguito entro 28 giorni prima dell’arruolamento. In caso di terapia con steroidi, la dose deve essere stabile per almeno 7 gg. prima e durante lo studio di diagnostica per immagini.
    d. Devono essere neurologicamente stabili, secondo quanto accertato dalla visita neurologica, per 7 gg. prima dell’arruolamento.
    4. Avere almeno 18 anni d’età.
    5. Scala di valutazione: punteggio del Gruppo cooperativo orientale di oncologia (ECOG) =3. In caso di arruolamento con tumore primitivo dell’SNC da valutare secondo RANO, punteggio dello stato di validità di Karnofsky(KPS) =50%.
    6. Tessuto tumorale prima del trattamento (obbligatorio). Se non fosse possibile ottenere il tessuto fresco o non fosse disponibile il tessuto d’archivio, i pazienti potrebbero essere arruolati previa consultazione con lo sponsor.
    7. Funzionalità organica adeguata definita da:
    a. Aspartato aminotransferasi (AST) e alanina aminotransferasi (ALT) sieriche <2,5 × il limite superiore della norma (ULN) oppure AST e ALT <5 × ULN se le anomalie della funzione epatica sono causate dalla neoplasia di fondo.
    b. Bilirubina totale <2,5 × ULN, tranne nel contesto di un’ostruzione biliare. I soggetti con anamnesi nota di malattia di Gilbert e innalzamento isolato della bilirubina indiretta sono idonei.
    c. Creatinina sierica <2,0 × ULN OPPURE velocità di filtrazione glomerulare stimata =30 ml/minuto calcolata usando la formula di Cockcroft-Gault con un risultato accettabile per l’arruolamento.
    8.Capacità di attenersi al trattamento ambulatoriale, al monitoraggio dei parametri di laboratorio e alle visite presso il centro richieste per la durata della partecipazione allo studio.
    9. Disponibilità di donne e uomini in età fertile a utilizzare metodi contraccettivi efficaci doppi, ovvero uno utilizzato dal soggetto e un altro utilizzato dal/la proprio/a partner, per la durata del trattamento e per 1 mese successivo al completamento dello studio.
    E.4Principal exclusion criteria
    1. Investigational agent or anticancer therapy within 2 weeks prior to planned start of larotrectinib or 5 half-lives, whichever is shorter, and without recovery of acute and/or clinically significant toxicities from that therapy.
    2. Prior progression while receiving approved or investigational tyrosine kinase inhibitors targeting TRK. Subjects who received less than 28 days of treatment and discontinued because of intolerance or toxicity are eligible.
    3.Symptomatic or unstable brain metastases. (Note: Subjects with asymptomatic brain metastases are eligible to participate in the study). Subjects with primary CNS tumors are eligible.
    4. Uncontrolled concurrent malignancy that would limit assessment of efficacy of larotrectinib. Allowed conditions may include but are not limited to in situ cancers of cervix, breast, or skin, superficial bladder cancer, limited stage prostate cancer, basal or squamous cancers of the skin.
    5.Active uncontrolled systemic bacterial, viral, or fungal infection, unstable cardiovascular disease or other systemic disease that would limit compliance with study procedures.
    Unstable cardiovascular disease is defined as:
    a. Persistently uncontrolled hypertension defined as systolic blood pressure (BP) >150 mmHg and/or diastolic BP >100 mmHg despite antihypertensive therapy
    In subjects <age 18 years, persistent uncontrolled hypertension defined as blood pressure in the 95th percentile or greater despite antihypertensive therapy.
    b. Myocardial infarction within 3 months of screening
    c. Stroke within 3 months of screening
    6. Inability to discontinue treatment with a strong CYP3A4 inhibitor or inducer (refer to Appendix C in section 12.3) prior to start of treatment initiation.
    7. Pregnancy or lactation.
    8. Currently recovering from adverse events (AEs) or adverse drug reactions (ADRs) due to previous treatments. Inclusion is only advised once the pre-existing AE/ADR resolves or recovers to baseline.
    9. Known or suspected hypersensitivity against the active substance or any of the ingredients of the investigational medicinal product (IMP).
    10. Known history of human immunodeficiency virus (HIV) infection. All patients must be screened for HIV up to 28 days prior to study drug start using a blood test for HIV according to local regulations.
    11. Hepatitis B (HBV) or C (HCV) infection. All patients must be screened for HBV and HCV up to 28 days prior to study drug start using the routine hepatitis virus laboratorial panel. Patients positive for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) will be eligible if they are negative for HBV-DNA, these patients should receive prophylactic antiviral therapy as per rituximab label. Patients positive for anti-HCV antibody will be eligible if they are negative for HCV-RNA.
    1. Farmaco sperimentale o terapia antitumorale entro 2 settimane prima dell’inizio programmato della terapia con larotrectinib o 5 emivite, in base a quale delle due dura di meno, e mancata risoluzione di eventuali tossicità acute e/o clinicamente significative conseguenti a tale terapia.
    2. Precedente progressione in corso di terapia con inibitori tirosin-chinasici approvati o sperimentali diretti contro TRK. I soggetti che sono stati sottoposti al trattamento per meno di 28 giorni e che hanno interrotto la terapia per intolleranza o tossicità sono idonei.
    3. Metastasi cerebrali sintomatiche o instabili (Nota: i soggetti con metastasi cerebrali asintomatiche sono idonei a partecipare allo studio). I soggetti con tumori dell’SNC primitivi sono idonei.
    4. Neoplasia concomitante non controllata che limiterebbe la valutazione dell’efficacia di larotrectinib. Le condizioni consentite possono includere, a titolo esemplificativo ma non esaustivo, carcinomi in situ del collo dell’utero, del seno o della pelle, carcinoma superficiale della vescica, carcinoma prostatico in stadio limitato e carcinomi cutanei a cellule basali o squamose.
    5. Infezione batterica, virale o micotica sistemica incontrollata in atto, patologia cardiovascolare instabile o altra malattia sistemica che limiterebbe la compliance alle procedure previste dallo studio.
    Per malattia cardiovascolare instabile si intende:
    a. Ipertensione incontrollata persistente definita come pressione arteriosa (PA) sistolica >150 mmHg e/o PA diastolica >100 mmHg nonostante la terapia antipertensiva. Nei soggetti di età <18 anni, l’ipertensione incontrollata persistente è definita come PA nel 95° percentile o superiore nonostante la terapia antipertensiva.
    b. Infarto miocardico entro 3 mesi dallo screening.
    c. Ictus entro 3 mesi dallo screening.
    6. Impossibilità a interrompere il trattamento con un forte inibitore o induttore del citocromo P450 (CYP450) 3A4 (CYP3A4) (si rimanda all’Appendice C nella Sezione 12.3) prima di iniziare il trattamento.
    7. Gravidanza o allattamento.
    8. Attualmente in fase di recupero da eventi avversi (EA) o reazioni avverse al farmaco (ADR) dovuti a trattamenti precedenti. L’inclusione è consigliata solo dopo che l’EA/ADR preesistente si risolve o ritorna al basale.
    9. Ipersensibilità nota o sospetta alla sostanza attiva o a qualsiasi ingrediente del prodotto medicinale sperimentale (IMP).
    10. Anamnesi nota di infezione da virus dell’immunodeficienza umana (HIV). Tutti i pazienti devono sottoporsi allo screening per l’HIV fino a 28 giorni prima dell’inizio del trattamento con il farmaco in studio, avvalendosi di un esame del sangue per l’HIV conforme alle normative locali.
    11. Infezione da virus dell’epatite B (HBV) o C (HCV). Tutti i pazienti devono sottoporsi allo screening per HBV e HCV fino a 28 giorni prima dell’inizio del trattamento con il farmaco in studio, utilizzando il pannello dei virus delle epatiti di routine del laboratorio. I pazienti positivi all’antigene di superficie dell’epatite B (HBsAg) o agli anticorpi anti-proteina core dell’epatite B (HBcAb) saranno idonei se risultano negativi all’HBV-DNA; questi pazienti devono ricevere una terapia antivirale profilattica come previsto dall’etichetta di rituximab. I pazienti positivi agli anticorpi anti-HCV saranno idonei se risultano negativi all’HCV-RNA.
    E.5 End points
    E.5.1Primary end point(s)
    Best overall response of confirmed complete response (CR) or partial response (PR) as determined by an independant radiology review committee using RECIST v1.1 or RANO criteria, as appropriate to tumor type. Confirmed CR or PR will be defined as a repeat assessment performed no less than 28 days after the criteria for response is first met.
    Migliore risposta complessiva di risposta completa (CR) o parziale (PR) confermata, come stabilito da un comitato indipendente di revisione radiologica utilizzando i criteri RECIST v1.1 o RANO, a seconda di quali siano appropriati al tipo di tumore. La CR o PR confermata sarà definita come valutazione ripetuta eseguita non meno di 28 giorni dopo l’iniziale conformità ai criteri di risposta.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Every 2-3 months from baseline until disease progression
    Ogni 2-3 mesi dal basale fino alla progressione della malattia
    E.5.2Secondary end point(s)
    • Best overall response of confirmed CR or PR as determined by the treating Investigator using RECIST v1.1 or RANO criteria, as appropriate to tumor type.
    • Duration of response (DOR): determined for subjects with best overall response of confirmed CR or PR by 1) an independent radiology review committee and 2) the treating Investigator; DOR is defined as the number of months from the start of CR or PR (whichever response is recorded first) and subsequently confirmed to the first date that recurrent or progressive disease is documented or death.
    • Clinical benefit rate (CBR): best overall response of confirmed CR, PR, or stable disease lasting 16 or more weeks following the initiation of Larotrectinib.
    • Progression-free survival (PFS): number of months from initiation of Larotrectinib to the earlier of disease progression or death due to any cause.
    • Overall survival (OS): number of months from the initiation of Larotrectinib to the date of death due to any cause.
    • Comparison of PFS following initiation of Larotrectinib to that following the line of therapy immediately preceding Larotrectinib in each subject who has received prior therapy.
    • Incidence, severity, and duration of adverse events, including all, serious, and those considered treatment-related.
    • Changes from baseline in clinical safety laboratory values and vital signs.
    • Migliore risposta globale di CR o PR confermata, come stabilito dallo sperimentatore curante usando i criteri RECIST v1.1 o RANO, a seconda di quali siano appropriati al tipo di tumore.
    • Durata della risposta (DOR): determinata per i soggetti con migliore risposta globale di CR o PR confermata da 1) un comitato di revisione radiologica indipendente e/o 2) dallo sperimentatore curante; per DOR s’intende il numero di mesi trascorsi dalla prima manifestazione di CR o PR (in funzione di quale risposta venga registrata per prima) e successivamente confermato alla prima data in cui viene documentata una progressione (PD) o recidiva della malattia o al decesso.
    • Tasso di beneficio clinico (CBR): migliore risposta globale di CR, PR o malattia stabile confermata che si protrae per 16 settimane o più dopo l’inizio della terapia con larotrectinib.
    • Sopravvivenza libera da progressione (PFS): numero di mesi trascorsi dall’inizio della terapia con larotrectinib alla progressione della malattia o al decesso per qualunque causa (a seconda di quale evento si verifica per primo).
    • Sopravvivenza complessiva (OS): numero di mesi trascorsi dall’inizio della terapia con larotrectinib alla data del decesso per qualunque causa.
    • Confronto fra la PFS dopo l’inizio della terapia con larotrectinib e quella ottenuta dopo la linea di terapia immediatamente precedente la somministrazione di larotrectinib nei soggetti che avevano ricevuto una precedente terapia.
    • Incidenza, gravità e durata degli eventi avversi (EA), inclusi tutti, quelli gravi e quelli ritenuti correlati al trattamento.
    • Variazioni rispetto al basale nei parametri di laboratorio attestanti la sicurezza clinica e nei segni vitali.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Every 2-3 months from baseline until disease progression or toxicity onset or death; Ogni 2-3 mesi dal basale fino alla progressione della malattia o all'insorgenza della tossicità o alla morte
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic 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 Yes
    E.8.1.7.1Other trial design description
    Studio basket - In aperto
    Basket design - Open
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned8
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA30
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Australia
    Belgium
    Brazil
    China
    Czechia
    Denmark
    European Union
    France
    Germany
    Greece
    Hungary
    Ireland
    Italy
    Japan
    Korea, Republic of
    New Zealand
    Norway
    Poland
    Portugal
    Russian Federation
    Singapore
    Slovakia
    Spain
    Sweden
    Taiwan
    Turkey
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    Ultima visita dell'ultimo soggetto (Last Visit Last Subject, 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 months10
    E.8.9.1In the Member State concerned days17
    E.8.9.2In all countries concerned by the trial years9
    E.8.9.2In all countries concerned by the trial months11
    E.8.9.2In all countries concerned by the trial days23
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    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) Yes
    F.1.1.6.1Number of subjects for this age range: 5
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 90
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 30
    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 Yes
    F.3.3.7.1Details of other specific vulnerable populations
    Children 12 years and above. All newly enrolled patients will be above 18
    Bambini dai 12 anni in su. Tutti i pazienti recentemente arruolati saranno sopra 18
    F.4 Planned number of subjects to be included
    F.4.1In the member state16
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 60
    F.4.2.2In the whole clinical trial 125
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    Nessuno
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-07-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-05-20
    P. End of Trial
    P.End of Trial StatusOngoing
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