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    Summary
    EudraCT Number:2020-004246-11
    Sponsor's Protocol Code Number:EDO-S101-1002
    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:2021-06-04
    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 number2020-004246-11
    A.3Full title of the trial
    A Phase 1/2 Study to Investigate the Safety, Pharmacokinetics and Efficacy of Tinostamustine, a First-in-Class Alkylating Histone Deacetylase Inhibition (HDACi) Fusion Molecule, in Patients with Advanced Solid Tumors
    Studio di fase I/II volto a valutare la sicurezza, la farmacocinetica e l'efficacia di tinostamustina, una molecola di fusione di inibizione dell'istone-deacetilasi (HDACi) alchilante di prima classe, in pazienti affetti da tumori solidi in stadio avanzato
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    This study will evaluate the safety, efficacy and tolerability of Tinostamustine in Patients with Advanced Solid Tumors (abnormal clumps of cells which may occur in several places in the body). The study will be performed in multiple countries and hospitals.
    Questo studio è volto a valutare la sicurezza, l'efficacia e la tollerabilità di Tinostamustina in pazienti affetti da tumori solidi (accumuli anomali di cellule che si possono sviluppare in molteplici porzioni del corpo) in stato avanzato. Lo studio sarà condotto in più paesi ed ospedali.
    A.3.2Name or abbreviated title of the trial where available
    EDO-S101-1002
    EDO-S101-1002
    A.4.1Sponsor's protocol code numberEDO-S101-1002
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02576496
    A.5.4Other Identifiers
    Name:INDNumber:125180
    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 SponsorMUNDIPHARMA RESEARCH LIMITED
    B.1.3.4CountryUnited Kingdom
    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 supportMundipharma Research Limited
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAdhoc Clinical
    B.5.2Functional name of contact pointNancy Cottigny
    B.5.3 Address:
    B.5.3.1Street AddressTer Waarde 45
    B.5.3.2Town/ cityIeper
    B.5.3.3Post code8900
    B.5.3.4CountryBelgium
    B.5.4Telephone number003257400530
    B.5.5Fax number003257401530
    B.5.6E-mailnancy.cottigny@adhoc-clinical.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 nameTinostamustina
    D.3.2Product code [EDO-S101]
    D.3.4Pharmaceutical form Lyophilisate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.2Current sponsor codeEDO-S101
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number80
    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
    • Cohort 1: Relapsed/refractory Small Cell Lung Cancer
    • Cohort 2: Relapsed/refractory Soft Tissue Sarcoma
    • Cohort 3: Relapsed/refractory Triple-Negative Breast Cancer
    • Cohort 4: Relapsed/refractory ovarian cancer
    • Cohort 5: Relapsed/refractory endometrial cancer
    • Coorte 1: Carcinoma polmonare a piccole cellule (Small Cell Lung Cancer, SCLC) recidivante/refrattario
    • Coorte 2: Sarcoma del tessuto molle (Soft Tissue Sarcoma, STS) recidivante/refrattario
    • Coorte 3: Cancro della mammella triplo negativo (Triple-Negative Breast Cancer, TNBC) recidivante/refrattario
    • Coorte 4: Cancro dell'ovaio recidivante/refrattario
    • Coorte 5: Cancro endometriale recidivante/refrattario
    E.1.1.1Medical condition in easily understood language
    "Relapse" means when a few of the original cancer cells survived the initial treatment. "Refractory" is a cancer that may be resistant at the beginning/becomes resistant during treatment.
    "Recidiva" si riferisce a quando alcune delle cellule tumorali originali sono sopravvissute al trattamento iniziale. "Refrattario" è un tumore resistente al trattamento, o che può diventarlo.
    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 LLT
    E.1.2Classification code 10033130
    E.1.2Term Ovarian cancer NOS
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10014735
    E.1.2Term Endometrial cancer NOS
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10041071
    E.1.2Term Small cell lung cancer stage unspecified
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10002479
    E.1.2Term Angiosarcoma NOS
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10057043
    E.1.2Term Dermatofibrosarcoma
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10015103
    E.1.2Term Epithelioid sarcoma NOS
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10024193
    E.1.2Term Leiomyosarcoma NOS
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10024631
    E.1.2Term Liposarcoma NOS
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10042866
    E.1.2Term Synovial sarcoma NOS
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10025556
    E.1.2Term Malignant fibrous histiocytoma NOS
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10029276
    E.1.2Term Neurofibrosarcoma NOS
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10045154
    E.1.2Term Tumor of fibrous tissue NOS
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Evaluation of Response Rate in Selected Solid Tumor Cohorts
    Primary objective: to determine the objective response rate (ORR) [complete response (CR) plus partial response (PR)] of any duration, plus the rate of patients with stable disease (SD) of at least 4 months duration at a dose of 80 mg/m2 administered over 1 hour on Day 1 and 15 of each 4-week treatment cycle.
    Valutazione del tasso di risposta nelle coorti dei tumori solidi selezionati.
    Obiettivo primario: determinare il tasso di risposta obiettiva (Objective Response Rate, ORR) (risposta completa [Complete Response, CR] più risposta parziale [Partial Response, PR]) di qualsiasi durata, più il tasso di pazienti con malattia stabile (Stable Disease, SD) di durata pari ad almeno 4 mesi alla dose di 80 mg/m2 somministrata nell'arco di un'ora i Giorni 1 e 15 di ciascun ciclo di trattamento di 4 settimane.
    E.2.2Secondary objectives of the trial
    Secondary Objectives:
    • To evaluate safety and tolerability of 80 mg/m2 of tinostamustine administered over 1 hour on Day 1 and 15 of each 4-week treatment cycle.
    • To determine the progression-free survival (PFS) time for patients who received 80 mg/m2 of tinostamustine administered over 1 hour on Day 1 and 15 of each 4-week treatment cycle.
    • To determine the overall survival (OS) for patients who received 80 mg/m2 of tinostamustine administered over 1 hour on Day 1 and 15 of each 4-week treatment cycle.
    • To determine duration of response.
    • To establish the whole PK profiles of tinostamustine.

    Exploratory Objective:
    • To correlate the extent of gene expression changes in tumor samples with anti-tumor activity.
    Obiettivi secondari:
    • Valutare la sicurezza e la tollerabilità della dose di tinostamustina pari a 80 mg/m2 somministrata nell'arco di 1 ora i Giorni 1 e 15 di ciascun ciclo di trattamento di 4 settimane.
    • Determinare il tempo di sopravvivenza libera da progressione (Progression Free Survival, PFS) per i pazienti che hanno ricevuto la dose di tinostamustina pari a 80 mg/m2 somministrata nell'arco di 1 ora i Giorni 1 e 15 di ciascun ciclo di trattamento di 4 settimane.
    • Determinare il tempo di sopravvivenza globale (Overall Survival, OS) per i pazienti che hanno ricevuto la dose di tinostamustina pari a 80 mg/m2 somministrata nell'arco di 1 ora i Giorni 1 e 15 di ciascun ciclo di trattamento di 4 settimane.
    • Determinare la durata della risposta.
    • Stabilire i profili farmacocinetici totali di tinostamustina.

    Obiettivo esplorativo:
    • Stabilire un nesso tra l'entità delle variazioni dell'espressione genica nei campioni tumorali con l'attività antitumorale.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Patient willing and able to sign the informed consent; Age at least 18 years; Life expectancy >3 months; Histologically confirmed diagnosis of advanced or metastatic solid tumors, progressed during or following at least 1 previous line of therapy and no other standard therapy with benefit is available or recommended; Patients with 2° metastasis to CNS are eligible if they have had brain metastases resected or have received radiation therapy ending at least 4 weeks and they meet all the criteria: (1) Residual neurological symptoms =Grade 1 (2) No glucocorticoids requirement or patients may be receiving low doses of glucocorticoids providing the dose has been stable for at least 2 weeks prior to starting the trial (3) No progression of treated lesions and no new lesions; Disease measurable on imaging as assessed by RECIST version 1.1; Discontinuation of previous cancer therapies at least 3 weeks; ECOG performance status =2; ANC >1,000/ µL; Platelets =100,000 / µL; AST/ALT =3× ULN. If liver ALT/ AST =5× ULN; Bilirubin =1.5 mg/dL; Creatinine =1.5 ULN; Serum potassium and magnesium at least above the lowest limit of normal;
    Cohort 1: 1. Confirmed limited or extensive disease stage of SCLC; 2. At least 1 line of prior combination chemotherapy or biological therapy and no other standard therapy with benefit is available or recommended; 3. At least 3 weeks since prior treatment; 4. Prior radiotherapy acceptable if the patient has recovered from any radiotherapy related acute toxicities; 5. Disease progressing during or relapsing after the previous treatment; 6. Presence of measurable disease as defined by RECIST version 1.1.
    Cohort 2: 1. Confirmed advanced, unresectable, or metastatic STS; 2. At least 1 prior line chemotherapy or biological therapy regimen and no other standard therapy with benefit is available or recommended; 3. Disease progressing during or relapsing after the previous treatment; 4. Presence of measurable disease as defined by RECIST version 1.1
    Cohort 3: 1. Confirmed locally advanced or metastatic Triple Negative Breast Cancer; 2. At least 1 line of chemotherapy/biological therapy and no other standard therapy with benefit is available or recommended; 3. At least 3 weeks should have elapsed since prior chemotherapy; 4. Prior radiotherapy is acceptable provided it was administered at least 4 weeks before; 5. Disease progressing during or relapsing after the previous treatment; 6. Presence of measurable disease as defined by RECIST version 1.1
    Cohort 4: 1. Confirmed advanced ovarian cancer epithelial ovarian cancer; 2. At least 3 weeks should have elapsed since prior chemotherapy; 3. Disease progressing during or relapsing after the previous treatment; 4. Presence of measurable disease as defined by RECIST version 1.1
    Cohort 5: 1. Confirmed locally advanced or metastatic endometrial cancer; 2. At least one line of chemotherapy or biological therapy and no other standard therapy with benefit is available or recommended; 3. At least 3 weeks should have elapsed since prior chemotherapy; 4. Prior radiotherapy is acceptable provided it was administered at least 4 weeks prior to starting treatment; 5. Disease progressing during or relapsing after the previous treatment; 6. Presence of measurable disease as defined by RECIST version 1.1
    Volontà e capacità di firmare il consenso informato; Età almeno 18 anni; Aspettativa di vita >3 mesi; Diagnosi confermata istologicamente tumori solidi avanzati o metastatici, con progressione della malattia durante o dopo almeno 1 precedente linea terapeutica e assenza di altra terapia standard con un beneficio comprovato o raccomandata; Pazienti con metastasi 2° al SNC se sottoposti a resezione delle metastasi cerebrali o a radioterapia conclusa almeno 4 settimane e se soddisfano tutti i criteri: (1) Sintomi neurologici residui di grado =1 (2) Nessuna necessità di glucocorticoidi o trattamento con basse dosi di glucocorticoidi, purché la dose sia rimasta stabile per almeno 2 settimane (3) Nessuna progressione delle lesioni trattate e assenza di nuove lesioni; Malattia misurabile tramite diagnostica per immagini secondo la valutazione dei criteri RECIST versione 1.1; Interruzione precedenti terapie antitumorali da almeno 3 settimane; Stato di performance ECOG =2; ANC >1.000/µl; Piastrine =100.000/µl; AST/ALT =3 × l'ULN. Se epatico, ALT/AST =5 × l'ULN; Bilirubina totale =1,5 mg/dl; Creatinina =1,5 l'ULN; Potassio e Magnesio almeno al di sopra dell'intervallo
    Coorte 1: 1. SCLC stadio esteso o limitato; 2. Ricezione di almeno 1 linea precedente di chemioterapia o terapia biologica e assenza di altra terapia standard con un beneficio disponibile o raccomandata; 3. Interruzione della precedente terapia da almeno 3 settimane; 4. Eventuale precedente radioterapia è accettabile a condizione che il paziente si sia ripreso da eventuali tossicità acute; 5. Malattia progredita durante o essersi ripresentata dopo il trattamento precedente; 6. Presenza di malattia misurabile secondo i criteri RECIST versione 1.1
    Coorte 2: 1. Diagnosi istologicamente confermata di STS avanzato, non resecabile o metastatico non suscettibile di trattamento; 2. Ricezione di almeno 1 linea precedente di regime chemioterapico o di terapia biologica e assenza di altra terapia standard con un beneficio disponibile o raccomandata; 3. Interruzione della precedente chemioterapia da almeno 3 settimane; 4. La malattia deve essere progredita durante o essersi ripresentata dopo il trattamento precedente. 5. Presenza di malattia misurabile secondo i criteri RECIST versione 1.1.
    Coorte 3: 1. Cancro della mammella triplo negativo localmente avanzato o metastatico confermato; 2. Ricezione di almeno 1 linea precedente di chemioterapia/terapia biologica e assenza di altra terapia standard con un beneficio disponibile o raccomandata; 3. Interruzione della precedente chemioterapia da almeno 3 settimane; 4. Radioterapia precedente è accettabile a condizione che sia stata somministrata almeno 4 settimane; 5. La malattia deve essere progredita durante o essersi ripresentata dopo il trattamento precedente; 6. Presenza di malattia misurabile secondo i criteri RECIST versione 1.1.
    Coorte 4: 1. Cancro dell'ovaio o cancro epiteliale dell'ovaio avanzato confermato; 2. Interruzione della precedente chemioterapia da almeno 3 settimane; 3. La malattia deve essere progredita durante o essersi ripresentata dopo il trattamento precedente; 4. Presenza di malattia misurabile secondo i criteri RECIST versione 1.1.
    Coorte 5: 1. Cancro endometriale metastatico o localmente avanzato confermato; 2. Ricezione di almeno 1 linea di chemioterapia o terapia biologica e assenza di altra terapia standard con beneficio disponibile o raccomandata; 3. Interruzione della precedente chemioterapia da almeno 3 settimane; 4. La radioterapia precedente è accettabile a condizione che sia stata somministrata almeno 4 settimane; 5. La malattia deve essere progredita durante o essersi ripresentata dopo il trattamento precedente; 6. Presenza di malattia misurabile secondo i criteri RECIST versione 1.1.
    E.4Principal exclusion criteria
    • Patients with primary central nervous system (CNS) cancer.
    • Patients with QTc interval (Fridericia’s formula) >450 ms.
    • Patients who are on treatment with drugs known to prolong the QT/QTc interval. Refer to CredibleMeds list of drugs with known risk of Torsade des pointes (TdP): http://crediblemeds.org/new-drug-list.
    • Patients who are being treated with Valproic Acid for any indication (epilepsy, mood disorder).
    • Any serious medical condition that interferes with adherence to trial procedures.
    • Prior history of another solid tumor malignancy diagnosed within the last 3 years of trial enrollment excluding adequately treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer, in situ breast cancer, in situ prostate cancer (patients must have shown no evidence of active disease for 2 years prior to enrollment)
    • Pregnant or breastfeeding women.
    • New York Heart Association (NYHA) stage III/IV congestive heart failure. The following arrhythmias: atrial fibrillation/flutter with poor rate control, documented sustained ventricular tachycardia (defined as >30 seconds or requiring cardioversion before 30 seconds have elapsed) or TdP.
    • Significant co-morbidities (e.g., active infection requiring systemic therapy, history of human immunodeficiency virus [HIV] infection, or active Hepatitis B or Hepatitis C).
    • Use of other investigational agents within 30 days or 5 half-lives prior to the first dose of tinostamustine, provided the patient has recovered from any related toxicities =Grade 1.
    • Steroid treatment within 7 days prior to trial treatment. Patients that require intermittent use of bronchodilators, topical steroids, or local steroid injections will not be excluded from the trial. Patients who have been stabilized to 10 mg prednisolone orally (PO) once daily (QD) (or equivalent), daily (or less) at least 7 days prior to Investigational Medicinal Product administration are allowed.

    Phase 2 patients must meet the cohort-specific inclusion/exclusion criteria in addition to the general inclusion/exclusion criteria previously noted.
    • Pazienti affetti da tumore primario a carico del sistema nervoso centrale (SNC)
    • Pazienti con un intervallo QTc >450 ms (formula di Fridericia)
    • Pazienti in trattamento con farmaci che notoriamente prolungano l'intervallo QT/QTc.
    • Pazienti trattati con acido valproico per qualsiasi indicazione (epilessia, disturbo dell'umore).
    • Qualsiasi altra condizione medica grave che interferisce con il rispetto delle procedure dello studio.
    • Anamnesi precedente di un'altra neoplasia maligna tumorale solida diagnosticata nei 3 anni precedenti all'arruolamento nello studio, fatta eccezione per casi adeguatamente trattati di carcinoma cutaneo basocellulare, carcinoma cutaneo a cellule squamose o carcinoma della cervice in situ, cancro mammario in situ e cancro alla prostata in situ (i pazienti non devono aver mostrato alcuna evidenza di malattia attiva per 2 anni prima dell'arruolamento).
    • Donne in gravidanza o allattamento.
    • Insufficienza cardiaca congestizia di III/IV stadio secondo la New York Heart Association (NYHA). Le seguenti aritmie: fibrillazione atriale/flutter scarsamente controllato, documentazione di tachicardia ventricolare sostenuta (>30 secondi o che rende necessaria la cardioversione prima di 30 secondi) o TdP.
    • Co-morbilità significative (ad es., infezione attiva che rende necessaria una terapia sistemica, anamnesi di infezione da virus dell'immunodeficienza umana [HIV] o epatite B o epatite C attiva).
    • Uso di altri agenti sperimentali entro 30 giorni o 5 emivite prima della prima dose di tinostamustina, a condizione che il paziente si sia ripreso da eventuali tossicità correlate di grado =1.
    • Trattamento con steroidi nei 7 giorni precedenti al trattamento sperimentale. I pazienti che necessitano di uso intermittente di broncodilatatori, steroidi topici o iniezioni locali di steroidi non saranno esclusi dallo studio. Sono ammessi i pazienti che assumono una dose stabile di 10 mg di prednisolone orale (PO) una volta al giorno (QD) (o equivalente), giornalmente (o meno) per almeno 7 giorni prima della somministrazione del prodotto medicinale sperimentale.

    Oltre ai criteri di inclusione/esclusione generali, i pazienti della Fase 2 devono soddisfare i criteri di inclusione/esclusione specifici per la coorte.
    E.5 End points
    E.5.1Primary end point(s)
    Phase 2 is designed to determine the ORR plus the rate of patients with SD of at least 4 months duration of the RP2D (80 mg/m2 of tinostamustine administered over 1 hour on Day 1 and 15 of each 4-week treatment cycle).
    La Fase 2 è strutturata per determinare il tasso di risposta obiettiva (Objective Response Rate, ORR) (risposta completa [Complete Response, CR] più risposta parziale [Partial Response, PR]) di qualsiasi durata, più il tasso di pazienti con malattia stabile (Stable Disease, SD) di durata pari ad almeno 4 mesi alla dose di 80 mg/m2 somministrata nell'arco di un'ora i Giorni 1 e 15 di ciascun ciclo di trattamento di 4 settimane.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Tumor response assessment by imaging will be performed at baseline and every 2 cycles during treatment and every 2 months after stopping treatment according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1
    La valutazione della risposta tumorale mediante diagnostica per immagini sarà eseguita al basale e ogni 2 cicli durante il trattamento e ogni 2 mesi dopo l'interruzione del trattamento in base ai Criteri di valutazione della risposta nei tumori solidi (RECIST), versione 1.1
    E.5.2Secondary end point(s)
    To establish the whole PK profiles of Tinostamustine.; The Exploratory Objective is to correlate the extent of gene expression changes in tumor samples with anti-tumor activity.; To determine the progression-free survival (PFS) time for patients who received 80 mg/m2 of Tinostamustine administered over 1 hour on Day 1 and 15 of each 4-week treatment cycle.; To determine the overall survival (OS) for patients who received 80 mg/m2 of Tinostamustine administered over 1 hour on Day 1 and 15 of each 4-week treatment cycle.; To determine duration of response.; To evaluate safety and tolerability of 80 mg/m2 of Tinostamustine administered over 1 hour on Day 1 and 15 of each 4-week treatment cycle.
    Stabilire i profili farmacocinetici totali di tinostamustina.; L'Obiettivo Esplorativo è stabilire un nesso tra l'entità delle variazioni dell'espressione genica nei campioni tumorali con l'attività antitumorale.; Determinare il tempo di sopravvivenza libera da progressione (Progression Free Survival, PFS) per i pazienti che hanno ricevuto la dose di tinostamustina pari a 80 mg/m2 somministrata nell'arco di 1 ora i Giorni 1 e 15 di ciascun ciclo di trattamento di 4 settimane.; Determinare il tempo di sopravvivenza globale (Overall Survival, OS) per i pazienti che hanno ricevuto la dose di tinostamustina pari a 80 mg/m2 somministrata nell'arco di 1 ora i Giorni 1 e 15 di ciascun ciclo di trattamento di 4 settimane.; Determinare la durata della risposta.; Valutare la sicurezza e la tollerabilità della dose di tinostamustina pari a 80 mg/m2 somministrata nell'arco di 1 ora i Giorni 1 e 15 di ciascun ciclo di trattamento di 4 settimane.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Safety evaluations will be performed at each study visit i.e. D1 and D15 of each treatment cycle.; Safety evaluations will be performed at each study visit i.e. D1 and D15 of each treatment cycle.; Safety evaluations will be performed at each study visit i.e. D1 and D15 of each treatment cycle.; Safety evaluations will be performed at each study visit i.e. D1 and D15 of each treatment cycle.; Safety evaluations will be performed at each study visit i.e. D1 and D15 of each treatment cycle.; Safety evaluations will be performed at each study visit i.e. D1 and D15 of each treatment cycle.
    Le valutazioni di sicurezza saranno effettuate ad ogni visita di studio, i.e. a Giorno 1 e Giorno 5 di ogni ciclo di trattamento.; Le valutazioni di sicurezza saranno effettuate ad ogni visita di studio, i.e. a Giorno 1 e Giorno 5 di ogni ciclo di trattamento.; Le valutazioni di sicurezza saranno effettuate ad ogni visita di studio, i.e. a Giorno 1 e Giorno 5 di ogni ciclo di trattamento.; Le valutazioni di sicurezza saranno effettuate ad ogni visita di studio, i.e. a Giorno 1 e Giorno 5 di ogni ciclo di trattamento.; Le valutazioni di sicurezza saranno effettuate ad ogni visita di studio, i.e. a Giorno 1 e Giorno 5 di ogni ciclo di trattamento.; Le valutazioni di sicurezza saranno effettuate ad ogni visita di studio, i.e. a Giorno 1 e Giorno 5 di ogni ciclo di trattamento.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety 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 No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    Phase 1 has been conducted and completed in US and Canada
    La Fase 1 è stata condotta e conclusa in US e Canada
    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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA7
    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
    Canada
    United States
    Italy
    Netherlands
    Spain
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    Last Follow up visit of the last patient in the trial
    Ultima visita di Follow-up dell'ultimo paziente in studio
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months36
    E.8.9.1In the Member State concerned days10
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months36
    E.8.9.2In all countries concerned by the trial days10
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 30
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 25
    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 state25
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 50
    F.4.2.2In the whole clinical trial 70
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Patients who have discontinued trial treatment for reasons other than PD will be assessed per RECIST 1.1 every 8 weeks (± 2 weeks) until documentation of PD or the initiation of a subsequent anti-cancer therapy, whichever comes first. Survival Follow-up: patients will be contacted every 3 to 4 months for the subsequent use of anti-cancer therapy as well as survival until 1 year after the last patient's first treatment.
    I pazienti che hanno interrotto la partecipazione allo studio per ragioni esterne alla PD, saranno valutati con RECIST 1.1 ogni 8 settimane (± 2 settimane) fino a documentazione di una PD o l'inizio di una successiva terapia antitumorale, la prima ad occorrere. Follow-up di sopravvivenza: i pazienti saranno contattati ogni 3-4 mesi per l'uso successivo di terapie antitumorali, così come per la sopravvivenza a 1 anno dopo il primo trattamento dell'ultimo paziente.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2021-08-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-03-24
    P. End of Trial
    P.End of Trial StatusOngoing
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