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    Summary
    EudraCT Number:2018-002761-19
    Sponsor's Protocol Code Number:OP201
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2021-01-29
    Trial results View 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 number2018-002761-19
    A.3Full title of the trial
    An Open-Label, Phase 1/2 Study of Melflufen and Dexamethasone for Patients with AL Amyloidosis Following at Least One Prior Line of Therapy
    Studio in aperto di Fase 1/2 di melflufen e desametasone per pazienti affetti da amiloidosi da catene leggere (AL) in seguito ad almeno una precedente linea di terapia
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    It is an early clinical trial to assess a new drug (Melflufen) when given together with a steroid (Dexamethasone) in the treatment of patients with a disease called the AL Amyloidosis. Patients should also have received treatment in the past for the disease.
    Si tratta di una sperimentazione clinica iniziale volta a valutare un nuovo farmaco (melflufen) quando somministrato insieme a uno steroide (desametasone) nel trattamento di pazienti con una malattia nota come amiloidosi da catene leggere (AL).
    I pazienti devono anche avere ricevuto in passato un trattamento per la loro malattia.
    A.3.2Name or abbreviated title of the trial where available
    NA
    NA
    A.4.1Sponsor's protocol code numberOP201
    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 SponsorONCOPEPTIDES AB
    B.1.3.4CountrySweden
    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 supportOncopeptides AB
    B.4.2CountrySweden
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationOncopeptides AB
    B.5.2Functional name of contact pointClinical Trials Information Desk
    B.5.3 Address:
    B.5.3.1Street AddressVästra Trädgårdsgatan 15
    B.5.3.2Town/ cityStockholm
    B.5.3.3Post codeSE-111 53
    B.5.3.4CountrySweden
    B.5.4Telephone number0000000000
    B.5.5Fax number0000000000
    B.5.6E-mailtrials@oncopeptides.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 nameMelflufen
    D.3.2Product code [Melflufen]
    D.3.4Pharmaceutical form Powder for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNmelphalan fulfenamide hydrochloride
    D.3.9.1CAS number 380449-54-7
    D.3.9.2Current sponsor codeMelflufen
    D.3.9.4EV Substance CodeSUB22033
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Dexamethasone 4 mg JENAPHARM
    D.2.1.1.2Name of the Marketing Authorisation holdermibe GmbH Arzneimittel
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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 nameDexamethasone
    D.3.2Product code [H02AB02]
    D.3.4Pharmaceutical form 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 INNDESAMETASONE
    D.3.9.1CAS number 50-02-2
    D.3.9.2Current sponsor codeDEXAMETHASONE
    D.3.9.4EV Substance CodeSUB07017MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/g milligram(s)/gram
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number4
    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
    Patients with AL Amyloidosis
    Pazienti con amiloidosi a catene leggere
    E.1.1.1Medical condition in easily understood language
    Patients with AL Amyloidosis
    Pazienti con amiloidosi a catene leggere
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10002022
    E.1.2Term Amyloidosis
    E.1.2System Organ Class 10021428 - Immune system disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Phase 1
    •To explore the safety and tolerability
    •To identify recommended Phase 2 dose (RP2D).
    Phase 2
    •To evaluate the hematologic ORR after 4 cycles at the RP2D determined in Phase 1
    Fase 1
    • Esplorare la sicurezza e la tollerabilità
    • Identificare la dose raccomandata per la fase 2 (RP2D)
    Fase 2
    • Valutare il tasso di risposta ematologica complessiva (ORR) dopo 4 cicli alla RP2D
    determinata nella Fase 1
    E.2.2Secondary objectives of the trial
    Phase 1
    •To assess pharmacokinetic profile of melflufen in this patient population
    •To assess best hematologic response
    •To assess duration of hematologic response
    •To assess the proportion of organ system responses
    •To assess duration of organ system responses
    •To assess hematologic ORR
    •To assess time to next AL amyloidosis treatment
    •To assess OS

    Phase 2

    •To assess safety and tolerability
    •To assess best hematologic response
    •To assess duration of hematologic response
    •To assess the proportion of organ system responses
    •To assess duration of organ system responses
    •To assess time to next AL amyloidosis treatment
    •To assess OS

    Exploratory

    •To assess MRD
    Fase 1
    • Valutare il profilo farmacocinetico di melflufen in questa popolazione di pazienti
    • Valutare la migliore risposta ematologica
    • Valutare la durata della risposta ematologica
    • Valutare la percentuale di risposte sistemico-organiche
    • Valutare la durata delle risposte sistemico-organiche
    • Valutare l’ORR ematologica
    • Valutare il tempo al successivo trattamento per l’amiloidosi AL
    • Valutare la sopravvivenza globale (OS)

    Fase 2
    • Valutare la sicurezza e la tollerabilità
    • Valutare la migliore risposta ematologica
    • Valutare la durata della risposta ematologica
    • Valutare la percentuale di risposte sistemico-organiche
    • Valutare la durata delle risposte sistemico-organiche
    • Valutare il tempo al successivo trattamento
    • Valutare l’OS

    Obiettivo esplorativo
    • Valutare la malattia minima residua (MRD)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female, age 18 years or older at the time of signing the informed consent.
    2. Proven histochemical diagnosis of AL amyloidosis based on tissue specimens with Congo red staining with exhibition of an apple-green birefringence confirmed with appropriate method of typing, e.g. mass spectrometry, immunofluorescence or immunohistochemistry (previous aspirate/biopsy tissue specimen result acceptable).
    3. At least one prior line of therapy, defined as either one non-transplant regimen, one ASCT, or one regimen of induction therapy followed by a single ASCT (without hematologic progression between induction and ASCT). No more than 4 cycles of melphalan containing chemotherapy is allowed.
    4. Measurable hematologic disease as defined by serum differential free light chain (dFLC) concentration = 20 mg/L (dFLC is the difference between amyloid forming [involved] and non-amyloid forming [uninvolved] FLC).
    5. Objectively measurable (cardiac, and/or renal and/or liver) organ amyloid involvement, as defined below (amyloid involvement of at least 1 required). See also Appendix 9:
    a. Cardiac involvement: mean wall thickness >12 mm on echocardiogram, with no other cardiac cause or an elevated NT-ProBNP (>332 ng/L) in the absence of renal failure or atrial fibrillation.
    b. Renal involvement is defined as proteinuria (predominantly albumin) >0.5 g/day in a 24-hour urine collection.
    c. Hepatic involvement: Total liver span >15 cm in the absence of heart failure, or alkaline phosphatase >1.5 times institutional upper limit of normal (ULN).
    Amyloid involvement of other organ systems is allowed, but not required.
    6. ECOG performance status = 2. See Appendix 5.
    7. Women of child bearing potential (WOCBP) must have a negative serum or urine pregnancy test (See Appendix 4).
    8. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information.
    9. Less than 30% plasma cells in bone marrow aspirate or biopsy.
    10. 12-lead screening safety ECG with PR < 220 msec and QTcF interval of = 470 msec calculated by Fridericia Formula (Appendix 12).
    11. Echocardiogram (ECHO) with left ventricular ejection fraction (LVEF) = 45%.
    12. The following laboratory results must be met:
    • Absolute neutrophil count (ANC) = 1,500 cells/mm3 (1.5 x 109/L) (Growth factors cannot be used within 10 days (14 days for pegfilgrastim) prior to initiation of therapy)
    • Platelet count = 100,000 cells/mm3 (100 x 109/L) without required transfusions during the 10 days prior to initiation of therapy).
    • Hemoglobin = 9.0 g/dl (RBC transfusions are permitted).
    • Total Bilirubin = 1.5 x ULN. Higher value may be accepted in participants diagnosed with Gilbert syndrome, if approved by the medical monitor.
    • AST and ALT = 1.5 x ULN.
    • Renal function: Estimated GFR (eGFR) by CKD-EPI formula = 45 mL/min (Appendix 11). A lower value may be acceptable after consultation and approval of the medical monitor.
    13. Male participant agrees to use contraception as detailed in Appendix 4 of this protocol during the treatment period and for at least 90 days after the last dose of melflufen and refrain from donating sperm during this period.
    OR
    Female participant meets one of the following conditions:
    i. Not of child bearing potential as defined in Appendix 4
    ii. Not currently pregnant or breastfeeding and agrees to follow the contraceptive guidance in Appendix 4 during the treatment period and for at least 30 days after the last dose of melflufen.
    1. Soggetti ambosesso, di età = 18 anni al momento della firma del consenso informato.
    2. Diagnosi istochimica accertata di amiloidosi AL in base a campioni di tessuto sottoposti a
    colorazione con rosso Congo in cui sia evidente una birifrangenza color verde mela confermata con un metodo di tipizzazione appropriato, per es. spettrometria di massa, immunofluorescenza o immunoistochimica (con risultato del precedente campione di aspirato/biopsia tissutale accettabile).
    3. Almeno una precedente linea di terapia, definita come un regime che non preveda trapianti, un trapianto allogenico di cellule staminali (ASCT) o un regime di terapia di induzione seguito da un unico ASCT (senza progressione ematologica tra l’induzione e l’ASCT). Sono consentiti non più di 4 cicli di chemioterapia contenente melfalan.
    4. Malattia ematologica misurabile, definita in base a una concentrazione differenziale di catene leggere libere del siero (dFLC) = 20 mg/l (dFLC è la differenza tra FLC formanti amiloide [coinvolte] e non formanti amiloide [non coinvolte]).
    5. Coinvolgimento organico dell’amiloide (a livello cardiaco e/o renale e/o epatico) oggettivamente misurabile, come definito di seguito (è necessario il coinvolgimento amiloideo di almeno 1 organo). Si veda anche l’Appendice 9:
    a. coinvolgimento cardiaco: spessore medio della parete > 12 mm all’ecocardiogramma, senza altre cause cardiache o aumento dei livelli di peptide natruiretico pro-tipo B N- terminale (NT-pro-BNP) (> 332 ng/l) in assenza di insufficienza renale o fibrillazione atriale;
    b. coinvolgimento renale, definito da un livello di proteinuria (prevalentemente albumina)
    > 0,5 g/giorno in un campione di urine raccolto nelle 24 ore;
    c. coinvolgimento epatico: ampiezza totale del fegato > 15 cm in assenza di insufficienza cardiaca, o fosfatasi alcalina > 1,5 volte il limite superiore della norma (ULN) istituzionale.
    È consentito, ma non necessario, il coinvolgimento amiloideo di altri sistemi d’organo.
    6. Stato di validità secondo il Gruppo cooperativo orientale di oncologia (ECOG) = 2. Si veda
    Appendice 5.
    7. Le donne in età fertile (WOCBP) devono risultare negative al test di gravidanza sul siero o sulle urine (si veda Appendice 4).
    8. Capacità di comprendere l’obiettivo e i rischi dello studio e fornire il consenso informato firmato e datato nonché l’autorizzazione all’uso di informazioni sanitarie protette.
    9. Concentrazione di plasmacellule < 30% nel campione di aspirato o biopsia del midollo osseo.
    10. Elettrocardiogramma (ECG) di screening di sicurezza a 12 derivazioni con PR < 220 msec e intervallo QTcF = 470 msec calcolato usando la formula di Fridericia (Appendice 12).
    11. Ecocardiogramma (ECO) con frazione di eiezione del ventricolo sinistro (FEVS) = 45%.
    12. Devono essere soddisfatti i seguenti parametri di laboratorio:
    • conta assoluta dei neutrofili (ANC) = 1.500 cellule/mm3 (1,5 x 109/l) (è vietato l’uso di fattori di crescita nei 10 giorni [14 giorni per pegfilgrastim] precedenti l’inizio della terapia);
    • conta piastrinica = 100.000 cellule/mm3 (100 x 109/l) senza necessità di trasfusioni durante i 10 giorni che precedono l’inizio della terapia;
    • emoglobina = 9,0 g/dl (sono consentite trasfusioni di globuli rossi [RBC]);
    • bilirubina totale = 1,5 x ULN; valori più alti possono essere accettati nei partecipanti con diagnosi di sindrome di Gilbert, previa approvazione da parte del responsabile del monitoraggio medico;
    • aspartato aminotransferasi (AST) e alanina aminotransferasi (ALT) = 1,5 x ULN;
    • funzione renale: velocità di filtrazione glomerulare stimata (eGFR) calcolata secondo l’equazione della Collaborazione epidemiologica per la malattia renale cronica )CKD- EPI) = 45 ml/min (Appendice 11). Un valore inferiore può essere accettato previa consultazione e approvazione da parte del responsabile del monitoraggio medico.
    (...) si prega di fare riferimento al protocollo.
    E.4Principal exclusion criteria
    1. Amyloidosis due to known mutations of the transthyretin gene or presence of another non-AL amyloidosis.
    2. Cardiac risk stage 3 with NT-pro-BNP >5000 pg/mL (Appendix 7).
    3. Evidence of gastro-intestinal bleeding
    • Frank bleeding within 6 months prior to initiation of therapy.
    • Positive feces-hemoglobin/ fecal occult blood test within 6 months prior to initiation of therapy if clinically relevant. In case of a positive test within the last 6 months, a colonoscopy is required to exclude clinically relevant conditions.
    4. Evidence of mucosal or internal bleeding and/or are platelet transfusion refractory (i.e. platelet count fails to increase by =10,000 cells/mm3 [10 x 109/L] after transfusion of an appropriate dose of platelets).
    5. Medically documented cardiac syncope, NYHA (Appendix 8) Class 3 or 4 congestive heart failure, myocardial infarction within the previous 6 months, unstable angina pectoris, clinically significant ventricular arhythmias, or atrioventricular (AV) block
    6. Clinically significant finding on 24 h Holter recording performed at screening, including but not limited to high degree AV block (2nd degree type 2 or 3rd degree AV block), ventricular arrythmias and sign of sick sinus syndrome. (Bundle branch block is acceptable if clinically stable for =6 months)
    7. Supine systolic blood pressure <90 mm Hg, or orthostatic hypotension defined as a decrease in systolic blood pressure upon standing of >20 mmHg or symptomatic orthostatic hypotension regardless of the amount of the drop in mmHg, despite medical management (e.g., midodrine, fludrocortisones) in the absence of volume depletion. See Section 8.3.2 for details on the assessment of orthostatic hypotension
    8. Clinically significant factor X deficiency (in investigator's opinion)
    9. Clinically important autonomic disease (in investigator's opinion)
    10. Any medical conditions that, in the Investigator's opinion, would impose excessive risk to the patient or would adversely affect his/her participating in this study.
    11. Known active infection requiring parenteral or oral anti-infective treatment within 14 days of initiation of treatment. Other wash out period may be considered after consultation and approval of the medical monitor.
    12. Other malignancy diagnosed or requiring treatment within the past
    3 years with the exception of adequately treated basal cell carcinoma, squamous cell skin cancer, carcinoma in-situ of the cervix or breast, and very-low and low risk prostate cancer in active surveillance as defined in NCCN Guideline: Prostate Cancer (NCCN 2019).
    13. Pregnant or breast-feeding females.
    14. Serious psychiatric illness, active alcoholism, or drug addiction that may hinder or confuse compliance or follow-up evaluation.
    15. Known HIV or active hepatitis B or C viral infection.
    16. Concurrent symptomatic multiple myeloma (symptomatic defined as presence of bone lesion, extramedullary plasmacytoma or hypercalcemia (Rajkumar et al. 2014))
    17. POEMS syndrome [plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein (M-protein) and skin changes].
    18. Previous cytotoxic therapies, including cytotoxic investigational agents, within 3 weeks (6 weeks for nitrosoureas) prior to start of study treatment (Prednisone up to, but no more than, 10 mg orally q.d. or its
    equivalent for symptom management of comorbid conditions is permitted, but dose should be stable for at least 7 days prior to study treatment). Monoclonal antibodies (mAbs) within 4 weeks. Concomitant immunotherapy, investigational therapy, and anticoagulation therapy are not permitted (low dose acetylsalicylic acid (ASA) permitted).
    19. Residual side effects to previous therapy > Grade 1 prior to initiation of therapy (Alopecia, or neuropathy without pain, are permitted).
    20. Prior autologous or allogeneic stem cell transplant within 12 weeks of initiation of therapy.

    (...) please refer to protocol.
    1. Amiloidosi dovuta a mutazioni note nel gene della transferrina o presenza di un altro tipo di amiloidosi non-AL.
    2. Stadio 3 del rischio cardiaco con NT-pro-BNP > 5.000 pg/ml (Appendice 7).
    3. Evidenza di sanguinamento gastrointestinale:
    • sanguinamento evidente nei 6 mesi precedenti l’inizio della terapia.
    • positività al test fecale dell’emoglobina/esame del sangue occulto fecale nei 6 mesi precedenti l’inizio della terapia se clinicamente rilevante. In caso di test positivo negli ultimi 6 mesi, è richiesta una colonscopia per escludere condizioni clinicamente rilevanti.
    4. Evidenza di sanguinamento mucosale o interno e/o refrattarietà alla trasfusione di piastrine (ovvero, la conta piastrinica non riesce ad aumentare di =10.000 cellule/mm3 [10 x 10^9/l] dopo la trasfusione di una dose appropriata di piastrine).
    5. Sincope cardiaca clinicamente documentata, insufficienza cardiaca congestizia di classe 3 o 4 secondo la New York Heart Association (NYHA) (Appendice 8), infarto miocardico nei 6 mesi precedenti, angina pectoris instabile, aritmie ventricolari clinicamente significative o blocco atrio-ventricolare (AV).
    6. Riscontro clinicamente significativo al monitoraggio Holter delle 24 ore eseguito allo screening, compresi, senza limitazione, blocco AV di alto grado (2° grado tipo 2 o 3° grado di blocco AV), aritmie ventricolari e segni di sindrome del seno malato. (il blocco di branca è accettabile se clinicamente stabile da =6 mesi)
    7. Pressione arteriosa sistolica supina <90 mm Hg, o ipotensione ortostatica definita come una diminuzione della pressione arteriosa sistolica in posizione eretta >20 mmHg o ipotensione ortostatica sintomatica indipendentemente dalla quantità del calo in mmHg, nonostante la gestione medica (p. Es., Midodrine, fludrocortisone) in assenza di riduzione del volume. Si veda la Sezione 8.3.2 per i dettagli sulla valutazione dell’ipotensione ortostatica.
    8. Deficit del fattore X clinicamente significativo (secondo il parere dello sperimentatore).
    9. Malattia del sistema autonomo clinicamente significativa (secondo il parere dello
    sperimentatore).
    10. Qualsiasi condizione medica che, secondo il parere dello sperimentatore, comporterebbe un
    rischio eccessivo per il paziente o avrebbe un impatto negativo sulla sua partecipazione allo studio.
    11. Infezione nota in fase attiva che richiede un trattamento antinfettivo per via parenterale od orale nei 14 giorni precedenti l’inizio del trattamento. Previa consultazione e approvazione
    da parte del responsabile del monitoraggio medico, è possibile valutare la possibilità di un altro periodo di washout.
    12. Altro tumore maligno diagnosticato o che richiede un trattamento negli ultimi 3 anni, ad eccezione di carcinoma a cellule basali adeguatamente trattato, carcinoma cutaneo a cellule squamose, carcinoma in situ della cervice o della mammella e carcinoma prostatico a basso e bassissimo rischio in fase di sorveglianza attiva, come definito nelle Linee guida del National Comprehensive Cancer Network (NCCN): carcinoma prostatico (NCCN 2019).
    13. Soggetti di sesso femminile in stato di gravidanza o allattamento.
    14. Malattia psichiatrica grave, alcolismo attivo o dipendenza da farmaci che potrebbe impedire o confondere la valutazione della conformità o del follow-up.
    15. Nota infezione da virus dell’immunodeficienza umana (HIV) o di epatite B o C in fase attiva.
    16. Mieloma multiplo sintomatico concomitante (per sintomatico si intende la presenza di lesioni ossee, plasmacitoma extramidollare o ipercalcemia [Rajkumar et al. 2014]).
    17. Sindrome di POEMS (discrasia delle plasmacellule con polineuropatia, organomegalia, endocrinopatia, proteina monoclonale [M] e alterazioni cutanee).
    (...) si prega di fare riferimento al protocollo.
    E.5 End points
    E.5.1Primary end point(s)
    Phase 1
    • Frequency and grade of adverse events (AE) and laboratory values
    • Dose-Limiting Toxicity (DLT) during Cycle 1 up to a maximum dose of melflufen of 40 mg
    Phase 2
    • The proportion of participants who achieve a hematologic Complete Response (CR), Very Good Partial Response (VGPR), or Partial Response (PR)
    Fase 1
    • Frequenza e grado degli eventi avversi (EA) e valori di laboratorio
    • Tossicità limitanti la dose (DLT) durante il Ciclo 1 fino a una dose massima di melflufen pari a 40 mg
    Fase 2
    • Percentuale di partecipanti che raggiungono una risposta ematologica complete (CR), risposta parziale molto buona (VGPR) o risposta parziale (PR)
    E.5.1.1Timepoint(s) of evaluation of this end point
    During the course of the study
    durante il corso dello studio
    E.5.2Secondary end point(s)
    Phase 1
    • Melphalan plasma concentration post melflufen administration
    • Best hematologic response (CR, VGPR, PR, NR, or PD)
    • Duration of hematologic response (CR, VGPR, PR)
    • Proportion of participants with kidney, cardiac or liver response, respectively
    • Duration of organ system specific responses (separately for kidney, cardiac, and liver)
    • The proportion of participants who achieve a hematologic CR, VGPR, or PR
    • Time to next AL amyloidosis treatment
    • OS
    Phase 2
    • Frequency and grade of AEs and laboratory values
    • Best hematologic response (CR, VGPR, PR, NR, or PD)
    • Duration of hematologic response (CR, VGPR, PR)
    • Proportion of participants with kidney, cardiac or liver response, respectively
    • Duration of organ system specific responses (separately for kidney, cardiac, and liver)
    • Time to next AL amyloidosis treatment
    • OS
    Fase 1
    • Concentrazione plasmatica di melfalan dopo la somministrazione di melflufen
    • Migliore risposta ematologica (CR, VGPR, PR, nessuna risposta [NR] o progressione della malattia [PD])
    • Durata della risposta ematologica (CR, VGPR, PR)
    • Percentuale di partecipanti con risposta renale, cardiaca o epatica, rispettivamente
    • Durata delle risposte specifiche per il sistema d’organi (separatamente per rene, cuore e fegato)
    • Percentuale di partecipanti che raggiungono una risposta ematologica di CR, VGPR o PR
    • Tempo al successivo trattamento per l’amiloidosi AL
    • OS

    Fase 2
    • Frequenza e grado degli EA e valori di laboratorio
    • Migliore risposta ematologica (CR, VGPR, PR, NR o PD)
    • Durata della risposta ematologica (CR, VGPR, PR)
    • Percentuale di partecipanti con risposta renale, cardiaca o epatica, rispettivamente
    • Durata delle risposte specifiche per il sistema d’organi (separatamente per rene, cuore e fegato)
    • Tempo al successivo trattamento per l’amiloidosi AL
    • OS
    E.5.2.1Timepoint(s) of evaluation of this end point
    During the course of the study
    durante il corso dello studio
    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 Yes
    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
    Valutazione terapeutica
    Valutazione terapeutica
    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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA9
    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
    Israel
    United States
    Czechia
    France
    Germany
    Greece
    Italy
    Norway
    Poland
    Spain
    United Kingdom
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LPLV
    LVLS
    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 months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months6
    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: 30
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 16
    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 state4
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 24
    F.4.2.2In the whole clinical trial 46
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Standard of Care.
    Standard of Care.
    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 Decision2019-10-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-10-23
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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