| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Refractory multiple myeloma (MM) or relapsed and refractory MM |
| mieloma multiplo refrattario o recidivante e refrattario |
|
| E.1.1.1 | Medical condition in easily understood language |
| Blood cancer:certain blood cells multiply abnormally in the bone marrow,impair the production of other blood cell and produce proteins that cumulate in other organs impairing the functions |
| Tumore ematico:alcune cell ematiche si moltiplicano in modo anomalo danneggiando la produzione di altre cell ematiche e producendo proteine che si accumulano in organi alterando la funzione |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | SOC |
| E.1.2 | Classification code | 10029104 |
| E.1.2 | Term | Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10028228 |
| E.1.2 | Term | Multiple myeloma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| Evaluate the safety of the combination of pomalidomide (POM) and low dose dexamethasone (LD-DEX) in a large cohort of subjects with refractory MM or relapsed and refractory MM |
| Valutare la sicurezza della combinazione di pomalidomide (POM) e di un basso dosaggio di desametasone (LD-DEX) in un’ampia coorte di soggetti con MM refrattario o MM recidivante e refrattario |
|
| E.2.2 | Secondary objectives of the trial |
| -Analyze the population pharmacokinetics of POM and assess POM exposure response relationships in subjects with refractory MM or relapsed and refractory MM administered POM and LD-DEX. -Evaluate efficacy of the combination of POM and LD-DEX in subjects with refractory MM or relapsed and refractory MM |
| -Analizzare la farmacocinetica del POM nella popolazione e valutare le relazioni della risposta all’esposizione al POM in soggetti con MM refrattario o MM recidivante e refrattario a cui vengono somministrati POM e LD-DEX. -Valutare l’efficacia della combinazione di POM e di LD-DEX in soggetti con MM refrattario o MM recidivante e refrattario |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| 1.Must be≥18yrs at the time of signing the ICD 2.pt must understand and sign an ICD prior to any study related assessments/procedures 3.Must be able to adhere to the study visit schedule/protocol requirements 4.Pts must have documented diagnosis of MM and measurable disease(serum M-protein≥0.5g/dL or urine M-protein≥200mg/24 hours) 5.Pts must have undergone prior treatment with ≥2treatment lines of anti-myeloma therapy.Induction therapy followed by ASCT and consolidation/maintenance will be considered as 1line.A new treatment line is always started after PD 6.Pts must have either refractory or relapsed and refractory disease defined as documented disease progression during or within 60days of completing their last myeloma therapy Primary refractory:Pts who never achieved any response better than PD to any previous line of anti-myeloma therapy Relapsed and refractory:Pts who relapsed after having achieved at least stable disease for at least 2cycles of treatment to at least one prior regimen and then developed PD on or within 60days of completing their last myeloma therapy 7.pts must have received at least 2consecutive cycles of prior treatment including lenalidomide and bortezomib,either alone or in combination regimens Pts must have failed both lenalidomide and bortezomib and medical records must be available to provide documentation of the refractoriness that make the subject eligible for the study -pts must have failed treatment with the last lenalidomide-containing regimen in one of the following ways: +Documented PD during or within 60days of completing last treatment with lenalidomide,regardless of the response achieved,or +In case of prior response(≥partial response-PR)to lenalidomide and PD >60days,pts must have relapsed within 6months after the last dose of treatment with lenalidomide-containing regimens -All pts must have failed treatment with the last bortezomib-containing regimen in one of the following ways: +Documented PD during or within 60days of completing treatment with bortezomib,regardless of the response achieved,or +In case of prior response(≥PR to bortezomib and PD>60days,pts must have relapsed within 6months after the last dose of treatment with bortezomib-containing regimens, Or for non-progressive pts: +pts who have less than minor response(MR and have developed intolerance/toxicity after a minimum of 2cycles of a bortezomib-containing regimen.Toxicity such as>grade2 peripheral neuropathy or≥grade2 painful neuropathy.Peripheral neuropathy must resolve to grade1prior to study entry 8.pts must have received adequate prior alkylator therapy in one of the following ways: a.As part of a stem cell transplant;or b.A minimum of 4consecutive cycles of an alkylator based therapy;or c.Progression on treatment with an alkylator;provided that the pt received at least 2 cycles of an alkylator-containing therapy 9.ECOG performance status score of 0,1,or2. 10.Females of childbearing potential(FCBP1)must utilize 2reliable forms of contraception simultaneously or practice complete abstinence from heterosexual contact for at least 28days before starting study drug,while participating in the study(including dose interruptions),and for at least 28days after study treatment discontinuation and must agree to regular pregnancy testing during this timeframe. 11.Females must abstain from breastfeeding during study participation and 28days after study drug discontinuation. 12.Males must use a latex condom during any sexual contact with FCBP while participating in the study and for28days following discontinuation from this study,even if he has undergone a successful vasectomy. 13.Males must refrain from donating semen or sperm while on POM and for28days after discontinuation from this study treatment 14.pts must agree to refrain from donating blood 15.pts must agree not to share IP |
| 1.avere≥18anni al momento della firma del cons.informato(ICD) 2.comprendere e firmare l'ICD prima di ogni valutazione/procedura per lo studio 3.rispettare le visite previste e altri requisiti dello studio 4.avere una diagnosi documentata di MM e patologia misurabile(proteina M nel siero ≥0,5g/dl oppure proteina M nelle urine ≥200mg/24ore) 5.essersi sottoposti precedentemente a trattamento con ≥2linee di trattamento anti-mieloma.La terapia d'induzione seguita da ASCT e relativo consolidamento/mantenimento è un’unica linea.Una nuova linea di trattamento inizia dopo una PD 6.essere affetti o da patologia refrattaria o da patologia recidivante e refrattaria definita come progressione documentata della patologia o che avviene entro 60gg dal completamento dell’ultima terapia contro il mieloma Refrattario primario:sogg.che non hanno mai ottenuto risposta migliore di una PD a ogni linea di terapia anti-mieloma precedente Recidivante e refrattaria:sogg.che hanno avuto una recidiva in seguito almeno a una stabilizzazione della patologia per almeno 2cicli di trattamento con almeno uno dei precedenti regimi terapeutici e in seguito hanno sviluppato una PD oppure entro 60gg dal completamento dell’ultima terapia contro il mieloma 7.aver ricevuto almeno 2cicli consecutivi del trattamento precedente che includeva lenalidomide e bortezomib singolarmente oppure in regimi terapeutici combinati Devono aver fallito con entrambi,lenalidomide e bortezomib,e le cartelle cliniche devono documentare i criteri di refrattarietà che rendono i soggetti elegibili •aver fallito il trattamento con l’ultimo regime terapeutico contenente lenalidomide in una delle seguenti modalità: -PD documentata durante o entro 60gg dal completamento dell’ultimo trattamento con lenalidomide a prescindere dalla risposta ottenuta oppure -in caso di precedente risposta(≥risposta parziale-PR)al lenalidomide e PD>60gg devono aver mostrato una recidiva entro 6mesi dall’ultima dose di trattamento con regimi terapeutici contenenti lenalidomide. •aver fallito il trattamento con l’ultimo regime terapeutico contenente bortezomib in una delle seguenti modalità: -PD documentata durante o entro 60gg dal completamento dell’ultimo trattamento con bortezomib a prescindere dalla risposta ottenuta oppure -in caso di precedente risposta(≥PR)al bortezomib e PD≥60gg devono aver mostrato una recidiva entro 6mesi dall’ultima dose di trattamento con regimi terapeutici contenenti bortezomib, oppure per i sogg.che non mostrano progressione: -sogg.che mostrano una risposta inferiore alla risposta minima(MR)e che hanno sviluppato intolleranza/tossicità dopo un minimo di 2cicli di un regime terapeutico contenente bortezomib.Tossicità come per es.neuropatia periferica di grado>2 o neuropatia dolorosa di grado≥2.La neuropatia periferica deve risolversi al grado1 prima dell’ingresso nello studio. 8.aver ricevuto un’adeguata terapia alchilante precedente in una delle seguenti modalità: a.come parte del trapianto di cellule staminali;oppure b.un minimo di 4cicli consecutivi di una terapia a base di alchilanti;oppure c.Progressione nel trattamento con un alchilante;ammesso che abbia ricevuto almeno 2cicli di una terapia contenente alchilanti. 9.Punteggio dello stato prestazionale di 0,1o2 sulla scala ECOG 10.donne potenzialmente fertili(FCBP)devono usare 2forme affidabili di contraccettivo contemporaneamente o praticare la completa astinenza per almeno 28gg prima di iniziare il farmaco e dopo e sottoporsi a test di gravidanza 11.Le donne devono astenersi dall’allattamento al seno durante lo studio 12.Gli uomini devono usare un profilattico durante lo studio anche se sottoposti a vasectomia 13.Gli uomini non devono donare seme o sperma durante lo studio 14.i sogg.non devono donare sangue 15.i sogg.non devono condividere il farmaco in studio |
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| E.4 | Principal exclusion criteria |
| 1.Any of the following lab abnormalities: -Absolute neutrophil count<1,000/μL -Platelet count<75,000/μL for subjects in whom <50%of bone marrow nucleated cells are plasma cells;or a platelet count<30,000/μL for subjects in whom ≥50%of bone marrow nucleated cells are plasma cells.Platelet transfusion is not allowed within the previous 3days before screening. -Creatinine Clearance(CrCl)<45mL/min according to Cockcroft-Gault formula. If CrCl calculated from the 24H urine sample is ≥45mL/min,subject will qualify for the study -Corrected serum calcium >14mg/dL(>3.5mmol/L) -Hemoglobin <8g/dL(<4.9mmol/L;prior red blood cells transfusion or recombinant human erythropoietin use is permitted) -Serum SGOT/AST or SGPT/ALT>3.0 x upper limit of normal(ULN) -Serum total bilirubin>2.0mg/dL(34.2μmol/L);or>3.0xULN for subjects with hereditary benign hyperbilirubinemia 2.Prior history of malignancies,other than MM unless the subject has been free of disease for≥5years.Exceptions include the following: -Basal or squamous cell carcinoma of the skin -Carcinoma in situ of the cervix or breast -Incidental histological finding of prostate cancer(TNM stage of T1a or T1b) 3.Previous therapy with POM 4.Hypersensitivity to thalidomide,lenalidomide,or DEX(this includes ≥Grade3 rash during prior thalidomide or lenalidomide therapy) 5.Peripheral neuropathy ≥Grade2 6.Subjects who received allogeneic bone marrow or allogeneic peripheral blood stem cell transplant less than 12months prior to study treatment and who have not discontinued immunosuppressive treatment for at least 4weeks prior to initiation of study treatment and are currently dependent on such treatment 7.Subjects who are planning for or who are eligible for stem cell transplant 8.Subjects with any one of the following: -Congestive heart failure(NY Heart Association Class III or IV) -Myocardial infarction within 12months prior to starting study treatment -Unstable or poorly controlled angina pectoris,including Prinzmetal variant angina pectoris 9.Subjects who received any of the following within the last 14days of initiation of study treatment: -Major surgery(kyphoplasty is not considered major surgery) -Use of any anti-myeloma drug therapy 10.Use of any investigational agents within 28days or 5half-lives(whichever is longer)of treatment,unless approved by the Sponsor 11.Incidence of gastrointestinal disease that may significantly alter the absorption of POM 12.Subjects unable or unwilling to undergo antithrombotic prophylactic treatment 13.Any serious medical condition,lab abnormality,or psychiatric illness that would prevent the subjects from signing the ICD 14.Pregnant or breastfeeding females 15.Known human immunodeficiency virus(HIV)positivity,active infectious hepatitis A,B or C or chronic hepatitis B or C. |
| 1.Una qualsiasi delle seguenti anomalie di lab: •Conta assoluta dei neutrofili<1.000/μl •Conta piastrinica<75.000/μl in sogg.in cui<50%delle cell nucleate del midollo osseo sono cell plasmatiche;oppure una conta piastrinica<30.000/μl in sogg in cui≥50%delle cell nucleate del midollo osseo sono cell plasmatiche.La trasfusione di piastrine non è permessa nei 3gg precedenti lo screening •Clearance della creatinina(CrCl)<45ml/min secondno la formula di Cockcroft-Gault.Se la CrCl calcolata sullle urine delle 24 ore è ≥45ml/min, il sogg sarà considerato idoneo allo studio •Calcio sierico corretto >14mg/dl(>3,5mmol/l) •Emoglobina <8g/dl(<4,9mmol/l;è consentito l’usoo di precedenti trasfusioni di globuli rossi o eritropoietina ricombinante umana) •Transaminasi sieriche:transaminasi glutammico-ossalacetica (SGOT)/aspartato-aminotransferasi(AST)oppure transaminasi glutammico-piruvica(SGPT)o/alanina-aminotransferasi(ALT)> 3,0volte il limite superiore alla norma(LSN) •Bilirubina sierica totale >2,0mg/dl(34,2μmol/l);oppure >3,0volte l’LSN per soggetti con iperbilirubinemia benigna ereditaria 2.Precedente anamnesi di malignità,diversa dall’MM,eccetto il caso in cui il sogg sia libero dalla patologia da ≥5anni.Le eccezioni includono quanto segue: •Carcinoma della pelle a cellule basali o squamose •Carcinoma in situ della cervice o del seno •Occasionali scoperte istologiche di cancro della prostata(stadio TNM di T1a o T1b) 3.Precedente terapia con POM 4.Ipersensibilità a talidomide,lenalidomide oppure DEX (compreso eruzione cutanea ≥Grado3 durante la precedente terapia con talidomide o lenalidomide) 5.Neuropatia periferica ≥Grado 2 6.sogg che hanno ricevuto un trapianto di midollo osseo allogenico o un trapianto di cellule staminali ematiche allogeniche periferiche meno di 12mesi prima dell’inizio dello studio e che non hanno interrotto un trattamento immunosoppressivo per almeno 4settimane prima dell’inizio dello studio e sono attualmente dipendenti da tale trattamento 7.Sogg che stanno programmando o che sono idonei per un trapianto di cellule staminali. 8.Sogg affetti da una delle seguenti patologie: •Insuff cardiaca congestizia(Classe III o IV secondo la New York Heart Association) •Infarto miocardico nei 12mesi precedenti l’inizio del trattamento •Angina pectoris instabile o scarsamente controllata,inclusa l’angina pectoris variante di Prinzmetal. 9.Sogg che sono stati sottoposti a un qualsiasi dei seguenti nei 14gg precedenti l’inizio del trattamento: •Operazioni importanti(la chifoplastica non è considerata un’operazione importante) •Utilizzo di un qualsiasi farmaco anti-mieloma 10.Uso di qualsiasi agente sperimentale durante i 28gg o le 5emivite(qualunque fosse più lungo)del trattamento,se non approvato dallo Sponsor. 11.Incidenza di patologie gastrointestinali che possono alterare l’assorbimento del POM. 12.sogg incapaci o non disposti a sottoporsi a un trattamento di profilassi antitrombotica 13.Qualsiasi condizione medica grave, anormalità di laboratorio,o patologia psichiatrica che potrebbe impedire ai soggetti di firmare l’ICD. 14.Donne in gravidanza o allattamento. 15.Nota positività al virus dell’immunodeficienza umana (HIV), epatite A, B o C infettiva attiva oppure epatite B o C cronica |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Adverse events (AEs) assessment (type, frequency, seriousness, severity, relationship to POM and/or DEX and outcomes), including second primary malignancies (SPM) |
| Valutazione (tipologia, frequenza, serietà, gravità, relazioni con POM e/o con DEX ed esiti) degli eventi avversi (EA), incluse le seconde malignità primarie (SPM) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| -AEs: After signing ICD and until 28 days after discontinuation from treatment. -SPM: Every 3 months after signing ICD and up to 5 years after last subject enrollment or longer if clinically indicated. |
| -EAs: a partire dalla firma dell’ICD fino a 28 giorni dopo l’interruzione del trattamento oggetto dello studio -SPM: ogni 3 mesi per 5 anni a partire dall’arruolamento dell’ultimo soggetto oppure più a lungo se clinicamente indicato |
|
| E.5.2 | Secondary end point(s) |
| 1)POM exposure. 2)POM population pharmacokinetics and exposure-response. 3)Overall response rate (ORR). 4)Time to response. 5)Duration of response (DoR). 6)Progression-free survival (PFS). 7)Time to progression (TTP). 8)Overall survival (OS). |
| •Esposizione a POM •Farmacocinetica di POM nella popolazione e risposta all’esposizione •Tasso di risposta complessivo (ORR) •Tempo alla risposta •Durata della risposta (DoR) •Sopravvivenza senza progressione (PFS) •Tempo alla progressione (TTP) •Sopravvivenza globale (SG) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 1)Day 1 (± 1) of every cycle,Treatment Discontinuation 2)Day 15 (± 2) Cycles 1-6 only,Day 1 (± 1) of every cycle 3)Percentage of confirmed responders, as well as being summarized by each response category (i.e., stringent complete response (SCR),CR,VGPR,PR,SD, &PD)in the ORR using the IMWG criteria. 4)time from study enrollment to the first documented response (PR/better) based on IMWG criteria. 5)time from the initial documented response(PR/better)to the first confirmed PD 6)death from any cause on study treatment 7)time from study enrollment until PD(as determined by the site investigator based on the IMWG criteria) 8)time from study enrollment until the time of death from any cause. |
| 1)giorno 1 (+-1) di ogni ciclo,discontinuazione dal trattamento 2)giorno 15 (+-2) solo per cicli 1-6,giorno 1 (+-1) di ogni ciclo, 3)percentuale di responders 4)tempo dall'arruolamento nello studio fino alla prima risposta (PR) su IMGW criteria 5)tempo dall'arruolamento nello studio fino alla prima PD 6)morte per qualsiasi causa 7)tempo dall'arruolamento nello studio fino alla prima PD (da giudizio medico basandosi suo criteri IMGW) 8)tempo dall'arruolamento nello studio fino alla morte |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | Information not present in EudraCT |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 11 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 78 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial 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
|
| Study consists of:Screening,Treatment and Follow-up(FU).Screening period may be up to 28days prior to start of study treatment.Treatment phase continues until documented progressive disease,discontinuation of study drug for any reason/as long as subjects benefit from therapy according to the opinion of the responsible study Investigator and discussed with the Sponsor.FU phase will start and continue for up to 5years from the last subject enrolled or longer if clinically indicated. |
| Lo studio comprende:Screening,Trattamento e Follow Up(FU).Screening può durare fino a 28gg dall'inizio del trattamento.Trattamento può durare fino a documentata progressione di malattia e/o interruzione del farmaco.FU dura 5aa dall’ultimo pz. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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