| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Liver Cancer |
| Carcinoma del fegato |
|
| 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 | LLT |
| E.1.2 | Classification code | 10049010 |
| E.1.2 | Term | Carcinoma hepatocellular |
| 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 | HLT |
| E.1.2 | Classification code | 10019814 |
| E.1.2 | Term | Hepatobiliary neoplasms malignancy unspecified |
| 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 | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of this study is to determine the time to progression (TTP) based on investigator assessment of OSI-906 in HCC patients who have failed first-line treatment with sorafenib, compared with placebo. For the primary objective, TTP is defined as time from randomization to radiological disease progression based on RECIST version 1.1 as assessed by investigator. |
| L'obiettivo primario di questo studio e' la determinazione del tempo alla progressione (TTP), basato sulla valutazione dell'investigatore, in pazienti trattati con OSI-906 affetti da HCC che non hanno risposto al trattamento di prima linea con sorafenib, rispetto al placebo. Per l'obiettivo primario il TTP e' stato definito come il tempo dalla randomizzazione alla progressione radiologica della malattia in base ai criteri RECIST versione 1.1, come valutato dall'investigatore. |
|
| E.2.2 | Secondary objectives of the trial |
| The secondary objectives are to evaluate:  Overall survival (OS);  Safety (including safety review for first 18 patients);  Progression-free survival (PFS);  Disease control rate (DCR);  Overall response rate (ORR);  TTP, PFS, OS, and ORR in patients with hepatitis B and/or C;  Pharmacokinetics;  Potential relationships between exploratory biomarkers associated with the IGF-1R and IR signaling axes and other predictive and prognostic markers related to clinical outcomes; and  TTP based on the following definition analyzed as exploratory analyses: – TTPc: defined as time from randomization to progression (either radiological disease progression based on RECIST version 1.1 orsymptomatic clinical progression as assessed by investigator). |
| Gli obiettivi secondari sono la valutazione di: • Sopravvivenza globale (OS), • sicurezza (incluso l`analisi della sicurezza per i primi 18 pazienti), • Sopravvivenza senza progressione (PFS), • Tasso di controllo della malattia (DCR), • Tasso di risposta globale (ORR), • TTP, PFS, OS e ORR in pazienti affetti da epatite B e/o C, • Farmacocinetica, • Possibile rapporto tra biomarcatori esplorativi associati alle vie del segnale di IGF-1R e IR e altri marcatori predittivi e prognostici correlati agli esiti clinici, • TTP basato sulla seguente definizione analizzato per le analisi esplorative: – TTPc: definito come tempo dalla randomizzazione alla progressione (o la progressione radiologica della malattia in base ai criteri RECIST versione 1.1 o la progressione clinica sintomatica valutata dall`investigatore). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| Histologically confirmed diagnosis of advanced HCC. Clinical diagnosis by American Association for the Study of Liver Diseases (AASLD) criteriain cirrhotic patients is acceptable. For patients without cirrhosis histological confirmation is mandatory; • Patient has received their last dose of sorafenib at least 14 days prior to randomization; • Patient has recovered from sorafenib or investigational agent related toxicity to </= grade 2; • Measurable disease according to RECIST (version 1.1); • ECOG PS 0 – 1; • Age >/= 18 years; • Child-Pugh Status A or B; • Barcelona Clinic Liver Cancer (BCLC) stage B/C; • Previous local therapy (eg, surgery, radiation therapy, hepatic arterial therapy, chemoembolization, radiofrequency ablation, percutaneous ethanol injection, or cryoablation) is permitted if >/= 21 days before randomization; • Fasting glucose </= 150 mg/dL (8.3 mmol/L). Concurrent use of noninsulinotropic oral antihyperglycemic therapy is permitted if the dose has been stable for >/= 4 weeks at the time of randomization; • Following laboratory parameters (determined by local laboratory): – Platelet count >/= 60 x 10^9/L; – Hemoglobin >/= 8.5 g/dL; – ANC >/= 1.5 x 10^9/L; – Potassium within normal limits (supplementation is permitted); – PTT </= 2.3 x ULN; – Magnesium within normal limits (supplementation is permitted); and – Calcium within normal limits (supplementation is permitted). • Adequate organ function (for a HCC population): – LFT </= 5 x ULN; – Albumin >/= 2.8 g/dL; – Total bilirubin </= 2.8 mg/dL; – Creatinine </= 1.5 x ULN; • Estimated Life Expectancy >/= 12 weeks based on an investigator assessment of recent changes in laboratory values, performance status, and other clinical criteria; • Patients – both males and females – with reproductive potential (ie, menopausal for less than 1 year and not surgically sterilized) must agree to practice effective contraceptive measures throughout the study. Women of childbearing potential must provide a negative pregnancy test (serum or urine) within 14 days prior to randomization; • Patients must provide written informed consent to participate in the study; • Prior radiation therapy is permitted provided patients have recovered from the acute, toxic effects of radiotherapy prior to randomization. A minimum of 21 days must have elapsed between the end of radiotherapy and randomization; and • Prior surgery is permitted provided that the surgery was done >/= 28 days prior to randomization and adequate wound healing has occurred prior to randomization. |
| •Diagnosi di HCC in stadio avanzato confermata istologicamente. E` accettabile la diagnosi clinica secondo i criteri dell`American Association for the Study of Liver Diseases (AASLD) in pazienti cirrotici (riferimento). Per i pazienti senza cirrosi, e` obbligatoria la conferma istologica. •I pazienti devono aver ricevuto l`ultima dose di sorafenib almeno 14 giorni prima della randomizzazione.•I pazienti devono essere guariti dalla tossicita` <= grado 2 verso sorafenib o il farmaco in studio. •Malattia misurabile secondo i criteri RECIST (versione 1.1). •ECOG PS 0 – 1 (riferimento). •Eta` >= 18 anni. •Classificazione Child-Pugh A o B (7) (riferimento).• Stadio B/C secondo la classificazione BCLC (Barcelona Clinic Liver Cancer) (riferimento). •La terapia locale precedente (per es., intervento chirurgico, radioterapia, terapia arteriosa epatica, chemioembolizzazione, ablazione con radiofrequenza, iniezione percutanea di etanolo o crioablazione) e` permessa, se terminata almeno 21 giorni prima della randomizzazione. •Glucosio a digiuno  150 mg/dL (8,3 mmol/L). Utilizzo concomitante della terapia anti-iperglicemica non insulinotropica per via orale, se la dosee` stabile da almeno 4 settimane al momento della randomizzazione. •Seguenti parametri di laboratorio (determinati dal laboratorio locale): –Conta delle piastrine  60 x 10 9/L –Emoglobina  8,5 g/dL –ANC  1,5 x 10 9/L –Potassio entro i limiti di normalita` (e` consentita un`integrazione) –PTT <= 2,3 x ULN –Magnesio entro i limiti di normalita` (e` consentita un`integrazione) –Calcio entro i limiti di normalita` (e` consentita un`integrazione) •Funzionalita` dell`organo adeguata (per una popolazione di HCC): –LFT <= 5 x ULN –Albumina >= 2,8 g/dL –Bilirubina totale>= 2,8 mg/dl –Creatinina <= 1,5 x ULN –INR  2,3• Aspettativa di vita stimata >= 12 settimane in base alla valutazione dell`investigatore sui recenti cambiamenti dei valori di laboratorio, dello stato di prestazione e di altri criteri clinici. • I pazienti, sia donne sia uomini, potenzialmente fertili (cioe` in menopausa da meno di 1 anno e non sterilizzati chirurgicamente), devono accettare di utilizzare un metodo contraccettivo efficace per l`intera durata dello studio (consultare la sezione di riferimento). Le donne in eta` fertile devono fornire un test di gravidanza negativo (siero o urina), eseguito nei 14 giorni precedenti la randomizzazione. •I pazienti devono presentare un consenso informato firmato per partecipare allo studio. •La radioterapia precedente e` concessa, purche` i pazienti abbiano recuperato gli effetti acuti, tossici della radioterapia prima della randomizzazione. Deve essere trascorso un periodo minimo di 21 giorni tra la conclusione della radioterapia e la randomizzazione. •Un intervento chirurgico pregresso e` concesso, purche` sia stato eseguito almeno 28 giorni prima della randomizzazione e vi sia stata un`adeguata guarigione della ferita prima della randomizzazione. |
|
| E.4 | Principal exclusion criteria |
| Child-Pugh B (8 – 9) or C (Appendix 13–5);  Patients who are candidates for potentially curative intervention (ie, surgical resection or transplantation);  Type 1 diabetes mellitus or Type 2 diabetes mellitus currently requiring insulinotropic or insulin therapy (Appendix 13–7);  Prior IGF-1R therapy;  Patients requiring interferon;  Patients with uncontrolled symptomatic ascites;  Prior investigational agent within 21 days prior to randomization;  History of poorly controlled gastrointestinal disorders that could affect the absorption of study drug (eg, Crohn’s disease, ulcerative colitis, etc);  History of organ allograft including liver transplant;  Malignancy other than HCC within the past 3 years:  Exceptions: resected basal cell or squamous cell carcinoma of the skin; cured in situ cervical carcinoma; cured ductal carcinoma in situ of the breast; and/or cured superficial bladder cancer.  History (within last 6 months) of significant cardiovascular disease unless the disease is well-controlled. Significant cardiac disease includes second/third degree heart block; clinically significant ischemic heart disease; superior vena cava (SVC) syndrome; poorly controlled hypertension; congestive heart failure of New York Heart Association (NYHA) Class II or worse (slight limitation of physical activity; comfortable at rest, but ordinary physical activity results in fatigue, palpitation, or dyspnea). History of arrhythmia (multifocal premature ventricular contractions [PVCs], bigeminy, trigeminy, ventricular tachycardia, or uncontrolled atrial fibrillation) that is symptomatic or requires treatment ( grade 3), left bundle branch block (LBBB), or asymptomatic sustained ventricular tachycardia are not allowed. Patients with atrial fibrillation controlled by medication are not excluded;  QTcF interval at screening 450 msec;  Use of drugs that have a risk of causing Torsades de Pointes (TdP) (‘Torsades List’ on www.azcert.org/medical-pros/druglists/ bycategory.cfm, see Appendix 13–3) are prohibited within 14 days prior to randomization;  Use of the potent CYP1A2 inhibitors ciprofloxacin and fluvoxamine. Other less potent CYP1A2 inhibitors/inducers are not excluded;  History of cerebrovascular accident (CVA) within 6 months prior to randomization or that resulted in ongoing neurologic instability;  Active infection or serious underlying medical condition (including any type of active seizure disorder within 12 months prior to randomization) that would impair the ability of the patient to receive study drug;  History of human immunodeficiency virus (HIV) infection or acquired immune deficiency syndrome (AIDS)-related illness or serious acute or chronic illness;  History of any psychiatric or neurologic condition that might impair the patient’s ability to understand or to comply with the requirements of the study or to provide informed consent;  Pregnant or breast-feeding females;  Symptomatic brain metastases that are not stable, require steroids, are potentially life-threatening, or that have required radiation within 28 days prior to randomization; and/or  History of allergic reactions attributed to compounds of similar chemicalor biologic composition to study drug. |
| • Classificazione Child-Pugh B (8 - 9) o C (riferimento). • Pazienti candidati per possibili interventi terapeutici (cioe`, resezione chirurgica o trapianto). • Diabete mellito di tipo 1 o 2 che al momento richiede terapia insulinotropica o insulinica (riferimento). • Precedente terapia -IGF-1R. • Pazienti che richiedono interferone. • Pazienti con ascite sintomatico non controllato. • Assunzione del farmaco in studio nei 21 giorni precedenti la randomizzazione. • Anamnesi di disturbi gastrointestinali scarsamente controllati che potrebbero influire sull`assorbimento del farmaco in studio (per es. malattia di Crohn, colite ulcerosa, ecc.). • Storia di allotrapianto di organo, tra cui trapianto del fegato. • Malignita` diversa dall`HCC nei 3 anni precedenti. • Eccezioni: carcinoma delle cellule squamose o basali della pelle asportato, carcinoma della cervice in situ curato, carcinoma duttale in sito della mammella curato e/o carcinoma superficiale della vescica curato. • Anamnesi (negli ultimi 6 mesi) di malattia cardiovascolare significativa, tranne nel caso in cui la malattia sia ben controllata. Cardiopatia significativa che include blocco cardiaco di grado II o III; cardiopatia ischemica clinicamente significativa; sindrome della vena cava superiore (SVC), ipertensione scarsamente controllata; insufficienza cardiaca congestizia di classe II secondo la New York Heart Association (NYHA) o peggiore (lieve limitazione dell`attivita` fisica, stato adeguato a riposo, ma l`attivita` fisica ordinaria da` affaticamento, palpitazione o dispnea). • Non e` consentita l`anamnesi di aritmia (contrazioni ventricolari premature multifocali [PVC], bigeminia, trigeminia, tachicardia ventricolare o fibrillazione atriale non controllata) che e` sintomatica o richiede trattamento ( grado 3), blocco di branca sinistra (LBBB) o tachicardia ventricolare asintomatica prolungata. I pazienti con fibrillazione atriale controllata da farmaci non sono esclusi. • Intervallo QTcF allo screening 450 msec. • Assunzione di farmaci che presentano il rischio di causare la sindrome di Torsades de Pointes (TdP) (‘Torsades List’ sul sito www.azcert.org/medical-pros/drug-lists/bycategory.cfm, vedere riferimento) e` proibita nei 14 giorni prima della randomizzazione. • Utilizzo di potenti inibitori CYP1A2 ciprofloxacina e fluvoxamina. Non sono esclusi gli inibitori/induttori CYP1A2 meno potenti. • Anamnesi di accidente cerebrovascolare (CVA) entro 6 mesi dalla randomizzazione o che porta a instabilita` neurologica in atto. • Infezione attiva o condizione medica preesistente grave (incluso qualsiasi tipo di disturbo convulsivo attivo nei 12 mesi precedenti la randomizzazione) che potrebbe alterare le capacita` del paziente di ricevere il farmaco in studio. • Anamnesi di infezione da virus dell`immunodeficienza umana (HIV) o di malattia correlata alla sindrome da immunodeficienza acquisita (AIDS) o malattia acuta grave o cronica. • Anamnesi di qualsiasi condizione psichiatrica o neurologica che potrebbe alterare le capacita` del paziente di comprendere o seguire i requisiti dello studio o di fornire il consenso informato. • Pazienti in gravidanza o allattamento • Metastasi cerebrali sintomatiche che non sono stabili, richiedono steroidi, sono potenzialmente pericolose per la vita o che hanno richiesto radioterapia nei 28 giorni precedenti la randomizzazione. • Anamnesi di reazioni allergiche attribuite ad agenti con composizione chimica o biologica simile al farmaco in studio. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy variable is time to progression. The secondary efficacy variables include: OS, PFS, DCR, ORR, and TTPc, and responses of the HBV and/or HCV subpopulations. E.6 |
| La variabile di efficacia primaria e' il tempo di progressione della malattia. Le variabili di efficacia secondarie includono: OS, PFS, DCR, ORR e TTPc e la risposta a sottopopolazioni all' HBV e/o HCV. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 25 |
| 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 |
| China |
| Hong Kong |
| Korea, Republic of |
| Singapore |
| Taiwan |
| United States |
|
| E.8.7 | Trial 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
|
| The end of the study will be deemed as the date of the last visit of the last patient participating in the clinical trial.The study will be unblinded approximately 1 month after the date when at least 96 OS events have occurred in patients partetipating in this clinical trial |
| La data della fine dello Studio è condiserata come data dell`ultima visita dell`ultimo paziente che partecipa alla sperimentazione. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| 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 | 2 |
| 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 |
Print
