| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Incurable/Non-metastatic Hepatocellular Carcinoma |
| Carcinoma Epatocellulare incurabile/non metastatico |
|
| E.1.1.1 | Medical condition in easily understood language |
| Incurable/Non-metastatic Hepatocellular Carcinoma |
| Carcinoma Epatocellulare incurabile/non metastatico |
|
| 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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10073071 |
| E.1.2 | Term | Hepatocellular carcinoma |
| 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 |
1. To compare pembrolizumab plus lenvatinib in combination with transarterial chemoembolization (TACE) versus placebo plus TACE with regard to progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) assessed by blinded, independent central review (BICR).
2. To compare pembrolizumab plus lenvatinib in combination with TACE versus placebo plus TACE with regard to overall survival (OS). |
1. Confrontare pembrolizumab più lenvatinib in combinazione con Chemioembolizzazione intra-arteriosa (TACE) rispetto a placebo più TACE per quanto riguarda la sopravvivenza libera da progressione (PFS) secondo RECIST 1.1 valutata mediante revisione centrale indipendente in cieco (BICR).
2. Confrontare pembrolizumab più lenvatinib in combinazione con TACE rispetto a placebo più TACE per quanto riguarda la sopravvivenza globale (OS). |
|
| E.2.2 | Secondary objectives of the trial |
1. To evaluate pembrolizumab plus lenvatinib in combination with TACE versus placebo plus TACE with regard to PFS, objective response rate (ORR), disease control rate (DCR), duration of response (DOR) and time to progression (TTP) per modified Response Evaluation Criteria in Solid Tumors (mRECIST) assessed by BICR.
2. To evaluate the safety and tolerability of pembrolizumab plus lenvatinib in combination with TACE versus placebo plus TACE.
3. To evaluate pembrolizumab plus lenvatinib in combination with TACE versus placebo plus TACE with regard to efficacy outcomes per RECIST 1.1 assessed by BICR. |
1. Valutare pembrolizumab più lenvatinib in combinazione con TACE rispetto a placebo più TACE in relazione a PFS, tasso di risposta obiettiva (ORR), tasso di controllo della malattia (DCR), durata della risposta (DOR) e tempo alla progressione (TTP) per mRECIST valutato con BICR.
2. Valutare la sicurezza e la tollerabilità di pembrolizumab più lenvatinib in combinazione con TACE rispetto a placebo più TACE.
3. Valutare pembrolizumab più lenvatinib in combinazione con TACE rispetto a placebo più TACE in relazione ai risultati di efficacia secondo RECIST 1.1 valutati con BICR. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1Has diagn ofHCC confirmed by radiol,histol,cytol(fibrolamellar and mixed hepatocel/cholangiocarcin subtypes arent eligible) Has radiol diagn ofHCC as per AASLDguidel,which requires:
-liver cirr and liver mass conf byBICR that shows arterial phase hyperenhancem on triphasic CTorMRI AND:
Is=20mm with either non-periph portal washout or enhancing capsule OR
Is10-19mm with non-periph port venous washoutANDenhancing caps
2HasHCC localiz to liver without port vein thromb,and not amenable to curat treatm such as resect, ablat,or liver transplant.No extrahep HCC is permit,conf byBICR
3Has at least 1measurable HCClesion based onRECIST 1.1 conf byBICR
4all les treatable withTACE in1or2sessions
5Is amenable,without contraindic,toTACEproced and chemother agent prespecified at study site
6Has CPclassA liver score within 7days prior first dose of study interv
7 predicted life expect of >3months
8 ECOG PS of 0to1 within 7days prior first dose of st interv
9Is male or fem=18years at time of signing inf consent
10Male particip are elig to part if they agree to the foll during interv period and for at least 180days postTACE or 30days after last dose of lenva/oral placebo, whichever occurs last:
-Be abstinent from heterosex intercourse as their preferred and usual lifestyle(abst on a long term and persistent basis) and agree to remain abst OR
-use contracept unless conf to be azoospermic(vasectomized or second to medical cause)
-Contracept use by men should be consistent with local regulat regarding the meth of contracept for those particip in clinical studies
-M particip must agree to refrain from donating sperm for 180days afterTACE
11female part is eligible to part if she isn’t pregnant or breastfeeding and at least1 of follow condit applies:
-Isnt a WOCBP OR
-Is WOCBP and using a contracept meth highly effect(with failure rate of <1%per year),with low user dependency,or be abst from heterosex interc as their pref and usual lifestyle(abst on a long term and persist basis), dur the interv period and for at least 180days postTACE,120days post pembro/IV placebo or 30days post lenva/oral plac,whichever occurs last. Investig should evaluate the pot for contracept meth failure(noncompl, recently initiated)in relationship to first dose of study interv
-WOCBP must have neg highly sensit pregnancy test(urine or serum as req by local regulations) within 24h before first dose of st interv
-If urine test cant be conf as neg(eg ambiguous result),serum pregn test is required. In such cases particip must be excluded from particip if serum pregn result is pos
Invest is respons for review of medical history,menstrual hist and recent sex activity to decrease risk for inclus of woman with early undetected pregn
Contracept use by women should be consistent with local regul regarding the meth of contraception for those particip in clinical stud
12Particip(or legally acceptable representat if appl) provides written inf consent/assent for study
13Part with past or ongoing HCVinfection will be eligible for study. Treated particip must have compl their treatm at least 1month prior to starting st interv
14Part with controlledHBV will be eligible as long as they meet following criteria:
-Antiviral ther forHBV must be given for at least4weeks and HBVviral load must be<500IU/mL prior to first dose of study interv.Particip on active HBV ther with viral loads<500IU/mL should stay on same ther throughout stu interv
-Part who are pos forHBc, negatfor HBsAg, and neg or pos forHBs, and who have undetectable HBV viral load,dont require HBVantiv prophylaxis
-Part not onHBV ther with undetectable HBVviral load, but pos forHBsAg, may begin anti-viral prophylaxis at any time prior to first dose of stu interv
15Has adeq controlled blood press(BP)with or without antihypert medications, defined as BP =150/90mmHg at screening and no change in antihypert medic within 1week before Cycle1 Day1
16adeq organ function. Specimens must be collected within 7days prior to start of stu interv |
1.Ha diagn di HCC conf da radiol,istol,citol(sottot fibrolamell e epatocell/colangiocarcin misti non idonei).Ha diagn radiolog diHCC sec linee guidaAASLD(App13 del protoc),che rich:
-cirr epat E massa epat conf da BICR che mostra iper-enhancement della fase arter suTAC trifase oRM, E:è =20mm con washout port non perif o enhanced capsula O è10-19mm con washout ven port non perif E enhanced caps
2.HCClocaliz nel feg senza tromb vena porta e non suscet a tratt curat come resez, ablaz,trapianto del feg. Non consent HCC extraep, conf da BICR
3.Ha alm 1 les HCC misurab basata suRECIST1.1,conf daBICR
4.Ha tutte les curab conTACE in1o2 sess(split-TACE)
5.Suscettib senza controindicaz a proced TACE e a ag chemioterapico pre-specificati nel centro di studio
6.Ha punteg epat di classeA di CP entro7gg prima della pr dose di interv di studio
7.Ha aspett vita prev >3mesi
8.HaECOG PS da 0a1 entro7gg prima di pr dose dei tratt di studio
9.Part Maschi o Femm = di 18anni al mom della firma del cons inform
10.Part di sesso M sono idonei a partecip se concordano quanto segue dur il per di interv e per alm 180gg dopoTACE o 30gg dopo ult dose di lenva/placebo orale,a sec dell'interv che occorre per ult:
-Pratic astin da rapp eteroses come stile di vita(astin continuat e a lungo term)e acconsent a riman astin O
- Accons tassativ a usare contrac a eccez degli individ con azoospermia conferm(otten tram vasectomia o per causa med second)
-Uso contrac da parte degli uom deve ess coer con normat loc relat a met contracc per chi part a st clinici
-Part di ses M dev accons a asten da donare sperma per180gg dopoTACE
11.Donna part è idonea a part se non grav o nn sta allatt e appl alm1di seg condiz:
-Non è in età fertile O
-È in età fert e utiliz met contrac altam effic(tasso di insuc<1% l'anno),con bassa dipend dell'utente,o che si ast dal rapp eteroses come st di vita abit(astin a lungo term e su base persist),dur il per di tratt e per alm180gg dopoTACE,120gg dopo pembro/placebo EV o 30gg dopo lenva/plac orale, a sec dell'ev che si verif per ultimo.Sperim dovreb valut il potenz insucces del met contrac(manc compliance, iniz rec di contrac)rispet alla pr dose del tratt di studio
-D in età fert deve otten risult neg da test gravid altam sensib(an urine,es sangue come rich da norm locali)entro24h prima della pr dose di tratt di studio
-Se non possib conferm risult neg con an urine(es risult ambiguo),è neces eseg test di gravid con l'es sangue. In questi casi, la part deve ess esclusa da studio se il risult del test gravid con es sangue è pos
•Sperim è resp della revis dell'anamn clin,mestruale e recente attiv sess per ridur rischio di inclus di 1donna con gravid prec non rilev
•Uso di contrac da parte di D dovreb ess coer con normat loc in mat di met di contracc per chi part a st clinici
12.Il/La part(o rappr legalm accettab, se pert)fornisce cons/assenso inform scritto per lo st
13.Part con infez daHCV passata o in corso saranno idonei per studio.Part trattati dev aver complet tratt alm1 mese pr di iniz il tratt di studio
14.Part conHBV control saranno id a condiz che soddisf i seg crit:
-terap antivirale perHBV deve ess somm per alm4sett e carica vir diHBV deve ess <500IU/mL prima della pr dose dei tratt di studio. I partecip in ter attiva perHBV con car vir<500IU/mL dev contin la stessa terap dur l'interv di studio
-Part che sono pos perHBc, neg perHBsAg e neg o pos perHBs e che hanno car virHBV non rilevab,non richied la profilassi antivirHBV
-Part non in ter conHBV con car virHBV non rilevab,ma pos perHBsAg, poss iniz la profilas antivir in quals mom prima della pr dose degli interv di studio
15.Ha controllo adeg della press arter(BP)con o senz farm antiipert, defin comeBP=150/90mmHg allo screening e ness variaz nei farm antiipert entro 1sett pr del Giorno1 del Ciclo1
16.Ha adeg funzion d'organo .I camp dev ess racc nei 7gg preced l'iniz dei tratt di studio |
|
| E.4 | Principal exclusion criteria |
1.Has HCC lesion(s) measuring =10 cm in any dimension, has more than 10 lesions on radiographic evaluation or has HCC lesions occupying = 50% of the liver volume, confirmed by BICR.
2.Has had esophageal or gastric variceal bleeding within the last 6 months.
3.Has bleeding or thrombotic disorders or is using factor X inhibitors or anticoagulants requiring therapeutic INR monitoring, eg, warfarin or similar agents. Treatment with antiplatelet agents and low molecular weight heparin is permitted.
4.Has clinically apparent ascites on physical examination that is not controlled with medication. Ascites detectable on imaging studies only is allowed.
5.Has any macrovascular tumor thrombosis in the portal veins, confirmed by BICR. Microvascular tumor thrombosis detected on biopsy, but not radiographic scan, is permitted.
6.Has had clinically diagnosed hepatic encephalopathy in the last 6 months unresponsive to therapy. Participants on rifaximin or lactulose during screening to control their hepatic encephalopathy are excluded.
7.Has received any systemic chemotherapy, including anti-VEGF therapy, or any systemic investigational anticancer agents for HCC.
8. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PDL2 agent or with an agent directed to another stimulatory or coinhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137). |
1. Ha lesioni HCC che misurano =10 cm in qualsiasi dimensione, ha più di 10 lesioni alla valutazione radiografica o ha lesioni HCC che occupano =50% del volume del fegato, confermato dal BICR.
2. Negli ultimi 6 mesi ha avuto sanguinamento da varici esofagee o gastriche.
3. Ha disturbi emorragici o trombotici o sta usando inibitori del fattore X o anticoagulanti che richiedono un monitoraggio terapeutico dell'INR, ad esempio warfarin o agenti simili. È consentito il trattamento con agenti antipiastrinici ed eparina a basso peso molecolare.
4. Ha un'ascite clinicamente evidente all'esame obiettivo che non è controllata con i farmaci. Sono consentite asciti rilevabili solo su studi di imaging.
5. Ha trombosi tumorale macrovascolare nelle vene porte, confermata dal BICR. E' consentita la trombosi tumorale microvascolare rilevata alla biopsia, ma non alla scansione radiografica.
6. Negli ultimi 6 mesi ha avuto diagnosi clinica di encefalopatia epatica non rispondente alla terapia. Sono esclusi i partecipanti che assumono rifaximina o lattulosio durante lo screening per controllare la loro encefalopatia epatica.
7. Ha ricevuto qualsiasi chemioterapia sistemica, inclusa la terapia anti-VEGF, o qualsiasi agente antitumorale sperimentale sistemico per l'HCC.
8. Ha ricevuto una terapia precedente con un agente anti PD-1, anti PD-L1 o anti PD-L2 o con un agente diretto a un altro stimolante o del recettore co-inibitorio delle cellule T (ad es. CTLA-4, OX-40, CD137). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
2. Overall Survival (OS) |
1.Sopravvivenza libera da progressione (PFS) secondo i criteri di valutazione della risposta sui tumori solidi versione 1.1 (RECIST 1.1)
2. Sopravvivenza globale (OS) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Up to ~ 5 years
2. Up to ~ 5 years |
1. Fino a circa 5 anni
2. Fino a circa 5 anni |
|
| E.5.2 | Secondary end point(s) |
1. PFS per Modified Response Evaluation Criteria in Solid Tumors (mRECIST)
2. Objective Response Rate (ORR) per mRECIST
3. Disease Control Rate (DCR) per mRECIST
4. Duration of Response (DOR) per mRECIST
5. Time to Progression (TTP) per mRECIST
6. Percentage of Participants Who Experience At Least One Adverse Event (AE)
7. Percentage of Participants Who Experience At Least One Serious Adverse Event (SAE)
8. Percentage of Participants Who Experience At Least One Hepatic Event of Clinical Interest (ECI)
9. Percentage of Participants Who Discontinue Study Drug Due to an AE
10. ORR per RECIST 1.1
11. DCR per RECIST 1.1
12. DOR per RECIST 1.1
13. TTP per RECIST 1.1 |
1. PFS secondo i criteri modificati di valutazione della risposta sui tumori solidi (mRECIST)
2. Tasso di risposta obiettiva (ORR) secondo mRECIST
3. Tasso di controllo della malattia (DCR) secondo mRECIST
4. Durata della risposta (DOR) secondo mRECIST
5. Tempo di progressione (TTP) secondo mRECIST
6. Percentuale di partecipanti che manifestano almeno un Evento Avverso (AE)
7. Percentuale di partecipanti che manifestano almeno un Evento Avverso Serio (SAE)
8. Percentuale di partecipanti che manifestano almeno un Evento Epatico di Interesse Clinico (ECI)
9. Percentuale di partecipanti che interrompono il trattamento a causa di un AE
10. ORR secondo RECIST 1.1
11. DCR per RECIST 1.1
12. DOR per RECIST 1.1
13. TTP per RECIST 1.1 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to ~ 5 years
2. Up to ~ 5 years
3. Up to ~ 5 years
4. Up to ~ 5 years
5. Up to ~ 5 years
6. Up to ~ 5 years
7. Up to ~ 5 years
8. Up to ~ 5 years
9. Up to ~ 5 years
10. Up to ~ 5 years
11. Up to ~ 5 years
12. Up to ~ 5 years
13. Up to ~ 5 years |
1. Fino a circa 5 anni
2. Fino a circa 5 anni
3. Fino a circa 5 anni
4. Fino a circa 5 anni
5. Fino a circa 5 anni
6. Fino a circa 5 anni
7. Fino a circa 5 anni
8. Fino a circa 5 anni
9. Fino a circa 5 anni
10. Fino a circa 5 anni
11. Fino a circa 5 anni
12. Fino a circa 5 anni
13. Fino a circa 5 anni |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| Health Utility Scores; anti-MK3475 antibody levels |
| Punteggi di Health Utility; Livelli di anticorpi anti-MK3475 |
|
| 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 | 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 90 |
| 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 | Information not present in EudraCT |
| 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 |
| Australia |
| Brazil |
| Chile |
| China |
| Colombia |
| Guatemala |
| Hong Kong |
| Israel |
| Japan |
| Korea, Republic of |
| Malaysia |
| Mexico |
| New Zealand |
| Puerto Rico |
| Russian Federation |
| Taiwan |
| Thailand |
| Turkey |
| Ukraine |
| United States |
| Denmark |
| France |
| Germany |
| Hungary |
| Ireland |
| Italy |
| Netherlands |
| Norway |
| Portugal |
| Spain |
| United Kingdom |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 8 |
| 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 | 8 |
| 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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