| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Unresectable Stage III and Stage IV melanoma |
| Melanoma di stadio III e stadio IV non resecabile |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced melanoma |
| Melanoma avanzato |
|
| 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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10053571 |
| E.1.2 | Term | Melanoma |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 progression-free survival (PFS) as assessed by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
2) To compare overall survival (OS) |
1) Confrontare la sopravvivenza libera da progressione (PFS) valutata mediante revisione centrale indipendente in cieco (BICR) secondo i criteri di valutazione della risposta nei tumori solidi (RECIST) 1.1.
2) Confrontare la sopravvivenza globale (OS). |
|
| E.2.2 | Secondary objectives of the trial |
1) To compare objective response rate (ORR) per RECIST 1.1 by BICR
2) To assess duration of response (DOR) per RECIST 1.1 by BICR
3) To assess safety and tolerability
4) To compare the mean change from baseline in PRO scores in global health status/quality of life (QoL) and physical functioning
5) To compare the time to true deterioration (TTD) in global health status/QoL and physical functioning |
1) Confrontare il tasso di risposta obiettiva (ORR) valutato mediante BICR secondo i criteri RECIST 1.1.
2) Valutare la durata della risposta (DOR) secondo i criteri RECIST 1.1 giudicati da BICR.
3) Valutare la sicurezza e la tollerabilità.
4) Confrontare il cambiamento medio dal basale nei punteggi PRO in termini di condizioni di salute globali/qualità della vita (QoL) e funzionalità fisica.
5) Confrontare il tempo al deterioramento reale (TTD) nelle condizioni di salute globali/QoL e funzionalità fisica. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Have histologically or cytologically confirmed melanoma
2. Have unresectable Stage III or Stage IV melanoma, as per American Joint Committee on Cancer 8th edition guidelines, not amenable to local therapy
3. Have been untreated for advanced or metastatic disease except as follows:
a. BRAF V600 mutation-positive melanoma may have received standard of care targeted therapy as first-line therapy for advanced or metastatic disease (eg, BRAF/MEK inhibitor, alone or in combination)
b. Prior adjuvant or neoadjuvant therapy, with targeted therapy or immunotherapy (such as anti-CTLA-4, anti-PD-1 therapy or Interferon). Immunotherapy will only be permitted if relapse did not occur during active treatment or within 6 months of treatment discontinuation. No other prior adjuvant or neoadjuvant therapy will be allowed
4. Have documentation of BRAF V600-activating mutation status or consent to BRAF V600 mutation testing during the screening period (participants with BRAF mutation positive melanoma as well as BRAF wild type or unknown are eligible)
5. Have an Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1
6. Have the presence of at least 1 measurable lesion by CT or MRI per RECIST 1.1 criteria as determined by the local site investigator/radiology assessment. Measurable disease will be verified by central imaging vendor (CIV) prior to randomization. Cutaneous lesions and other superficial lesions are not considered measurable lesions for the purposes of this protocol, but may be considered as nontarget lesions. Photographs of cutaneous lesions do not need to be submitted to the CIV
7. Provide a tumor biopsy
8. Have resolution of toxic effect(s) of the most recent prior therapy to Grade 1 or less (except alopecia). If participant received major surgery or radiation therapy of >30 Gy, they must have recovered from the toxicity and/or complications from the intervention
9. Participant is Male or Female and is at least 18 years of age at the time of signing the informed consent
10. Male participants are eligible to participate if they agree to the following during the intervention period and for at least 30 days after the last dose of lenvatinib/placebo:
a. Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agree to remain abstinent
OR
b. Must agree to use contraception unless confirmed to be azoospermic.
11. A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least 1 of the following conditions applies:
a. Not a woman of childbearing poential (WOCBP)
b. A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 120 days post pembrolizumab or 30 days post lenvatinib/placebo, whichever occurs last
c. A WOCBP must have a negative highly sensitive pregnancy test
12. The participant provides written informed consent for the study
13. Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP =150/90 mmHg at screening and no change in antihypertensive medications within 1 week prior to randomization
14. Have adequate organ function. |
1. Avere un melanoma confermato istologicamente o citologicamente.
2. Presenza di un melanoma non resecabile in stadio III o stadio IV, in base alle linee guida dell’American Joint Committee on Cancer 8a edizione, non suscettibile di terapia locale.
3. Non essere stato trattato per malattia avanzata o metastatica, eccetto che per quanto segue:
a. Il melanoma positivo alla mutazione BRAF V600 può aver ricevuto una terapia mirata secondo lo standard di cura come una terapia di prima linea per la malattia avanzata o metastatica (ad esempio inibitore di BRAF/MEK, da solo o in combinazione).
b. La previa terapia adiuvante o neoadiuvante con una terapia mirata o un’immunoterapia (come terapia con anti-CTLA-4, anti-PD-1 o interferone). L'immunoterapia sarà consentita solo se la recidiva non si è manifestata durante il trattamento attivo o nei 6 mesi successivi all’interruzione del trattamento. Non sarà consentita un’altra previa terapia adiuvante o neoadiuvante.
4. Presentare la documentazione dello stato mutazionale attivante BRAF V600 o consenso a sottoporsi al test della mutazione BRAF V600 durante il periodo di screening (non sono idonei i partecipanti con melanoma positivo alla mutazione BRAF e BRAF wild type o non noto).
5. Presentare uno stato di validità secondo l’Eastern Cooperative Oncology Group (ECOG) da 0 a 1
6. Presentare almeno 1 lesione misurabile mediante TAC o RM secondo i criteri RECIST 1.1, come determinato dalla valutazione dello sperimentatore/con esame radiologico eseguita localmente dai centri. La malattia misurabile sarà verificata dal fornitore dell’apparecchiatura per l’acquisizione delle immagini (CIV) centrale prima della randomizzazione. Le lesioni cutanee e altre lesioni superficiali non sono considerate lesioni misurabili ai fini di questo protocollo, ma possono essere considerate come lesioni non target. Le fotografie delle lesioni cutanee non devono essere inviate al CIV.
7. Fornire una biopsia tumorale.
8. Essersi ripreso dall’effetto o dagli effetti tossici della terapia precedente più recente fino a un grado 1 o inferiore (eccetto alopecia). Se il partecipante ha subito un intervento chirurgico importante o è stato sottoposto a radioterapia a una dose >30 Gy, deve essersi ripreso dalla tossicità e/o dalle complicanze del trattamento.
9. Il partecipante è un soggetto maschile o femminile di almeno 18 anni di età al momento della firma del consenso informato.
10. I partecipanti di sesso maschile sono idonei alla partecipazione se accettano le seguenti condizioni durante il periodo di trattamento e per almeno 30 giorni dopo l'ultima dose di lenvatinib/placebo:
a. Astenersi dal rapporto eterosessuale come stile di vita preferito ed usuale (astinenza a lungo termine e persistente) ed accettare di rimanere in astinenza
O
b. Accettare di utilizzare metodi contraccettivi a meno che non sia confermato essere azoospermici.
11. Le partecipanti di sesso femminile sono idonee alla partecipazione qualora non siano in gravidanza, non stiano allattando al seno e soddisfino almeno una delle seguenti condizioni:
a. Non sia una donna in età fertile (WOCBP)
b. Sia una WOCBP che accetta di attenersi alle indicazioni sui metodi contraccettivi durante il periodo di trattamento e per almeno 120 giorni dopo pembrolizumab o 30 giorni dopo lenvatinib/placebo, a seconda di quale condizione si verifichi per ultima
c. Sia una WOCBP che ha un test di gravidanza altamente sensibile negativo
12. Il partecipante fornisce consenso informato scritto per lo studio.
13. Pressione arteriosa (PA) adeguatamente controllata con o senza farmaci antipertensivi, definita come PA =150/90 mmHg allo screening, in assenza di modifiche ai farmaci antipertensivi nella settimana precedente alla randomizzazione.
14. Evidenziare un’adeguata funzionalità degli organo. |
|
| E.4 | Principal exclusion criteria |
1Has diagn of immunodef o is receiv chronic syst steroid therap(in dos exced10mgdaily of prednisone equival)o any form of immunosup thera within7dys bef first dose of stu interv
2Has know addit malignancy that progess or requires active treat.Except include early stage cancers(carci in situ or stage1,noulcerat primarymelanoma<1mmdepthwith no nodal involvement)treat with curative intent,basal cell carci of the skin,squamous cellcarci of skin,in situ cervical cancer,or in situ breast cancer that has undergone potentially curative therap
3Hasknow active CNSmetastases and/or carcitous menitis.Partecip with previously treat brain met may particip provid they are stable(without evidence progress by imag for least4weeks bef first dose of stu interv and any neurologic sympt have return to baseline),have no ev new or enlarg brain metastases confirm by repeat imag,and have not requir steroids for least14dys bef stu interv
4Has ocular mel
5Has know invest active substces or any their excipients includ previous cliniy signif investivity react treat with another mAb
6Has active autoime disease that has requie syst treat past2years(with use disease modify agents,corticosteroids or immunosup drugs)
7Has active infection requir systemic therap
8Hasknow hist of(HIV)(HIV1/2antibd)NotestingHIVis requi unless mandat by local health authority
9Has known hist of or is positive for hepatitisB(hepatitisBsurface antigen[HBsAg]reactive)or hepatitisC(HCVRNA [qualitative]is detected).No test of
hepatitisBorCis requir unless mandated by local health authority
10Has hist of(noinfectious)pneumonitis that requie steroids or cur pneumonitis
11Has hist of active tuberculosis(Bacillustuberculosis)
12Has presence of gastrl cond includ malabsorption,gastroinstinal anastomosis,or any other condi that might affect the absorption of lenvatinib
13Has had a major surgery within 4weeks prior to C1D1. Adeq wound healing after major surgery must be assessed clinically and have resolved completely prior to C1D1
14Has prexistingGrade=3gastr or nongastr fistula
15Has radiographic evidence of major blood vessel invasion/infilton
16Has clically significant hemoptysis or tumor bleeding within2weeks prior 1° dose stu interv
17Has clically significant cardiovascular disease within12months of first dose stu interven includingNewYork Heart Association ClassIIIorIVcongestive heart failure,unstable angina,myocardial infarction,cerebral vascular accident,or cardiac arrhythmia associated with hemodynamic instability
18Has urineprotin=1g/24h
19Has prolongat of QTc intervto>480msec
20Has left ventricular ejection fractionbelow institutional normal range as determin multi-gat acquis scan(MUGA)or echocardiogram
21Has receiv prior syst treat for unresectable or metastatic melanoma other than target therap
22Has receiv prior therap adjuvant setting
23Has receiv prior therap mAb,chemotherap,or an invest agent or device within4weeksor5half lives(whichever is longer)bef admin of stu interv or not
recover(=Grade1oratbaseline)fromAEs due previously administer agents.Exception to this rule would be use of denosumab,which isnot exclud
24Has receiv prior radiotherap within2weeksofCycle1Day1.Partecip must have recover from all radiation-relat toxicities,not require corticosteroids,and not have had radiation pneumonitis
25Has receiv live vaccine within30dys bef the first dose of stu interv
26Is currently particip in or has partic in stu ofan invest agent or has used an invest device within4weeks prior to first dose stu interv
27Has hist or current evidence of any cond,therap,or lab abnorlity that might confound results stu, interfere with particip's participat for full durat stu,or is not best interest particip to participate,opinion of treating investor
28Had allogeneic tissue/solid organ transplant
29Has know psychiatric or subst abuse disorder would interf with cooperation with requirnts of stu |
1Pres diag immunod o ricevendo terap cronica cn steroidi via siste(a dosag sup a10mg gg equival prednisone)o quals altr forma terap immusopp7gg preced prima dose tratt stu
2Pres tum maligno noto sia progress o richieda tratt attivo.Le eccez comprendono tum stad prec(carcin in situ o in stadio1,melanoma primario nn ulcerato<1mmprofondità snz coinv notale)trattati cn intento cur,carcin basocell cute,carcin cell squamocute,carcin in situ cervice o carcin in situ mam stato sottop a terap potenz curativa
3Pres metas attive sist nerv centr(SNC)e/o meningite carcintosa.Partecip cn metas cereb trattate preced pssn partecip siano stabili(snz evid progress esami diagno immagini almeno4sett prima dlla prima dose tratt stu e cn ritorno valre basale eventuali sintomi neurol),nn abbiano evidnz metas cerebrali nuove o ingrossate cnfermata ripetiz esami diagno immgini e nn abbiano rich assunz steroidi almeno14gg prim tratt stu
4Pres melanoma oculare
5Pres ipersensib princ attivi o quals relativi eccip,inclusa preced reaz ipersensib tratt altro mAbche stata clinicam significativa.Per elenco eccip, cnsultare relativi dossier dll sperim(IB)
6Pres malat autoimmune fase attiva rich un tratt sistem ultimi2anni(o impiego ag modificanti malat,corticoster o farmaci immunosop)La terap sostituz(es terap sostituz cn tiroxina,insulina o corticoster fisiol caso insuff surrenalica o ipof,ec)nn cnsiderata forma tratt sistemico
7Infez attiva necessità terap siste
8Pres an nota (HIV)(anticHIV1/2)Salvo rich autorità sanitaria locale,nn necessa eseguire il test perHIV.
9Anamnesi nota o positività epatiteB(reattiva antig superf depatiteB[HbsAg])o epatiteCattiva(HCV RNA[qualitativa])rilevata.Salvo se richiesto autorità sanitaria locale,nn necess eseguire alcun test epatite BoC
10Anam polmon(nn infet)rich uso steroidi o pres polmonite corrente
11Anamtubercolosi(Bacillus tuberculosis)attiva.
12Pres cndiz gastroint malassorb,anastomosi gastroint o quals altra cndiz potreb compr assorb lenvatinib
13Ha subito un inter chi im 4sett precedenti il C1D1. L’adeg guarig delle ferite dp interchirurg dv essere valut clinic e risolta compl primadelC1D1
14Pres fistola gastroint o nn gastroint presistente grado=3
15Pres evid radiol invasione/infiltraz vasi sanguigni grosso calibro
16Pres emottisi o sanguin o tum clinicam signif entro2sett prima dell prima dose trattam di stu
17Pres malat cardiovas clinicam signif12mesi prima dll prima dose tratt stu,compresi insuf card cngestizia classe IIIoIVsecndo NewYorkHeartAssociation,angina instabile,inf miocardio,accidente cerebrovasc o arit card assoc instab emodimica
18Pres prot urinarie=1g/24ore
19Pres prolung intervalloQTc(calcolato usando formulFridericia)>480msec
20Pres fraz eiez ventric sinistra(FEVS)sotto range istituz normale,data med scans cn acquisiz gate multipli(MUGA)o ecocardiogramma
21ricev preced tratt sist melanoma nn resecabile o metast divro dlla terap mirata indicata criterio inclus n3
22ricev preced terap in cntesto adiuvante.
23ricev preced terap cn mAb o agente o disp sperimen entro4sett o5emivite(a secnda period lungo)prima della somministraz trattam dello stu o nn ripreso(grado=1obasale)da AE dovuti ag sommin in prec.Può rappresre eccez regola uso denosumab,nn escluso
24ricev previa radioterap2sett precedGg1Ciclo1.I partecip dev essersi ristabiliti tossicità corrlate radioterap,nn neces corticost e nn presre polmonite radiaz
25ricev vaccino vivo30gg preced a1dose tratt stu
26Par corso o pregr stu agent sper o uso disp sperimen entro4sett prima dose tratt stu
27Anam o attuale evidenza quals cndizione,terap o anomalia lab potrebbe cnfondere risultati stu,interferire cn partecipaz sogg durata stu o ritenere tale partecip nn miglior interesse sogg,secndo opin dello sperim responsabile tratt
28Trap org solido/tessuto allogenico
29Pres disturbi psich o abuso sost noti interferirebbero collabora e requi stu |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1) Progression-free survival (PFS) as assessed by BICR per RECIST 1.1
2) Overall survival (OS) |
1) Sopravvivenza libera da progressione (PFS) per RECIST 1.1 valutata da BICR
2) Sopravvivenza globale (OS) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Interim analysis 1, PFS and OR: approximately 24 months after 1st participant randomized (after enrollment is completed, and ~369 PFS events observed and ~209 OS events observed).
Interim analysis 2, PFS and OR: approximately 34 months after 1st participant randomized (~397 PFS events observed, ~263 OS events observed)
Final OS analysis: approximately 62 months after 1st participant randomized (~316 OS events) |
Analisi ad interim 1, PFS e OR: circa 24 mesi dopo il primo partecipante randomizzato (dopo arruolamento completato e ~369 eventi PFS osservati e ~209 eventi OS osservati).
Analisi ad interim 2, PFS e OR: circa 34 mesi dopo il primo partecipante randomizzato (~397 eventi PFS osservati, ~263 eventi OS osservati)
Analisi dell’OS finale: circa 62 mesi dopo il primo partecipante randomizzato (~316 eventi OS) |
|
| E.5.2 | Secondary end point(s) |
1) Objective response (OR) as assessed by BICR per RECIST 1.1
2) DOR as assessed by BICR per RECIST 1.1. |
1) Risposta obiettiva (OR) come valutato da BICR per RECIST 1.1
2) DOR come valutato da BICR per RECIST 1.1 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
OR: approximately 11-13 months after 1st participant randomized
DOR: will be evaluated on an ongoing basis
|
OR: circa 11-13 mesi dopo il 1 ° partecipante randomizzato
DOR: sarà valutato su base continuativa |
|
| 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 | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| 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 | 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 46 |
| 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 |
| Canada |
| Chile |
| China |
| Israel |
| Korea, Republic of |
| United States |
| France |
| Germany |
| Italy |
| Spain |
| Sweden |
| Switzerland |
| 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 | 5 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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