| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Treatment of advanced NSCLC |
| Trattamento di NSCLC in stadio avanzato |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced Non-small cell lung cancer |
| Carcinoma polmonare non a piccole cellule in stadio 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 | PT |
| E.1.2 | Classification code | 10029522 |
| E.1.2 | Term | Non-small cell lung cancer stage IV |
| 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 |
| To evaluate the clinical activity (as assessed by objective response rate [ORR]) of specific pembrolizumab-based combinations |
| Valutare l’attività clinica (accertata mediante il tasso di risposta obiettiva [objective response rate, ORR]) di specifiche combinazioni basate su pembrolizumab |
|
| E.2.2 | Secondary objectives of the trial |
1) To evaluate the clinical activity (as assessed by progression-free survival [PFS] and overall survival [OS]) of specific pembrolizumab based combinations. PFS and OS to different specific pembrolizumab based combinations will be assessed independently in each biomarkerdefined group
2) To determine the safety and tolerability of pembrolizumab in combination with either MK- 4280 or lenvatinib. Safety and tolerability to different specific pembrolizumab-based combinations will be assessed independently in each biomarker-defined group |
1) Valutare l’attività clinica (accertata mediante sopravvivenza libera da progressione [progression-free survival, PFS] e sopravvivenza complessiva [overall survival, OS]) di specifiche combinazioni basate su pembrolizumab. La PFS e la OS relative a differenti specifiche combinazioni basate su pembrolizumab saranno accertate in modo indipendente in ciascun gruppo definito dai biomarcatori
2) Stabilire la sicurezza e la tollerabilità di pembrolizumab in combinazione con MK-4280 o lenvatinib. La sicurezza e la tollerabilità relative a differenti specifiche combinazioni basate su pembrolizumab saranno accertate in modo indipendente in ciascun gruppo definito dai biomarcatori. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Other types of substudies
Specify title, date and version of each substudy with relative objectives: Merck will conduct Future Biomedical Research on DNA, RNA and tumor specimens collected during this clinical trial. Such research is for biomarker testing to address emergent questions not described elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens from appropriately consented subjects. The objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding of diseases and/or their therapeutic treatments. The overarching goal is to use such information to develop safer, more effective drugs, and/or to ensure that subjects receive the correct dose of the correct drug at the correct time.
|
Altre tipologie di sottostudi
specificare il titolo, la data e la versione di ogni sottostudio con i relativi obiettivi: Merck condurrà una Ricerca Biomedica Futura su campioni di DNA, RNA e tessuto tumorale raccolti nel corso di questo studio clinico. Tale ricerca ha lo scopo di esaminare vari biomarcatori per rispondere a domande che stanno emergendo e che non sono descritte in altre parti del protocollo (nell’ambito dello studio principale), e verrà condotta solo su campioni di soggetti che abbiano rilasciato apposito consenso. L'obiettivo della raccolta dei campioni per la Ricerca Biomedica Futura è quello di esplorare e identificare biomarcatori che contribuiscano scientificamente alla comprensione delle malattie e/o della relative terapie. L'obiettivo ultimo è quello di utilizzare tali informazioni per sviluppare farmaci più sicuri e più efficaci, e/o per garantire che i soggetti ricevano la dose giusta del giusto farmaco al momento giusto.
|
|
| E.3 | Principal inclusion criteria |
1. Have a histologically or cytologically confirmed diagnosis of Stage IV (American Joint Committee on Cancer [AJCC] v. 8) NSCLC and study participants should not have had prior systemic therapy for advanced disease.
2. Have confirmation that epidermal growth factor receptor– (EGFR-), anaplastic lymphoma kinase– (ALK-), c-ros oncogene 1 (ROS1), or B isoform of rapidly accelerated fibrosarcoma (B-Raf) directed therapy is not indicated as primary therapy (documentation of absence of tumor activating EGFR or B-Raf mutations AND absence of ALK or ROS1 gene rearrangements). If participant's tumor is known to have a predominantly squamous histology, molecular testing for EGFR mutation and ALK and ROS1 translocations will not be required, as this is not part of current diagnostic guidelines.
3. Have measurable disease per RECIST 1.1 as assessed by the local site investigator/radiology. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
4. Male/female subjects who are at least 18 years of age on the day of signing the informed consent.
5. A male participant must agree to use a contraceptive as detailed in the protocol during the treatment period and for at least 120 days after the last dose of study treatment and refrain from donating sperm during this period.
6. A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
a.) Not a woman of childbearing potential (WOCBP)
OR
b.) A WOCBP who agrees to follow the contraceptive guidance in the protocol during the treatment period and for at least 120 days after the last dose of study treatment.
7. The participant (or legally acceptable representative if applicable) provides written informed consent for the study. The participant may also provide consent for Future Biomedical Research. However, the participant may participate in the main study without participating in Future Biomedical Research.
8. Have provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. Newly obtained biopsies are preferred to archival tissue. Repeat samples may be required if adequate tissue is not provided.
9. Participants must have adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP =150/90 mm Hg at Screening and no change in antihypertensive medications within 1 week before Cycle 1/Day 1.
10. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
11. Have adequate organ function as defined in the protocol. Specimens must be collected within 10 days prior to the start of study treatment. |
1. Avere una diagnosi istologicamente o citologicamente confermata di NSCLC di stadio IV (American Joint Committee on Cancer [AJCC] v 8) e i partecipanti allo studio non dovrebbero aver ricevuto una terapia sistemica per malattia in stadio avanzato.
2. Avere una conferma che la terapia diretta al recettore del fattore di crescita epidermica (EGFR-) alla chinasi del linfoma anaplastico (ALK), all’oncogene 1 c-ros (ROS1) o all’isoforma B del fibrosarcome accelerato rapidamente (B-Raf) non sia indicata come terapia primaria (doc di assenza di mutazioni tumorali attivanti EGFR e mutazioni di B-Raf e assenza di riarrangemento genico di ALK e ROS1) e assenza di riarrangiamenti genici di ALK). Se è noto che il tumore del partecipante abbia un’istologia squamosa predominante, non sarà richiesto il test molecolare per la mutazione dell’EGFR e delle traslocazioni ALK e ROS1, in quanto ciò non rientra nelle attuali linee guida diagnostiche.
3. Avere una malattia misurabile in base ai criteri RECIST 1.1, come determinato da sperimentatore/esami radiologici del centro locale. Le lesioni localizzate in una zona già sottoposta a radiazioni sono considerate misurabili se ne è stata dimostrata la progressione.
4. Soggetti maschi/femmine che abbiano compiuto 18 anni d’età al momento della firma del consenso informato.
5. Un partecipante di sesso maschile deve acconsentire ad usare un metodo contraccettivo come indicato nel protocollo nel corso del trattamento e per almeno 120 gg dopo l’assunzione dell’ultima dose del trattamento in studio ed evitare di donare sperma durante questo periodo.
6. Una partecipante di sesso femminile è idonea alla partecipazione qualora non sia in stato di gravidanza, non stia allattando e soddisfi almeno una delle seguenti condizioni:
a.) Non sia una donna in età fertile (WOCBP) come def. dall’App.5
OPPURE
b.) Sia una WOCBP che accetti di attenersi alla guida sui metodi contraccettivi durante il periodo di trattamento e per almeno 120 giorni dopo l’ultima dose del trattamento di studio.
7. Il/La partecipante (o il rappresentante legale qualora applicabile) deve fornire consenso informato scritto per lo studio. Il/La partecipante può inoltre decidere di fornire il consenso per la Ricerca Biomedica Futura. Tuttavia, il partecipante può prender parte allo studio principale anche senza prender parte alla Ricerca Biomedica Futura.
8. Avere fornito campioni di tessuto tumorale archiviato o biopsia incisionale o escissionale ottenuta ex-novo da una lesione tumorale non precedentemente irradiata. Le biopsie ottenute ex-novo sono preferibili
rispetto al tessuto archiviato. Potrebbe essere richiesto un nuovo campione se non è stato fornito un campione adeguato. Nota: I vetrini bioptici devono essere inviati al laboratorio per gli esami entro 14 giorni dalla data di preparazione (i dettagli relativi all’invio del tessuto tumorale possono essere trovati nel manuale delle procedure).
9. I partecipanti devono avere una pressione arteriosa adeguatamente controllata con o senza terapia antipertensiva, definita come pressione sanguigna =150/90 mm Hg allo screening e nessuna modifica dei farmaci antipertensivi entro 1 settimana prima del Giorno 1 /Ciclo 1.
10. Presentare uno stato di validità secondo il Gruppo cooperativo orientale di oncologia (Eastern Cooperative Oncology Group, ECOG) da 0 a 1.
11. Avere un’adeguata funzionalità d’organi, come definito in tab. 2 del Protocollo. I campioni devono essere prelevati entro 10 giorni prima dell’inizio del trattamento dello studio. |
|
| E.4 | Principal exclusion criteria |
1. Has significant cardiovascular impairment within 12 months of the first dose of study drug: such as history of congestive heart failure greater than NYHA Class II, unstable angina, myocardial infarction or cerebrovascular accident (CVA) stroke, cardiac arrhythmia associated with hemodynamic instability, or a left ventricular ejection fraction (LVEF) below the institutional normal range as determined by multigated acquisition scan (MUGA) or echocardiogram.
2. Prolongation of QTc interval to >480 ms.
3. Has symptomatic ascites or pleural effusion. A participant who is clinically stable following treatment for these conditions is eligible.4. Has had an allogenic tissue/solid organ transplant.
5. A WOCBP who has a positive urine pregnancy test within 72 hours before the first dose of study treatment.
6. Subjects with proteinuria >1+ on urine dipstick testing will undergo 24-hour urine collection for quantitative assessment of proteinuria. Subjects with urine protein =1 g/24 h will be ineligible.
7. Subjects who have not recovered adequately from any toxicity and/or complications from major surgery prior to starting therapy.
8. Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that might affect the absorption of lenvatinib
9. Radiographic evidence of major blood vessel invasion/infiltration. The degree of tumor invasion/infiltration of major blood vessels should be considered because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis following lenvatinib therapy.
10. Clinically significant hemoptysis or tumor bleeding within 2 weeks prior to the first dose of study drug.
11. Has received prior systemic chemotherapy treatment for metastatic/recurrent NSCLC.
12. Has current NSCLC disease that can be treated with curative intent with surgical resection, localized radiotherapy, or chemoradiation.
13. Is expected to require any other form of systemic or localized antineoplastic therapy while on study.
14. Has received prior therapy with an anti–PD-1, anti–PD-L1, or anti–PD-L2 agent or with an agent directed to another stimulatory or coinhibitory T cell receptor (eg, CTLA-4, OX 40, CD137).
15. Has received previous treatment with another agent targeting the LAG3 receptor.
16. Has received previous treatment with another agent targeting VEGF or the VEGF receptor.
17. Has received prior anticancer therapy including investigational agents within 4 weeks prior to randomization.
18. Has received prior radiotherapy within 3 weeks of start of study treatment.
19. Has received a live vaccine within 30 days prior to the first dose of study treatment.
20. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment.
21. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study treatment.
22. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.
23. Has known active CNS metastases and/or carcinomatous meningitis.
24. Has severe hypersensitivity (=Grade 3) to pembrolizumab, MK-4280, or lenvatinib and/or any of its excipients.
25. Has an active autoimmune disease that has required systemic treatment in past 2 years (ie, with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy is not considered a form of systemic treatment and is allowed.
26. Has a history of (noninfectious) pneumonitis that required steroids or has current pneumonitis.
27. Has an active infection requiring systemic therapy.
For criteria n. 28, 29, 30, 31, 32, 33 refer to the protocol. |
1. Evidenzia una significativa compromissione cardiovascolare entro 126 mesi dalla prima dose di farmaco in studio: anamnesi di insufficienza cardiaca congestizia superiore alla Classe II secondo l’Associazione di cardiologia di New York (New York Heart Association, NYHA), angina instabile, infarto del miocardio o ictus CVA (cerebrovascular accident), aritmia cardiaca in associazione a instabilità emodinamica oppure frazione di eiezione ventricolare sinistra (left ventricular ejection fraction, LVEF) al di sotto dell’intervallo normale istituzionale come determinato tramite scansione con acquisizione a gate multipli (Multi Gated Acquisition Scan, MUGA) o ecocardiogramma.
2. Prolungamento dell’intevallo QTc superiore a 480 ms.
3. Presenta ascite sintomatica o effusione pleurica. Un partecipante che è clinicamente stabile in seguito al trattamento di queste condizioni (compresa la terapia toracica o la paracentesi) è idoneo.
4. Ha subito un trapianto di organo solido/tessuto allogenico.
5. WOCBP con test di gravidanza sulle urine positivo nelle 72 ore precedenti la prima dose del trattamento dello studio (vedere l’Appendice 5). In caso non sia possibile confermare la negatività del test sulle urine, sarà richiesto un test di gravidanza sul siero. Nota: nel caso in cui siano passate 72 ore tra il test di gravidanza allo screening e la prima dose del trattamento dello studio, è necessario eseguire un altro test di gravidanza (sulle urine o sul siero) che deve risultare negativo affinché il soggetto possa iniziare a ricevere il farmaco dello studio.
6. I soggetti che presentino proteinuria >1+ alla striscia reattiva sulle urine saranno sottoposti a raccolta delle urine delle 24 ore per una valutazione quantitativa della proteinuria. I soggetti che evidenzino proteine nelle urine =1 g/24 ore non saranno idonei.
7. I soggetti che non hanno manifestato una ripresa adeguata da eventuali tossicità e/o complicanze dovute a un intervento chirurgico importante prima di iniziare la terapia.
8. Malassorbimento gastrointestinale, anastomosi gastrointestinale o qualsiasi altra condizione che potrebbe influenzare l’assorbimento di lenvatinib.
9. Evidenza radiografica di invasione/infiltrazione dei vasi sanguigni maggiori. Deve essere preso in considerazione il grado di invasione/infiltrazione tumorale dei principali vasi sanguigni per via del potenziale rischio di grave emorragia associato alla contrazione/necrosi tumorale conseguente alla terapia a base di lenvatinib.
10. Emottisi clinicamente significativa oppure emorragia tumorale entro le 2 settimane precedenti la prima dose di farmaco dello studio.
....... Per l'elenco completo fare riferimento al Protocollo ...... |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| objective response rate (ORR) based on RECIST 1.1 as assessed by local site review |
| ORR in base ai criteri RECIST 1.1 come accertato mediante revisione da parte del centro locale |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| ORR will be used at interim analysis and first database lock |
| ORR valutato nell'analisi ad iterim e al primo data base lock |
|
| E.5.2 | Secondary end point(s) |
1. PFS based on RECIST 1.1 as assessed by local site review
2. OS
3. Safety as assessed by the number of participants experiencing AEs and the number of participants discontinuing study drug due to AEs. |
1. PFS in base ai criteri RECIST 1.1 come accertato mediante revisione da parte del centro locale
2. OS
3. Sicurezza determinata in base al numero di partecipanti che manifestano eventi avversi (AE) e al numero di partecipanti che interrompono il farmaco dello studio a causa di AE. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Secondary endpoints will be analysed at final database lock |
| Gli endpoints secondari saranno analizzati al database lock finale |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| 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 | 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 | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Si tratta di uno studio di randomizzazione adattativa |
| Adaptive randomization design |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 43 |
| 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 |
| Canada |
| Hong Kong |
| Korea, Republic of |
| Russian Federation |
| Singapore |
| South Africa |
| Taiwan |
| United States |
| France |
| Ireland |
| Italy |
| Poland |
| Spain |
| Switzerland |
| United Kingdom |
|
| 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
|
|
| 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 | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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