| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic colorectal cancer |
| Tumore del colon-retto metastatico |
|
| E.1.1.1 | Medical condition in easily understood language |
| Colorectal cancer |
| Tumore del colon-retto |
|
| 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 | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10052362 |
| E.1.2 | Term | Metastatic colorectal cancer |
| 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 |
Parts 1, and 1A (no EU subjects):
- To characterize the safety and tolerability of combination therapies
- To establish recommended dosing regimen for the combination (nivolumab plus ipilimumab plus trametinib OR nivolumab plus trametinib)
Parts 1B and 2:
- To evaluate the ORR in all participants treated with nivolumab plus ipilimumab and trametinib in the 2L and 3L setting (Parts 1B and 2) and regorafenib in 3L (Part 2 only) |
Parti 1, e 1A (nessun soggetto nell’EU):
- caratterizzare la sicurezza e tollerabilità delle terapie di combinazione
- stabilire la dose raccomandata per la combinazione (nivolumab più ipilimumab più trametininb OPPURE nivolumab più trametinib)
Parte 1B e 2:
- Valutare il tasso di risposta obiettiva (ORR) in tutti i soggetti partecipanti trattati con nivolumab più ipilimumab e trametinib nel contesto della 2a Linea e 3a Linea (Parte 1B e Parte 2) e regorafenib in 3a Linea (solo Parte 2) |
|
| E.2.2 | Secondary objectives of the trial |
Parts 1, and 1A (no EU subjects):
- To evaluate preliminary efficacy
Parts 1B and 2:
- To evaluate efficacy in all participants treated with nivolumab plus ipilimumab and trametinib in the 2L and 3L setting (Parts 1B and 2); and regorafenib in 3L (Part 2 only)
- To evaluate efficacy in subgroups of CMS in 3L MSS CRC patients treated with nivolumab plus ipilimumab and trametinib vs. regorafenib (Part 2), as well as explore efficacy in relation to CMS
subgroups in 2L MSS CRC patients (Part 1B)
- To characterize the safety and tolerability of combination therapies
|
Parti 1, e 1A (nessun soggetto nell’EU):
- Valutare l’efficacia preliminare
Parte 1B e 2:
- Valutare l’efficacia in tutti i partecipanti trattati con nivolumab più ipilimumab e trametinib nel contesto della 2a Linea e 3a Linea (Parte 1B e 2); e regorafenib in 3a Linea (solo Parte 2)
- Valutare l’efficacia in sottogruppi CMS di pazienti CRC con MSS in 3° Linea trattati con nivolumab più ipilimumab e trametinib rispetto a regorafenib (Parte 2), cosi come esplorare l’efficacia in relazione ai sottogruppi CMS di pazienti CRC MSS in 2° Linea (Parte 1B)
-Caratterizzare la sicurezza e tollerabilità delle terapie di combinazione |
|
| 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 |
Pharmacogenetics
Version: Revised Protocol N: 02
Date: 06/10/2020
Title: A Study Of Nivolumab In Combination With Trametinib With Or Without Ipilimumab In Participants With Previously Treated Metastatic Colorectal Cancers
Objectives: Please refer to Revised Protocol 02 Section 9.8.5 Additional Research Collection
Pharmacogenomics
Version: Revised Protocol N: 02
Date: 06/10/2020
Title: A Study Of Nivolumab In Combination With Trametinib With Or Without Ipilimumab In Participants With Previously Treated Metastatic Colorectal Cancers
Objectives: Please refer to Revised Protocol 02 Section 9.8.5 Additional Research Collection
|
Farmacogenetica
Versione: Revised Protocol N: 02
Data: 06/10/2020
Titolo: Studio di nivolumab in combinazione con trametinib con o senza ipilimumab in soggetti con cancro colon-retto metastatico precedentemente trattato
Obiettivi: si veda il revised protocol 2 sezione 9.8.5 Additional Research Collection
Farmacogenomica
Versione: Revised Protocol N: 02
Data: 06/10/2020
Titolo: Studio di nivolumab in combinazione con trametinib con o senza ipilimumab in soggetti con cancro colon-retto metastatico precedentemente trattato
Obiettivi: si veda il revised protocol 2 sezione 9.8.5 Additional Research Collection
|
|
| E.3 | Principal inclusion criteria |
• Age = 18, signed written informed consent
• Histological or cytological confirmed diagnosis of previously treated mCRC with adenocarcinoma histology and in Stage IV per AJCC
• Confirmed microsatellite status: only participants with pMMR/MSS mCRC are eligible
• Verified KRAS, NRAS (extended RAS) and BRAF mutation status: BRAF V600 mutant are not eligible
• Measurable disease per RECIST 1.1
• Provide Tumor Tissue sample at screening.
• ECOG Performance Status of 0-1
|
• Età = 18 anni, consenso informato scritto firmato
• Cancro del colon-retto metastatico precedentemente trattato confermato istologicamente o citologicamente con istologia di adenocarcinoma e stadio IV per AJCC
• Status della stabilità microsatellitare confermato: sono elegibili solo i partecipanti con cancro del colon retto metastatico con pMMR/MSS
• Status delle mutazioni KRAS, NRAS (pannello di mutazioni RAS) e BRAF verificato: i pazienti con la mutazione BRAF V600 non sono elegibili
• Malattia misurabile secondo RECIST 1.1
• Possibilità di fornire un campione di tessuto tumorale allo screening
• ECOG performance status di 0 o 1 |
|
| E.4 | Principal exclusion criteria |
1) Target Disease Exceptions
a) Participants with BRAF V600 mutant colorectal cancer are NOT eligible for this study in Part 1, 1A, and 1B only.
2) Medical History and Concurrent Diseases
a) Any serious or uncontrolled medical disorder.
b) Prior malignancy active within the previous 3 years
c) Participants with an active, known or suspected autoimmune disease.
d) Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration.
e) Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways.
f) All toxicities attributed to prior anti-cancer therapy
g) Toxicities from the prior anti-cancer treatment have not been resolved to Grade 1
h) Current use of a prohibited medication.
i) Prior treatment with any MEK inhibitor
j) History of interstitial lung disease or pneumonitis.
k) Inability to take oral medication
l) Psychological, familial, or sociological condition potentially hampering compliance with the study protocol.
m) Additional criteria for Part 2 only:
i) Prior treatment with regorafenib or TAS-102
ii) Severe hepatic impairment (Child-Pugh C)
iii) Any evidence of active bleeding
iv) Prior or current gastrointestinal perforation or fistula
v) Arterial or venous thrombotic or embolic events within 6 months before the start of study medication
vi) Non-healing wound, non-healing ulcer, or non-healing bone fracture
vii) Active infection
3) Physical and Laboratory Test Findings
4) Allergies/Adverse Drug Reaction
5) Other Exclusion Criteria |
1) Eccezioni della Malattia Target
a) Solo per la Parte 1, 1A e 1B dello studio i partecipanti con tumore del colon-retto BRAF V600 mutato
2) Storia Clinica e Malattie Concomitanti
a) Qualsiasi patologia grave o non controllata
b) Precedente tumore maligno attivo nei 3 anni precedenti
c) Partecipanti con una malattia autoimmune attiva, nota o sospetta.
d) Partecipanti con una patologia che richiede un trattamento sistemico con corticosteroidi (> 10 mg giornalieri di prednisone equivalenti) o altri farmaci immunosoppressori entro 14 giorni dalla somministrazione del farmaco in studio.
e) Precedente trattamento con un anticorpo anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-
4, o qualsiasi altro anticorpo o farmaco mirato specificamente alla costimolazione delle cellule T o i pathway di checkpoint immunitario
f) Tossicità attribuibili a una precedente terapia antitumorale
g) Tossicità del precedente trattamento antitumorale non ridotte a grado 1
h) Uso corrente di un farmaco non ammesso.
i) Precedente trattamento con qualsiasi inibitore del MEK
j) Storia di malattia polmonare interstiziale o polmonite.
k) Incapacità di assumere farmaci per via orale
l) Condizione psicologica, familiare o sociologica che potrebbe ostacolare il rispetto del protocollo.
m) Criteri aggiuntivi solo per la parte 2:
i) Precedente trattamento con regorafenib o TAS-102
ii) Grave insufficienza epatica (Child-Pugh C)
iii) Qualsiasi evidenza di sanguinamento attivo
iv) Perforazione o fistola gastrointestinale precedente o attuale
v) Eventi trombotici o embolici entro 6 mesi prima dell'inizio del farmaco in studio
vi) Ferita, ulcera o frattura ossea che non guariscono
vii) Infezione attiva
3) Risultati di alcuni test di laboratorio e esame obiettivo (si faccia riferimento al protocollo)
4) Allergie / reazioni avverse ai farmaci
5) Altri Criteri di Esclusione definiti nel Protocollo |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| ORR by investigator |
| Tasso di risposta obiettiva (ORR) in base al giudizio dello sperimentatore |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Under current accrual assumption, approximately 12 months from the FPFT. |
| Secondo le ipotesi attuali, a circa 12 mesi dal FPFT |
|
| E.5.2 | Secondary end point(s) |
| BOR, DCR, DOR, TTR, and PFS by investigator, OS and Safety |
| BOR, DCR, DOR, TTR e PFS in base al giudizio dello Sperimentatore, OS e Sicurezza |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Under current accrual assumption, approximately 19 months from the FPFT. |
| Secondo le ipotesi attuali, a circa 19 mesi dal FPFT |
|
| 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 | Yes |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| It is the first time that subjects will be admnistered Nivo/Tram and Nivo/Ipi/Tram together |
| E' la prima volta che verranno somministrate a pazienti le combinazioni Nivolumab/Trametinib e Nivol |
|
| 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 | Yes |
| 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 | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 7 |
| 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 | 26 |
| 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 |
| United States |
| Belgium |
| Germany |
| Italy |
| 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
|
| LVLS |
| LVLS: ultima visita dell' ultimo soggetto indicare. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 23 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 29 |
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