| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| HER2-overexpressing Locally Advanced, Unresectable or Metastatic Colorectal Cancer |
| carcinoma colorettale metastatico localmente avanzato, non resecabile con sovraespressione di HER2 |
|
| E.1.1.1 | Medical condition in easily understood language |
| Colorectal Cancer |
| carcinoma colorettale |
|
| 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 | SOC |
| E.1.2 | Classification code | 10029104 |
| E.1.2 | Term | Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
| 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 assess the efficacy of T-DXd, as measured by the confirmed ORR by BICR in HER2-overexpressing (defined as IHC 3+ or IHC 2+/ISH+) mCRC subjects treated at the 5.4 mg/kg and 6.4 mg/kg doses |
| Valutare l’efficacia di trastuzumab deruxtecan (T-DXd), misurata mediante ORR confermato da BICR in soggetti affetti da mCRC con sovraespressione di HER2 (definita come IHC 3+ o IHC 2+/ISH+) trattati con dosi da 5,4 mg/kg e 6,4 mg/kg |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the clinical efficacy of T-DXd by confirmed ORR by
Investigator assessment;
• To evaluate the clinical efficacy of T-DXd by DoR;
• To further evaluate the clinical efficacy of T-DXd by DCR, CBR, PFS and
OS;
• To further evaluate the safety and tolerability of T-DXd;
• To evaluate HEOR endpoints including patient-reported HRQoL,
symptoms, and physical functioning;
• To evaluate healthcare resource utilization for both treatment arms;
• To evaluate PK of T-DXd;
• To evaluate immunogenicity of T-DXd. |
- Valutare l’efficacia clinica di T-DXd in base all’ORR confermato dalla valutazione dello sperimentatore
- Valutare l’efficacia clinica di T-DXd mediante DoR
- Valutare ulteriormente l’efficacia clinica di T-DXd mediante DCR, CBR, PFS e OS
- Valutare ulteriormente la sicurezza e la tollerabilità di T-DXd
- Valutare gli endpoint HEOR inclusa HRQoL riferita dal paziente, sintomi e funzionalità fisica
- Valutare l’utilizzo delle risorse sanitarie per entrambi i bracci di trattamento
- Valutare la PK di T-DXd
- Valutare l’immunogenicità di T-DXd |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Sign and date the Tissue Pre-Screening and Main ICFs, prior to the start of any respective study-specific qualification procedures.
- Adults aged =20 years in Japan, Taiwan, and Korea, or those aged =18 years in other countries, at the time the ICFs are signed. (Please follow local regulatory requirements if the legal age of consent for study participation is >18 years).
- Pathologically-documented, unresectable, recurrent, or metastatic colorectal adenocarcinoma. Subject must have BRAF wild-type cancer and RAS status identified in primary or metastatic site, tested by a Clinical Laboratory Improvement Act (CLIA), ISO15189, or equivalent-certified laboratory.
- The following therapies should be included in prior lines of therapy:
o Fluoropyrimidine, oxaliplatin, and irinotecan, unless contraindicated
o Anti-epidermal growth factor receptor (EGFR) treatment, if RAS wild-type and if clinically indicated
o Anti-vascular endothelial growth factor (VEGF) treatment, if clinically indicated
o Anti-programmed death-ligand 1 (PD-[L]-1) therapy, if tumor is microsatellite instable (MSI)-high/deficient mismatch repair (dMMR), or tumor mutational burden (TMB)-high, if clinically indicated
¿¿Is willing and able to provide an adequate tumor sample for tissue pre-screening to confirm HER2 status by central laboratory (most recent tumor tissue preferred).
- Confirmed HER2-overexpressing status assessed by central laboratory and defined as IHC 3+ or IHC 2+/ISH+.
- Presence of at least one measurable lesion assessed by the Investigator per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Lesions situated in a previously-irradiated area are considered measurable if progression has been demonstrated in such lesions after the end of radiotherapy.
- ECOG PS of 0 or 1.
- Has left ventricular ejection fraction (LVEF) =50% within 28 days before randomization/registration.
- Has adequate organ function within 14 days before randomization/registration,
- Has adequate treatment washout period before randomization/registration |
- Firmare e datare l’ICF per il Pre-screening tissutale e l’ICF principale prima di iniziare qualsiasi rispettiva procedura di qualificazione specifica dello studio.
- Soggetti adulti di età =20 anni in Giappone, Taiwan, e Corea del Sud, o quelli di età =18 anni in altri Paesi, al momento in cui gli ICF vengono firmati. (Si prega di attenersi ai requisiti normativi locali se l’età legale del consenso per la partecipazione allo studio è >18 anni).
-Adenocarcinoma colorettale documentato a livello patologico, non resecabile, ricorrente o metastatico. Il soggetto deve avere un tumore con stato di BRAF wild-type e RAS identificato nel sito primario o metastatico, testato da un laboratorio accreditato CLIA (Clinical Laboratory Improvement Act), ISO15189, o laboratorio con certificato equivalente.
-Le seguenti terapie devono essere incluse nelle linee precedenti di terapia:
o fluoropirimidina, oxaliplatino e irinotecan, a meno che non siano controindicati
o Trattamento mirato al recettore del fattore di crescita dell’epidermide (EGFR), in caso di RAS wild-type e se clinicamente indicato
o Trattamento mirato al fattore di crescita endoteliale vascolare (VEGF), se clinicamente indicato
oTerapia mirata al ligando di morte cellulare programmata 1 (PD-[L]-1), se il tumore è altamente instabile a livello microsatellitare (MSI)/ha un deficit di riparazione del mismatch (dMMR) o ha un elevato carico mutazionale del tumore (TMB), se clinicamente indicato
- Soggetto disposto a e in grado di fornire un campione tumorale adeguato per il Pre-screening tissutale per la conferma dello stato di HER2 da parte del laboratorio centrale (preferibile il tessuto tumorale più recente).
- Stato di sovraespressione di HER2 confermato valutato dal laboratorio centrale e definito come IHC 3+ o IHC 2+/ISH+.
- Presenza di almeno una lesione misurabile valutata dallo Sperimentatore secondo i Criteri di valutazione della risposta nei tumori solidi (RECIST) versione 1.1. Le lesioni localizzate in una zona precedentemente irradiata sono considerate misurabili se in tali lesioni viene dimostrata la progressione dopo la fine della radioterapia. |
|
| E.4 | Principal exclusion criteria |
Medical history of myocardial infarction (MI) within 6 mths before randomization/registration, symptomatic congestive heart failure (CHF) (New York Heart Association Class II to IV). Subjects with troponin levels above ULN at Screening (as defined by the manufacturer), and without any MI-related symptoms, should have a cardiologic consultation before randomization/registration to rule out MI
Has a corrected QT interval (QTcF) prolongation to >470 msec (female subjects) or >450 msec (male subjects) based on the average of the Screening triplicate 12-lead ECGs
Has a history of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at Screening.
Lung-specific intercurrent clinic significant illnesses including, but not limited to, any underlying pulmonary disorder (eg, pulmonary emboli within 3 months of the randomization/registration, severe asthma, severe chronic obstructive pulmonary disease [COPD], restrictive lung disease, pleural effusion, etc.)
autoimmune, connective tissue, or inflammatory disorders (eg, rheumatoid arthritis, Sjögren syndrome, sarcoidosis, etc.) where there is documented, or a suspicion of, pulmonary involvement at the time of Screening. Full details of the disorder should be recorded in the eCRF for subjects who are included in the study
Prior pneumonectomy
Spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. Subjects with clinically inactive brain metastases may be included in the study. Subjects with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 2 weeks must have elapsed between the end of whole brain radiotherapy and randomization/registration
Subjects with leptomeningeal carcinomatosis
Has multiple primary malignancies within 3 years, except adequately resected non-melanoma skin cancer, curatively treated in situ disease, or other solid tumors curatively treated
Has a history of severe hypersensitivity reactions to either the drug substances or inactive ingredients in the drug product.
Has a history of severe hypersensitivity reactions to other monoclonal antibodies
Has an uncontrolled infection requiring intravenous antibiotics, antivirals, or antifungals
Has substance abuse or any other medical conditions such as clinically significant cardiac or psychological conditions that may in the opinion of the Investigator, interfere with the subject’s partic. in the clinical study or evaluation of the clinical study results
Has known human immunodeficiency virus (HIV) infection. Unless required by local regulations or institutional review board IRB/EC, an HIV antigen/antibody test is not required prior to randomization/enrollment
Active hepatitis B and/or hepatitis C infection, such as those with serologic evidence of viral infection within 28 days before study randomization/registration. Subjects with past or resolved hepatitis B virus (HBV) infection are eligible if hepatitis B surface antigen (HBsAg) negative (-) and antibody to hepatitis B core antigen (anti-HBc) positive (+). Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA
Unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0, Grade =1 or baseline. Subjects with chronic Grade 2 toxicities may be eligible at the discretion of the Investigator and approval of the Sponsor
Previous treatment with a DXd-containing antibody-drug conjugate ADC |
Anamnesi infarto del miocardio (MI) entro 6 mesi prima della randomizz/registrazione, insuffic. cardiaca congestizia (CHF) sintomatica (di Classe da II a IV della New York Heart Association). sogg con i livelli di troponina sopra l’ULN allo Screen (come definito dal produttore), e senza alcun sintomo correlato all’infarto miocardico, devono effettuare un consulto cardiol. prima della randomizz/registrazione per escludere il MI.
Presenta un prolung. dell’intervallo QT corretto (QTcF) a >470 msec (sogg di sesso femminile) o >450 msec (soggetto di sesso masch) in base alla media dell’ECG a 12 derivazioni in triplicato allo Screening.
Anamnesi di malattia polm. interstiziale (ILD)/polmonite (non infettiva) che abbia richiesto un tratt. con steroidi, ILD/polmonite in atto o sospetto di ILD/polmonite non escludibile dagli esami di diagnostica per immagini eseguiti allo Screening.
Malattie polmonari intercorrenti clinicam. Signif., tra cui qualsiasi disturbo polm. sottostante (es, embolia polm. entro 3 mesi dalla randomizz/registrazione, asma grave, BPCO grave, malattia polm. restrittiva, versamento pleurico, ecc.).
Qls disturbo autoimmune, del tessuto conn. o infiamm. (es., artrite reumatoide, sindrome di Sjögren, sarcoidosi, ecc.) in cui vi sia un coinvolg. polm. documentato o sospetto al momento dello Screen. I dettagli completi del disturbo devono essere registrati nell’eCRF per i sogg inclusi nello studio.
Pneumonectomia preced.
Compress del midollo spinale o metastasi a carico del sist. nervoso centrale clinic attive, definite come non trattate e sintom. o che richiedano terapia con corticosteroidi o anticonvulsivanti per il controllo dei sintomi associati. sogg con metastasi cerebr clinic. inattive possono essere inclusi nello studio. sogg con metastasi cerebrali trattate che non sono più sintomatiche e che non richiedono il tratt con corticosteroidi o anticonvulsivanti possono essere inclusi se si sono ripresi dagli effetti tossici acuti della radioterapia. trascorso un minimo di 2 sett. tra la fine della radioterapia panencefalica e la randomizz/registrazione.
Sogg con carcinomatosi leptomeningea.
Malignità primarie multiple entro 3 anni, eccetto tumore cutaneo non-melanoma sottop. a resezione adeguata, malattia in situ trattata in modo curativo, altri tumori solidi trattati in modo curativo.
anamnesi di gravi reazioni da ipersensibilità alle sostanze farmaceutiche o agli ingredienti inattivi presenti nel prodotto medic.
Anamnesi di gravi reazioni da ipersens ad altri anticorpi monocl.
Infezione non controllata che richiede antibiotici per via endov., antivirali o antimicotici.
Abuso di sostanze o presenta condizione medica quali cardiopatia clinicamente signific. o condizioni psicologiche, che, secondo il parere del PI, potrebbero interferire con la partec. del sogg o alla valut. dei risultati dello studio.
infezione nota da HIV. Salvo laddove richiesto dalle normative locali o da IRB/CE, un test per antigeni/anticorpi anti-HIV non necessario prima della randomizzazione/arruolamento.
Inf. attiva da epatite B e/o epatite C, come nei casi di evidenza sierol. di infez. virale entro 28 gg prima della registrazione/randomizz dello studio. Sogg con infezione da virus dell’epatite B (HBV) pregr o risolta sono idonei se sono negativi (-) all’antigene di superficie dell’epatite B (HBsAg) e positivi (+) all’anticorpo anti-antigene core dell’epatite B (anti-HBc). I pz positivi per l’anticorpo del virus dell’epatite C (HCV) saranno idonei solo se la reazione a catena della polimerasi sarà negativa per l’RNA HCV.
Tossicità non risolte dalla preced. terapia antitum, definite come tossicità (diverse dall’alopecia) non ancora risolte a un Grado =1 dei criteri terminol. comuni per gli eventi avversi dell’Istituto oncol naz. (NCI-CTCAE) v 5.0 o al basale. sogg con tossicità di Grado 2 cronica possono essere idonei, a discrezione del PI e con l’approv. dello Sponsor.
Prec. Tratt. con un coniugato anticorpo-farmaco ADC con DXd. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Confirmed ORR defined as the proportion of subjects with CR or PR, assessed by BICR based on RECIST version 1.1 |
| l’ORR confermato, definito come la percentuale di soggetti con CR o PR, valutate mediante BICR in base ai criteri RECIST versione 1.1 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 12 weeks after the first 80 subjects are randomized for the IA and 6 months after the last subject is registered for the primary analysis |
| 12 settimane dopo che i primi 80 soggetti sono stati randomizzati per IA e 6 mesi dopo che l’ultimo soggetto è stato registrato per l’analisi primaria |
|
| E.5.2 | Secondary end point(s) |
- Confirmed ORR;
- Duration of response (DoR);
- Disease control rate (DCR);
- Clinical benefit rate (CBR);
- Progression-free survival (PFS);
- Overall survival (OS);
- TEAEs (including SAEs and AESIs);
- PROs;
- PK profile;
- incidenza di anticorpi anti-farmaco (ADA) e anticorpi neutralizzanti NAb
- Incidence of ADA and NAb |
- ORR confermato
- Durata della risposta (DoR);
- tasso di controllo della malattia (DCR);
- asso di beneficio clinico (CBR);
- opravvivenza libera da progressione (PFS);
- sopravvivenza complessiva (OS);
- eventi avversi emergenti dal trattamento (incluso SAEs e AESIs);
- PROs;
- profilo farmacocinetica;
- incidenza di anticorpi anti-farmaco (ADA) e anticorpi neutralizzanti NAb |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Confirmed ORR, DoR, TEAEs: 12 weeks after the first 80 subjects are
randomized for the IA and 6 months after the last subject is registered
for the primary analysis
DCR, PFS, DCR, CBR, OS: 12 weeks after the first 80 subjects are
randomized for the IA (DCR, PFS) and 6 months after the last subject is
registered for the primary analysis (DCR, CBR, PFS, OS)
PROs, PK Profile, Incidence of ADA and NAb: 6 months after the last
subject is registered or later |
ORR confermato, DoR, TEAEs: 12 settimane dopo che i primi 80 soggetti sono stati randomizzati per IA e 6 mesi dopo che l’ultimo soggetto è stato registrato per l’analisi primaria
DCR, PFS, DCR, CBR, OS: 12 settimane dopo che i primi 80 soggetti sono stati randomizzati per IA (DCR, PFS) e 6 mesi dopo che l’ultimo soggetto è stato registrato per l’analisi primaria (DCR, CBR, PFS, OS)
PROs, PK, incidenza di anticorpi anti-farmaco (ADA) e anticorpi neutralizzanti NAb: 6 mesi dopo che l’ultimo soggetto è stato registrato od oltre |
|
| 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 | 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| Tolerability, Biomarker Analysis, Immunogenicity, Health economics and outcomes research (HEOR), Quality of Life (QoL), Healthcare resource utilization etc. E. |
| Tollerabilità, analisi biomarker, Immunogenicicità, Health economics and outcomes research (HEOR), Qualità della vita (QoL), Healthcare resource utilization etc. E. |
|
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| differenti dosi dello stesso IMP |
| Different dose of the same IMP |
|
| 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 | 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 24 |
| 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 |
| Japan |
| Korea, Republic of |
| Taiwan |
| United States |
| Belgium |
| France |
| Italy |
| Spain |
| 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
|
Overall end of study will occur when the last subject last visit has
occurred or the study is discontinued by the Sponsor for other reasons
(administrative, program-level, or class-related). |
La fine complessiva dello studio avverrà quando l'ultima visita dell'ultimo soggetto avrà avuto luogo o lo studio è interrotto dallo Sponsor per altri motivi
(amministrativi, a livello di programma o relativo alla classe). |
|
| 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 | 6 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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