| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Unresectable and/or metastatic breast cancer that is human epidermal growth factor receptor 2 (HER2)-low |
| Carcinoma mammario non resecabile e/o metastatico esprimente bassi livelli del recettore 2 per il fattore di crescita epidermico umano (HER2) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced-stage breast cancer |
| cancro al seno ad uno stadio avanzato |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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 compare the progression-free survival (PFS) benefit of DS-8201a to physician’s choice in HER2-low, hormone receptor (HR)-positive breast cancer, based on blinded independent central review (BICR). |
| Confrontare il beneficio di DS-8201a in termini di sopravvivenza libera da progressione (progression-free survival, PFS) rispetto alla scelta del medico nel carcinoma mammario positivo al recettore ormonale (HR) esprimente bassi livelli di HER2, in base alla revisione centrale indipendente in cieco (blinded independent central review, BICR). |
|
| E.2.2 | Secondary objectives of the trial |
• To investigate the efficacy of DS-8201a compared to physician’s choice on the following parameters:
- PFS in HR-positive subjects, based on Investigator assessment
- Overall survival (OS) in HR-positive subjects
- Confirmed objective response rate (ORR), based on BICR and Investigator assessment in HR-positive subjects
- Duration of response (DoR), based on BICR and Investigator assessment in HR-positive subjects
- PFS, OS, ORR, and DoR in all subjects, regardless of HR status.
• To determine pharmacokinetics (PK) of DS-8201a
• To evaluate safety of DS-8201a compared to physician’s choice of treatment
• To evaluate Health Economics and Outcomes Research (HEOR) endpoints for DS-8201a compared to physician’s choice |
Valutare l’efficacia di DS-8201a rispetto alla scelta del medico sui seguenti parametri:
- PFS in soggetti HR-positivi, in base alla valutazione dello sperimentatore;
- sopravvivenza complessiva (overall survival, OS) in soggetti HR-positivi;
- tasso di risposta obiettiva (objective response rate, ORR) confermata in base alla BICR e alla valutazione dello sperimentatore in soggetti HR-positivi;
- durata della risposta (duration of response, DoR) in base alla BICR e alla valutazione dello sperimentatore in soggetti HR-positivi;
- PFS, OS, ORR e DoR in tutti i soggetti, indipendentemente dallo stato HR.
• Determinare la farmacocinetica (pharmacokinetics, PK) di DS8201a
• Valutare la sicurezza di DS8201a rispetto al trattamento scelto dal medico
• Valutare gli endpoint di economia sanitaria e ricerca sugli esiti (health economics and outcomes research, HEOR) di DS8201a rispetto al trattamento scelto dal medico
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Men or women ≥18 years old. (Please follow local regulatory requirements if the legal age of consent for study participation is >18 years old.)
• Pathologically documented breast cancer that:
- Is unresectable or metastatic.
- Has a history of low HER2 expression, defined as IHC 2+/ISH- or IHC 1+ (ISH- or untested).
- Is assessed as low HER2 expression, defined as IHC 2+/ISH- or IHC 1+ according to American Society of Clinical Oncology – College of American Pathologists (ASCO-CAP) 2018 guidelines (adapted by Daiichi Sankyo Inc. and Ventana – please see the study laboratory manual for details) evaluated at a central laboratory.
- Is HR-positive or HR-negative. After ~60 HR-negative subjects are enrolled, further enrollment will be limited to only subjects who are HR-positive (either estrogen receptor positive or progesterone receptor positive per ASCO-CAP 2018 guidelines (adapted by Daiichi Sankyo Inc. and Ventana – please see the study laboratory manual for details)
- Is documented refractory to endocrine therapy, defined as having progressed on at least 1 endocrine therapy and determined by the Investigator that subject would no longer benefit from further treatment from endocrine therapy.
- If HR-positive, has or has not been treated with a CDK4/6 inhibitor. After ~240 HR-positive subjects have been enrolled who have not had prior therapy with a CDK4/6 inhibitor, further enrollment of HR-positive subjects will be limited to subjects who have had prior therapy with a CDK4/6 inhibitor.
- Has been treated with at least 1 and at most 2 prior lines of chemotherapy in the metastatic setting. If recurrence occurred within 6 months of adjuvant chemotherapy, adjuvant therapy would count as 1 line of chemotherapy.
- Was never previously HER2-positive (IHC 3+ or ISH+) on prior pathology testing (per ASCO-CAP 2018 guidelines [adapted by Daiichi Sankyo Inc. and Ventana – please see the study laboratory manual for details]).
- Was never previously treated with anti-HER2 therapy.
• Documented radiologic progression (during or after most recent treatment).
• Must have an adequate archival tumor sample available for assessment of HER2 status by central laboratory (based on
most recent available tumor tissue sample). If archival tissue is not available, a fresh biopsy is required.
• All subjects must have a recent tumor sample after the most recent treatment regimen or agree to undergo a tissue biopsy
prior to randomization.
• Presence of at least 1 measurable lesion based on computed tomography (CT) or magnetic resonance imaging (MRI), per
modified Response Evaluation Criteria in Solid Tumors (mRECIST) version 1.1
• Left ventricular ejection fraction (LVEF) ≥50%
• Adequate renal function, defined as:
- Creatinine clearance ≥30 mL/min, as calculated using the Cockcroft-Gault equation
• Adequate hepatic function, defined as:
- Aspartate aminotransferase (AST)/ alanine aminotransferase (ALT) ≤5 × upper limit of normal (ULN)
- Total bilirubin ≤1.5 × ULN) if no liver metastases or <3 × ULN in the presence of documented Gilbert’s syndrome (unconjugated hyperbilirubinemia) or liver metastases at baseline
• Males and females of reproductive/childbearing potential must agree to follow instructions for method(s) of contraception |
• Uomini o donne di età ≥18 anni (rispettare i requisiti normativi locali qualora l’età legale per il consenso alla partecipazione allo studio sia >18 anni).
• Documentazione patologica di carcinoma mammario che:
- Sia non resecabile o metastatico.
- Presenti un’anamnesi di bassa espressione di HER2, definita come IHC 2+/ISH- o IHC 1+ (ISH- o non analizzato).
- Sia valutato come a bassa espressione di HER2, definita come IHC 2+/ISH- o IHC 1+ secondo le linee guida della Società americana di oncologia clinica - Collegio dei patologi americani (American Society of Clinical Oncology – College of American Pathologists, ASCO-CAP), valutata presso un laboratorio centrale.
- Sia HR-positivo o HR-negativo. Dopo l’arruolamento di circa 60 soggetti HR-negativi, l’ulteriore arruolamento sarà limitato solo a soggetti HR-positivi (positivi al recettore estrogenico o al recettore del progesterone secondo le linee guida ASCO-CAP).
- Sia documentato refrattario alla terapia endocrina, dove per refrattario si intende che il soggetto ha manifestato progressione durante almeno 1 terapia endocrina e lo sperimentatore ha stabilito che il soggetto non trarrebbe più beneficio dall’ulteriore trattamento con la terapia endocrina.
- Se HR-positivo, sia stato o meno trattato con un inibitore della CDK4/6. Una volta arruolati circa 240 soggetti HR-positivi che in precedenza non sono stati in terapia con un inibitore della CDK4/6, l’ulteriore arruolamento di soggetti HR-positivi sarà limitato a soggetti che in precedenza sono stati in terapia con un inibitore della CDK4/6.
- Sia stato trattato con almeno 1 e al massimo 2 precedenti linee di chemioterapia nel contesto metastatico. In caso di recidiva verificatasi nei 6 mesi della chemioterapia adiuvante, la terapia adiuvante andrebbe conteggiata come 1 linea di chemioterapia.
- Non sia mai stato in precedenza HER2-positivo (IHC 3+ o ISH+) alla precedente analisi patologica (secondo le linee guida ASCO-CAP).
- Non sia mai stato trattato in precedenza con una terapia anti-HER2.
• Progressione radiologica documentata (durante o dopo il trattamento più recente).
• I soggetti devono disporre di un campione tumorale d’archivio adeguato per la valutazione dello stato di HER2 da parte del laboratorio centrale (in base al campione di tessuto tumorale disponibile più recente). Qualora non sia disponibile il tessuto d’archivio, è necessaria una biopsia fresca.
• Tutti i soggetti devono disporre di un campione tumorale recente dopo il regime di trattamento più recente o acconsentire a sottoporsi a una biopsia tissutale prima della randomizzazione.
• Presenza di almeno 1 lesione misurabile mediante tomografia computerizzata (TC) o risonanza magnetica (RM), secondo i Criteri modificati di valutazione della risposta nei tumori solidi (modified Response Evaluation Criteria in Solid Tumors, mRECIST), versione 1.1.
• Frazione di eiezione del ventricolo sinistro (FEVS) ≥50%
• Funzionalità renale adeguata, definita come:
- clearance della creatinina ≥30 ml/min calcolata mediante l’equazione di Cockcroft-Gault
• Funzionalità epatica adeguata, definita come:
- aspartato aminotransferasi (AST)/alanina aminotransferasi (ALT) ≤5 volte il limite superiore della normalità (ULN);
- bilirubina totale ≤1,5 x ULN in assenza di metastasi epatiche o <3 x ULN in presenza di sindrome di Gilbert documentata (iperbilirubinemia non coniugata) o metastasi epatiche al basale
• I soggetti di sesso maschile e femminile in età riproduttiva/fertile devono acconsentire a seguire le istruzioni per uno o più metodi contraccettivi
|
|
| E.4 | Principal exclusion criteria |
• Ineligible for all 5 of the options in the physician’s choice arm either because of previously receiving treatment in the metastatic setting with the comparator or having a contraindication to treatment
• Has medical history of myocardial infarction within 6 months before randomization
• Has history of symptomatic congestive heart failure (New York Heart Association Class II to IV)
• Has corrected QT interval (QTc) prolongation to >470 ms (females) or >450 ms (male) based on average of Screening triplicate 12-lead electrocardiograms (ECGs)
• Has a history of (noninfectious) 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.
• Has spinal cord compression or clinically active central nervous system metastases, defined as untreated or symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms.
- 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 study enrollment. |
• Inidoneità a tutte e 5 le opzioni nel braccio di scelta del medico per via di un precedente trattamento nel contesto metastatico con il prodotto di confronto o per la presenza di controindicazioni al trattamento
• Anamnesi medica di infarto miocardico nei 6 mesi precedenti la randomizzazione
• Anamnesi di insufficienza cardiaca congestizia sintomatica (classe da II a IV in base alla New York Heart Association)
• Prolungamento dell’intervallo QT corretto (QTc) fino a >470 ms (donne) o >450 ms (uomini) in base alla media degli elettrocardiogrammi (ECG) a 12 derivazioni eseguiti in triplicato allo screening
• Anamnesi di pneumopatia interstiziale (interstitial lung disease, ILD)/polmonite (non infettiva) che necessiti di steroidi, ILD/polmonite in corso o impossibilità di escludere il sospetto di ILD/polmonite mediante diagnostica per immagini allo screening.
• Compressione del midollo spinale o metastasi del sistema nervoso centrale clinicamente attive, definite come non trattate e sintomatiche, o che richiedono terapia a base di corticosteroidi o anticonvulsivi per il controllo dei sintomi associati.
- I soggetti con metastasi cerebrali trattate, che non siano più sintomatiche e non richiedano trattamento con corticosteroidi o anticonvulsivi, possono essere inclusi nello studio a condizione che si siano ripresi dall’effetto tossico acuto della radioterapia. Devono essere trascorse almeno 2 settimane tra la fine della radioterapia panencefalica e l’arruolamento nello studio.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| PFS, based on BICR |
| PFS in base alla BICR |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary analyses for PFS will be performed when ~318 PFS events per BICR are observed in the HR-positive population, which is expected to occur in ~16 months. |
| Le analisi primarie per la PFS saranno eseguite quando saranno stati osservati circa 318 eventi di PFS secondo la BICR nella popolazione HR-positiva, il che si prevede dovrebbe verificarsi entro circa 16 mesi. |
|
| E.5.2 | Secondary end point(s) |
• PFS, based on Investigator assessment
• OS
• Confirmed ORR, based on BICR and Investigator assessment
• DoR, based on BICR and Investigator assessment |
• PFS in base alla valutazione dello sperimentatore
• OS
• ORR confermato in base alla BICR e alla valutazione dello sperimentatore
• DoR in base alla BICR e alla valutazione dello sperimentatore
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The end of the study hypothesis-testing period is defined as the date when approximately 318 PFS events per BICR have been observed in the HR-positive population. |
| La fine del periodo di verifica delle ipotesi dello studio viene definita come la data alla quale saranno stati osservati circa 318 eventi di PFS secondo la BICR nella popolazione HR-positiva. |
|
| 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 | 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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) | 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 | 14 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 80 |
| 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 | No |
| 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 |
| Austria |
| Belgium |
| Canada |
| China |
| France |
| Germany |
| Greece |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Portugal |
| Spain |
| Sweden |
| Switzerland |
| Taiwan |
| United Kingdom |
| United States |
|
| 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
|
| The end of the study hypothesis-testing period is defined as the date when approximately 318 PFS events per BICR have been observed in the HR-positive population. The study closure is defined as the date when the last subject discontinues study treatment and applicable follow-up occurs, or the study is ended by the Sponsor. |
| La fine del periodo di verifica delle ipotesi dello studio viene definita come la data alla quale saranno stati osservati circa 318 eventi di PFS secondo la BICR nella popolazione HR-positiva. La chiusura dello studio viene definita come la data in cui l’ultimo soggetto interrompe il trattamento dello studio e viene effettuato il follow-up pertinente, o in cui lo studio viene interrotto dallo sponsor. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 49 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 49 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
