| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Unresectable locally advanced or metastatic triple-negative breast cancer |
| Cancro al seno triplo-negativo in stadio localmente avanzato o metastatico, non resecabile |
|
| E.1.1.1 | Medical condition in easily understood language |
| Unresectable locally advanced or metastatic triple-negative breast cancer |
| Cancro al seno triplo-negativo in stadio localmente avanzato o metastatico, non resecabile |
|
| 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 | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10006212 |
| E.1.2 | Term | Breast carcinoma recurrent |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10006215 |
| E.1.2 | Term | Breast carcinoma stage III |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10006216 |
| E.1.2 | Term | Breast carcinoma stage IV |
| 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 |
| This study will evaluate the efficacy of ceralasertib followed by durvalumab plus Nab-paclitaxel in patients with TNBC, whose tumor relapsed following treatment with curative intent for early disease, which must have included ICIs and chemotherapy as part of the radical locoregional therapy (either adjuvant, neoadjuvant or both). |
| Questo studio valuterà l'efficacia di ceralasertib seguito da durvalumab più nab-paclitaxel in pazienti con TNBC, il cui tumore è ricaduto dopo il trattamento con intento curativo per la malattia precoce, compresa terapia radicale locoregionale e terapia sistemica (adiuvante, neoadiuvante o entrambe) con chemioterapia e immunoterapia (ICI). |
|
| E.2.2 | Secondary objectives of the trial |
| This study will further evaluate the efficacy and safety of the study treatments. |
| Questo studio valuterà l’efficacia e la sicurezza dei trattamenti dello studio. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Metastatic TNBC patients, chemotherapy naïve therapy for metastatic treatment and whose tumor have relapsed from treatment with curative intent for early disease, which must include ICI and chemotherapy as
part of radical locoregional therapy;
2. Documented disease progression (e.g., with biopsy sample, pathology or imaging report) since the last treatment in early setting with curative intent (neo/adjuvant regimen);
3. ATRiBRAVE trial written informed consent;
4. Age =18 years old;
5. Ability to comply with the study protocol in the investigator’s judgment, including ability to swallow and retain oral medication;
6. Availability of a formalin-fixed, paraffin-embedded block (FFPE) containing primary tumor tissue or at least 10-20 unstained tumor slides;
7. Negative ER/PgR and HER2 status, confirmed in the most recent tumor sample (primary and/or metastatic);
8. Evaluable disease as defined by RECIST 1.1;
9. ECOG performance status 0-1;
10. Acceptable organ functions measured within 28 days prior to trial;
11. Negative pregnancy test and willingness to use effective contraceptive methods from screening to 90 days from the last dose of durvalumab. |
1. Pazienti con TNBC metastatico, naïve alla chemioterapia per il trattamento metastatico e il cui tumore è recidivato dal trattamento con intento curativo per la malattia precoce compresa l’immunoterapia (ICI);
2. Progressione documentata della malattia (ad esempio, con un campione di biopsia, referto da anatomia patologia o di radiologia) dall'ultimo trattamento con intento curativo come regime neo/adiuvante;
3. Consenso informato scritto dello studio ATRiBRAVE;
4. Età =18 anni;
5. Pazienti in grado di attenersi al protocollo di studio a giudizio dello sperimentatore, compresa la capacità di deglutire e trattenere i farmaci per via orale;
6. Disponibilità del blocchetto (FFPE) contenente tessuto tumorale primario o almeno 10 vetrini tumorali non colorati;
7. Stato ER/PgR e HER2 negativo, confermato nel campione tumorale più recente (primario e/o metastatico);
8. Malattia valutabile/misurabile, come definito dai criteri RECIST 1.1;
9. Stato della condizione secondo ECOG 0-1;
10. Funzioni d'organo normali entro 28 giorni dalla prima somministrazione;
11. Test di gravidanza negativo per donne in età fertile e disponibilità a utilizzare metodi contraccettivi altamente efficaci. |
|
| E.4 | Principal exclusion criteria |
1. Diagnosis of ataxia telangiectasia.
2. Any previous treatment with ATR inhibitors, or DNA-damage repair inhibitors.
3. An adequate washout period prior to the start of study for any anticancer therapy.
4. Second primary cancer, except: non-melanoma skin cancer, or solid tumours curatively treated with no evidence of disease for =3 years;
5. Active or prior documented autoimmune or inflammatory disorders;
6. Patients with confirmed COVID-19 infection by PCR test who have not made a full recovery;
7. Leptomeningeal disease or symptomatic untreated CNS metastatic disease or cord compression. Asymptomatic metastases are conditionally eligible;
8. Any unresolved toxicity NCI CTCAE Grade =2 from previous anticancer therapy with the exception of alopecia and vitiligo;
9. Any evidence of severe or uncontrolled organ or systemic disease;
10. Any other clinical condition that may render the patient at high risk from treatment complications |
1. Diagnosi di atassia telangiectasia.
2. Qualsiasi trattamento precedente con ATR inibitori o inibitori della riparazione del danno al DNA.
3. Un periodo adeguato di washout prima dell'inizio dello studio per qualsiasi terapia antitumorale.
4. Storia di un’altra malattia neoplastica eccetto: cancro della pelle non melanoma, o tumori solidi trattati in modo curativo senza evidenza di malattia per = 3 anni;
5. Malattie autoimmuni o infiammatorie attivi o precedentemente documentate;
6. Pazienti con infezione confermata da COVID-19 mediante test PCR che non hanno avuto un recupero completo;
7. Malattia leptomeningea o malattia metastatica sintomatica non trattata del SNC o compressione del midollo. Le metastasi asintomatiche sono ammissibili condizionatamente;
8. Qualsiasi tossicità irrisolta NCI CTCAE Grade =2 da una precedente terapia antitumorale con l'eccezione di alopecia e vitiligine;
9. Qualsiasi evidenza di malattia d'organo o sistemica grave o incontrollata;
10. Qualsiasi altra condizione clinica che possa rendere il paziente ad alto rischio di complicazioni del trattamento |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is the progression free survival (PFS). PFS is defined as the number of days between the first study treatment administration to the date of first documented disease progression, relapse or death from any cause. |
| L'endpoint primario di efficacia è la sopravvivenza libera da progressione (PFS). La PFS è definita come il numero di giorni tra la prima somministrazione del trattamento dello studio e la data della prima progressione documentata della malattia, della ricaduta o della morte per qualsiasi causa. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At the first documented disease progression, relapse or death from any cause. |
| Prima progressione documentata della malattia, della ricaduta o della morte per qualsiasi causa. |
|
| E.5.2 | Secondary end point(s) |
| Disease Control Rate (DCR) defined as the percentage of subjects whose disease shrinks or remains stable at 12 weeks. DCR is the sum of the complete response (CR), partial response (PR) and stable disease (SD) rates; Clinical Benefit Rate (CBR) defined as the proportion of patients with no disease progression at 24 weeks; Duration of Response (DoR) defined as the time from the date of first documented confirmed response until date of documented progression per RECIST v1.1 or death due to any cause;; Overall Survival (OS) defined as the number of days between the first study treatment administration and death; Occurrence of Adverse Events (AEs), including treatment-related AEs and AEs of special interest; Overall Response Rate (ORR) according to RECIST v 1.1 criteria |
| Tasso di controllo della malattia (DCR) definito come la percentuale di soggetti la cui malattia si riduce o rimane stabile a 12 settimane. Il DCR è la somma dei tassi di risposta completa (CR), risposta parziale (PR) e malattia stabile (SD); Tasso di risposta del beneficio clinico (CBR) definito come la proporzione di pazienti senza progressione di malattia a 24 settimane; Durata della risposta (DOR) definita come il tempo che intercorre dalla data della prima documentata risposta fino alla data della documentata progressione secondo RECIST v1.1, o della morte per qualsiasi causa; Sopravvivenza complessiva (OS) definita come il numero di giorni tra la prima somministrazione del trattamento dello studio e la morte; Insorgenza di eventi avversi (AEs), compresi gli AEs correlati al trattamento e gli AEs di particolare interesse; Tasso di risposta complessiva (ORR) secondo i criteri RECIST v 1.1 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 12 weeks from the start of the treatment; 24 weeks from the start of the treatment; At the first documented disease progression, relapse or death from any cause.; Death; During the whole study duration; During the whole study duration |
| 12 settimane dall'inizio del trattamento; 24 settimane dall'inizio del trattamento; Prima progressione documentata della malattia, della ricaduta o della morte per qualsiasi causa.; Decesso; Durante tutto lo studio; Durante tutto lo studio |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| 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 | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Exploratory biomarker assessments will be conducted to investigate mechanism of the study treatments within the tumor microenvironment, possible resistance mechanisms, potential predictive and prognostic markers. |
| Le valutazioni esplorative di biomarcatori saranno condotte per indagare il meccanismo dei trattamenti all'interno del microambiente tumorale, i possibili meccanismi di resistenza, i potenziali marcatori predittivi e prognostici. |
|
| 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 | No |
| 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 | 1 |
| 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 | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| 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 | 3 |
| 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 | 3 |
| 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 | 0 |
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