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Condition médicale (spécialité visée)
Choix aire thérapeutique
Cancérologie / Radio-oncologie/ tumeurs solides
Oncologie – Sein
Oncologie
Stades de cancer
Autre
Previously Untreated Triple-Negative or Hormone Receptor-low/HER2-negative Breast Cancer
Biomarqueur
Her2/neu
Pharmacocinétique et immunogénécité
TROP2
Génomique et expression divers
Analyse CHIP
ADN recirculant
Profil des participants
Limites d'âge
Sexe(s) des participants
TOUS
Aptitude des participants
Majeurs aptes
Critères de sélection
Critères d'inclusion
Critères d'inclusion :
* Le participant doit avoir ≥ 18 ans, au moment de la signature du formulaire de consentement éclairé (ICF).
* Cancer du sein invasif primaire unilatéral ou bilatéral de stade II ou III, TNBC ou à faible récepteur hormonal/HER2-négatif, confirmé histologiquement
* Score ECOG PS de 0 ou 1
* Fourniture d'un échantillon tumoral acceptable
* Réserve de moelle osseuse adéquate et fonction organique
* L'utilisation de contraceptifs par les hommes ou les femmes doit être conforme aux réglementations locales concernant les méthodes de contraception pour ceux participant à des études cliniques et alignée sur les exigences du protocole.
Critères d'exclusion :
* Antécédents de toute autre malignité mammaire invasive
* Antécédents d'une autre malignité primaire, sauf pour une malignité traitée avec intention curative sans maladie active connue dans les 5 années précédant la randomisation.
* Troubles auto-immuns ou inflammatoires actifs ou documentés antérieurement.
* Présence de maladie à distance.
* Maladie cornéenne cliniquement significative.
* Infection active ou non contrôlée par le virus de l'hépatite B ou C.
* Infection par le VIH connue qui n'est pas bien contrôlée.
* Infection non contrôlée nécessitant des antibiotiques, antiviraux ou antifongiques i.v.; infections suspectées; ou incapacité à exclure les infections.
* Infection tuberculeuse active connue
* Intervalle QTcF corrigé au repos moyen > 470 ms obtenu à partir de l'ECG
* Maladie cardiaque non contrôlée ou significative.
* Antécédents de ILD/pneumonie non infectieuse
* Compromission sévère de la fonction pulmonaire
* Toute chirurgie, radiothérapie ou thérapie anticancéreuse systémique antérieure ou concomitante pour TNBC ou cancer du sein à faible récepteur hormonal/HER2-négatif
* Pour les femmes uniquement : est enceinte (confirmée par un test de grossesse sérique positif) ou allaite, ou prévoit de devenir enceinte.
* Les participantes doivent s'abstenir d'allaiter du recrutement tout au long de l'étude et pendant au moins 7 mois après la dernière dose de l'intervention à l'étude, ou selon les directives du PI local pour SoC si plus long.
* Utilisation concomitante d'un traitement hormonal systémique de substitution ou d'une contraception hormonale orale
Inclusion Criteria:
* Participant must be ≥ 18 years, at the time of signing the ICF.
* Histologically confirmed Stage II or III unilateral or bilateral primary invasive TNBC or hormone receptor-low/HER2-negative breast cancer
* ECOG PS of 0 or 1
* Provision of acceptable tumor sample
* Adequate bone marrow reserve and organ function
* Contraceptive use by males or females should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies and aligned with protocol requirements.
Exclusion criteria:
* History of any prior invasive breast malignancy
* History of another primary malignancy except for malignancy treated with curative intent with no known active disease within 5 years before randomization.
* active or prior documented autoimmune or inflammatory disorders.
* Evidence of distant disease.
* Clinically significant corneal disease.
* Has active or uncontrolled hepatitis B or C virus infection.
* Known HIV infection that is not well controlled.
* Uncontrolled infection requiring i.v. antibiotics, antivirals or antifungals; suspected infections; or inability to rule out infections.
* Known to have active tuberculosis infection
* Mean resting corrected QTcF interval \> 470 ms obtained from ECG
* Uncontrolled or significant cardiac disease.
* History of non-infectious ILD/pneumonitis
* Has severe pulmonary function compromise
* Any prior or concurrent surgery, radiotherapy or systemic anticancer therapy for TNBC or hormone receptor-low/HER2-negative breast cancer
* For females only: is pregnant (confirmed with positive serum pregnancy test) or breastfeeding, or planning to become pregnant.
* Female participants should refrain from breastfeeding from enrolment throughout the study and for at least 7 months after last dose of study intervention, or as dictated by local PI for SoC if longer.
* Concurrent use of systemic hormone replacement therapy or oral hormonal contraception
Critères d'exclusion
1- As judged by the investigator, any evidence of diseases such as severe or uncontrolled systemic diseases, including active infection, serious chronic gastrointestinal conditions associated with diarrhoea, active bleeding diseases and significant cardiac or psychological illness/social situations, chronic diverticulitis or previous complicated diverticulitis, history of allogenic organ transplant, and/or substance abuse which, in the investigator’s opinion, makes it undesirable for the participant to participate in the study or that would jeopardise compliance with the protocol.
2- Refractory nausea and vomiting, inability to swallow a formulated product, or previous significant bowel resection, that would preclude adequate absorption, distribution, metabolism, or excretion of capecitabine or olaparib.
3- History of another primary malignancy except for malignancy treated with curative intent with no known active disease within 3 years before randomisation and of low potential risk for recurrence. Exceptions include adequately resected non-melanoma skin cancer (basal cell carcinoma of the skin or squamous cell carcinoma of the skin) and curatively treated in situ disease. Note: for synchronous tumours with contralateral DCIS, curative surgery for DCIS may be performed as part of the surgery after the neoadjuvant phase.
4- Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis or Crohn’s disease], systemic lupus erythematosus, sarcoidosis, granulomatosis with polyangiitis, Graves’ disease, rheumatoid arthritis, hypophysitis, uveitis, etc), autoimmune pneumonitis, and autoimmune myocarditis. The following are exceptions to this criterion:
(a) Participants with vitiligo or alopecia.
(b) Participants with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement.
(c) Any chronic skin condition that does not require systemic therapy.
(d) Participants without active disease in the last 5 years may be included but only after consultation with the study clinical lead.
(e) Participants with coeliac disease controlled by diet alone.
5 Evidence of distant disease. Note: Participants must have evidence of M0 disease based on the assessments from their initial diagnosis. In the event of suspected regional or distant metastases during screening, participants should be thoroughly evaluated as clinically indicated, and those with metastatic disease should be excluded.
6- Clinically significant corneal disease.
7- Has active or uncontrolled hepatitis B or C virus infection. Participants are eligible if they:
(a) Have been curatively treated for HCV infection as demonstrated clinically and by viral serologies.
(b) Have received HBV vaccination with only anti-HBs positivity and no clinical signs of hepatitis.
(c) Are HBsAg-negative and anti-HBc-positive (ie, those who have cleared HBV after infection) and meet criteria i to iii below:
(i) HBV DNA viral load < 2000 IU/mL.
(ii) Have normal transaminase values, or, if liver metastases are present, abnormal transaminases, with a result of AST/ALT < 3 × ULN, which are not attributable to HBV infection.
(iii) Start or maintain antiviral treatment if clinical indicated as per the investigator.
(d) Are HBsAg-positive with chronic HBV infection (lasting 6 months or longer) and meet criteria i-iii below:
i) HBV DNA viral load < 2000 IU/mL.
ii) Have normal transaminase values, or, if liver metastases are present, abnormal transaminases, with a result of AST/ALT < 3 × ULN, which are not attributable to HBV infection.
iii) Start or maintain antiviral treatment if clinically indicated as per the investigator.
8- Known HIV infection that is not well controlled. All of the following criteria are required to define an HIV infection that is well controlled:
(a) Undetectable viral RNA.
(b) CD4+ count ≥ 350
(c) No history of acute immunodeficiency syndrome (AIDS)-defining opportunistic infection within the past 12 months, and stable for at least 4 weeks on the same anti-HIV medications (meaning there are no expected further changes in that time to the number or type of antiretroviral drugs in the regimen). If an HIV infection meets the above criteria, monitoring of viral RNA load and CD4+ count is recommended. Participants must be tested for HIV during the screening period if acceptable by local regulations or an IRB/EC.
9- Uncontrolled infection requiring i.v. antibiotics, antivirals or antifungals; suspected infections (eg, prodromal symptoms); or inability to rule out infections (participants with localised fungal infections of skin or nails are eligible).
10- Known to have active tuberculosis infection (clinical evaluation that may include clinical history, physical examination and radiographic findings, or tuberculosis testing in line with local practice).
11- Resting ECG with clinically significant abnormal findings.
12- Uncontrolled or significant cardiac disease including:
(a) Myocardial infarction or uncontrolled/unstable angina within 6 months before randomisation.
(b) Congestive heart failure (New York Heart Association Class II to IV).
(c) Uncontrolled hypertension (resting systolic blood pressure > 180 mmHg or diastolic blood pressure > 110 mmHg).
(d) Cardiac arrhythmia (multifocal premature ventricular contractions, bigeminy
trigeminy, ventricular tachycardia), which is symptomatic or requires treatment (CTCAE Grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Participants with atrial fibrillation controlled by medication or arrhythmias controlled by pacemakers may be permitted based on the investigator judgement with cardiologist consultation recommended.
13- History of non-infectious ILD/pneumonitis including radiation pneumonitis that required steroids, has current ILD/pneumonitis, or has suspected ILD/pneumonitis that cannot be ruled out by imaging at screening.
14- Has severe pulmonary function compromise.
15- Any concomitant medication known to be associated with torsades de pointes.
16- Any prior or concurrent surgery, radiotherapy or systemic anticancer therapy for TNBC or hormone receptor-low/HER2-negative breast cancer (including chemotherapy, radiation therapy, endocrine therapy, immune-mediated therapy [non-antibody-based therapy or antibody-based therapy including but not limited to other anti-cytotoxic T-lymphocyte associated protein 4, anti-PD-1, anti-PD-L1 and anti-PD-L2 antibodies, excluding therapeutic anticancer vaccines], retinoid therapy, or targeted therapy).
17- Prior exposure to chloroquine/hydroxychloroquine without an adequate treatment washout period of > 14 days before randomisation (see Appendix H 2).
18- Current or prior use of immunosuppressive medication within 14 days before the first dose of study intervention. The following are exceptions to this criterion:
- Intranasal, inhaled, topical steroids or local steroid injections (eg, intra-articular injection)
- Systemic corticosteroids at physiological doses not to exceed 10 mg/day of prednisone or its equivalent
- Steroids as premedication for hypersensitivity reactions or as an antiemetic (eg, CT scan premedication)
19- Receipt of live, attenuated vaccine within 30 days prior to the first dose of study
intervention.
20- Participation in another clinical study with a study intervention or investigational medicinal device administered in the last 4 weeks prior to randomisation, randomisation into a prior Dato-DXd, T-DXd, or durvalumab study regardless of treatment assignment, or concurrent enrolment in another clinical study (unless the study is observational [non-interventional], or the participant is in the follow-up period of an interventional study).
21- Participants with a known history of severe hypersensitivity reactions to any of the study drugs or any excipients (including but not limited to polysorbate 80 for Dato-DXd).
22- Participants with a known history of severe hypersensitivity reactions to other mAbs.
23- Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
24- Judgement by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements.
25- Previous enrolment or randomisation in the present study.
26- For females only: is pregnant (confirmed with positive serum pregnancy test) or breastfeeding, or planning to become pregnant.
27- Female participants should refrain from breastfeeding from enrolment throughout the study and for at least 7 months after last dose of study intervention, or as dictated by local PI for SoC if longer.