Condition médicale (spécialité visée)
Choix aire thérapeutique
Cancérologie / Radio-oncologie/ tumeurs solides
Oncologie – Sein
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
Sexe(s) des participants
Hommes
Femmes
Aptitude des participants
Majeurs aptes
Critères de sélection
Critères d'inclusion
1- Participant must be ≥ 18 years, at the time of signing the ICF.
2- Histologically confirmed Stage II or III unilateral or bilateral primary invasive TNBC or hormone receptor-low/HER2-negative breast cancer defined as the following combined primary tumour (T) and regional lymph node (N) staging per AJCC for breast cancer staging system edition 8 (Hortobagyi et al 2017) as assessed by the investigator based on radiological and/or clinical assessment (T1c, N1 to N2; T2, N0 to N2; T3, N0 to N2; T4a-d, N0 to N2).
Note: bilateral tumour (ie, synchronous cancers in both breasts) and/or multifocal primary tumour is allowed, as well as inflammatory breast cancer, and the tumour with the most advanced T stage should be used to assess the eligibility. If multifocal/multicentric disease, TNBC or hormone receptor-low/HER2-negative breast cancer needs to be confirmed for each focus. Synchronous contralateral DCIS will be allowed if ipsilateral breast cancer meets the criteria.
TNBC or hormone receptor-low/HER2-negative breast cancer is defined as:
(a) Negative for ER with < 1% of tumour cells positive for ER on IHC and negative for PR with < 1% of tumour cells positive for PR on IHC, or hormone receptor-low (ER 1% to < 10% and/or PR 1% to < 10%; neither hormone receptor may be ≥ 10%);
and
(b) Negative for HER2 with 0 or 1+ intensity on IHC, or 2+ intensity on IHC and no evidence of amplification on ISH (Allison et al 2020; Wolff et al 2018; Yoder et al 2022).
3- ECOG PS of 0 or 1, with no deterioration over the previous 2 weeks prior to baseline at screening and prior to randomisation.
4- Provision of acceptable tumour sample prior to randomisation as defined in the Laboratory Manual and summarised in Section 8.8. Note: Sample collected in China will comply with local regulatory approval.
5- Adequate bone marrow reserve and organ function within 7 days before randomisation, defined as:
(a) Haemoglobin ≥ 9.0 g/dL (red blood cell/plasma transfusion is not allowed within 1 week prior to screening assessment).
(b) Absolute neutrophil count ≥ 1.5 × 109/L (granulocyte colony stimulating factor administration is not allowed within 1 week prior to screening assessment).
(c) Platelet count ≥ 100 × 109/L (platelet transfusion is not allowed within 1 week prior to screening assessment).
(d) TBL ≤ 1.5 × ULN or ≤ 3 × ULN in the presence of documented Gilbert’s syndrome (unconjugated hyperbilirubinaemia).
(e) Except in the setting of HBV, ALT and AST ≤ 2.5 × ULN. See Exclusion Criterion 7 for requirements in the setting of HBV.
(f) Calculated CrCL ≥ 50 mL/min as determined by Cockcroft Gault (using actual body weight).
6- Male and/or female
Contraceptive use by males or females should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies; see Appendix F for further details.
(a) Male participants:
i) Use of a condom plus an additional contraceptive method, or avoid intercourse from enrolment and throughout study for at least 6 months after the last dose of study intervention, or as dictated by local PI for SoC if longer, in addition to the female partner using a highly effective contraceptive method.
ii) Starting at the time of screening, male participants must not freeze or donate sperm at any time during this study and for at least 6 months after the last dose of study intervention, or as dictated by local PI for SoC if longer. Preservation of sperm should be considered prior to randomisation in this study.
(b) Female participants:
i) Females not of child-bearing potential, see Appendix F for definition.
ii) Females receiving HRT and whose menopausal status is in doubt will be required to use one of the contraception methods outlined for FOCBP if they wish to continue using HRT during the study. Otherwise, HRT must be discontinued to allow confirmation of post-menopausal status prior to randomisation; see Appendix F for further details.
iii) Female participants of child-bearing potential must use one highly effective form of contraception or avoid intercourse from enrolment throughout study and for at least 7 months after the last dose of study intervention, or as dictated by local PI for SoC if longer; see Appendix F for further details. All FOCBP must have a negative serum pregnancy test documented during screening.
iv) Starting at the time of screening, female participants must not donate, or retrieve for their own use, ova at any time during this study and for at least 7 months after the last dose of study intervention, or as dictated by local PI for SoC if longer. Preservation of ova should be considered prior to randomisation in this study.
7- Capable of giving signed informed consent as described in Appendix A which includes compliance with the requirements and restrictions listed in the ICF and in this CSP.
8- Provision of signed and dated written optional genetic research information informed consent prior to collection of samples for optional genetic research that supports the Genomic Initiative (see Appendix D).
9- All races, gender and ethnic groups are eligible for this study.
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.