Phase II Study of Dato-DXd in Triple-negative Breast Cancer Patients With Newly Diagnosed or Progressing Brain Metastases

Inclusion Criteria:

• Histologically confirmed breast cancer

• Triple-negative disease as defined by immunohistochemistry (IHC) and/or c-erb-B2gene amplification status. For the definition of hormone-receptor negative disease,a cut-off of <10% tumour cells with positive staining of oestrogen- andprogresteron-receptors is required

• Newly diagnosed untreated brain metastases or brain metastases progressing afterprior local therapy

• Measurable disease (RANO-BM criteria)

• No indication for immediate local treatment

• Accompanying type II leptomeningeal disease allowed (suspected LMD by clinicalfindings and neuroimaging)

• KPS ≥70%, ECOG ≤2 Indication for systemic anti-cancer treatment

• Prior exposure to PD-1, PD-L1 inhibitors and TROP-2 targeted agents allowed

• Life expectancy of at least 3 months

• Age ≥18 years

• Patient must be able to tolerate therapy

• Adequate bone-marrow, liver and kidney function

• Adequate treatment washout period before enrolment, defined as:

• Major Surgery: ≥3 weeks

• Radiation therapy to the chest: ≥4 weeks

• Palliative radiation therapy to other areas: ≥2 weeks

• Chemotherapy, small-molecule targeted agents: ≥3 weeks

• Antibody-based treatment: ≥4 weeks (concurrent therapy with denosumab allowed)

• Patient must be capable of understanding the purpose of the study and have givenwritten informed consent

Exclusion Criteria:

• Known hypersensitivity to Dato-DXd or any of the drug components

• Use of any investigational agent within 28 days prior to initiation of treatment

• History of malignancies other than squamous cell carcinoma, basal cell carcinoma ofthe skin or carcinoma in situ of the cervix within the last 3 years includingcontralateral breast cancer

• Other anticancer therapy, including cytotoxic, targeted agents, immunotherapy,antibody, retinoid, or anti-cancer hormonal treatment with the exception ofosteoprotective therapies such as denosumab or bisphosphonates

• Concomitant radiotherapy

• A history of uncontrolled seizures, central nervous system disorders or psychiatricdisability judged by the investigator to be clinically significant and adverselyaffecting compliance to study drugs

• Clinically significant cardiac disease including unstable angina, acute myocardialinfarction within six months prior to randomization, congestive heart failure (NYHAIII-IV), left ventricular ejection fraction <50%, arrhythmia unless controlled bytherapy, with the exception of extra systoles or minor conduction abnormalities, andlong QT syndrome (QTc interval >470 ms)

• Inadequate bone marrow function at baseline prior to study entry

• Inadequate kidney function

• Subjects who have current active hepatic or biliary disease (with exception ofpatients with Gilbert's syndrome, asymptomatic gallstones, liver metastases orstable chronic liver disease including active or uncontrolled infections withhepatitis B and C

• Participants with known hepatitis B and C are eligible if they:

1. Have been curatively treated for HCV infection as demonstrated clinically andby viral serologies

2. Have received HBV vaccination with only anti-HBs positivity and no clinicalsigns of hepatitis

3. Are HBsAg- and anti-HBc+ (i.e., those who have cleared HBV after infection) andmeet conditions i-iii below:

4. Are HBsAg+ with chronic HBV infection (lasting 6 months or longer) and meetconditions 1-3 below:

5. HBV DNA viral load <2000 IU/mL

6. Have normal transaminase values, or, if liver metastases are present, abnormaltransaminases, with a result of AST/ALT <3 × ULN, which are not attributable toHBV infection

7. Start or maintain antiviral treatment

• Clinically severe pulmonary compromise resulting from intercurrent pulmonaryillnesses

• Has a history of non-infectious ILD/pneumonitis that required steroids, has currentILD/pneumonitis, or has suspected ILD/pneumonitis that cannot be ruled out byimaging at screening

• Subjects with bronchopulmonary disorders who require intermittent use ofbronchodilators (such as albuterol) will not be excluded from this study

• Patients with active opportunistic infections

• Known human immunodeficiency virus (HIV) infection that is not well controlled

• Pregnant or lactating women

• Women with childbearing potential, including women whose last menstrual period wasless than one year prior to screening, unable or unwilling to use adequatecontraception from study start to one year after the last dose of protocol therapy.

• Male subjects unable or unwilling to use adequate contraception methods

• Patients with known substance abuse or any other medical conditions such asclinically significant cardiac or psychological conditions, that may, in the opinionof the investigator, interfere with the subject's participation in the clinicalstudy or evaluation of the clinical study results

• Patients requiring concomitant use of chronic systemic (IV or oral) corticosteroidsat doses higher than 8 mg dexamethasone per day or other immunosuppressivemedications except for managing adverse events; (inhaled steroids or intra articularsteroid injections are permitted in this study)

• Patients with significant corneal disease