DATO-BASE: DATOpotamab-deruxtecan for Breast Cancer Brain metAstaSEs

Inclusion Criteria :

• Metastatic breast cancer that is pathologically confirmed to be HER2-negativeaccording to 2018 ASCO/CAP guidelines 55.

• Radiological confirmation of metastatic disease.

• Cohorts A and B: Presence of newly diagnosed brain metastases or brain metastasesprogressing after prior local and/or systemic therapy.

• Cohorts A and B: Participants must have a baseline MRI of the brain performed withand without gadolinium contrast, and must have central nervous system metastaseswith at least one measurable brain metastasis ≥ 1.0 cm in size (per RANO-BM) thathas not been irradiated, or has progressed despite prior radiation therapy and/orsystemic therapy (in the opinion of the treating physician). For cohorts A and B,head CT with contrast may be used in place of MRI at baseline and throughout thetrial if MRI is contraindicated and the participant's CNS metastases are clearlymeasurable by head CT.

• Cohorts C: Radiological evidence of evaluable leptomeningeal disease and clinicaldiagnosis of LMD per treating investigator. A positive CSF cytology is not required.

• Cohort A: prior progression to treatment with at least one line of endocrinetreatment (with or without CDK4/6 inhibition) in the metastatic setting ismandatory. Patients experiencing recurrence during adjuvant endocrine treatment willbe also considered eligible for the trial. There is no limit on the number of priorlines acceptable for the purpose of enrollment in this study.

• Cohort B and C: no prior treatment is required (i.e., previously untreated patientsare eligible). There is no limit on the number of prior lines of therapy acceptablefor the purpose of enrollment in this study.

• Participants may have measurable or non-measurable extracranial disease.Participants are NOT required to have extracranial disease, but must have imagingdone to document disease status at baseline.

• Age ≥ 18 years.

• ECOG Performance Status 0-2

• Participants must have adequate treatment washout period before registration,defined as > 4 weeks from major surgery, > 2 weeks from radiation treatment. Forweekly chemotherapy regimens, > 2 weeks from chemotherapy; for every 3 weeklyregimens, > 3 weeks from chemotherapy. At least 2 weeks from other systemic ortargeted or investigational therapies (other than endocrine therapy) for breastcancer. No washout is required for endocrine therapy (e.g. aromatase inhibitors,tamoxifen, fulvestrant) but patients should discontinue prior to start of protocoltherapy. Patients on ovarian suppression are allowed (but not required) to continueovarian suppression at the discretion of their treating provider.

• Left ventricular ejection fraction (LVEF) ≥ 50% by echocardiogram (ECHO) ormultigated acquisition (MUGA) scan.

• Adequate organ function as defined by the following values:

• Hemoglobin ≥ 9.0 g/dL. Red blood cell/plasma transfusion is not permittedwithin 1 week prior to screening assessment.

• Absolute neutrophil count ≥1,500/mm3. Granulocyte colony-stimulating factoradministration is not permitted within 1 week prior to screening assessment.

• Platelets ≥100,000/mm3. Platelet transfusion is not permitted within 1 weekprior to screening assessment.

• Total bilirubin ≤ 1.5 institutional ULN if no liver metastases; or ≤ 3 x ULN inthe presence of documented Gilbert's syndrome (unconjugated hyperbilirubinemia)or liver metastases at baseline.

• AST(SGOT)/ALT(SGPT) ≤ 2.5 × institutional ULN OR ≤ 5.0 x institutional ULN forpatients with documented liver metastases

• Serum creatinine ≤ 1.5 mg/dL (or glomerular filtration rate ≥ 30 ml/min asdetermined by the Cockcroft-Gault equation)

• Participants with a history of chronic viral conditions such as HIV, Hepatitis B/C,should not be systemically excluded but have thoughtful consideration of inclusion,unless safety is a concern. Testing for these conditions is not required atbaseline.

• Female subjects of childbearing potential must have a negative serum or urinepregnancy test within 14 days of initiating protocol therapy.

• Ability to understand and the willingness to sign a written informed consentdocument.

Exclusion Criteria:

• Visceral crisis or impending visceral crisis

• CNS complications for whom urgent neurosurgical intervention is indicated (i.e.,resection, shunt placement)

• Indication for immediate local therapy to CNS lesion(s) as defined by local standard

• Evidence of significant (i.e., symptomatic) intracranial hemorrhage

-> 2 seizures within 4 weeks prior to study entry (registration)

• Ongoing/persistent toxicities caused by previous anti-cancer therapy (exceptalopecia) not yet improved to Grade ≤ 1 OR baseline prior to study entry (registration)

• Known contraindication to MRI (e.g., due to pacemaker, ferromagnetic implants,claustrophobia, extreme obesity, hypersensitivity). However, for cohorts A and B,head CT with contrast may be used in place of MRI at baseline and throughout thetrial if MRI is contraindicated and the participant's CNS metastases are clearlymeasurable by head CT.

• Concurrent administration of other anti-cancer therapy during the course of thisstudy is not allowed. Concurrent use of supportive care medications is allowed, andcertain medications are required (see Section 5.1).

• Uncontrolled intercurrent illness, including (but not limited to) active infection,severely compromised pulmonary function, unstable angina pectoris, uncontrolledcardiac arrhythmia, active ischemic heart disease, myocardial infarction within theprevious six months, gastric or duodenal ulceration diagnosed within the previoussix months, chronic liver or renal disease, or severe malnutrition. Note that if apatient has controlled diabetes mellitus, but is unable to monitor blood glucose athome, they will be excluded from the trial.

• Participants must not have a condition requiring ongoing systemic treatment withcorticosteroids (>4 mg daily dexamethasone (or bioequivalent)) or otherimmunosuppressive medications within 7 days prior to the baseline MRI.Corticosteroids administration must be stable and planned to remain ≤ 4 mg daily forthe duration of protocol treatment. However, use of corticosteroids for clinicalsymptoms is allowed based upon treating physician discretion.

• History of non-infectious interstitial lung disease (ILD)/pneumonitis that requiredsteroids, current ILD/pneumonitis, or suspected ILD/pneumonitis that cannot be ruledout by imaging at screening.

• A history of uncontrolled seizures, CNS disorders, or psychiatric disability judgedby the investigator to be clinically significant and adversely affecting complianceto study drugs.

• A history of malignancy other than breast cancer, except (a) adequately resectednon-melanoma skin cancer, (b) curatively treated in situ disease, or (c) other solidtumors curatively treated, with no evidence of disease for ≥ 3 years.

• Major surgery, open biopsy, or significant traumatic injury within 28 days prior tothe initiation of protocol therapy, or anticipation of need for a major surgicalprocedure during the study.

• Clinically significant corneal disease.

• Has a history of severe hypersensitivity reactions to either the drug or inactiveingredients (including but not limited to polysorbate 80) of datopotamab deruxtecan.

• History of severe hypersensitivity reactions to other monoclonal antibodies

• Negative pregnancy test (urine and/or serum) is required for women of childbearingpotential. Pregnant or lactating women are excluded from participation due topotential teratogenic effects of study drug.

• Female participants must be either:

• post-menopausal for at least 1 year

• surgically sterile, or

• if of childbearing potential and sexually active with a non-sterilized malepartner, must agree to use one highly effective form of birth control for theentire treatment period and for at least 7 months after the last dose ofdatopotamab deruxtecan (see Section 5.4 for complete list of highly effectivebirth control methods).

• Female participants must not donate, or retrieve for their own use, ova at any timeduring this study and for at least 7 months after the last dose of datopotamabderuxtecan.

• Female participants must refrain from breastfeeding while on study and for at least 7 months after the last dose of datopotamab deruxtecan.

• Male participants who intend to be sexually active with a female partner ofchildbearing potential must be surgically sterile or using an acceptable method ofcontraception (see Section 5.4 for complete list of highly effective birth controlmethods) from the time of screening throughout the total duration of the study andthe drug washout period (at least 4 months after the last dose of studyintervention) to prevent pregnancy in a partner. Male participants must not donateor bank sperm during this same time period.