Inclusion Criteria :
- - Metastatic breast cancer that is pathologically confirmed to be HER2-negative
according to 2018 ASCO/CAP guidelines 55.
- - Radiological confirmation of metastatic disease.
- - Cohorts A and B: Presence of newly diagnosed brain metastases or brain metastases
progressing after prior local and/or systemic therapy.
- - Cohorts A and B: Participants must have a baseline MRI of the brain performed with and
without gadolinium contrast, and must have central nervous system metastases with at
least one measurable brain metastasis ≥ 1.0 cm in size (per RANO-BM) that has not been
irradiated, or has progressed despite prior radiation therapy and/or systemic 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 the trial if MRI is
contraindicated and the participant's CNS metastases are clearly measurable by head
CT.
- - Cohorts C: Radiological evidence of evaluable leptomeningeal disease and clinical
diagnosis of LMD per treating investigator.
A positive CSF cytology is not required.
- - Cohort A: prior progression to treatment with at least one line of endocrine treatment
(with or without CDK4/6 inhibition) in the metastatic setting is mandatory.
Patients
experiencing recurrence during adjuvant endocrine treatment will be also considered
eligible for the trial. There is no limit on the number of prior lines acceptable for
the purpose of enrollment in this study.
- - Cohort B and C: no prior treatment is required (i.e., previously untreated patients
are eligible).
There is no limit on the number of prior lines of therapy acceptable
for 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 imaging done to document
disease status at baseline.
- - 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.
For weekly
chemotherapy regimens, > 2 weeks from chemotherapy; for every 3 weekly regimens, > 3
weeks from chemotherapy. At least 2 weeks from other systemic or targeted or
investigational therapies (other than endocrine therapy) for breast cancer. No washout
is required for endocrine therapy (e.g. aromatase inhibitors, tamoxifen, fulvestrant)
but patients should discontinue prior to start of protocol therapy. Patients on
ovarian suppression are allowed (but not required) to continue ovarian suppression at
the discretion of their treating provider.
- - Left ventricular ejection fraction (LVEF) ≥ 50% by echocardiogram (ECHO) or multigated
acquisition (MUGA) scan.
- - Adequate organ function as defined by the following values:
- Hemoglobin ≥ 9.0 g/dL.
Red blood cell/plasma transfusion is not permitted within
1 week prior to screening assessment.
- - Absolute neutrophil count ≥1,500/mm3.
Granulocyte colony-stimulating factor
administration is not permitted within 1 week prior to screening assessment.
- - Platelets ≥100,000/mm3.
Platelet transfusion is not permitted within 1 week prior
to screening assessment.
- - Total bilirubin ≤ 1.5 institutional ULN if no liver metastases; or ≤ 3 x ULN in
the 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 for
patients with documented liver metastases.
- - Serum creatinine ≤ 1.5 mg/dL (or glomerular filtration rate ≥ 30 ml/min as
determined 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 at baseline.
- - Female subjects of childbearing potential must have a negative serum or urine
pregnancy test within 14 days of initiating protocol therapy.
- - Ability to understand and the willingness to sign a written informed consent document.
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 (except alopecia)
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 the trial if
MRI is contraindicated and the participant's CNS metastases are clearly measurable by
head CT.
- - Concurrent administration of other anti-cancer therapy during the course of this study
is not allowed.
Concurrent use of supportive care medications is allowed, and certain
medications are required (see Section 5.1).
- - Uncontrolled intercurrent illness, including (but not limited to) active infection,
severely compromised pulmonary function, unstable angina pectoris, uncontrolled
cardiac arrhythmia, active ischemic heart disease, myocardial infarction within the
previous six months, gastric or duodenal ulceration diagnosed within the previous six
months, chronic liver or renal disease, or severe malnutrition.
Note that if a patient
has controlled diabetes mellitus, but is unable to monitor blood glucose at home, they
will be excluded from the trial.
- - Participants must not have a condition requiring ongoing systemic treatment with
corticosteroids (>4 mg daily dexamethasone (or bioequivalent)) or other
immunosuppressive medications within 7 days prior to the baseline MRI.
Corticosteroids
administration must be stable and planned to remain ≤ 4 mg daily for the duration of
protocol treatment. However, use of corticosteroids for clinical symptoms is allowed
based upon treating physician discretion.
- - History of non-infectious interstitial lung disease (ILD)/pneumonitis that required
steroids, current ILD/pneumonitis, or suspected ILD/pneumonitis that cannot be ruled
out by imaging at screening.
- - A history of uncontrolled seizures, CNS disorders, or psychiatric disability judged by
the investigator to be clinically significant and adversely affecting compliance to
study drugs.
- - A history of malignancy other than breast cancer, except (a) adequately resected
non-melanoma skin cancer, (b) curatively treated in situ disease, or (c) other solid
tumors curatively treated, with no evidence of disease for ≥ 3 years.
- - Major surgery, open biopsy, or significant traumatic injury within 28 days prior to
the initiation of protocol therapy, or anticipation of need for a major surgical
procedure during the study.
- - Clinically significant corneal disease.
- - Has a history of severe hypersensitivity reactions to either the drug or inactive
ingredients (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 childbearing
potential.
Pregnant or lactating women are excluded from participation due to
potential 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 male
partner, must agree to use one highly effective form of birth control for the
entire treatment period and for at least 7 months after the last dose of
datopotamab deruxtecan (see Section 5.4 for complete list of highly effective
birth control methods).
- - 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 datopotamab
deruxtecan.
- - 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 of
childbearing potential must be surgically sterile or using an acceptable method of
contraception (see Section 5.4 for complete list of highly effective birth control
methods) from the time of screening throughout the total duration of the study and the
drug washout period (at least 4 months after the last dose of study intervention) to
prevent pregnancy in a partner.
Male participants must not donate or bank sperm during
this same time period.
