This is a multi-center, open-label, two-cohort study. The purpose of this study is to evaluate the safety, tolerability and efficacy of SHR-A1811 in the treatment of HER2-positive breast cancer with brain and leptomeningeal metastases, and the efficacy and safety of SHR-A1811 in the treatment of HER2-positive breast cancer with brain but without leptomeningeal metastases.
Women aged 18-75 years (inclusive).
Histologically or cytologically confirmed HER2-positive advanced breast cancer (IHC 3+, or IHC 2+ with ISH amplification).
Cohort A (leptomeningeal metastasis cohort): leptomeningeal involvement demonstrated by contrast-enhanced MRI or positive cerebrospinal fluid (CSF) cytology.
Cohort B (no leptomeningeal metastasis cohort): ≥1 measurable intracranial lesion; either CNS-naïve or progressive after prior local therapy.
Cerebrospinal fluid (CSF) circulation obstruction that cannot be adequately controlled by therapeutic measures.
MRI evidence of nodular leptomeningeal (LM) disease in the setting of negative CSF cytology.
Active central nervous system (CNS) infection.
Clinically significant coagulopathy.
Parallel
SHR-A1811
DrugSystemic therapy: 4.8 mg/kg administered as an intravenous infusion on Day 1 of each cycle. 3 weeks a cycle. Continuous medication until study completion, occurrence of intolerable toxicity, disease progression, withdrawal from the study for any reason, or death, whichever occurs first, or until the investigator deems that the patient would no longer benefit from the treatment.
SHR-A1811
DrugIntrathecal therapy: Administered intrathecally on Day 1 of each cycle. Dose escalation follows a Bayesian Optimal Interval (BOIN) design with three predefined dose levels-15 mg, 30 mg, and 40 mg. The starting dose level is 15 mg. Patients are enrolled in cohorts of three per dose level. If no dose-limiting toxicities (DLTs) are observed, escalation proceeds to the next higher dose level according to the BOIN algorithm. Treatment is administered for a minimum of two cycles and is continued until cerebrospinal fluid (CSF) cytology achieves negative conversion, completion of six cycles, or intolerable adverse events, whichever occurs first. Extension beyond six cycles may be permitted following investigator's discussion and must be documented with justification.
radiotherapy
Radiationradiotherapy is determined by investigator's choice
1. Number of Dose-Limiting Toxicities (DLTs) in the Sequential Dose-Escalation Cohort
For cohort A. DLT is defined as any of the following events judged by the investigator to be related or possibly related to SHR-A1811 occurring within Cycle 1 (21 days), graded according to NCI-CTCAE v5.0: 1. Grade ≥3 neurologic toxicity; 2. Any death unless unequivocally attributable to tumor progression or an unrelated exogenous cause.
CNS-PFS
For cohort B: Central nervous system- progression free survival: time from the date when the subject first received SHR-A1811 to the first observation of tumor progression of central nervous system or death from any cause.
CNS-PFS
For cohort A: Central nervous system- progression free survival: time from the date when the subject first received SHR-A1811 to the first observation of tumor progression of central nervous system or death from any cause.
CNS-ORR
For cohort B. Central nervous system- objective response rate: proportion of subjects who achieved complete remission (CR) or partial remission (PR) of central nervous system by primary tumor imaging evaluation.
PFS
Progression free survival: time from the date when the subject first received SHR-A1811 to the first observation of tumor progression or death from any cause.
OS
Overall survival: time from the date when the subject first received SHR-A1811 to death from any cause.
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Peking University Cancer Hospital & Institute
Lead sponsor
Beijing Tiantan Hospital
Collaborator
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