A Two-cohort Study of SHR-A1811 in the Treatment of HER2-positive Breast Cancer With Brain Metastases

Official title

A Two-cohort Study of SHR-A1811 in the Treatment of HER2-positive Breast Cancer With Brain Metastases, With or Without Leptomeningeal Metastases.

Overview

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.

Interventions

• Drug SHR-A1811
  Systemic 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.
• Drug SHR-A1811
  Intrathecal 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
• Radiation radiotherapy
  radiotherapy is determined by investigator's choice

Primary outcome measures

• 1. Number of Dose-Limiting Toxicities (DLTs) in the Sequential Dose-Escalation Cohort [Time frame: Start of treatment until 3-week follow-up]
• CNS-PFS [Time frame: Start of treatment until 2-year follow-up]

Secondary outcome measures (6)

• CNS-PFS [Time frame: Start of treatment until 2-year follow-up]
• CNS-ORR [Time frame: Start of treatment until 2-year follow-up]
• PFS [Time frame: Start of treatment until 2-year follow-up]
• OS [Time frame: Start of treatment until 2-year follow-up]
• Quality of life score [Time frame: Start of treatment until 2-year follow-up]
• Incidence and severity of adverse events (AE) and serious adverse events (SAE) [Time frame: Start of treatment until 2-year follow-up]

Eligibility criteria

Inclusion criteria

• Women aged 18-75 years (inclusive).
• Histologically or cytologically confirmed HER2-positive advanced breast cancer (IHC 3+, or IHC 2+ with ISH amplification).
• Radiologically documented brain metastases, with or without baseline leptomeningeal disease:

• 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.
• Anticipated life expectancy >12 weeks.
• ECOG performance status 0-2.
• Adequate organ function as defined by the following laboratory criteria:

• Hematologic: absolute neutrophil count (ANC) ≥1.5 × 10⁹/L, platelet count (PLT) ≥100 × 10⁹/L, hemoglobin (HGB) ≥90 g/L.
• Hepatic: alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × upper limit of normal (ULN) (≤5 × ULN in patients with liver metastases); total serum bilirubin (TBIL) ≤1.5 × ULN; serum albumin ≥30 g/L.
• Renal: serum creatinine (Cr) ≤1.5 × ULN or calculated creatinine clearance ≥50 mL/min using the Cockcroft-Gault formula.
• Coagulation: prothrombin time (PT) and activated partial thromboplastin time (APTT) ≤1.5 × ULN.
• Cardiac: left ventricular ejection fraction (LVEF) ≥50%.
• Negative serum pregnancy test; women of childbearing potential must use a highly effective contraceptive method from study initiation until at least 6 months after the last dose of study medication.
• Voluntary participation with written informed consent obtained prior to any study-related procedures.

Exclusion criteria

• Cohort A participants must be excluded if any of the following apply:

• 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.
• Cohort B participants must be excluded if leptomeningeal metastasis is documented, defined as either: radiographic evidence of leptomeningeal involvement, or positive CSF cytology, or unequivocal clinical signs or symptoms attributable to leptomeningeal disease.
• Presence of clinically significant third-space fluid accumulation (e.g., massive pleural or peritoneal effusion) that cannot be adequately controlled by drainage or other interventions.
• Known hypersensitivity to any study drug or its excipients, or to any prior humanized monoclonal antibody products (e.g., trastuzumab, pertuzumab).
• Prior or current exposure to antibody-drug conjugates (ADCs) containing a topoisomerase I inhibitor, including but not limited to fam-trastuzumab deruxtecan (DS-8201a).
• Clinically significant cardiovascular disease, including but not limited to: severe or unstable angina pectoris, symptomatic congestive heart failure (New York Heart Association class ≥ II), clinically relevant supraventricular or ventricular arrhythmias requiring therapy or intervention, myocardial infarction within 6 months prior to first study dose, or cerebrovascular accident (including transient ischemic attack).
• Participants known or suspected to interstitial lung disease.
• Concurrent participation in any other interventional drug clinical trial.
• Refusal to comply with protocol-mandated follow-up.
• Presence of any additional severe physical or psychiatric disorder, or any laboratory abnormality that, in the investigator's judgment, could increase the subject's risk, confound study results, or render the patient unsuitable for enrollment.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT07177950 · MA-BC-II-113

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗