ctDNA-Guided Intraventricular Therapy for CNS Malignancies

Leptomeningeal disease (LMD) and other advanced CNS malignancies remain associated with poor prognosis and limited tools for monitoring disease activity and treatment response. Conventional CSF cytology has limited sensitivity, particularly in the early stages of disease. Circulating tumor DNA (ctDNA) analysis of cerebrospinal fluid has emerged as a promising liquid biopsy approach for detecting molecular evidence of CNS disease and monitoring treatment response.

This prospective, single-center investigator-initiated study will evaluate the clinical utility of the Belay Summit CSF ctDNA assay in patients with malignant gliomas or brain metastases from NSCLC or breast cancer undergoing clinically indicated CSF evaluation. Patients may be enrolled either before or after clinically indicated lumbar puncture, provided eligibility criteria are met. Clinical management, including consideration of Ommaya reservoir placement, intraventricular therapy, systemic therapy modification, radiation therapy, or other CNS-directed interventions, will remain at the discretion of the treating multidisciplinary neuro-oncology team. The study does not mandate treatment assignment based on ctDNA results.

• CSF ctDNA-Guided Clinical Management (Device): Participants undergo clinically indicated cerebrospinal fluid (CSF) evaluation, including CSF cytology and the Belay Summit CSF circulating tumor DNA (ctDNA) assay. Results are incorporated into multidisciplinary neuro-oncology evaluation to inform CNS-directed clinical management. Treatment decisions, including intraventricular therapy, systemic therapy modification, radiation therapy, or other interventions, remain at the discretion of the treating physicians and are not mandated by the study protocol. The primary objective is to evaluate cCNS-PFS at 6 months. Secondary objectives include evaluating the safety of CNS-directed management and assessing the relationship between longitudinal CSF ctDNA dynamics and clinical outcomes.

Primary outcomes

• Clinical central nervous system progression-free survival at 6 months (cCNS-PFS6) [6 months]: Clinical CNS progression-free survival (cCNS-PFS6) will be assessed using the Neurologic Assessment in Neuro-Oncology Leptomeningeal Metastases (NANO-LM) scorecard. Disease progression will be determined by multidisciplinary adjudication based on neurologic assessment, radiographic findings, CSF cytology, and other relevant clinical information to distinguish leptomeningeal disease progression from alternative causes of neurologic deterioration.

Secondary outcomes

• Incidence of treatment-related neurologic and procedure-related adverse events [From enrollment through 6 months]: Frequency and severity of clinically significant neurologic toxicities, Ommaya reservoir-related complications, CNS-directed therapy-related complications, treatment-related hospitalizations, and other clinically relevant adverse events, graded according to CTCAE version 5.0 where applicable.
• Change in cerebrospinal fluid circulating tumor DNA (CSF ctDNA) burden [Baseline, Month 3, and Month 6]: Quantitative changes in CSF ctDNA variant allele frequency (VAF), including reduction or clearance of baseline VAF, and their association with clinical CNS progression-free survival. Exploratory analyses will evaluate whether a ≥50% reduction or complete clearance of baseline VAF is associated with durable clinical stability at 6 months.

Sex: All, ages: 18 Years to 120 Years

Inclusion Criteria:

* Age ≥ 18 years.
* Diagnosis of histologically or cytologically confirmed HER2+ breast cancer, or triple negative breast cancer, or Stage IV non-small cell lung cancer, or recurrent high-grade glioma).
* Undergoing clinically indicated cerebrospinal fluid (CSF) collection as part of routine clinical care: CSF may be obtained via lumbar puncture or existing CSF access device. Decision for CSF collection must be made independently by the treating clinical team and not solely for research purposes.
* Detectable CSF ctDNA and/or positive CSF cytology, with consideration for CNS-directed management by the treating neuro-oncology team.
* Ability to provide informed consent, or availability of a legally authorized representative (LAR).

Exclusion Criteria:

* Age <18 years.
* Inability to provide informed consent and no legally authorized representative (LAR) available.
* Not undergoing clinically indicated CSF collection as part of standard clinical care.
* Absence of detectable CSF ctDNA and absence of positive CSF cytology.
* Not being considered for CNS-directed management by the treating neuro-oncology team.
* Clinical contraindications to CSF collection, including but not limited to: Significant intracranial mass effect; (e.g., midline shift >5 mm or effacement of basal cisterns); Obstructive hydrocephalus or posterior fossa mass effect; Coagulopathy or bleeding risk precluding lumbar puncture or CSF access; Inability to safely obtain CSF access.