Intrathecal deferoxamine in patients with leptomeningeal metastases: Phase 1a analysis.

2032 Background: Leptomeningeal metastases (LM), the spread of cancer to the cerebrospinal fluid (CSF), is associated with high morbidity and mortality. LM employ the iron-binding transporter and receptor system, lipocalin-2/SLC22A17, to scavenge iron from the CSF to sustain their metabolic needs. In preclinical models of LM, intrathecal administration of deferoxamine (IT-DFO), an iron chelator, resulted in reduction of LM growth and improvement of survival. We evaluated this novel treatment strategy in this first-in-human clinical trial in patients with solid tumor LM. Methods: This is a phase 1a, single-institution, clinical trial to determine safety and maximum tolerated dose (MTD) of IT-DFO in patients with LM. Eligibility criteria included LM from any solid tumor, age ≥ 18 years, Karnofsky Performance Status ≥ 60, life expectancy ≥ 8 weeks, and Ommaya reservoir. Patients were enrolled in an accelerated 3+3 dose escalation design with a primary endpoint of dose-limiting toxicity (DLT), defined as a grade 3 non-hematologic or grade 4 hematologic toxicity in the first cycle of treatment. All patients received IT-DFO twice weekly (cycle 1), once weekly (cycle 2), then once every two weeks (cycle 3+) in 28-day cycles. Patients were monitored for LM progression by neurological examination, neuraxial magnetic resonance imaging, and CSF cytology as per modified Response Assessment in Neuro-Oncology LM criteria. Results: A total of 8 patients received treatment with IT-DFO from May 2022 to January 2025 at the time of data cut-off. The median age at enrollment was 50 years (range, 26-69). The primary malignancy included breast (n = 4), lung (n = 2), colon (n = 1), and sarcoma (n = 1). Patients were treated with IT-DFO at doses of 10 mg (level 1, n = 4) and 30 mg (level 2, n = 4). IT-DFO was well tolerated, and the majority of adverse events (AEs) were grade 1-2. The most common any grade AEs were vomiting (50%), nausea (37.5%), chills (25%), myalgias (25%), and tremor (25%). Two patients experienced DLTs at 30 mg (grade 3 vomiting, grade 3 syncope). No grade 4-5 AEs were observed. The MTD was determined to be 10 mg. In this heterogenous heavily pretreated population, median overall survival for the evaluable cohort (n = 7) was 10.0 months (95% CI, 6.5 – NA). Conclusions: IT-DFO is a novel, well tolerated investigational treatment for LM. A phase 1b dose expansion study at a dose of 10 mg is currently underway to better define safety and efficacy endpoints. Clinical trial information: NCT05184816 .