A randomized phase III/IV study to determine benefit and safety of cytarabine liposome injection for treatment of neoplastic meningitis

Abstract

1528 Background: Cytarabine liposome injection (CLI) maintains cytotoxic concentrations in the cerebral spinal fluid (CSF) for >14 days with a single 50 mg dose. This study compared patient benefit and safety of intrathecal CLI with methotrexate (MTX) or nonliposomal cytarabine (Cyt) against solid tumor neoplastic meningitis (STNM) and lymphomatous neoplastic meningitis (LNM), respectively. Methods: This multicenter, randomized, open-label, active-controlled study was powered to detect a 50% hazard ratio for progression-free survival (PFS; i.e., days from randomization to neurological progression or death) in STNM patients. STNM patients (n=103) were randomized to CLI or MTX and LNM patients (n=25) to CLI or Cyt. Patients had either histologically documented STNM or LNM confirmed by ventricular or lumbar CSF cytology or symptomatic meningeal tumor verified by magnetic resonance imaging or computed tomography. CLI treatment consisted of 6 Induction Cycles (2 weeks per cycle) and 4 Maintenance Cycles (4 weeks per cycle). Results: By per-protocol Cox regression analysis, CLI (STNM and LNM combined) was noninferior to MTX and Cyt combined (Control Group). The median PFS was 35 days and 43 days (p=0.7321), respectively; the hazard ratio (95% CI) was 0.98 (0.65, 1.46). CLI was also noninferior to MTX in the STNM group, where the hazard ratio was 0.94 (0.58; 1.53). In the LNM group, superiority of CLI over Cyt was demonstrated a hazard ratio of 0.12 (0.02, 0.77). Median PFS was 34 and 50 days, respectively. More LNM patients had complete response (clearance of tumor cells from CSF) with CLI (33.3%) than with Cyt (16.7%; p=0.3640). All patients experienced AEs; 48% and 60% of the patients in CLI and Control Group, respectively, experienced drug-related AEs. The incidence of serious AEs was 86% and 77%, respectively. Conclusions: These results demonstrate at least comparable patient benefit between CLI and control treatments for STNM and improved benefit for CLI in LNM patients. Intrathecal CLI provides patients with the added convenience of bimonthly treatment. [Table: see text]