Neurological Toxicity Profile of Weekly Vincristine Sulfate Liposomes Injection (Marqibo^®) 2.25 mg/m² Compared to Historical Standard Vincristine Sulfate 1.4 mg/m², 2 mg, and 4 mg Administered Less Frequently

Abstract 4247

The accumulated clinical experience with standard vincristine sulfate (VCR) describes a safety profile most notable for the occurrence of a dose-related, symmetrical, sensorimotor and autonomic polyneuropathy. The various manifestations of neuropathy are the usual dose-limiting toxicities associated with standard VCR that limit the extent to which patients can derive clinical benefit from this therapy. Vincristine sulfate liposomes injection (VSLI, Marqibo^®) is a sphingomyelin-based, liposomal formulation of VCR designed to intensify dose, prolong encapsulated drug circulation time, and target drug to sites of active cancer. We report here the neurological toxicity profile (Graded using CTCAE criteria v3.0) of weekly, single-agent IV VSLI 2.25 mg/m² in 83 adult subjects with heavily pre-treated, relapsed and/or refractory acute lymphoblastic leukemia (ALL) and 100% past standard VCR exposure. Neuropathy signs and symptoms were rigorously evaluated at baseline and weekly during VSLI treatment in order to maximize adverse event detection. Findings were compared to baseline (post-standard VCR and before VSLI) neuropathy in the same VSLI treated population and to the best available published neurotoxicity data regarding standard VCR administration. In the study by Haim et al ([1] Cancer 1994; 73:2515–9), 104 VCR-naïve patients with lymphoma received multi-agent therapy including standard VCR 1.4 mg/m² weekly to once every 28 days. In the study by Verstappen et al ([2] Neurology 2005; 64:1076–7), 114 VCR-naïve patients with lymphoma received multi-agent therapy including fixed dose standard VCR 2 mg or 4 mg every 3 weeks. Results are provided in the table below. NR = not reported.

The baseline frequency of residual neuropathy in adults with ALL treated with weekly VSLI 2.25 mg/m² was not unexpected considering that all patients received prior standard VCR. The on-study, incremental neuropathy burden was relatively modest. On-study neuropathy rates during and immediately following weekly VSLI 2.25 mg/m² were comparable to or less than those reported in lymphoma patients receiving standard VCR at 1.4 mg/m² every 1 to 3 weeks or at a fixed dose of 2 mg or 4 mg every 3 weeks, despite the dose intensification afforded by VSLI. Constipation, the most commonly reported neurological toxicity associated with standard VCR and VSLI, resulted in standard VCR dose reduction in 22% of patients reported by Haim et al compared to weekly VSLI dose reduction in only 5% of patients due to constipation. Frequent neurological assessments combined with a dose adjustment algorithm facilitated continued VSLI dosing in order to induce remission and minimization of Grade 3 or greater neurotoxicity. One VSLI patient developed peripheral motor neuropathy requiring drug discontinuation after 11 weekly doses. In the VSLI study, neurological toxicity was considered predictable and manageable.