Neurotoxicity Profile of Vincristine Sulfate Liposome Injection (VSLI, Marqibo®) Monotherapy in Adults with Relapsed Acute Lymphoblastic Leukemia and Universal Prior Standard Vincristine Exposure

Abstract 3568 Background: VinCRIStine sulfate LIPOSOME injection (VSLI, Marqibo®) is a nanoparticle formulation of vincristine sulfate (VCR) that encapsulates the drug in long-circulating sphingomyelin and cholesterol liposomes. The unique pharmacologic properties of VSLI impart superior nonclinical efficacy and pharmacokinetic properties versus standard VCR. Decades of clinical experience with standard VCR has established peripheral neuropathy as the most notable toxicity and one that underpins the common practice of individual dose capping which limits cumulative dosing. We recently conducted clinical trials to support VSLI accelerated approval for the treatment of adults with relapsed and refractory Philadelphia chromosome negative acute lymphoblastic leukemia (ALL). Here we present data on the neurotoxicity profile of weekly VSLI at the approved dose. Methods: Eighty-three subjects received weekly VSLI 2.25 mg/m2as a 1-hour infusion, with no dose cap, for treatment of advanced, relapsed and/or refractory ALL; Sixty-five patients were enrolled in a pivotal, Phase 2 study and 18 patients were enrolled in an expanded cohort in a Phase 1 study. Signs and symptoms of peripheral neuropathy were proactively assessed using a detailed 15-point evaluation. The pooled data from these studies are the primary safety population for VSLI. Neurotoxicity data are presented here in comparison to two published studies that prospectively evaluated standard VCR induced peripheral neuropathy in patients with Hodgkin disease, non-Hodgkin lymphoma or acute lymphoblastic leukemia (Haim et al, Cancer 1994; 73:2515–2519 and Verstappen et al Neurology 2005; 64:1076–1077. Results: The median individual VSLI dose per infusion was 4.1 mg (range 3.1–5.5) and the median cumulative dose was 18.4 mg (range 3.5–70.1). All patients had prior exposure to VCR containing regimens that resulted in 80% of patients entering the studies with Grade 1 or Grade 2 residual neuropathy. The most common neurological adverse events were constipation (56.6%) and peripheral neuropathy (37.3%). Serious adverse events (SAEs) were reported in 76% of patients and were consistent with advanced ALL. The most frequently reported neuropathy-associated SAEs in patients treated with VSLI were peripheral neuropathy (4.8%) and constipation (3.6%). Incidence of paraesthesia, the only neuropathy uniformly reported across VSLI and VCR studies, was greater in the VCR studies than following much higher dosages and dose density (based on BSA of 1.8) of VSLI. Conclusions: Experience with VCR has established a clear relationship between dose intensity and symptoms of peripheral neuropathy. Administration of VSLI at a dose of 2.25 mg/m2with no dose cap did not result in any new or unexpected toxicity. Although neuropathy remains a significant toxicity associated with VSLI, the frequency and severity of neuropathic AEs was no greater than what would be expected from a standard VCR regimen. Despite administration of higher doses and dose density, incidence of peripheral neuropathy following exposure to VSLI was lower than previously reported with standard VCR. This is significant given that the individual and cumulative doses of VSLI were 2–3 fold greater than what is generally achieved with standard VCR. VSLI facilitates increasing the tolerable dose and dose density and may result in improved clinical response with similar or less toxicity than VCR. *On behalf of the RALLY trial investigators Disclosures: Deitcher: Talon Therapeutics: Employment, Equity Ownership. Silverman:Talon Therapeutics: Employment.