Peripheral Neuropathy Profile of Vincristine Sulfate Liposomes Injection (VSLI, Marqibo®), a Nanoparticle Vincristine Formulation, in Adult Subjects with Relapsed/Refractory Acute Lymphoblastic Leukemia (ALL) and Non-Hodgkin’s Lymphoma (NHL)
Authors: Lu Biao , Hagey Anne E , Zhou Feng , Deitcher Steven R. 
Published: April 2020

Abstract
VSLI is a nanoparticle formulation of vincristine sulfate (VCR) encapsulated in sphingomyelin/cholesterol (SM/Chol) liposomes called Optisomes™. In preclinical studies, VSLI has provided targeted, increased, and sustained delivery of VCR to tumor cells compared to administration of conventional or non-SM/Chol liposome-encapsulated VCR. VSLI is being developed to improve patient outcomes without increased VCR-related peripheral neuropathy (PN). We report an integrated analysis of the PN profile of VSLI from two distinct multi-center clinical studies: A Phase 1 dose-escalation study in adult subjects with relapsed/refractory ALL of weekly VSLI plus pulse dexamethasone at doses ranging from 1.8 to 2.4 mg/m2 without dose capping
A Phase 2 study in adult subjects with relapsed/refractory NHL of biweekly VSLI at a dose of 2.0 mg/m2 without dose capping
Subjects with prior history of Grade 3 or 4 PN related to chemotherapeutic agents were not eligible for either study. Subject characteristics, VSLI dosing details, and relevant clinical outcomes are provided in the Table. Results are presented as median (range) unless otherwise stated.
ALL (N=36, 12F/24M) NHL (N=119, 55F/64M) Age (years) 32 (19–2) 60 (25–87) Body surface area (m2) 2.1 (1.5–2.8) 1.9 (1.3–2.6) Prior VCR exposure 100% 97% Total VSLI dose (mg) 19 (10–8) 14 (3–66) Objective Response rate 22% 25% VSLI dose to complete response (mg) 12 (9–3) n/a VSLI dose to objective response (mg) n/a 14 (8–9) Peripheral neuropathy (PN) rate, n (%) 22 (61) 50 (42) Grade 1 12 (33) 24 (20) Grade 2 7 (19) 18 (15) Grade 3 2 (6) 8 (7) Grade 4 1 (3) 0 VSLI dose to PN onset (mg) 14 (4–2) 12 (3–4) VSLI dose to Grade 3/4 PN (mg) 23 (20–3) 19 (3–4) Discontinuations due to PN, n (%) 3 (8) 7 (6)
The median cumulative VSLI doses (including pre- and post-PN onset) for ALL and NHL subjects who experienced PN were 24 mg (range: 10–38 mg) and 18 mg (range: 3–66 mg), respectively, compared to 12 mg (range: 11–28 mg) and 11 mg (range: 3–54 mg) in ALL and NHL subjects who did not experience PN. Six of the 22 ALL subjects (27%) who experienced PN achieved CR, compared to 1 of 14 (7%) subjects without PN (p&gt;0.05). Nineteen of the 50 NHL subjects (38%) who experienced PN responded to VSLI, compared to 11 of 69 (16%) subjects without PN (p=0.01). In general, the PN observed in these lymphoid malignancy populations, with near universal prior VCR exposure, was primarily mild and moderate in grade and rarely required VSLI discontinuation. Despite prior VCR exposure, and residual PN in some, the amount of VCR delivered as VSLI in both ALL and NHL subjects prior to PN onset was greater than the PN trigger cumulative doses reported for conventional VCR (5 mg for PN; 15 mg for severe PN). In both studies, subjects who experienced PN received higher cumulative doses of VSLI and achieved more responses compared to subjects who had not experienced PN. The pharmacokinetic profile, targeted delivery, and VCR dose-intensification facilitated by VSLI have the potential to produce meaningful response rates without therapy-limiting PN.