Pivotal Phase 2 Study of Weekly Vincristine Sulfate Liposomes Injection (VSLI, Marqibo®) in Adults with Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia (ALL) in Second Relapse or Progressing Following Two Anti-leukemia Treatment Lines.

Abstract 3088

Poster Board III-25

Adult ALL is a disease of primarily young and middle-aged adults that is associated with a high relapse rate following initial remission induction and a short overall survival following relapse. Patients in second relapse must deal with the lingering toxicities of prior therapies, organ dysfunction secondary to extramedullary disease, and the absence of fully approved and standard of care therapies for this advanced disease setting. Realistic goals of treatment in second relapse include eradication of leukemia, bridging to stem cell transplant, and prolongation of survival.

Vincristine is active against leukemia and is typically used as part of multi-agent regimens to treat relapsed disease, but the pharmacokinetic profile and dosing cap are suboptimal and contribute to poor disease control and abysmal overall survival.

VSLI is a nanoparticle formulation of vincristine sulfate USP encapsulated in sphingomyelin/cholesterol liposomes called Optisomes™. The Optisomal formulation permits dose intensification beyond that attainable with conventional vincristine sulfate injection, USP (VSI). VSLI provides a long circulation time and slow release of encapsulated vincristine sulfate resulting in enhanced tumor penetration and concentration. Preclinical studies of VSLI showed enhanced efficacy versus VSI in a variety of solid and hematologic malignancies. VSLI has a maximum tolerated dose of 2.25 mg/m² weekly with no dose cap, while conventional vincristine sulfate is dosed at 1.4 mg/m² with a 2 mg dose cap. A previous study involving VSLI in relapsed ALL showed a complete response rate of 19%, suggesting activity in the relapsed setting and prompting further study.

This international, multicenter, single-arm study has completed enrollment of its target 56 subjects at 21 centers in 4 countries over 27 months. Major endpoints include response rate (CR/CRi) and overall survival (OS).

56 adult subjects received single agent intravenous VSLI at a dose of 2.25 mg/m² weekly with no dose cap. The highest single dose of VSLI given to date in this study was 5.22 mg contrasted to the 2 mg dose this subject would have received with conventional vincristine. Subjects were monitored for disease response every 4 weeks and could be treated until disease progression. Of the demographic data available for 48 subjects, 24 were female and 24 male with a mean age of 38.7 years (range 19.3-79.6). All subjects received at least one prior vincristine-containing regimen and 21 subjects (44%) received vincristine sulfate in two prior regimens. 18 subjects (37%) had a prior stem cell transplant and 2 subjects (4%) had 2 prior stem cell transplants before receiving single agent VSLI. 71% of subjects had an ECOG Performance Status of 1 or greater, with 21% ECOG 2 or 3. Seven subjects (15%) had evidence of extramedullary disease at study entry.

At interim analysis, treatment with single agent VSLI produced morphologic and cytogenetic CR in several of these heavily pretreated subjects, suggesting significant activity of VSLI in second relapsed leukemia. Of investigator-reported responses on 48 subjects with data available to date, 71% have evidence of either disease response or disease stabilization and 29% have reported disease progression. Of the subjects experiencing CR/CRi, at least 5 subjects subsequently underwent allogeneic stem cell transplant after receiving VSLI. At the time of this abstract the median OS is estimated to be 4.7 months (Q1-Q3: 3.4-10.5) using Kaplan-Meier methodology.

The 5 most frequently reported adverse event are peripheral neuropathy, 14.6% Grade 3 or 4 (100% attributed to study drug); constipation, 2.4% Grade 3 (100% attributed to study drug); nausea, no Grade 3 or higher; pyrexia, 9.8% Grade 3 (2.4% attributed to study drug); and febrile neutropenia, 34.2% Grade 3 or 4 (7.3% attributed to study drug). VSLI is a promising new agent for the treatment of acute lymphoblastic leukemia in second relapse, a situation where there is high unmet need and no approved therapies exist. VSLI may be used as a single agent as a bridge to transplant in these heavily pretreated, multiply-relapsed subjects, or considered as a substitute for conventional vincristine sulfate. The ability to complete enrollment rapidly internationally with compelling evidence of objective responses in this study underscores the enthusiasm for and importance of developing VSLI for the treatment of this orphan leukemia indication.

Efficacy data and preliminary PK results from the target 56 subjects will be presented.