Safety and Efficacy of Marqibo (Vincristine Sulfate Liposomes Injection, OPTISOME™) in for the Treatment of Adults with Relapsed or Refractory Acute Lymphoblastic Leukemia (ALL).

Introduction: Vincristine sulfate (VCR) is a lipophilic, cell-cycle specific, antineoplastic agent that inhibits cell division by specifically binding to tubulin in mitotic spindles. The activity of VCR is dose and time-dependent, but central and peripheral neuropthy prohibits its use beyond doses of 1.4 mg/m² (capped at 2 mg). Marqibo is a formulation of VCR encapsulated in a sphingomyelin/cholesterol liposome (OPTISOME) with a longer half-life than VCR. In murine models using L1210 or P388 lymphoid leukemia cell lines, Marqibo demonstrated greater anti-tumor activity compared with VCR. Marqibo was therefore an appropriate agent to study in relapsed or refractory ALL.

Methods: Two clinical trials have been completed. First, a phase II trial of single agent Marqibo given at 2 mg/m² (no dose capping) every 2 weeks enrolled 16 patients (pts) [Thomas et al, Cancer 106:120, 2006]. A multicenter dose escalation phase I trial using weekly Marqibo (1.5, 1.825, 2.0, 2.25, 2.4 mg/m²) in combination with pulse dexamethasone followed. There were no restrictions on the number of prior therapies. Subjects with grade 2 or greater central or peripheral neuropathy were ineligible.

Results: In total, 52 pts with relapsed or refractory ALL were treated in the two studies combined. Median age was 34 years (range, 19–77), 31 males/21 females, with a median number of prior salvage regimens of 2 (range, 1–3). Nine pts had confirmed Philadelphia positive disease (8 in the pre-imatinib era, 1 resistant to tyrosine kinase inhibitor therapy). All pts had previously received conventional VCR therapy. There were 8 complete remissions and 3 partial remissions for an overall response rate of 21% [95% CI, 11, 35]. An additional 12 pts (23%) achieved hematological improvements (e.g., clearance of marrow blasts, platelet transfusion independence). Five responders were able to undergo allogeneic stem cell transplantation following therapy with Marqibo. The maximum tolerated dose in the phase I trial was 2.25 mg/m² owing to grade 3 motor neuropathy, grade 4 seizure, and grade 4 hepatotoxicity observed in 1 patient each at the 2.4 mg/m² dose level. Grade 1–2 peripheral neuropathy was manageable with dose modifications and anti-neuralgia agents such as gabapentin. Commonly observed toxicities included febrile neutropenia, myelosuppression, abdominal pain, nausea, constipation, diarrhea, fatigue, and infusion-related pyrexia.

Conclusions: In reviewing the clinical experience to date, Marqibo with or without pulse dexamethasone has provided clinically meaningful activity in heavily pre-treated adults with ALL. A multicenter trial of single agent Marqibo in the setting of second salvage therapy for adults with relapsed ALL is underway. A phase III multicenter trial of Marqibo in combination with standard chemotherapy for de novo elderly ALL is in the planning phase.