Marqibo^® (vincristine sulfate liposomes injection; VSLI) In the Treatment of Adult Patients with Advanced, Relapsed/Refractory Acute Lymphoblastic Leukemia (ALL): A Combined Analysis of the VSLI-06 and RALLY Studies

The outcome of adults with relapsed/refractory ALL, and of those whose disease recurs after first salvage, in particular, is extremely poor. Second salvage therapy with single agents has historically produced a complete response (CR) in only 4% of patients. (O'Brien, S, et al. Cancer 2008; 113:3186-3191). Third salvage therapy has not been studied but would be expected to be even less effective. Conventional vincristine sulfate (VCR) is an effective anti-leukemia agent, widely used in the treatment of ALL as part of several intensive regimens. VCR is dosed at 1.4 mg/m² with a 2 mg cap due to early onset of peripheral neuropathy. VSLI (Marqibo) is a nano-particle encapsulated formulation of VCR designed to facilitate dose intensification, improve duration of drug exposure, and enhance cancer and bone marrow drug delivery.

Two distinct studies investigated VSLI in adult patients with advanced, relapsed/refractory ALL. Study VSLI-06 was a Phase 1/2, multi-center, 36 patient, dose-escalation study to determine safety, maximum tolerated dose, and anti-leukemia activity. Patients received VSLI intravenously (IV) weekly at doses of 1.5, 1.825, 2.0, 2.25 or 2.4 mg/m² with no dose cap plus dexamethasone 40 mg on days 1–4 and 11–14 of each 4 week cycle. The RALLY Study was a Phase 2, multi-national, 65 patient study of single-agent VSLI (2.25 mg/m² IV weekly without dose cap) in adults with ALL in second relapse or who had progressed following at least two prior lines of anti-leukemia therapy. All subjects had been previously treated with VCR, and all received at least one dose of VSLI. The median age in both studies was 32 years with a combined range of 19 to 83 years. Other than one subject in VSLI-06, all subjects were Philadelphia chromosome negative.

The combined overall response rate was 31% (31 of 101). The combined complete response (CR) rate including CR with incomplete platelet (CRp) or hematologic (CRi) recovery was 20% (20/101). This response rate was consistent across the studies (19.4% and 20%, respectively). Hematologic improvement (HI) was achieved in 4 patients (11%) in VSLI-06 and 9 (14%) in RALLY, thus reducing transfusions and hospital visits. Five patients were able to receive a post-VSLI hematopoietic stem cell transplant (HSCT) in VSLI-06, and 10 patients were able to receive a post-VSLI HSCT in RALLY. The table below summarizes key study characteristics.

The most commonly reported safety events in the studies were similar and included constipation, neuropathy, fatigue, nausea, pyrexia, febrile neutropenia, and anemia.

These two studies totaling 101 patients with similar populations of advanced relapsed/refractory ALL showed a combined 20% CR/CRp/CRi rate, dwarfing the rate in historical studies. This is particularly encouraging, given that 100% of subjects had received prior VCR and that historical control data were largely in a less heavily pre-treated population. Both VSLI alone and combined with pulse dexamethasone appear to be highly active. In total, 15% of combined study patients were able to “bridge” to HSCT. Use of VSLI in the frontline setting and in combination regimens should further improve ALL patient outcomes.

Messerschmidt: Hana Biosciences, Inc.: Employment. Hagey: Hana Biosciences, Inc.: Employment. Deitcher: Hana Biosciences: Employment. Kantarjian: Hana Biosciences, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees.